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FDA approves controversial Alzheimer’s drug aducanumab (Aduhelm)
In November, the Peripheral and Central Nervous System Drugs Advisory Committee voted eight to one against approving the drug because, based on clinical trial results, evidence of efficacy was not strong enough. Two other members said they were uncertain on the issue of efficacy.
In a company release Michel Vounatsos, Biogen’s Chief Executive Officer, said, “this historic moment is the culmination of more than a decade of groundbreaking research in the complex field of Alzheimer’s disease. We believe this first-in-class medicine will transform the treatment of people living with Alzheimer’s disease and spark continuous innovation in the years to come.
Rocky road
The road to approval has been extremely rocky for aducanumab, an anti-amyloid-beta human monoclonal antibody, previously known as BIIB037.
As reported by this news organization, two phase 3 trials evaluating the drug were initially scrapped in March 2019 because of interim futility analysis. At the time, Biogen released a statement saying that aducanumab was unlikely to meet primary endpoints in the ENGAGE and EMERGE randomized controlled trials.
However, in an about-face 7 months later, Biogen and Eisai announced that a new analysis showed the drug met its primary endpoint of reduction in clinical decline, including cognition and function, in the EMERGE trial.
Although ENGAGE still didn’t meet its primary endpoint, data from its new analysis “supported” the EMERGE findings, the drug companies said at the time.
However, 1 year later, a majority of the members of the FDA’s advisory panel were against the drug’s approval. Details of that decision were published online March 30 in the Journal of the American Medical Association.
As reported by this news organization, a Viewpoint written by three of the committee members notes that results from the drug’s only large positive clinical trial fell short.
“There is no persuasive evidence to support approval of aducanumab at this time,” they write.
Groups such as Public Citizen’s Health Research Group not only agree with the Viewpoint’s authors, they also criticized the FDA for its collaboration with the drug’s manufacturers on briefing documents and more.
On April 1, Health Research Group members sent a letter to the U.S. Secretary of Health and Human Services requesting the temporary suspension of the FDA’s neuroscience chief, Bill Dunn, MD, because of his role in supervising the collaboration.
Alzheimer association weighs in
The Alzheimer’s Association has been a proponent of the drug throughout its development.
Ahead of today’s news, the organization noted in a statement that a decision to approve “would be historic” because it would make aducanumab “the first drug to slow Alzheimer’s disease” and would mark the beginning of a new future for AD treatments.
“The Alzheimer’s Association urgently supports FDA approval of the treatment based on clinical trial results that showed a 22% reduction in cognitive and function decline — something that could make a meaningful difference” for patients with AD, it said.
Kristen Clifford, chief program officer for the Alzheimer’s Association, said in an interview at the time that approval would be considered a “victory” for patients with AD and for the field overall.
“For individuals who would potentially be eligible for the treatment, this drug could mean more quality time. Slowing decline, particularly in early diagnosis, could add weeks or months or maybe even years of active life,” Clifford said.
“If approved, this would really be a landmark moment. And it could provide hope for those living with Alzheimer’s and their families,” she added.
Clifford noted that approval of this type of drug would also underscore the importance of early detection for AD. “This treatment would encourage earlier diagnosis of the disease,” she said.
In a new statement released just after approval for aducanumab was announced, the organization said that today’s news is a win-win for all patients with AD and their families.
A version of this article first appeared on Medscape.com.
In November, the Peripheral and Central Nervous System Drugs Advisory Committee voted eight to one against approving the drug because, based on clinical trial results, evidence of efficacy was not strong enough. Two other members said they were uncertain on the issue of efficacy.
In a company release Michel Vounatsos, Biogen’s Chief Executive Officer, said, “this historic moment is the culmination of more than a decade of groundbreaking research in the complex field of Alzheimer’s disease. We believe this first-in-class medicine will transform the treatment of people living with Alzheimer’s disease and spark continuous innovation in the years to come.
Rocky road
The road to approval has been extremely rocky for aducanumab, an anti-amyloid-beta human monoclonal antibody, previously known as BIIB037.
As reported by this news organization, two phase 3 trials evaluating the drug were initially scrapped in March 2019 because of interim futility analysis. At the time, Biogen released a statement saying that aducanumab was unlikely to meet primary endpoints in the ENGAGE and EMERGE randomized controlled trials.
However, in an about-face 7 months later, Biogen and Eisai announced that a new analysis showed the drug met its primary endpoint of reduction in clinical decline, including cognition and function, in the EMERGE trial.
Although ENGAGE still didn’t meet its primary endpoint, data from its new analysis “supported” the EMERGE findings, the drug companies said at the time.
However, 1 year later, a majority of the members of the FDA’s advisory panel were against the drug’s approval. Details of that decision were published online March 30 in the Journal of the American Medical Association.
As reported by this news organization, a Viewpoint written by three of the committee members notes that results from the drug’s only large positive clinical trial fell short.
“There is no persuasive evidence to support approval of aducanumab at this time,” they write.
Groups such as Public Citizen’s Health Research Group not only agree with the Viewpoint’s authors, they also criticized the FDA for its collaboration with the drug’s manufacturers on briefing documents and more.
On April 1, Health Research Group members sent a letter to the U.S. Secretary of Health and Human Services requesting the temporary suspension of the FDA’s neuroscience chief, Bill Dunn, MD, because of his role in supervising the collaboration.
Alzheimer association weighs in
The Alzheimer’s Association has been a proponent of the drug throughout its development.
Ahead of today’s news, the organization noted in a statement that a decision to approve “would be historic” because it would make aducanumab “the first drug to slow Alzheimer’s disease” and would mark the beginning of a new future for AD treatments.
“The Alzheimer’s Association urgently supports FDA approval of the treatment based on clinical trial results that showed a 22% reduction in cognitive and function decline — something that could make a meaningful difference” for patients with AD, it said.
Kristen Clifford, chief program officer for the Alzheimer’s Association, said in an interview at the time that approval would be considered a “victory” for patients with AD and for the field overall.
“For individuals who would potentially be eligible for the treatment, this drug could mean more quality time. Slowing decline, particularly in early diagnosis, could add weeks or months or maybe even years of active life,” Clifford said.
“If approved, this would really be a landmark moment. And it could provide hope for those living with Alzheimer’s and their families,” she added.
Clifford noted that approval of this type of drug would also underscore the importance of early detection for AD. “This treatment would encourage earlier diagnosis of the disease,” she said.
In a new statement released just after approval for aducanumab was announced, the organization said that today’s news is a win-win for all patients with AD and their families.
A version of this article first appeared on Medscape.com.
In November, the Peripheral and Central Nervous System Drugs Advisory Committee voted eight to one against approving the drug because, based on clinical trial results, evidence of efficacy was not strong enough. Two other members said they were uncertain on the issue of efficacy.
In a company release Michel Vounatsos, Biogen’s Chief Executive Officer, said, “this historic moment is the culmination of more than a decade of groundbreaking research in the complex field of Alzheimer’s disease. We believe this first-in-class medicine will transform the treatment of people living with Alzheimer’s disease and spark continuous innovation in the years to come.
Rocky road
The road to approval has been extremely rocky for aducanumab, an anti-amyloid-beta human monoclonal antibody, previously known as BIIB037.
As reported by this news organization, two phase 3 trials evaluating the drug were initially scrapped in March 2019 because of interim futility analysis. At the time, Biogen released a statement saying that aducanumab was unlikely to meet primary endpoints in the ENGAGE and EMERGE randomized controlled trials.
However, in an about-face 7 months later, Biogen and Eisai announced that a new analysis showed the drug met its primary endpoint of reduction in clinical decline, including cognition and function, in the EMERGE trial.
Although ENGAGE still didn’t meet its primary endpoint, data from its new analysis “supported” the EMERGE findings, the drug companies said at the time.
However, 1 year later, a majority of the members of the FDA’s advisory panel were against the drug’s approval. Details of that decision were published online March 30 in the Journal of the American Medical Association.
As reported by this news organization, a Viewpoint written by three of the committee members notes that results from the drug’s only large positive clinical trial fell short.
“There is no persuasive evidence to support approval of aducanumab at this time,” they write.
Groups such as Public Citizen’s Health Research Group not only agree with the Viewpoint’s authors, they also criticized the FDA for its collaboration with the drug’s manufacturers on briefing documents and more.
On April 1, Health Research Group members sent a letter to the U.S. Secretary of Health and Human Services requesting the temporary suspension of the FDA’s neuroscience chief, Bill Dunn, MD, because of his role in supervising the collaboration.
Alzheimer association weighs in
The Alzheimer’s Association has been a proponent of the drug throughout its development.
Ahead of today’s news, the organization noted in a statement that a decision to approve “would be historic” because it would make aducanumab “the first drug to slow Alzheimer’s disease” and would mark the beginning of a new future for AD treatments.
“The Alzheimer’s Association urgently supports FDA approval of the treatment based on clinical trial results that showed a 22% reduction in cognitive and function decline — something that could make a meaningful difference” for patients with AD, it said.
Kristen Clifford, chief program officer for the Alzheimer’s Association, said in an interview at the time that approval would be considered a “victory” for patients with AD and for the field overall.
“For individuals who would potentially be eligible for the treatment, this drug could mean more quality time. Slowing decline, particularly in early diagnosis, could add weeks or months or maybe even years of active life,” Clifford said.
“If approved, this would really be a landmark moment. And it could provide hope for those living with Alzheimer’s and their families,” she added.
Clifford noted that approval of this type of drug would also underscore the importance of early detection for AD. “This treatment would encourage earlier diagnosis of the disease,” she said.
In a new statement released just after approval for aducanumab was announced, the organization said that today’s news is a win-win for all patients with AD and their families.
A version of this article first appeared on Medscape.com.
Once-nightly sodium oxybate agent effective in narcolepsy
, new research suggests. Top-line results from the phase 3 REST-ON trial released earlier this year showed that the agent known as FT218 (Avadel Pharmaceuticals) met all three of its coprimary efficacy endpoints at all three doses assessed (6 g, 7.5 g, and 9 g). Patients receiving the drug showed significantly greater improvements on the Maintenance of Wakefulness Test (MWT), the Clinical Global Impression of Improvement (CGI-I), and mean weekly attacks of cataplexy, compared with those who received placebo.
The new analyses, which focused on key secondary outcomes, showed that all three doses of the novel agent were associated with significant improvements in sleep quality, refreshing nature of sleep, sleep paralysis, disturbed nocturnal sleep, and scores on the Epworth Sleepiness Scale (ESS).
Principal investigator Michael J. Thorpy, MD, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center, New York, said in a news release that the results represent “the promise of a potential new treatment strategy for physicians and patients.”
“I am particularly impressed by the consistency of results as early as 3 weeks with only a 6-g dose,” he added.
Dr. Thorpy, who is also a professor of neurology at the Albert Einstein College of Medicine, noted that the new formulation will be more convenient for patients. “The advantage of this medication is its once-nightly formulation, so patients don’t need to awaken during the night and can actually have a better night’s sleep,” he said.
Dr. Thorpy presented the study findings at the 2021 annual meeting of the American Academy of Neurology.
FT218 is currently under review by the U.S. Food and Drug Administration, which has set Oct. 15 as the Prescription Drug User Fee Act target date.
Forced awakening
Sodium oxybate was first approved by the FDA in 2002 to treat cataplexy in adults with narcolepsy and was expanded in 2005 to also treat excessive daytime sleepiness (EDS). That formulation is indicated for twice-nightly administration, with the second dose taken 2.5-4 hours after the first.
“The need for forced awakening to take the second dose ... may result in noncompliance, which may lead to reduced efficacy and/or mistimed doses,” the investigators noted.
FT218 is a modified-release version of sodium oxybate. A single 6-g dose of the investigational agent “has shown bioequivalent exposure to twice-nightly immediate-release [sodium oxybate] given as two 3-g doses,” wrote the researchers.
It also currently has Orphan Drug Designation from the FDA for the treatment of narcolepsy.
The randomized, double-blind, placebo-controlled, multicenter REST-ON study was conducted from November 2016 to March 2020 and included patients 16 years or older who had narcolepsy type 1 or type 2.
Patients received the active treatment (n = 107; mean age, 30.9 years; 64.5% women) or placebo (n = 105; mean age, 31.6 years; 71.4% women) according to a four-period forced uptitration dosing schedule of 4.5 g for 1 week, 6 g for 2 weeks, 7.5 g for 5 weeks, and 9 g for 5 weeks.
Secondary outcome measures included the ESS, sleep quality/refreshing nature of sleep on a visual analog scale, sleep paralysis and hypnagogic hallucinations on a sleep symptoms diary, disturbed nocturnal sleep on polysomnographic measures, and number of arousals as defined per the American Academy of Sleep Medicine Score Manual.
Reports of adverse events (AEs) were collected from time of informed consent until 7 days after the last dose received.
Improvement across doses
Results showed that, compared with placebo, improvement in disturbed nocturnal sleep from baseline was significantly greater for the active treatment at 6 g at week 3 (mean between-group difference, –11; P < .001), at 7.5 g at week 8 (mean difference, –17.7; P < .001), and at 9 g at week 13 (mean difference, –22.6; P < .001).
The mean difference between the three doses and placebo for reduction in number of arousals was –11.3 (P < .05), –19.4 (P < .001), and –23.7 (P < .001), respectively. And the 6 g at week 3, 7.5 g at week 8, and 9 g at week 13 doses showed significant (P < .001) improvements versus placebo on the ESS (mean difference, –2.1, –3.2, and –3.9, respectively).
All three doses also showed significant improvement in sleep quality and refreshing nature of sleep (P < .001 for all comparisons), as well as improvement of sleep paralysis (P = .04, P = .02, and P = .04, respectively).
There were no significant differences between FT218 and placebo for improvement in hypnagogic hallucinations. Dr. Thorpy noted that the number of patients with baseline hallucinations “was relatively small,” which may have led to this finding. “Had there been a much larger population with hallucinations, I suspect that we would have seen a statistically significant improvement there as well,” he said.
Generally well tolerated
The investigators noted that FT218 was “generally well tolerated, and the most common adverse reactions were well-known and established sodium oxybate adverse reactions.”
Treatment-related AEs that occurred in more than 2% of the patients receiving FT218 included nausea, dizziness, enuresis, headache, decreased appetite, and vomiting.
Seven serious AEs were reported, including five in those assigned to the active treatment. This included one case each of diabetes inadequate control, paresthesia, perirectal abscess, hypertension, and suicidal ideation. Only the case of suicidal ideation was considered to be a treatment-related AE.
The investigators noted that, although they have not yet delved into subgroup analysis to look for differences among sex, age, or race, they plan to do so in the future.
Overall, the results indicate that “FT218 is an effective agent not only for the major symptoms of sleepiness and cataplexy, but also the quality of sleep at night,” said Dr. Thorpy.
Asked whether he thinks the FDA will approve the drug, he said that it should be “straightforward” because it’s just a different formulation of an already-approved agent. “I very much expect there will not be any problems in this medication being approved,” Dr. Thorpy said.
Benefits ‘sleep architecture’
Commenting on the findings, Logan Schneider, MD, codirector of the Stanford/VA Alzheimer’s Center and clinical assistant professor at the Stanford Sleep Center, Redwood City, Calif., said that the investigators’ focus on these secondary outcomes “was really worthwhile.”
Dr. Schneider, who was not involved in the research, noted that, because the study only included patients with narcolepsy, the results can’t be extrapolated to groups who have other sleep disorders.
Still, “it is worthwhile now to expand beyond the two primary symptoms that are, in my consideration, life threatening: daytime sleepiness and cataplexy. We should also address more of the quality of life and other aspects of narcolepsy, including disturbed nocturnal sleep and sleep quality issues related to that,” he said.
“Being able to address those aspects and say, ‘I have a therapy that clearly helps the multidimensionality of our patients’ is very vindicating,” Dr. Schneider noted.
He was also impressed with the various measures the researchers used, rather than relying just on patient reports, “which are subject to recollection difficulties. This was a nice way to quantify possibly as a diagnostic marker the underlying disruption of sleep, as well as a possible treatment marker to show how well a therapy works.”
“It actually shows a beneficial effect on sleep architecture,” Dr. Schneider said.
The study was funded by Avadel Pharmaceuticals. Dr. Thorpy is a consultant/advisory board member for Avadel, Axsome, Balance Therapeutics, Eisai, Harmony Biosciences, Jazz Pharmaceuticals, NLS Pharmaceuticals, Suven Life Sciences, and Takeda Pharmaceutical. Dr. Schneider reports being an adviser and/or on the speakers’ bureau for similar drugs by Jazz Pharmaceuticals and Harmony Biosciences.
A version of this article first appeared on Medscape.com.
, new research suggests. Top-line results from the phase 3 REST-ON trial released earlier this year showed that the agent known as FT218 (Avadel Pharmaceuticals) met all three of its coprimary efficacy endpoints at all three doses assessed (6 g, 7.5 g, and 9 g). Patients receiving the drug showed significantly greater improvements on the Maintenance of Wakefulness Test (MWT), the Clinical Global Impression of Improvement (CGI-I), and mean weekly attacks of cataplexy, compared with those who received placebo.
The new analyses, which focused on key secondary outcomes, showed that all three doses of the novel agent were associated with significant improvements in sleep quality, refreshing nature of sleep, sleep paralysis, disturbed nocturnal sleep, and scores on the Epworth Sleepiness Scale (ESS).
Principal investigator Michael J. Thorpy, MD, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center, New York, said in a news release that the results represent “the promise of a potential new treatment strategy for physicians and patients.”
“I am particularly impressed by the consistency of results as early as 3 weeks with only a 6-g dose,” he added.
Dr. Thorpy, who is also a professor of neurology at the Albert Einstein College of Medicine, noted that the new formulation will be more convenient for patients. “The advantage of this medication is its once-nightly formulation, so patients don’t need to awaken during the night and can actually have a better night’s sleep,” he said.
Dr. Thorpy presented the study findings at the 2021 annual meeting of the American Academy of Neurology.
FT218 is currently under review by the U.S. Food and Drug Administration, which has set Oct. 15 as the Prescription Drug User Fee Act target date.
Forced awakening
Sodium oxybate was first approved by the FDA in 2002 to treat cataplexy in adults with narcolepsy and was expanded in 2005 to also treat excessive daytime sleepiness (EDS). That formulation is indicated for twice-nightly administration, with the second dose taken 2.5-4 hours after the first.
“The need for forced awakening to take the second dose ... may result in noncompliance, which may lead to reduced efficacy and/or mistimed doses,” the investigators noted.
FT218 is a modified-release version of sodium oxybate. A single 6-g dose of the investigational agent “has shown bioequivalent exposure to twice-nightly immediate-release [sodium oxybate] given as two 3-g doses,” wrote the researchers.
It also currently has Orphan Drug Designation from the FDA for the treatment of narcolepsy.
The randomized, double-blind, placebo-controlled, multicenter REST-ON study was conducted from November 2016 to March 2020 and included patients 16 years or older who had narcolepsy type 1 or type 2.
Patients received the active treatment (n = 107; mean age, 30.9 years; 64.5% women) or placebo (n = 105; mean age, 31.6 years; 71.4% women) according to a four-period forced uptitration dosing schedule of 4.5 g for 1 week, 6 g for 2 weeks, 7.5 g for 5 weeks, and 9 g for 5 weeks.
Secondary outcome measures included the ESS, sleep quality/refreshing nature of sleep on a visual analog scale, sleep paralysis and hypnagogic hallucinations on a sleep symptoms diary, disturbed nocturnal sleep on polysomnographic measures, and number of arousals as defined per the American Academy of Sleep Medicine Score Manual.
Reports of adverse events (AEs) were collected from time of informed consent until 7 days after the last dose received.
Improvement across doses
Results showed that, compared with placebo, improvement in disturbed nocturnal sleep from baseline was significantly greater for the active treatment at 6 g at week 3 (mean between-group difference, –11; P < .001), at 7.5 g at week 8 (mean difference, –17.7; P < .001), and at 9 g at week 13 (mean difference, –22.6; P < .001).
The mean difference between the three doses and placebo for reduction in number of arousals was –11.3 (P < .05), –19.4 (P < .001), and –23.7 (P < .001), respectively. And the 6 g at week 3, 7.5 g at week 8, and 9 g at week 13 doses showed significant (P < .001) improvements versus placebo on the ESS (mean difference, –2.1, –3.2, and –3.9, respectively).
All three doses also showed significant improvement in sleep quality and refreshing nature of sleep (P < .001 for all comparisons), as well as improvement of sleep paralysis (P = .04, P = .02, and P = .04, respectively).
There were no significant differences between FT218 and placebo for improvement in hypnagogic hallucinations. Dr. Thorpy noted that the number of patients with baseline hallucinations “was relatively small,” which may have led to this finding. “Had there been a much larger population with hallucinations, I suspect that we would have seen a statistically significant improvement there as well,” he said.
Generally well tolerated
The investigators noted that FT218 was “generally well tolerated, and the most common adverse reactions were well-known and established sodium oxybate adverse reactions.”
Treatment-related AEs that occurred in more than 2% of the patients receiving FT218 included nausea, dizziness, enuresis, headache, decreased appetite, and vomiting.
Seven serious AEs were reported, including five in those assigned to the active treatment. This included one case each of diabetes inadequate control, paresthesia, perirectal abscess, hypertension, and suicidal ideation. Only the case of suicidal ideation was considered to be a treatment-related AE.
The investigators noted that, although they have not yet delved into subgroup analysis to look for differences among sex, age, or race, they plan to do so in the future.
Overall, the results indicate that “FT218 is an effective agent not only for the major symptoms of sleepiness and cataplexy, but also the quality of sleep at night,” said Dr. Thorpy.
Asked whether he thinks the FDA will approve the drug, he said that it should be “straightforward” because it’s just a different formulation of an already-approved agent. “I very much expect there will not be any problems in this medication being approved,” Dr. Thorpy said.
Benefits ‘sleep architecture’
Commenting on the findings, Logan Schneider, MD, codirector of the Stanford/VA Alzheimer’s Center and clinical assistant professor at the Stanford Sleep Center, Redwood City, Calif., said that the investigators’ focus on these secondary outcomes “was really worthwhile.”
Dr. Schneider, who was not involved in the research, noted that, because the study only included patients with narcolepsy, the results can’t be extrapolated to groups who have other sleep disorders.
Still, “it is worthwhile now to expand beyond the two primary symptoms that are, in my consideration, life threatening: daytime sleepiness and cataplexy. We should also address more of the quality of life and other aspects of narcolepsy, including disturbed nocturnal sleep and sleep quality issues related to that,” he said.
“Being able to address those aspects and say, ‘I have a therapy that clearly helps the multidimensionality of our patients’ is very vindicating,” Dr. Schneider noted.
He was also impressed with the various measures the researchers used, rather than relying just on patient reports, “which are subject to recollection difficulties. This was a nice way to quantify possibly as a diagnostic marker the underlying disruption of sleep, as well as a possible treatment marker to show how well a therapy works.”
“It actually shows a beneficial effect on sleep architecture,” Dr. Schneider said.
The study was funded by Avadel Pharmaceuticals. Dr. Thorpy is a consultant/advisory board member for Avadel, Axsome, Balance Therapeutics, Eisai, Harmony Biosciences, Jazz Pharmaceuticals, NLS Pharmaceuticals, Suven Life Sciences, and Takeda Pharmaceutical. Dr. Schneider reports being an adviser and/or on the speakers’ bureau for similar drugs by Jazz Pharmaceuticals and Harmony Biosciences.
A version of this article first appeared on Medscape.com.
, new research suggests. Top-line results from the phase 3 REST-ON trial released earlier this year showed that the agent known as FT218 (Avadel Pharmaceuticals) met all three of its coprimary efficacy endpoints at all three doses assessed (6 g, 7.5 g, and 9 g). Patients receiving the drug showed significantly greater improvements on the Maintenance of Wakefulness Test (MWT), the Clinical Global Impression of Improvement (CGI-I), and mean weekly attacks of cataplexy, compared with those who received placebo.
The new analyses, which focused on key secondary outcomes, showed that all three doses of the novel agent were associated with significant improvements in sleep quality, refreshing nature of sleep, sleep paralysis, disturbed nocturnal sleep, and scores on the Epworth Sleepiness Scale (ESS).
Principal investigator Michael J. Thorpy, MD, director of the Sleep-Wake Disorders Center at the Montefiore Medical Center, New York, said in a news release that the results represent “the promise of a potential new treatment strategy for physicians and patients.”
“I am particularly impressed by the consistency of results as early as 3 weeks with only a 6-g dose,” he added.
Dr. Thorpy, who is also a professor of neurology at the Albert Einstein College of Medicine, noted that the new formulation will be more convenient for patients. “The advantage of this medication is its once-nightly formulation, so patients don’t need to awaken during the night and can actually have a better night’s sleep,” he said.
Dr. Thorpy presented the study findings at the 2021 annual meeting of the American Academy of Neurology.
FT218 is currently under review by the U.S. Food and Drug Administration, which has set Oct. 15 as the Prescription Drug User Fee Act target date.
Forced awakening
Sodium oxybate was first approved by the FDA in 2002 to treat cataplexy in adults with narcolepsy and was expanded in 2005 to also treat excessive daytime sleepiness (EDS). That formulation is indicated for twice-nightly administration, with the second dose taken 2.5-4 hours after the first.
“The need for forced awakening to take the second dose ... may result in noncompliance, which may lead to reduced efficacy and/or mistimed doses,” the investigators noted.
FT218 is a modified-release version of sodium oxybate. A single 6-g dose of the investigational agent “has shown bioequivalent exposure to twice-nightly immediate-release [sodium oxybate] given as two 3-g doses,” wrote the researchers.
It also currently has Orphan Drug Designation from the FDA for the treatment of narcolepsy.
The randomized, double-blind, placebo-controlled, multicenter REST-ON study was conducted from November 2016 to March 2020 and included patients 16 years or older who had narcolepsy type 1 or type 2.
Patients received the active treatment (n = 107; mean age, 30.9 years; 64.5% women) or placebo (n = 105; mean age, 31.6 years; 71.4% women) according to a four-period forced uptitration dosing schedule of 4.5 g for 1 week, 6 g for 2 weeks, 7.5 g for 5 weeks, and 9 g for 5 weeks.
Secondary outcome measures included the ESS, sleep quality/refreshing nature of sleep on a visual analog scale, sleep paralysis and hypnagogic hallucinations on a sleep symptoms diary, disturbed nocturnal sleep on polysomnographic measures, and number of arousals as defined per the American Academy of Sleep Medicine Score Manual.
Reports of adverse events (AEs) were collected from time of informed consent until 7 days after the last dose received.
Improvement across doses
Results showed that, compared with placebo, improvement in disturbed nocturnal sleep from baseline was significantly greater for the active treatment at 6 g at week 3 (mean between-group difference, –11; P < .001), at 7.5 g at week 8 (mean difference, –17.7; P < .001), and at 9 g at week 13 (mean difference, –22.6; P < .001).
The mean difference between the three doses and placebo for reduction in number of arousals was –11.3 (P < .05), –19.4 (P < .001), and –23.7 (P < .001), respectively. And the 6 g at week 3, 7.5 g at week 8, and 9 g at week 13 doses showed significant (P < .001) improvements versus placebo on the ESS (mean difference, –2.1, –3.2, and –3.9, respectively).
All three doses also showed significant improvement in sleep quality and refreshing nature of sleep (P < .001 for all comparisons), as well as improvement of sleep paralysis (P = .04, P = .02, and P = .04, respectively).
There were no significant differences between FT218 and placebo for improvement in hypnagogic hallucinations. Dr. Thorpy noted that the number of patients with baseline hallucinations “was relatively small,” which may have led to this finding. “Had there been a much larger population with hallucinations, I suspect that we would have seen a statistically significant improvement there as well,” he said.
Generally well tolerated
The investigators noted that FT218 was “generally well tolerated, and the most common adverse reactions were well-known and established sodium oxybate adverse reactions.”
Treatment-related AEs that occurred in more than 2% of the patients receiving FT218 included nausea, dizziness, enuresis, headache, decreased appetite, and vomiting.
Seven serious AEs were reported, including five in those assigned to the active treatment. This included one case each of diabetes inadequate control, paresthesia, perirectal abscess, hypertension, and suicidal ideation. Only the case of suicidal ideation was considered to be a treatment-related AE.
The investigators noted that, although they have not yet delved into subgroup analysis to look for differences among sex, age, or race, they plan to do so in the future.
Overall, the results indicate that “FT218 is an effective agent not only for the major symptoms of sleepiness and cataplexy, but also the quality of sleep at night,” said Dr. Thorpy.
Asked whether he thinks the FDA will approve the drug, he said that it should be “straightforward” because it’s just a different formulation of an already-approved agent. “I very much expect there will not be any problems in this medication being approved,” Dr. Thorpy said.
Benefits ‘sleep architecture’
Commenting on the findings, Logan Schneider, MD, codirector of the Stanford/VA Alzheimer’s Center and clinical assistant professor at the Stanford Sleep Center, Redwood City, Calif., said that the investigators’ focus on these secondary outcomes “was really worthwhile.”
Dr. Schneider, who was not involved in the research, noted that, because the study only included patients with narcolepsy, the results can’t be extrapolated to groups who have other sleep disorders.
Still, “it is worthwhile now to expand beyond the two primary symptoms that are, in my consideration, life threatening: daytime sleepiness and cataplexy. We should also address more of the quality of life and other aspects of narcolepsy, including disturbed nocturnal sleep and sleep quality issues related to that,” he said.
“Being able to address those aspects and say, ‘I have a therapy that clearly helps the multidimensionality of our patients’ is very vindicating,” Dr. Schneider noted.
He was also impressed with the various measures the researchers used, rather than relying just on patient reports, “which are subject to recollection difficulties. This was a nice way to quantify possibly as a diagnostic marker the underlying disruption of sleep, as well as a possible treatment marker to show how well a therapy works.”
“It actually shows a beneficial effect on sleep architecture,” Dr. Schneider said.
The study was funded by Avadel Pharmaceuticals. Dr. Thorpy is a consultant/advisory board member for Avadel, Axsome, Balance Therapeutics, Eisai, Harmony Biosciences, Jazz Pharmaceuticals, NLS Pharmaceuticals, Suven Life Sciences, and Takeda Pharmaceutical. Dr. Schneider reports being an adviser and/or on the speakers’ bureau for similar drugs by Jazz Pharmaceuticals and Harmony Biosciences.
A version of this article first appeared on Medscape.com.
FROM AAN 2021
AHA guidance on blood clots linked to COVID-19 vaccine
A newly released report is offering guidance concerning rare conditions associated with COVID-19 as well as vaccines against the virus.
The report was released April 29, 2021, by the American Heart Association/American Stroke Association Stroke Council Leadership in answer to the decision April 23 by the Centers for Disease Control and Prevention and the Food and Drug Administration to lift an earlier “pause” in administration of the Johnson & Johnson (Janssen) vaccine.
That pause had been put in place after reports were received of a possible association between the J&J vaccine and cerebral venous sinus thrombosis (CVST) and thrombosis-thrombocytopenia syndrome (TTS, blood clots plus low blood platelets). CVST and TTS were also linked to patients in Europe and Canada who received the AstraZeneca COVID-19 vaccine.
However, the new report noted that these conditions are very rare.
“The risk of CVST due to infection with COVID-19 is 8-10 times higher than the risk of CVST after receiving a COVID-19 vaccine,” lead author Karen L. Furie, MD, chair of the department of neurology at Brown University, Providence, R.I., said in a press release.
“The public can be reassured by the CDC’s and FDA’s investigation and these statistics – the likelihood of developing CVST after a COVID-19 vaccine is extremely low,” said Dr. Furie, adding that the authors “urge all adults to receive any of the approved COVID-19 vaccines.”
The new guidance, which was published online April 29, 2021, in Stroke, discusses signs and symptoms of CVST and TTS, as well as vaccine-induced immune thrombotic thrombocytopenia (VITT). It also recommends best options for treating these conditions.
Assessing 81 million patients
In their analysis, the investigators assessed a database of 59 health care organizations and 81 million patients, 98% of whom were in the United States.
Of almost 514,000 patients diagnosed with COVID-19 between January 2020 and March 2021, 20 also received a diagnosis of CVST.
Among about 490,000 adults who received either the Pfizer or Moderna vaccines, there were no diagnosed cases of thrombocytopenia.
Dr. Furie reiterated that CVST blood clots “are very rare adverse events,” but recommended that any patient in the ED with a suspected clot should be screened immediately to determine if they received a COVID vaccine during the previous few weeks.
For those who have recently received the COVID-19 vaccine, a suspected clot should be treated with nonheparin anticoagulants, Dr. Furie said.
“No heparin products in any dose should be given for suspected CVST, TTS, or VITT. With the right treatment, most patients can have a full recovery,” she added. The report includes additional, detailed treatment recommendations if one of these conditions are suspected.
Rare events
The authors noted that cases of TTS/VITT occurred up to 2.5 weeks after receiving the J&J vaccine in the United States and up to 3.5 weeks after receiving the AstraZeneca vaccine in Europe.
An April 23 report from the CDC and FDA noted that, out of almost 7 million adults who received the J&J vaccine, the agencies investigated only 15 reported cases of TTS.
An April 7 report from the European Medicines Agency noted that, out of more than 25 million people who received the AstraZeneca vaccine in the European Union, it found 62 cases of CVST.
A statement put out by the American Heart Association/American Stroke Association urges “everyone to receive a COVID-19 vaccine” as soon as possible.
“We are confident the benefits of vaccination far exceed the very small, rare risks,” the organizations said. “The risks of vaccination are also far smaller than the risk of COVID-19 and its potentially fatal consequences.”
A version of this article first appeared on Medscape.com.
A newly released report is offering guidance concerning rare conditions associated with COVID-19 as well as vaccines against the virus.
The report was released April 29, 2021, by the American Heart Association/American Stroke Association Stroke Council Leadership in answer to the decision April 23 by the Centers for Disease Control and Prevention and the Food and Drug Administration to lift an earlier “pause” in administration of the Johnson & Johnson (Janssen) vaccine.
That pause had been put in place after reports were received of a possible association between the J&J vaccine and cerebral venous sinus thrombosis (CVST) and thrombosis-thrombocytopenia syndrome (TTS, blood clots plus low blood platelets). CVST and TTS were also linked to patients in Europe and Canada who received the AstraZeneca COVID-19 vaccine.
However, the new report noted that these conditions are very rare.
“The risk of CVST due to infection with COVID-19 is 8-10 times higher than the risk of CVST after receiving a COVID-19 vaccine,” lead author Karen L. Furie, MD, chair of the department of neurology at Brown University, Providence, R.I., said in a press release.
“The public can be reassured by the CDC’s and FDA’s investigation and these statistics – the likelihood of developing CVST after a COVID-19 vaccine is extremely low,” said Dr. Furie, adding that the authors “urge all adults to receive any of the approved COVID-19 vaccines.”
The new guidance, which was published online April 29, 2021, in Stroke, discusses signs and symptoms of CVST and TTS, as well as vaccine-induced immune thrombotic thrombocytopenia (VITT). It also recommends best options for treating these conditions.
Assessing 81 million patients
In their analysis, the investigators assessed a database of 59 health care organizations and 81 million patients, 98% of whom were in the United States.
Of almost 514,000 patients diagnosed with COVID-19 between January 2020 and March 2021, 20 also received a diagnosis of CVST.
Among about 490,000 adults who received either the Pfizer or Moderna vaccines, there were no diagnosed cases of thrombocytopenia.
Dr. Furie reiterated that CVST blood clots “are very rare adverse events,” but recommended that any patient in the ED with a suspected clot should be screened immediately to determine if they received a COVID vaccine during the previous few weeks.
For those who have recently received the COVID-19 vaccine, a suspected clot should be treated with nonheparin anticoagulants, Dr. Furie said.
“No heparin products in any dose should be given for suspected CVST, TTS, or VITT. With the right treatment, most patients can have a full recovery,” she added. The report includes additional, detailed treatment recommendations if one of these conditions are suspected.
Rare events
The authors noted that cases of TTS/VITT occurred up to 2.5 weeks after receiving the J&J vaccine in the United States and up to 3.5 weeks after receiving the AstraZeneca vaccine in Europe.
An April 23 report from the CDC and FDA noted that, out of almost 7 million adults who received the J&J vaccine, the agencies investigated only 15 reported cases of TTS.
An April 7 report from the European Medicines Agency noted that, out of more than 25 million people who received the AstraZeneca vaccine in the European Union, it found 62 cases of CVST.
A statement put out by the American Heart Association/American Stroke Association urges “everyone to receive a COVID-19 vaccine” as soon as possible.
“We are confident the benefits of vaccination far exceed the very small, rare risks,” the organizations said. “The risks of vaccination are also far smaller than the risk of COVID-19 and its potentially fatal consequences.”
A version of this article first appeared on Medscape.com.
A newly released report is offering guidance concerning rare conditions associated with COVID-19 as well as vaccines against the virus.
The report was released April 29, 2021, by the American Heart Association/American Stroke Association Stroke Council Leadership in answer to the decision April 23 by the Centers for Disease Control and Prevention and the Food and Drug Administration to lift an earlier “pause” in administration of the Johnson & Johnson (Janssen) vaccine.
That pause had been put in place after reports were received of a possible association between the J&J vaccine and cerebral venous sinus thrombosis (CVST) and thrombosis-thrombocytopenia syndrome (TTS, blood clots plus low blood platelets). CVST and TTS were also linked to patients in Europe and Canada who received the AstraZeneca COVID-19 vaccine.
However, the new report noted that these conditions are very rare.
“The risk of CVST due to infection with COVID-19 is 8-10 times higher than the risk of CVST after receiving a COVID-19 vaccine,” lead author Karen L. Furie, MD, chair of the department of neurology at Brown University, Providence, R.I., said in a press release.
“The public can be reassured by the CDC’s and FDA’s investigation and these statistics – the likelihood of developing CVST after a COVID-19 vaccine is extremely low,” said Dr. Furie, adding that the authors “urge all adults to receive any of the approved COVID-19 vaccines.”
The new guidance, which was published online April 29, 2021, in Stroke, discusses signs and symptoms of CVST and TTS, as well as vaccine-induced immune thrombotic thrombocytopenia (VITT). It also recommends best options for treating these conditions.
Assessing 81 million patients
In their analysis, the investigators assessed a database of 59 health care organizations and 81 million patients, 98% of whom were in the United States.
Of almost 514,000 patients diagnosed with COVID-19 between January 2020 and March 2021, 20 also received a diagnosis of CVST.
Among about 490,000 adults who received either the Pfizer or Moderna vaccines, there were no diagnosed cases of thrombocytopenia.
Dr. Furie reiterated that CVST blood clots “are very rare adverse events,” but recommended that any patient in the ED with a suspected clot should be screened immediately to determine if they received a COVID vaccine during the previous few weeks.
For those who have recently received the COVID-19 vaccine, a suspected clot should be treated with nonheparin anticoagulants, Dr. Furie said.
“No heparin products in any dose should be given for suspected CVST, TTS, or VITT. With the right treatment, most patients can have a full recovery,” she added. The report includes additional, detailed treatment recommendations if one of these conditions are suspected.
Rare events
The authors noted that cases of TTS/VITT occurred up to 2.5 weeks after receiving the J&J vaccine in the United States and up to 3.5 weeks after receiving the AstraZeneca vaccine in Europe.
An April 23 report from the CDC and FDA noted that, out of almost 7 million adults who received the J&J vaccine, the agencies investigated only 15 reported cases of TTS.
An April 7 report from the European Medicines Agency noted that, out of more than 25 million people who received the AstraZeneca vaccine in the European Union, it found 62 cases of CVST.
A statement put out by the American Heart Association/American Stroke Association urges “everyone to receive a COVID-19 vaccine” as soon as possible.
“We are confident the benefits of vaccination far exceed the very small, rare risks,” the organizations said. “The risks of vaccination are also far smaller than the risk of COVID-19 and its potentially fatal consequences.”
A version of this article first appeared on Medscape.com.
COVID-19 linked to novel epileptic seizures
, new research shows. In a retrospective study of more than 900 patients admitted to the hospital with COVID-19, those without a known history of epilepsy had three times greater odds of experiencing novel seizures than those with a known history of epilepsy.
In addition, among patients with new-onset seizures, hospital stays were about 15 days longer – and mortality rates were significantly higher.
“We’re finding that there are many neurological consequences that can happen with COVID-19 infections, and it’s important for clinicians to keep that in mind as they monitor people long term,” said study investigator Neeraj Singh, MD, neurologist and epileptologist with Northwell Health System, Great Neck, New York.
Dr. Singh noted that although seizures “might not be the most common thing we see in people with COVID-19, they seem to be new seizures and not just a seizure we knew would happen in someone with epilepsy.”
“So there’s definitely a need now for more prospective research and following people over time to fully understand all the different things that might be newly a problem for them in the long term,” he added.
Dr. Singh and Hardik Bhaskar, an undergraduate student at Hunter College, New York, presented the study findings at the American Academy of Neurology’s 2021 annual meeting.
Largest sample to date
“This study explores the relationship between the incidences of COVID-19 infections and [novel] epileptic seizures in the largest sample to date in a single New York–based hospital system,” the investigators noted. Novel seizures included both new-onset and breakthrough seizures.
Dr. Singh told meeting attendees that the “early epicenter” of the COVID pandemic was in New York and occurred from Feb. 29, 2020 to June 1, 2020. Patients with COVID-19 “had multiple neurological sequelae, including seizures, strokes, and encephalopathy,” he said.
However, the effects of COVID-19 on individuals with epilepsy “remain unclear,” Dr. Singh said.
For their study, the researchers assessed 917 patients in 13 New York City metropolitan hospitals. All participants had received a confirmed positive test result on PCR for COVID and had received an antiepileptic medication upon admission. The patients were admitted between Feb. 14 and June 14, 2020.
For the study, the patients were first divided into two groups: those with a history of epilepsy (n = 451), and those without such a history (n = 466).
The first group was further divided on the basis of those who presented with breakthrough seizures and those who presented without them. The second group was further divided on the basis of those who presented with new-onset seizures and those who presented without them.
Significant adverse outcomes
Results showed that 27% of the patients without a history of epilepsy experienced a novel/new-onset seizure and that 11% of the patients with a history of epilepsy experienced a novel/breakthrough seizure (odds ratio, 3.15; P < .0001).
In addition, participants with new-onset seizures had a longer stay in the hospital (mean, 26.9 days) than the subgroup with a history of epilepsy and no breakthrough seizures (10.9 days) and the subgroup with a history of epilepsy who did experience breakthrough seizures (12.8 days; P < .0001 for both comparisons).
In the group of patients with a history of epilepsy, there were no significant differences in lengths of stay between those with and those without breakthrough seizures (P = .68).
Although mortality rates did not differ significantly between the full group with a history of epilepsy versus the full group without epilepsy (23% vs. 25%; OR, 0.9), the mortality rate was significantly higher among patients who experienced novel seizures than among those who did not experience such seizures (29% vs. 23%; OR, 1.4; P = .045).
Mr. Bhaskar noted that there are “many hypotheses for the mechanism by which COVID-19 might cause seizures.” Those mechanisms include proinflammatory cytokine storms, which may increase the rate of apoptosis, neuronal necrosis, and glutamate concentrations and may disrupt the blood-brain barrier. Another hypothesis is that SARS-CoV-2 infection may lead to hypoxia and abnormal coagulation, resulting in stroke and a subsequent increase in the risk for seizures.
Interestingly, “the presence of antiepileptic medications in patients with epilepsy may confer a protective effect against breakthrough seizures,” Dr. Singh said. “However, some subclinical seizures may be misdiagnosed as encephalopathy when patients present with COVID-19 infections.”
He added that further research is needed into the mechanisms linking these infections and new-onset seizures and to “identify subclinical seizures in encephalopathic patients.”
Asked during the question-and-answer session whether the investigators had assessed differences by demographics, such as age or sex, Dr. Singh said, “We have not subdivided them that way yet,” but he said he would like to do so in the future. He also plans to look further into which specific medications were used by the participants.
The investigators have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research shows. In a retrospective study of more than 900 patients admitted to the hospital with COVID-19, those without a known history of epilepsy had three times greater odds of experiencing novel seizures than those with a known history of epilepsy.
In addition, among patients with new-onset seizures, hospital stays were about 15 days longer – and mortality rates were significantly higher.
“We’re finding that there are many neurological consequences that can happen with COVID-19 infections, and it’s important for clinicians to keep that in mind as they monitor people long term,” said study investigator Neeraj Singh, MD, neurologist and epileptologist with Northwell Health System, Great Neck, New York.
Dr. Singh noted that although seizures “might not be the most common thing we see in people with COVID-19, they seem to be new seizures and not just a seizure we knew would happen in someone with epilepsy.”
“So there’s definitely a need now for more prospective research and following people over time to fully understand all the different things that might be newly a problem for them in the long term,” he added.
Dr. Singh and Hardik Bhaskar, an undergraduate student at Hunter College, New York, presented the study findings at the American Academy of Neurology’s 2021 annual meeting.
Largest sample to date
“This study explores the relationship between the incidences of COVID-19 infections and [novel] epileptic seizures in the largest sample to date in a single New York–based hospital system,” the investigators noted. Novel seizures included both new-onset and breakthrough seizures.
Dr. Singh told meeting attendees that the “early epicenter” of the COVID pandemic was in New York and occurred from Feb. 29, 2020 to June 1, 2020. Patients with COVID-19 “had multiple neurological sequelae, including seizures, strokes, and encephalopathy,” he said.
However, the effects of COVID-19 on individuals with epilepsy “remain unclear,” Dr. Singh said.
For their study, the researchers assessed 917 patients in 13 New York City metropolitan hospitals. All participants had received a confirmed positive test result on PCR for COVID and had received an antiepileptic medication upon admission. The patients were admitted between Feb. 14 and June 14, 2020.
For the study, the patients were first divided into two groups: those with a history of epilepsy (n = 451), and those without such a history (n = 466).
The first group was further divided on the basis of those who presented with breakthrough seizures and those who presented without them. The second group was further divided on the basis of those who presented with new-onset seizures and those who presented without them.
Significant adverse outcomes
Results showed that 27% of the patients without a history of epilepsy experienced a novel/new-onset seizure and that 11% of the patients with a history of epilepsy experienced a novel/breakthrough seizure (odds ratio, 3.15; P < .0001).
In addition, participants with new-onset seizures had a longer stay in the hospital (mean, 26.9 days) than the subgroup with a history of epilepsy and no breakthrough seizures (10.9 days) and the subgroup with a history of epilepsy who did experience breakthrough seizures (12.8 days; P < .0001 for both comparisons).
In the group of patients with a history of epilepsy, there were no significant differences in lengths of stay between those with and those without breakthrough seizures (P = .68).
Although mortality rates did not differ significantly between the full group with a history of epilepsy versus the full group without epilepsy (23% vs. 25%; OR, 0.9), the mortality rate was significantly higher among patients who experienced novel seizures than among those who did not experience such seizures (29% vs. 23%; OR, 1.4; P = .045).
Mr. Bhaskar noted that there are “many hypotheses for the mechanism by which COVID-19 might cause seizures.” Those mechanisms include proinflammatory cytokine storms, which may increase the rate of apoptosis, neuronal necrosis, and glutamate concentrations and may disrupt the blood-brain barrier. Another hypothesis is that SARS-CoV-2 infection may lead to hypoxia and abnormal coagulation, resulting in stroke and a subsequent increase in the risk for seizures.
Interestingly, “the presence of antiepileptic medications in patients with epilepsy may confer a protective effect against breakthrough seizures,” Dr. Singh said. “However, some subclinical seizures may be misdiagnosed as encephalopathy when patients present with COVID-19 infections.”
He added that further research is needed into the mechanisms linking these infections and new-onset seizures and to “identify subclinical seizures in encephalopathic patients.”
Asked during the question-and-answer session whether the investigators had assessed differences by demographics, such as age or sex, Dr. Singh said, “We have not subdivided them that way yet,” but he said he would like to do so in the future. He also plans to look further into which specific medications were used by the participants.
The investigators have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research shows. In a retrospective study of more than 900 patients admitted to the hospital with COVID-19, those without a known history of epilepsy had three times greater odds of experiencing novel seizures than those with a known history of epilepsy.
In addition, among patients with new-onset seizures, hospital stays were about 15 days longer – and mortality rates were significantly higher.
“We’re finding that there are many neurological consequences that can happen with COVID-19 infections, and it’s important for clinicians to keep that in mind as they monitor people long term,” said study investigator Neeraj Singh, MD, neurologist and epileptologist with Northwell Health System, Great Neck, New York.
Dr. Singh noted that although seizures “might not be the most common thing we see in people with COVID-19, they seem to be new seizures and not just a seizure we knew would happen in someone with epilepsy.”
“So there’s definitely a need now for more prospective research and following people over time to fully understand all the different things that might be newly a problem for them in the long term,” he added.
Dr. Singh and Hardik Bhaskar, an undergraduate student at Hunter College, New York, presented the study findings at the American Academy of Neurology’s 2021 annual meeting.
Largest sample to date
“This study explores the relationship between the incidences of COVID-19 infections and [novel] epileptic seizures in the largest sample to date in a single New York–based hospital system,” the investigators noted. Novel seizures included both new-onset and breakthrough seizures.
Dr. Singh told meeting attendees that the “early epicenter” of the COVID pandemic was in New York and occurred from Feb. 29, 2020 to June 1, 2020. Patients with COVID-19 “had multiple neurological sequelae, including seizures, strokes, and encephalopathy,” he said.
However, the effects of COVID-19 on individuals with epilepsy “remain unclear,” Dr. Singh said.
For their study, the researchers assessed 917 patients in 13 New York City metropolitan hospitals. All participants had received a confirmed positive test result on PCR for COVID and had received an antiepileptic medication upon admission. The patients were admitted between Feb. 14 and June 14, 2020.
For the study, the patients were first divided into two groups: those with a history of epilepsy (n = 451), and those without such a history (n = 466).
The first group was further divided on the basis of those who presented with breakthrough seizures and those who presented without them. The second group was further divided on the basis of those who presented with new-onset seizures and those who presented without them.
Significant adverse outcomes
Results showed that 27% of the patients without a history of epilepsy experienced a novel/new-onset seizure and that 11% of the patients with a history of epilepsy experienced a novel/breakthrough seizure (odds ratio, 3.15; P < .0001).
In addition, participants with new-onset seizures had a longer stay in the hospital (mean, 26.9 days) than the subgroup with a history of epilepsy and no breakthrough seizures (10.9 days) and the subgroup with a history of epilepsy who did experience breakthrough seizures (12.8 days; P < .0001 for both comparisons).
In the group of patients with a history of epilepsy, there were no significant differences in lengths of stay between those with and those without breakthrough seizures (P = .68).
Although mortality rates did not differ significantly between the full group with a history of epilepsy versus the full group without epilepsy (23% vs. 25%; OR, 0.9), the mortality rate was significantly higher among patients who experienced novel seizures than among those who did not experience such seizures (29% vs. 23%; OR, 1.4; P = .045).
Mr. Bhaskar noted that there are “many hypotheses for the mechanism by which COVID-19 might cause seizures.” Those mechanisms include proinflammatory cytokine storms, which may increase the rate of apoptosis, neuronal necrosis, and glutamate concentrations and may disrupt the blood-brain barrier. Another hypothesis is that SARS-CoV-2 infection may lead to hypoxia and abnormal coagulation, resulting in stroke and a subsequent increase in the risk for seizures.
Interestingly, “the presence of antiepileptic medications in patients with epilepsy may confer a protective effect against breakthrough seizures,” Dr. Singh said. “However, some subclinical seizures may be misdiagnosed as encephalopathy when patients present with COVID-19 infections.”
He added that further research is needed into the mechanisms linking these infections and new-onset seizures and to “identify subclinical seizures in encephalopathic patients.”
Asked during the question-and-answer session whether the investigators had assessed differences by demographics, such as age or sex, Dr. Singh said, “We have not subdivided them that way yet,” but he said he would like to do so in the future. He also plans to look further into which specific medications were used by the participants.
The investigators have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
From AAN 2021
Common MS treatment wears off more quickly in Black patients
new research suggests. In a study of almost 200 patients, Black participants with MS or NMOSD showed significantly more rapid B-cell repopulation 6-12 months after receiving anti-CD20 infusion therapy with rituximab or ocrelizumab (Rituxan, Ocrevus, Genentech) than did White participants.
“The results showed that this B-cell targeted therapy wore off more quickly in African Americans,” said study coinvestigator Gregg J. Silverman, MD, a professor at New York University.
He said that, although the study was more observational in design, “over time when people come back to the clinic, it gives you an idea of whether the agent is still working in their bodies.”
Overall, “our findings raise the question of whether the same therapy dose may be equally effective for all people,” coinvestigator Ilya Kister, MD, also from NYU, added in a press release.
Dr. Kister noted that this could have implications for the way Black patients with autoimmune diseases are treated in the future.
The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
More severe disease in Black patients
Anti-CD20 infusion therapy, or B-cell depletion therapy, is commonly used to treat autoimmune diseases, including MS and NMOSD. “While previous research has shown that this type of infusion therapy is effective for people with these diseases, we also know that Black people tend to have more severe courses of MS,” Dr. Kister said.
“We wanted to compare how quickly the B cells came back in Black people and White people after treatment,” he added.
Dr. Silverman noted that he has been “studying this agent in autoimmune disease for many years. And from all the different studies, I don’t think we had the right population to ask this question. Demographics were just reviewed as they were.”
The current study included 168 participants (mean age, 44 years; 71% women) who had a diagnosis of MS (n = 134) or NMOSD (n = 32) or who were considered to have MS or NMOSD (n = 2). In addition, 36% of the participants self-identified as Black or African American, 36% self-identified as White, and 28% self-identified as another race.
Flow cytometry results were available for all patients after undergoing anti-CD20 infusions at the NYU MS Care Center. Cluster analyses were conducted on the following B-cell subsets: CD19, CD20, IgD, and CD27. “B-cell repopulation was defined as any detectable number of CD19+ cells on flow cytometry,” the investigators reported.
Clinical implications?
Results showed that 29.8% of the full study group showed B-cell repopulation a mean of 6.8 months after infusion. In those with B-cell repopulation, 80.3% had IgD+/CD27– subsets, 11.6% had IgD–/CD27+, 6.2% had IgD–/CD27–, and 1.8% had IgD+/CD27+. These B-cell subset ratios did not differ significantly between the Black and White participants.
Interestingly, no patients showed B-cell repopulation before 4 months after infusion. From 4 to 6 months after infusion, there were no significant differences between the Black and White participants in terms of frequency of B-cell repopulation (20.8% vs. 17.9%, respectively; P = .79).
However, repopulation was significantly more frequent in the Black patients 6-12 months after infusion (76.2% vs. 33.3%; P = .02).
Overall, the findings “may have implications for clinical management of MS/NMOSD” in Black individuals, the investigators wrote.
“I was impressed by the differences we saw in responses of patients that were self-declaring as African Americans versus those who were Whites,” Dr. Silverman said. However, “as we say in science: it gives us an answer but it raises even more questions, which may well be important for helping us understand how the agent works and how the disease affects different people.”
Still, Dr. Silverman noted that the findings give clinicians using the agent “a signal that they should be very vigilant. It was an observation at one center, but we’re asking our colleagues [at other clinics] to think about being more careful as they review data with their patients.”
He added that future multicenter studies will allow these issues to be assessed more comprehensively. “This was a discovery study; it now needs validation; and maybe the next step would be looking into the mechanism.”
Dr. Silverman pointed out that the Food and Drug Administration–approved label for this type of therapy “allows for somewhat more frequent dosing. So that might be indicated if it’s found that it’s wearing off in an individual. Perhaps they should be treated more frequently?”
“At a minimum, this has raised our vigilance – and we’re interested to see what the feedback will be at the [AAN] meeting,” he added.
Real-world data
Commenting on the findings, Eric Klawiter, MD, associate professor of neurology at Harvard Medical School and director of the Multiple Sclerosis and NMO unit at Massachusetts General Hospital, both in Boston, noted that an important study factor was the focus on repopulation to identify specific groups “who may be early repopulators” as it relates to disease activity and disability progression in MS.
“I thought this was a nicely designed study that made good use of real-world data in MS and NMOSD,” added Dr. Klawiter, who was not involved with the research. He pointed out that timing was another interesting aspect of the study. “As we typically use these cell-depleting agents on an ‘every-6-month’ basis, the most pertinent time frame surrounds those that repopulate prior to 6 months.”
If the current study would have shown differences between the Black and White participants at that time point, “I think that would have been most pertinent from a clinical standpoint and a greater opportunity for intervention,” Dr. Klawiter said. “But we saw that, before 4 and 6 months, [the difference] wasn’t significant.”
Still, “after 6 months, the study demonstrates that Black people with MS and NMOSD may repopulate faster,” he added.
“The only real change a clinician could make would be to modify the frequency of the dosing. So if we can identify certain characteristics that would lead you to want to evaluate for the need of redosing sooner, I think that would be useful,” he said.
Specific characteristics identified in previous research include body mass index. “If there are also ethnicity factors, that would be an additional demographic factor that a clinician should pay close attention to,” said Dr. Klawiter.
He noted that his current practice is to check flow cytometry and B-cell counts at the time of a patient’s next infusion. “And if I’m seeing that B-cell levels are repleting at that time point, I am already then making adjustments with their next infusion as to the dosing frequency,” he added.
“This [study] may elucidate some of the potential reasons why we see some people replete their B cells faster than others, but I think additional studies are necessary to make that determination,” Dr. Klawiter concluded.
Genentech provided funding for the study. Dr. Silverman reported no relevant financial relationships. Dr. Klawiter reported having received research funds and consulting fees from Genentech.
A version of this article first appeared on Medscape.com.
new research suggests. In a study of almost 200 patients, Black participants with MS or NMOSD showed significantly more rapid B-cell repopulation 6-12 months after receiving anti-CD20 infusion therapy with rituximab or ocrelizumab (Rituxan, Ocrevus, Genentech) than did White participants.
“The results showed that this B-cell targeted therapy wore off more quickly in African Americans,” said study coinvestigator Gregg J. Silverman, MD, a professor at New York University.
He said that, although the study was more observational in design, “over time when people come back to the clinic, it gives you an idea of whether the agent is still working in their bodies.”
Overall, “our findings raise the question of whether the same therapy dose may be equally effective for all people,” coinvestigator Ilya Kister, MD, also from NYU, added in a press release.
Dr. Kister noted that this could have implications for the way Black patients with autoimmune diseases are treated in the future.
The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
More severe disease in Black patients
Anti-CD20 infusion therapy, or B-cell depletion therapy, is commonly used to treat autoimmune diseases, including MS and NMOSD. “While previous research has shown that this type of infusion therapy is effective for people with these diseases, we also know that Black people tend to have more severe courses of MS,” Dr. Kister said.
“We wanted to compare how quickly the B cells came back in Black people and White people after treatment,” he added.
Dr. Silverman noted that he has been “studying this agent in autoimmune disease for many years. And from all the different studies, I don’t think we had the right population to ask this question. Demographics were just reviewed as they were.”
The current study included 168 participants (mean age, 44 years; 71% women) who had a diagnosis of MS (n = 134) or NMOSD (n = 32) or who were considered to have MS or NMOSD (n = 2). In addition, 36% of the participants self-identified as Black or African American, 36% self-identified as White, and 28% self-identified as another race.
Flow cytometry results were available for all patients after undergoing anti-CD20 infusions at the NYU MS Care Center. Cluster analyses were conducted on the following B-cell subsets: CD19, CD20, IgD, and CD27. “B-cell repopulation was defined as any detectable number of CD19+ cells on flow cytometry,” the investigators reported.
Clinical implications?
Results showed that 29.8% of the full study group showed B-cell repopulation a mean of 6.8 months after infusion. In those with B-cell repopulation, 80.3% had IgD+/CD27– subsets, 11.6% had IgD–/CD27+, 6.2% had IgD–/CD27–, and 1.8% had IgD+/CD27+. These B-cell subset ratios did not differ significantly between the Black and White participants.
Interestingly, no patients showed B-cell repopulation before 4 months after infusion. From 4 to 6 months after infusion, there were no significant differences between the Black and White participants in terms of frequency of B-cell repopulation (20.8% vs. 17.9%, respectively; P = .79).
However, repopulation was significantly more frequent in the Black patients 6-12 months after infusion (76.2% vs. 33.3%; P = .02).
Overall, the findings “may have implications for clinical management of MS/NMOSD” in Black individuals, the investigators wrote.
“I was impressed by the differences we saw in responses of patients that were self-declaring as African Americans versus those who were Whites,” Dr. Silverman said. However, “as we say in science: it gives us an answer but it raises even more questions, which may well be important for helping us understand how the agent works and how the disease affects different people.”
Still, Dr. Silverman noted that the findings give clinicians using the agent “a signal that they should be very vigilant. It was an observation at one center, but we’re asking our colleagues [at other clinics] to think about being more careful as they review data with their patients.”
He added that future multicenter studies will allow these issues to be assessed more comprehensively. “This was a discovery study; it now needs validation; and maybe the next step would be looking into the mechanism.”
Dr. Silverman pointed out that the Food and Drug Administration–approved label for this type of therapy “allows for somewhat more frequent dosing. So that might be indicated if it’s found that it’s wearing off in an individual. Perhaps they should be treated more frequently?”
“At a minimum, this has raised our vigilance – and we’re interested to see what the feedback will be at the [AAN] meeting,” he added.
Real-world data
Commenting on the findings, Eric Klawiter, MD, associate professor of neurology at Harvard Medical School and director of the Multiple Sclerosis and NMO unit at Massachusetts General Hospital, both in Boston, noted that an important study factor was the focus on repopulation to identify specific groups “who may be early repopulators” as it relates to disease activity and disability progression in MS.
“I thought this was a nicely designed study that made good use of real-world data in MS and NMOSD,” added Dr. Klawiter, who was not involved with the research. He pointed out that timing was another interesting aspect of the study. “As we typically use these cell-depleting agents on an ‘every-6-month’ basis, the most pertinent time frame surrounds those that repopulate prior to 6 months.”
If the current study would have shown differences between the Black and White participants at that time point, “I think that would have been most pertinent from a clinical standpoint and a greater opportunity for intervention,” Dr. Klawiter said. “But we saw that, before 4 and 6 months, [the difference] wasn’t significant.”
Still, “after 6 months, the study demonstrates that Black people with MS and NMOSD may repopulate faster,” he added.
“The only real change a clinician could make would be to modify the frequency of the dosing. So if we can identify certain characteristics that would lead you to want to evaluate for the need of redosing sooner, I think that would be useful,” he said.
Specific characteristics identified in previous research include body mass index. “If there are also ethnicity factors, that would be an additional demographic factor that a clinician should pay close attention to,” said Dr. Klawiter.
He noted that his current practice is to check flow cytometry and B-cell counts at the time of a patient’s next infusion. “And if I’m seeing that B-cell levels are repleting at that time point, I am already then making adjustments with their next infusion as to the dosing frequency,” he added.
“This [study] may elucidate some of the potential reasons why we see some people replete their B cells faster than others, but I think additional studies are necessary to make that determination,” Dr. Klawiter concluded.
Genentech provided funding for the study. Dr. Silverman reported no relevant financial relationships. Dr. Klawiter reported having received research funds and consulting fees from Genentech.
A version of this article first appeared on Medscape.com.
new research suggests. In a study of almost 200 patients, Black participants with MS or NMOSD showed significantly more rapid B-cell repopulation 6-12 months after receiving anti-CD20 infusion therapy with rituximab or ocrelizumab (Rituxan, Ocrevus, Genentech) than did White participants.
“The results showed that this B-cell targeted therapy wore off more quickly in African Americans,” said study coinvestigator Gregg J. Silverman, MD, a professor at New York University.
He said that, although the study was more observational in design, “over time when people come back to the clinic, it gives you an idea of whether the agent is still working in their bodies.”
Overall, “our findings raise the question of whether the same therapy dose may be equally effective for all people,” coinvestigator Ilya Kister, MD, also from NYU, added in a press release.
Dr. Kister noted that this could have implications for the way Black patients with autoimmune diseases are treated in the future.
The findings were released ahead of the study’s scheduled presentation at the annual meeting of the American Academy of Neurology.
More severe disease in Black patients
Anti-CD20 infusion therapy, or B-cell depletion therapy, is commonly used to treat autoimmune diseases, including MS and NMOSD. “While previous research has shown that this type of infusion therapy is effective for people with these diseases, we also know that Black people tend to have more severe courses of MS,” Dr. Kister said.
“We wanted to compare how quickly the B cells came back in Black people and White people after treatment,” he added.
Dr. Silverman noted that he has been “studying this agent in autoimmune disease for many years. And from all the different studies, I don’t think we had the right population to ask this question. Demographics were just reviewed as they were.”
The current study included 168 participants (mean age, 44 years; 71% women) who had a diagnosis of MS (n = 134) or NMOSD (n = 32) or who were considered to have MS or NMOSD (n = 2). In addition, 36% of the participants self-identified as Black or African American, 36% self-identified as White, and 28% self-identified as another race.
Flow cytometry results were available for all patients after undergoing anti-CD20 infusions at the NYU MS Care Center. Cluster analyses were conducted on the following B-cell subsets: CD19, CD20, IgD, and CD27. “B-cell repopulation was defined as any detectable number of CD19+ cells on flow cytometry,” the investigators reported.
Clinical implications?
Results showed that 29.8% of the full study group showed B-cell repopulation a mean of 6.8 months after infusion. In those with B-cell repopulation, 80.3% had IgD+/CD27– subsets, 11.6% had IgD–/CD27+, 6.2% had IgD–/CD27–, and 1.8% had IgD+/CD27+. These B-cell subset ratios did not differ significantly between the Black and White participants.
Interestingly, no patients showed B-cell repopulation before 4 months after infusion. From 4 to 6 months after infusion, there were no significant differences between the Black and White participants in terms of frequency of B-cell repopulation (20.8% vs. 17.9%, respectively; P = .79).
However, repopulation was significantly more frequent in the Black patients 6-12 months after infusion (76.2% vs. 33.3%; P = .02).
Overall, the findings “may have implications for clinical management of MS/NMOSD” in Black individuals, the investigators wrote.
“I was impressed by the differences we saw in responses of patients that were self-declaring as African Americans versus those who were Whites,” Dr. Silverman said. However, “as we say in science: it gives us an answer but it raises even more questions, which may well be important for helping us understand how the agent works and how the disease affects different people.”
Still, Dr. Silverman noted that the findings give clinicians using the agent “a signal that they should be very vigilant. It was an observation at one center, but we’re asking our colleagues [at other clinics] to think about being more careful as they review data with their patients.”
He added that future multicenter studies will allow these issues to be assessed more comprehensively. “This was a discovery study; it now needs validation; and maybe the next step would be looking into the mechanism.”
Dr. Silverman pointed out that the Food and Drug Administration–approved label for this type of therapy “allows for somewhat more frequent dosing. So that might be indicated if it’s found that it’s wearing off in an individual. Perhaps they should be treated more frequently?”
“At a minimum, this has raised our vigilance – and we’re interested to see what the feedback will be at the [AAN] meeting,” he added.
Real-world data
Commenting on the findings, Eric Klawiter, MD, associate professor of neurology at Harvard Medical School and director of the Multiple Sclerosis and NMO unit at Massachusetts General Hospital, both in Boston, noted that an important study factor was the focus on repopulation to identify specific groups “who may be early repopulators” as it relates to disease activity and disability progression in MS.
“I thought this was a nicely designed study that made good use of real-world data in MS and NMOSD,” added Dr. Klawiter, who was not involved with the research. He pointed out that timing was another interesting aspect of the study. “As we typically use these cell-depleting agents on an ‘every-6-month’ basis, the most pertinent time frame surrounds those that repopulate prior to 6 months.”
If the current study would have shown differences between the Black and White participants at that time point, “I think that would have been most pertinent from a clinical standpoint and a greater opportunity for intervention,” Dr. Klawiter said. “But we saw that, before 4 and 6 months, [the difference] wasn’t significant.”
Still, “after 6 months, the study demonstrates that Black people with MS and NMOSD may repopulate faster,” he added.
“The only real change a clinician could make would be to modify the frequency of the dosing. So if we can identify certain characteristics that would lead you to want to evaluate for the need of redosing sooner, I think that would be useful,” he said.
Specific characteristics identified in previous research include body mass index. “If there are also ethnicity factors, that would be an additional demographic factor that a clinician should pay close attention to,” said Dr. Klawiter.
He noted that his current practice is to check flow cytometry and B-cell counts at the time of a patient’s next infusion. “And if I’m seeing that B-cell levels are repleting at that time point, I am already then making adjustments with their next infusion as to the dosing frequency,” he added.
“This [study] may elucidate some of the potential reasons why we see some people replete their B cells faster than others, but I think additional studies are necessary to make that determination,” Dr. Klawiter concluded.
Genentech provided funding for the study. Dr. Silverman reported no relevant financial relationships. Dr. Klawiter reported having received research funds and consulting fees from Genentech.
A version of this article first appeared on Medscape.com.
FROM AAN 2021
Simple blood test plus AI may flag early-stage Alzheimer’s disease
, raising the prospect of early intervention when effective treatments become available.
In a study, investigators used six AI methodologies, including Deep Learning, to assess blood leukocyte epigenomic biomarkers. They found more than 150 genetic differences among study participants with Alzheimer’s disease in comparison with participants who did not have Alzheimer’s disease.
All of the AI platforms were effective in predicting Alzheimer’s disease. Deep Learning’s assessment of intragenic cytosine-phosphate-guanines (CpGs) had sensitivity and specificity rates of 97%.
“It’s almost as if the leukocytes have become a newspaper to tell us, ‘This is what is going on in the brain,’ “ lead author Ray Bahado-Singh, MD, chair of the department of obstetrics and gynecology, Oakland University, Auburn Hills, Mich., said in a news release.
The researchers noted that the findings, if replicated in future studies, may help in providing Alzheimer’s disease diagnoses “much earlier” in the disease process. “The holy grail is to identify patients in the preclinical stage so effective early interventions, including new medications, can be studied and ultimately used,” Dr. Bahado-Singh said.
“This certainly isn’t the final step in Alzheimer’s research, but I think this represents a significant change in direction,” he told attendees at a press briefing.
The findings were published online March 31 in PLOS ONE.
Silver tsunami
The investigators noted that Alzheimer’s disease is often diagnosed when the disease is in its later stages, after irreversible brain damage has occurred. “There is currently no cure for the disease, and the treatment is limited to drugs that attempt to treat symptoms and have little effect on the disease’s progression,” they noted.
Coinvestigator Khaled Imam, MD, director of geriatric medicine for Beaumont Health in Michigan, pointed out that although MRI and lumbar puncture can identify Alzheimer’s disease early on, the processes are expensive and/or invasive.
“Having biomarkers in the blood ... and being able to identify [Alzheimer’s disease] years before symptoms start, hopefully we’d be able to intervene early on in the process of the disease,” Dr. Imam said.
It is estimated that the number of Americans aged 85 and older will triple by 2050. This impending “silver tsunami,” which will come with a commensurate increase in Alzheimer’s disease cases, makes it even more important to be able to diagnose the disease early on, he noted.
The study included 24 individuals with late-onset Alzheimer’s disease (70.8% women; mean age, 83 years); 24 were deemed to be “cognitively healthy” (66.7% women; mean age, 80 years). About 500 ng of genomic DNA was extracted from whole-blood samples from each participant.
The researchers used the Infinium MethylationEPIC BeadChip array, and the samples were then examined for markers of methylation that would “indicate the disease process has started,” they noted.
In addition to Deep Learning, the five other AI platforms were the Support Vector Machine, Generalized Linear Model, Prediction Analysis for Microarrays, Random Forest, and Linear Discriminant Analysis.
These platforms were used to assess leukocyte genome changes. To predict Alzheimer’s disease, the researchers also used Ingenuity Pathway Analysis.
Significant “chemical changes”
Results showed that the Alzheimer’s disease group had 152 significantly differentially methylated CpGs in 171 genes in comparison with the non-Alzheimer’s disease group (false discovery rate P value < .05).
As a whole, using intragenic and intergenic/extragenic CpGs, the AI platforms were effective in predicting who had Alzheimer’s disease (area under the curve [AUC], ≥ 0.93). Using intragenic markers, the AUC for Deep Learning was 0.99.
“We looked at close to a million different sites, and we saw some chemical changes that we know are associated with alteration or change in gene function,” Dr. Bahado-Singh said.
Altered genes that were found in the Alzheimer’s disease group included CR1L, CTSV, S1PR1, and LTB4R – all of which “have been previously linked with Alzheimer’s disease and dementia,” the researchers noted. They also found the methylated genes CTSV and PRMT5, both of which have been previously associated with cardiovascular disease.
“A significant strength of our study is the novelty, i.e. the use of blood leukocytes to accurately detect Alzheimer’s disease and also for interrogating the pathogenesis of Alzheimer’s disease,” the investigators wrote.
Dr. Bahado-Singh said that the test let them identify changes in cells in the blood, “giving us a comprehensive account not only of the fact that the brain is being affected by Alzheimer’s disease but it’s telling us what kinds of processes are going on in the brain.
“Normally you don’t have access to the brain. This gives us a simple blood test to get an ongoing reading of the course of events in the brain – and potentially tell us very early on before the onset of symptoms,” he added.
Cautiously optimistic
During the question-and-answer session following his presentation at the briefing, Dr. Bahado-Singh reiterated that they are at a very early stage in the research and were not able to make clinical recommendations at this point. However, he added, “There was evidence that DNA methylation change could likely precede the onset of abnormalities in the cells that give rise to the disease.”
Coinvestigator Stewart Graham, PhD, director of Alzheimer’s research at Beaumont Health, added that although the initial study findings led to some excitement for the team, “we have to be very conservative with what we say.”
He noted that the findings need to be replicated in a more diverse population. Still, “we’re excited at the moment and looking forward to seeing what the future results hold,” Dr. Graham said.
Dr. Bahado-Singh said that if larger studies confirm the findings and the test is viable, it would make sense to use it as a screen for individuals older than 65. He noted that because of the aging of the population, “this subset of individuals will constitute a larger and larger fraction of the population globally.”
Still early days
Commenting on the findings, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, noted that the investigators used an “interesting” diagnostic process.
“It was a unique approach to looking at and trying to understand what might be some of the biological underpinnings and using these tools and technologies to determine if they’re able to differentiate individuals with Alzheimer’s disease” from those without Alzheimer’s disease, said Dr. Snyder, who was not involved with the research.
“Ultimately, we want to know who is at greater risk, who may have some of the changing biology at the earliest time point so that we can intervene to stop the progression of the disease,” she said.
She pointed out that a number of types of biomarker tests are currently under investigation, many of which are measuring different outcomes. “And that’s what we want to see going forward. We want to have as many tools in our toolbox that allow us to accurately diagnose at that earliest time point,” Dr. Snyder said.
“At this point, [the current study] is still pretty early, so it needs to be replicated and then expanded to larger groups to really understand what they may be seeing,” she added.
Dr. Bahado-Singh, Dr. Imam, Dr. Graham, and Dr. Snyder have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, raising the prospect of early intervention when effective treatments become available.
In a study, investigators used six AI methodologies, including Deep Learning, to assess blood leukocyte epigenomic biomarkers. They found more than 150 genetic differences among study participants with Alzheimer’s disease in comparison with participants who did not have Alzheimer’s disease.
All of the AI platforms were effective in predicting Alzheimer’s disease. Deep Learning’s assessment of intragenic cytosine-phosphate-guanines (CpGs) had sensitivity and specificity rates of 97%.
“It’s almost as if the leukocytes have become a newspaper to tell us, ‘This is what is going on in the brain,’ “ lead author Ray Bahado-Singh, MD, chair of the department of obstetrics and gynecology, Oakland University, Auburn Hills, Mich., said in a news release.
The researchers noted that the findings, if replicated in future studies, may help in providing Alzheimer’s disease diagnoses “much earlier” in the disease process. “The holy grail is to identify patients in the preclinical stage so effective early interventions, including new medications, can be studied and ultimately used,” Dr. Bahado-Singh said.
“This certainly isn’t the final step in Alzheimer’s research, but I think this represents a significant change in direction,” he told attendees at a press briefing.
The findings were published online March 31 in PLOS ONE.
Silver tsunami
The investigators noted that Alzheimer’s disease is often diagnosed when the disease is in its later stages, after irreversible brain damage has occurred. “There is currently no cure for the disease, and the treatment is limited to drugs that attempt to treat symptoms and have little effect on the disease’s progression,” they noted.
Coinvestigator Khaled Imam, MD, director of geriatric medicine for Beaumont Health in Michigan, pointed out that although MRI and lumbar puncture can identify Alzheimer’s disease early on, the processes are expensive and/or invasive.
“Having biomarkers in the blood ... and being able to identify [Alzheimer’s disease] years before symptoms start, hopefully we’d be able to intervene early on in the process of the disease,” Dr. Imam said.
It is estimated that the number of Americans aged 85 and older will triple by 2050. This impending “silver tsunami,” which will come with a commensurate increase in Alzheimer’s disease cases, makes it even more important to be able to diagnose the disease early on, he noted.
The study included 24 individuals with late-onset Alzheimer’s disease (70.8% women; mean age, 83 years); 24 were deemed to be “cognitively healthy” (66.7% women; mean age, 80 years). About 500 ng of genomic DNA was extracted from whole-blood samples from each participant.
The researchers used the Infinium MethylationEPIC BeadChip array, and the samples were then examined for markers of methylation that would “indicate the disease process has started,” they noted.
In addition to Deep Learning, the five other AI platforms were the Support Vector Machine, Generalized Linear Model, Prediction Analysis for Microarrays, Random Forest, and Linear Discriminant Analysis.
These platforms were used to assess leukocyte genome changes. To predict Alzheimer’s disease, the researchers also used Ingenuity Pathway Analysis.
Significant “chemical changes”
Results showed that the Alzheimer’s disease group had 152 significantly differentially methylated CpGs in 171 genes in comparison with the non-Alzheimer’s disease group (false discovery rate P value < .05).
As a whole, using intragenic and intergenic/extragenic CpGs, the AI platforms were effective in predicting who had Alzheimer’s disease (area under the curve [AUC], ≥ 0.93). Using intragenic markers, the AUC for Deep Learning was 0.99.
“We looked at close to a million different sites, and we saw some chemical changes that we know are associated with alteration or change in gene function,” Dr. Bahado-Singh said.
Altered genes that were found in the Alzheimer’s disease group included CR1L, CTSV, S1PR1, and LTB4R – all of which “have been previously linked with Alzheimer’s disease and dementia,” the researchers noted. They also found the methylated genes CTSV and PRMT5, both of which have been previously associated with cardiovascular disease.
“A significant strength of our study is the novelty, i.e. the use of blood leukocytes to accurately detect Alzheimer’s disease and also for interrogating the pathogenesis of Alzheimer’s disease,” the investigators wrote.
Dr. Bahado-Singh said that the test let them identify changes in cells in the blood, “giving us a comprehensive account not only of the fact that the brain is being affected by Alzheimer’s disease but it’s telling us what kinds of processes are going on in the brain.
“Normally you don’t have access to the brain. This gives us a simple blood test to get an ongoing reading of the course of events in the brain – and potentially tell us very early on before the onset of symptoms,” he added.
Cautiously optimistic
During the question-and-answer session following his presentation at the briefing, Dr. Bahado-Singh reiterated that they are at a very early stage in the research and were not able to make clinical recommendations at this point. However, he added, “There was evidence that DNA methylation change could likely precede the onset of abnormalities in the cells that give rise to the disease.”
Coinvestigator Stewart Graham, PhD, director of Alzheimer’s research at Beaumont Health, added that although the initial study findings led to some excitement for the team, “we have to be very conservative with what we say.”
He noted that the findings need to be replicated in a more diverse population. Still, “we’re excited at the moment and looking forward to seeing what the future results hold,” Dr. Graham said.
Dr. Bahado-Singh said that if larger studies confirm the findings and the test is viable, it would make sense to use it as a screen for individuals older than 65. He noted that because of the aging of the population, “this subset of individuals will constitute a larger and larger fraction of the population globally.”
Still early days
Commenting on the findings, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, noted that the investigators used an “interesting” diagnostic process.
“It was a unique approach to looking at and trying to understand what might be some of the biological underpinnings and using these tools and technologies to determine if they’re able to differentiate individuals with Alzheimer’s disease” from those without Alzheimer’s disease, said Dr. Snyder, who was not involved with the research.
“Ultimately, we want to know who is at greater risk, who may have some of the changing biology at the earliest time point so that we can intervene to stop the progression of the disease,” she said.
She pointed out that a number of types of biomarker tests are currently under investigation, many of which are measuring different outcomes. “And that’s what we want to see going forward. We want to have as many tools in our toolbox that allow us to accurately diagnose at that earliest time point,” Dr. Snyder said.
“At this point, [the current study] is still pretty early, so it needs to be replicated and then expanded to larger groups to really understand what they may be seeing,” she added.
Dr. Bahado-Singh, Dr. Imam, Dr. Graham, and Dr. Snyder have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, raising the prospect of early intervention when effective treatments become available.
In a study, investigators used six AI methodologies, including Deep Learning, to assess blood leukocyte epigenomic biomarkers. They found more than 150 genetic differences among study participants with Alzheimer’s disease in comparison with participants who did not have Alzheimer’s disease.
All of the AI platforms were effective in predicting Alzheimer’s disease. Deep Learning’s assessment of intragenic cytosine-phosphate-guanines (CpGs) had sensitivity and specificity rates of 97%.
“It’s almost as if the leukocytes have become a newspaper to tell us, ‘This is what is going on in the brain,’ “ lead author Ray Bahado-Singh, MD, chair of the department of obstetrics and gynecology, Oakland University, Auburn Hills, Mich., said in a news release.
The researchers noted that the findings, if replicated in future studies, may help in providing Alzheimer’s disease diagnoses “much earlier” in the disease process. “The holy grail is to identify patients in the preclinical stage so effective early interventions, including new medications, can be studied and ultimately used,” Dr. Bahado-Singh said.
“This certainly isn’t the final step in Alzheimer’s research, but I think this represents a significant change in direction,” he told attendees at a press briefing.
The findings were published online March 31 in PLOS ONE.
Silver tsunami
The investigators noted that Alzheimer’s disease is often diagnosed when the disease is in its later stages, after irreversible brain damage has occurred. “There is currently no cure for the disease, and the treatment is limited to drugs that attempt to treat symptoms and have little effect on the disease’s progression,” they noted.
Coinvestigator Khaled Imam, MD, director of geriatric medicine for Beaumont Health in Michigan, pointed out that although MRI and lumbar puncture can identify Alzheimer’s disease early on, the processes are expensive and/or invasive.
“Having biomarkers in the blood ... and being able to identify [Alzheimer’s disease] years before symptoms start, hopefully we’d be able to intervene early on in the process of the disease,” Dr. Imam said.
It is estimated that the number of Americans aged 85 and older will triple by 2050. This impending “silver tsunami,” which will come with a commensurate increase in Alzheimer’s disease cases, makes it even more important to be able to diagnose the disease early on, he noted.
The study included 24 individuals with late-onset Alzheimer’s disease (70.8% women; mean age, 83 years); 24 were deemed to be “cognitively healthy” (66.7% women; mean age, 80 years). About 500 ng of genomic DNA was extracted from whole-blood samples from each participant.
The researchers used the Infinium MethylationEPIC BeadChip array, and the samples were then examined for markers of methylation that would “indicate the disease process has started,” they noted.
In addition to Deep Learning, the five other AI platforms were the Support Vector Machine, Generalized Linear Model, Prediction Analysis for Microarrays, Random Forest, and Linear Discriminant Analysis.
These platforms were used to assess leukocyte genome changes. To predict Alzheimer’s disease, the researchers also used Ingenuity Pathway Analysis.
Significant “chemical changes”
Results showed that the Alzheimer’s disease group had 152 significantly differentially methylated CpGs in 171 genes in comparison with the non-Alzheimer’s disease group (false discovery rate P value < .05).
As a whole, using intragenic and intergenic/extragenic CpGs, the AI platforms were effective in predicting who had Alzheimer’s disease (area under the curve [AUC], ≥ 0.93). Using intragenic markers, the AUC for Deep Learning was 0.99.
“We looked at close to a million different sites, and we saw some chemical changes that we know are associated with alteration or change in gene function,” Dr. Bahado-Singh said.
Altered genes that were found in the Alzheimer’s disease group included CR1L, CTSV, S1PR1, and LTB4R – all of which “have been previously linked with Alzheimer’s disease and dementia,” the researchers noted. They also found the methylated genes CTSV and PRMT5, both of which have been previously associated with cardiovascular disease.
“A significant strength of our study is the novelty, i.e. the use of blood leukocytes to accurately detect Alzheimer’s disease and also for interrogating the pathogenesis of Alzheimer’s disease,” the investigators wrote.
Dr. Bahado-Singh said that the test let them identify changes in cells in the blood, “giving us a comprehensive account not only of the fact that the brain is being affected by Alzheimer’s disease but it’s telling us what kinds of processes are going on in the brain.
“Normally you don’t have access to the brain. This gives us a simple blood test to get an ongoing reading of the course of events in the brain – and potentially tell us very early on before the onset of symptoms,” he added.
Cautiously optimistic
During the question-and-answer session following his presentation at the briefing, Dr. Bahado-Singh reiterated that they are at a very early stage in the research and were not able to make clinical recommendations at this point. However, he added, “There was evidence that DNA methylation change could likely precede the onset of abnormalities in the cells that give rise to the disease.”
Coinvestigator Stewart Graham, PhD, director of Alzheimer’s research at Beaumont Health, added that although the initial study findings led to some excitement for the team, “we have to be very conservative with what we say.”
He noted that the findings need to be replicated in a more diverse population. Still, “we’re excited at the moment and looking forward to seeing what the future results hold,” Dr. Graham said.
Dr. Bahado-Singh said that if larger studies confirm the findings and the test is viable, it would make sense to use it as a screen for individuals older than 65. He noted that because of the aging of the population, “this subset of individuals will constitute a larger and larger fraction of the population globally.”
Still early days
Commenting on the findings, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, noted that the investigators used an “interesting” diagnostic process.
“It was a unique approach to looking at and trying to understand what might be some of the biological underpinnings and using these tools and technologies to determine if they’re able to differentiate individuals with Alzheimer’s disease” from those without Alzheimer’s disease, said Dr. Snyder, who was not involved with the research.
“Ultimately, we want to know who is at greater risk, who may have some of the changing biology at the earliest time point so that we can intervene to stop the progression of the disease,” she said.
She pointed out that a number of types of biomarker tests are currently under investigation, many of which are measuring different outcomes. “And that’s what we want to see going forward. We want to have as many tools in our toolbox that allow us to accurately diagnose at that earliest time point,” Dr. Snyder said.
“At this point, [the current study] is still pretty early, so it needs to be replicated and then expanded to larger groups to really understand what they may be seeing,” she added.
Dr. Bahado-Singh, Dr. Imam, Dr. Graham, and Dr. Snyder have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM PLOS ONE
Borderline personality disorder diagnosis: To tell or not to tell patients?
News of actor/comedian Pete Davidson expressing relief after finally receiving a diagnosis of borderline personality disorder (BPD) prompted a recent Twitter discussion among physicians regarding the ongoing debate on whether or not to tell a patient he or she has this diagnosis.
“I’ve heard from [many] trainees that they were told never to tell a patient they had BPD, but I can hardly think of anything more paternalistic and stigmatizing,” Amy Barnhorst, MD, vice chair of community psychiatry at University of California, Davis, tweeted.
“Most patients, when I explain it to them, have this kind of reaction – they feel relieved and understood,” she added.
“I was told that as well [not to tell] in one of my practicum placements,” one respondent who identified herself as a clinical/forensic psychologist tweeted back. “I said it anyway and the person was relieved there was a name for what they were living with.”
However, others disagreed with Dr. Barnhorst, noting that BPD is a very serious, stigmatizing, and challenging disorder to treat and, because of this, may cause patients to lose hope.
Still, Dr. Barnhorst stands by her position. Although “there is a negative stigma against a diagnosis of BPD,” that idea more often comes from the clinician instead of the patient, she said.
“I’ve never had a patient say, ‘how dare you call me that!’ like it was an insult,” she said in an interview. Not disclosing a diagnosis “is like you’re not trusting a patient to be a reasonable adult human about this.”
‘Hard diagnosis’
Although BPD is a “hard diagnosis, we would never withhold a diagnosis of cancer or liver disease or something else we knew patients didn’t want but that we were going to try and treat them for,” said Dr. Barnhorst.
BPD is linked to significant morbidity because of its common association with comorbid conditions, such as major depressive disorder, substance use disorders, and dysthymia. A history of self-harm is present in 70%-75% of these patients and some estimates suggest up to 9% of individuals with BPD die by suicide.
In an article published in Innovations in Clinical Neuroscience investigators discussed “ethical and clinical questions psychiatrists should consider” when treating BPD, including whether a diagnosis should be shared with a patient.
After such a diagnosis a patient may “react intensely in negative ways and these responses may be easily triggered,” the researchers wrote.
“A propensity that will likely cause psychiatrists anguish, however, is BPD patients’ increased likelihood of attempting suicide,” they added. Part of the problem has been that, in the past, it was thought that a BPD prognosis was untreatable. However, the researchers note that is no longer the case.
Still, Kaz Nelson, MD, associate professor of psychiatry and behavioral sciences at the University of Minnesota, Minneapolis, has labeled BPD a so-called “asterisk” disorder.
As she wrote in a recent blog, “We tell patients when they meet criteria for a medical diagnosis.* We show compassion and nonjudgmentalism to patients.* We do not discriminate against patients.*” However, the asterisk for each of these statements is: *Except for those with BPD.
Ongoing debate
Starting around the 1980s, the DSM listed personality disorders under the No. 2 Axis, which is for conditions with symptoms that are “not mitigatable,” said Dr. Nelson.
“It really started as well-meaning therapists who care about their patients who wanted to develop some precision in understanding people, and them starting to notice some patterns that can get in the way of optimal function,” she said in an interview.
The thought was not to disclose these diagnoses “because that was for you to understand, and for the patient to discover these patterns over time in the course of your work together,” Dr. Nelson added.
Although treatment for BPD used to be virtually nonexistent, there is now hope – especially with dialectic-behavior therapy (DBT), which uses mindfulness to teach patients how to control emotions and improve relationships.
According to the National Education Alliance for BPD, other useful treatments include mentalization-based therapy, transference-focused therapy, and “good psychiatric management.” Although there are currently no approved medications for BPD, some drugs are used to treat comorbid conditions such as depression or anxiety.
“We now know that people recover, and the whole paradigm has been turned on its head,” Dr. Nelson said. For example, “we no longer categorize these things as treatable or untreatable, which was a very positive move.”
So why is the field still debating the issue of diagnosis disclosure?
“To this day there are different psychiatrists and some medical school curricula that continue to teach that personality disorders are long-term, fixed, and nontreatable – and that it’s kind of disparaging to give this kind of diagnosis to a patient,” Dr. Nelson said.
Dr. Nelson, also the vice chair for education at the University of Minnesota, Minneapolis, medical school, reported that there “we acknowledge BPD’s painful history and that there are these misconceptions. They’re going to be on the front line of combating discrimination and the idea that if you see a patient with possible BPD coming you should run. That’s just unacceptable.”
Dr. Nelson noted that the idea of disclosing a BPD diagnosis is less controversial now than in the past, but “the whole thing is still under debate, and treatment guidelines [on BPD] are old and expired.”
Criteria for BPD were not updated when the DSM-5 was published in 2013, and that needs to be fixed, Dr. Nelson added. “In the meantime, we’re trying to get the word out that it’s okay to interact with people about the diagnosis, discuss treatment plans, and manage it as one would with any other psychiatric or medical illness.”
An evolution, not a debate
Paul Appelbaum, MD, past president of the American Psychiatric Association and current chair of the organization’s DSM steering committee, said in an interview that he hasn’t been involved in any recent debate on this issue.
“I think practice has changed to the point where the general practice is to discuss patient diagnoses with [patients] openly. Patients appreciate that and psychiatrists have come to see the advantages of it,” said Dr. Appelbaum, a professor of psychiatry, medicine, and law at Columbia University, New York.
Dr. Appelbaum noted that patients also increasingly have access to their medical records, “so the reality is that it’s no longer possible in many cases to withhold a diagnosis.”
he said. “Maybe not everyone is entirely on board yet but there has been a sea change in psychiatric practices.”
Asked whether there needs to be some type of guideline update or statement released by the APA regarding BPD, Dr. Appelbaum said he doesn’t think the overall issue is BPD specific but applies to all psychiatric diagnoses.
“To the extent that there are still practitioners today that are telling students or residents [not to disclose], I would guess that they were trained a very long time ago and have not adapted to the new world,” he said.
“I don’t want to speak for the APA, but speaking for myself: I certainly encourage residents that I teach to be open about a diagnosis. It’s not just clinically helpful in some cases, it’s also ethically required from the perspective of allowing patients to make appropriate decisions about their treatment. And arguably it’s legally required as well, as part of the informed consent requirement,” Dr. Appelbaum said.
Regarding DSM updates, he noted that the committee “looks to the field to propose to us additions or changes to the DSM that are warranted by data that have been gathered since the DSM-5 came out.” There is a process set up on the DSM’s website to review such proposals.
In addition, Dr. Appelbaum said that there have been discussions about using a new model “that focuses on dimensions rather than on discreet categories” in order to classify personality disorders.
“There’s a group out there that is formulating a proposal that they will submit to us” on this, he added. “That’s the major discussion that is going on right now and it would clearly have implications for borderline as well as all the other personality disorders.”
In a statement, the APA said practice guidelines for BPD are currently under review and that the organization does not have a “position statement” on BPD for clinicians. The last update to its guideline was in the early 2000s.
A version of this article first appeared on Medscape.com.
News of actor/comedian Pete Davidson expressing relief after finally receiving a diagnosis of borderline personality disorder (BPD) prompted a recent Twitter discussion among physicians regarding the ongoing debate on whether or not to tell a patient he or she has this diagnosis.
“I’ve heard from [many] trainees that they were told never to tell a patient they had BPD, but I can hardly think of anything more paternalistic and stigmatizing,” Amy Barnhorst, MD, vice chair of community psychiatry at University of California, Davis, tweeted.
“Most patients, when I explain it to them, have this kind of reaction – they feel relieved and understood,” she added.
“I was told that as well [not to tell] in one of my practicum placements,” one respondent who identified herself as a clinical/forensic psychologist tweeted back. “I said it anyway and the person was relieved there was a name for what they were living with.”
However, others disagreed with Dr. Barnhorst, noting that BPD is a very serious, stigmatizing, and challenging disorder to treat and, because of this, may cause patients to lose hope.
Still, Dr. Barnhorst stands by her position. Although “there is a negative stigma against a diagnosis of BPD,” that idea more often comes from the clinician instead of the patient, she said.
“I’ve never had a patient say, ‘how dare you call me that!’ like it was an insult,” she said in an interview. Not disclosing a diagnosis “is like you’re not trusting a patient to be a reasonable adult human about this.”
‘Hard diagnosis’
Although BPD is a “hard diagnosis, we would never withhold a diagnosis of cancer or liver disease or something else we knew patients didn’t want but that we were going to try and treat them for,” said Dr. Barnhorst.
BPD is linked to significant morbidity because of its common association with comorbid conditions, such as major depressive disorder, substance use disorders, and dysthymia. A history of self-harm is present in 70%-75% of these patients and some estimates suggest up to 9% of individuals with BPD die by suicide.
In an article published in Innovations in Clinical Neuroscience investigators discussed “ethical and clinical questions psychiatrists should consider” when treating BPD, including whether a diagnosis should be shared with a patient.
After such a diagnosis a patient may “react intensely in negative ways and these responses may be easily triggered,” the researchers wrote.
“A propensity that will likely cause psychiatrists anguish, however, is BPD patients’ increased likelihood of attempting suicide,” they added. Part of the problem has been that, in the past, it was thought that a BPD prognosis was untreatable. However, the researchers note that is no longer the case.
Still, Kaz Nelson, MD, associate professor of psychiatry and behavioral sciences at the University of Minnesota, Minneapolis, has labeled BPD a so-called “asterisk” disorder.
As she wrote in a recent blog, “We tell patients when they meet criteria for a medical diagnosis.* We show compassion and nonjudgmentalism to patients.* We do not discriminate against patients.*” However, the asterisk for each of these statements is: *Except for those with BPD.
Ongoing debate
Starting around the 1980s, the DSM listed personality disorders under the No. 2 Axis, which is for conditions with symptoms that are “not mitigatable,” said Dr. Nelson.
“It really started as well-meaning therapists who care about their patients who wanted to develop some precision in understanding people, and them starting to notice some patterns that can get in the way of optimal function,” she said in an interview.
The thought was not to disclose these diagnoses “because that was for you to understand, and for the patient to discover these patterns over time in the course of your work together,” Dr. Nelson added.
Although treatment for BPD used to be virtually nonexistent, there is now hope – especially with dialectic-behavior therapy (DBT), which uses mindfulness to teach patients how to control emotions and improve relationships.
According to the National Education Alliance for BPD, other useful treatments include mentalization-based therapy, transference-focused therapy, and “good psychiatric management.” Although there are currently no approved medications for BPD, some drugs are used to treat comorbid conditions such as depression or anxiety.
“We now know that people recover, and the whole paradigm has been turned on its head,” Dr. Nelson said. For example, “we no longer categorize these things as treatable or untreatable, which was a very positive move.”
So why is the field still debating the issue of diagnosis disclosure?
“To this day there are different psychiatrists and some medical school curricula that continue to teach that personality disorders are long-term, fixed, and nontreatable – and that it’s kind of disparaging to give this kind of diagnosis to a patient,” Dr. Nelson said.
Dr. Nelson, also the vice chair for education at the University of Minnesota, Minneapolis, medical school, reported that there “we acknowledge BPD’s painful history and that there are these misconceptions. They’re going to be on the front line of combating discrimination and the idea that if you see a patient with possible BPD coming you should run. That’s just unacceptable.”
Dr. Nelson noted that the idea of disclosing a BPD diagnosis is less controversial now than in the past, but “the whole thing is still under debate, and treatment guidelines [on BPD] are old and expired.”
Criteria for BPD were not updated when the DSM-5 was published in 2013, and that needs to be fixed, Dr. Nelson added. “In the meantime, we’re trying to get the word out that it’s okay to interact with people about the diagnosis, discuss treatment plans, and manage it as one would with any other psychiatric or medical illness.”
An evolution, not a debate
Paul Appelbaum, MD, past president of the American Psychiatric Association and current chair of the organization’s DSM steering committee, said in an interview that he hasn’t been involved in any recent debate on this issue.
“I think practice has changed to the point where the general practice is to discuss patient diagnoses with [patients] openly. Patients appreciate that and psychiatrists have come to see the advantages of it,” said Dr. Appelbaum, a professor of psychiatry, medicine, and law at Columbia University, New York.
Dr. Appelbaum noted that patients also increasingly have access to their medical records, “so the reality is that it’s no longer possible in many cases to withhold a diagnosis.”
he said. “Maybe not everyone is entirely on board yet but there has been a sea change in psychiatric practices.”
Asked whether there needs to be some type of guideline update or statement released by the APA regarding BPD, Dr. Appelbaum said he doesn’t think the overall issue is BPD specific but applies to all psychiatric diagnoses.
“To the extent that there are still practitioners today that are telling students or residents [not to disclose], I would guess that they were trained a very long time ago and have not adapted to the new world,” he said.
“I don’t want to speak for the APA, but speaking for myself: I certainly encourage residents that I teach to be open about a diagnosis. It’s not just clinically helpful in some cases, it’s also ethically required from the perspective of allowing patients to make appropriate decisions about their treatment. And arguably it’s legally required as well, as part of the informed consent requirement,” Dr. Appelbaum said.
Regarding DSM updates, he noted that the committee “looks to the field to propose to us additions or changes to the DSM that are warranted by data that have been gathered since the DSM-5 came out.” There is a process set up on the DSM’s website to review such proposals.
In addition, Dr. Appelbaum said that there have been discussions about using a new model “that focuses on dimensions rather than on discreet categories” in order to classify personality disorders.
“There’s a group out there that is formulating a proposal that they will submit to us” on this, he added. “That’s the major discussion that is going on right now and it would clearly have implications for borderline as well as all the other personality disorders.”
In a statement, the APA said practice guidelines for BPD are currently under review and that the organization does not have a “position statement” on BPD for clinicians. The last update to its guideline was in the early 2000s.
A version of this article first appeared on Medscape.com.
News of actor/comedian Pete Davidson expressing relief after finally receiving a diagnosis of borderline personality disorder (BPD) prompted a recent Twitter discussion among physicians regarding the ongoing debate on whether or not to tell a patient he or she has this diagnosis.
“I’ve heard from [many] trainees that they were told never to tell a patient they had BPD, but I can hardly think of anything more paternalistic and stigmatizing,” Amy Barnhorst, MD, vice chair of community psychiatry at University of California, Davis, tweeted.
“Most patients, when I explain it to them, have this kind of reaction – they feel relieved and understood,” she added.
“I was told that as well [not to tell] in one of my practicum placements,” one respondent who identified herself as a clinical/forensic psychologist tweeted back. “I said it anyway and the person was relieved there was a name for what they were living with.”
However, others disagreed with Dr. Barnhorst, noting that BPD is a very serious, stigmatizing, and challenging disorder to treat and, because of this, may cause patients to lose hope.
Still, Dr. Barnhorst stands by her position. Although “there is a negative stigma against a diagnosis of BPD,” that idea more often comes from the clinician instead of the patient, she said.
“I’ve never had a patient say, ‘how dare you call me that!’ like it was an insult,” she said in an interview. Not disclosing a diagnosis “is like you’re not trusting a patient to be a reasonable adult human about this.”
‘Hard diagnosis’
Although BPD is a “hard diagnosis, we would never withhold a diagnosis of cancer or liver disease or something else we knew patients didn’t want but that we were going to try and treat them for,” said Dr. Barnhorst.
BPD is linked to significant morbidity because of its common association with comorbid conditions, such as major depressive disorder, substance use disorders, and dysthymia. A history of self-harm is present in 70%-75% of these patients and some estimates suggest up to 9% of individuals with BPD die by suicide.
In an article published in Innovations in Clinical Neuroscience investigators discussed “ethical and clinical questions psychiatrists should consider” when treating BPD, including whether a diagnosis should be shared with a patient.
After such a diagnosis a patient may “react intensely in negative ways and these responses may be easily triggered,” the researchers wrote.
“A propensity that will likely cause psychiatrists anguish, however, is BPD patients’ increased likelihood of attempting suicide,” they added. Part of the problem has been that, in the past, it was thought that a BPD prognosis was untreatable. However, the researchers note that is no longer the case.
Still, Kaz Nelson, MD, associate professor of psychiatry and behavioral sciences at the University of Minnesota, Minneapolis, has labeled BPD a so-called “asterisk” disorder.
As she wrote in a recent blog, “We tell patients when they meet criteria for a medical diagnosis.* We show compassion and nonjudgmentalism to patients.* We do not discriminate against patients.*” However, the asterisk for each of these statements is: *Except for those with BPD.
Ongoing debate
Starting around the 1980s, the DSM listed personality disorders under the No. 2 Axis, which is for conditions with symptoms that are “not mitigatable,” said Dr. Nelson.
“It really started as well-meaning therapists who care about their patients who wanted to develop some precision in understanding people, and them starting to notice some patterns that can get in the way of optimal function,” she said in an interview.
The thought was not to disclose these diagnoses “because that was for you to understand, and for the patient to discover these patterns over time in the course of your work together,” Dr. Nelson added.
Although treatment for BPD used to be virtually nonexistent, there is now hope – especially with dialectic-behavior therapy (DBT), which uses mindfulness to teach patients how to control emotions and improve relationships.
According to the National Education Alliance for BPD, other useful treatments include mentalization-based therapy, transference-focused therapy, and “good psychiatric management.” Although there are currently no approved medications for BPD, some drugs are used to treat comorbid conditions such as depression or anxiety.
“We now know that people recover, and the whole paradigm has been turned on its head,” Dr. Nelson said. For example, “we no longer categorize these things as treatable or untreatable, which was a very positive move.”
So why is the field still debating the issue of diagnosis disclosure?
“To this day there are different psychiatrists and some medical school curricula that continue to teach that personality disorders are long-term, fixed, and nontreatable – and that it’s kind of disparaging to give this kind of diagnosis to a patient,” Dr. Nelson said.
Dr. Nelson, also the vice chair for education at the University of Minnesota, Minneapolis, medical school, reported that there “we acknowledge BPD’s painful history and that there are these misconceptions. They’re going to be on the front line of combating discrimination and the idea that if you see a patient with possible BPD coming you should run. That’s just unacceptable.”
Dr. Nelson noted that the idea of disclosing a BPD diagnosis is less controversial now than in the past, but “the whole thing is still under debate, and treatment guidelines [on BPD] are old and expired.”
Criteria for BPD were not updated when the DSM-5 was published in 2013, and that needs to be fixed, Dr. Nelson added. “In the meantime, we’re trying to get the word out that it’s okay to interact with people about the diagnosis, discuss treatment plans, and manage it as one would with any other psychiatric or medical illness.”
An evolution, not a debate
Paul Appelbaum, MD, past president of the American Psychiatric Association and current chair of the organization’s DSM steering committee, said in an interview that he hasn’t been involved in any recent debate on this issue.
“I think practice has changed to the point where the general practice is to discuss patient diagnoses with [patients] openly. Patients appreciate that and psychiatrists have come to see the advantages of it,” said Dr. Appelbaum, a professor of psychiatry, medicine, and law at Columbia University, New York.
Dr. Appelbaum noted that patients also increasingly have access to their medical records, “so the reality is that it’s no longer possible in many cases to withhold a diagnosis.”
he said. “Maybe not everyone is entirely on board yet but there has been a sea change in psychiatric practices.”
Asked whether there needs to be some type of guideline update or statement released by the APA regarding BPD, Dr. Appelbaum said he doesn’t think the overall issue is BPD specific but applies to all psychiatric diagnoses.
“To the extent that there are still practitioners today that are telling students or residents [not to disclose], I would guess that they were trained a very long time ago and have not adapted to the new world,” he said.
“I don’t want to speak for the APA, but speaking for myself: I certainly encourage residents that I teach to be open about a diagnosis. It’s not just clinically helpful in some cases, it’s also ethically required from the perspective of allowing patients to make appropriate decisions about their treatment. And arguably it’s legally required as well, as part of the informed consent requirement,” Dr. Appelbaum said.
Regarding DSM updates, he noted that the committee “looks to the field to propose to us additions or changes to the DSM that are warranted by data that have been gathered since the DSM-5 came out.” There is a process set up on the DSM’s website to review such proposals.
In addition, Dr. Appelbaum said that there have been discussions about using a new model “that focuses on dimensions rather than on discreet categories” in order to classify personality disorders.
“There’s a group out there that is formulating a proposal that they will submit to us” on this, he added. “That’s the major discussion that is going on right now and it would clearly have implications for borderline as well as all the other personality disorders.”
In a statement, the APA said practice guidelines for BPD are currently under review and that the organization does not have a “position statement” on BPD for clinicians. The last update to its guideline was in the early 2000s.
A version of this article first appeared on Medscape.com.
Novel Alzheimer’s drug slows cognitive decline in phase 2 trial
Results from the TRAILBLAZER-ALZ trial were presented at the 2021 International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD) and were simultaneously published online March 13 in the New England Journal of Medicine.
As previously reported by Medscape Medical News, topline results showed that donanemab slowed cognitive decline by 32% on the Integrated AD Rating Scale (iADRS) from baseline to 76 weeks relative to placebo.
The newly released detailed findings showed that “the use of donanemab resulted in a better composite score for cognition and for the ability to perform activities of daily living than placebo at 76 weeks, although results for secondary outcomes were mixed,” the investigators, with first author Mark A. Mintun, MD, an employee of Eli Lilly, reported.
Results revealed improvement in scores on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) and the 13-item cognitive subscale of the AD Assessment Scale (ADAS-Cog13), but the differences between the two treatment groups were not significant. In addition, score changes on the AD Cooperative Study–Instrumental Activities of Daily Inventory (ADCS-iADL) and the Mini-Mental State Examination (MMSE) were not “substantial.”
However, the donanemab group did show an 85-centiloid greater reduction in amyloid plaque level at 76 weeks, as shown on PET, compared with the placebo group.
Proof of concept?
The humanized antibody donanemab, which was previously known as LY3002813, targets a modified form of deposited amyloid-beta (A-beta) peptide called N3pG.
The randomized, placebo-controlled, double-blind TRAILBLAZER-ALZ trial, which was described as a “phase 2 proof of concept trial” in the AD/PD program, was conducted at 56 sites in the United States and Canada and included 257 patients between the ages of 60 and 85 years (52% were women). PET confirmed tau and amyloid deposition in all participants.
The active treatment group (n = 131) was randomly assigned to receive donanemab 700 mg for three doses; after that, treatment was bumped up to 1,400 mg. Both the donanemab and placebo groups (n = 126) received treatment intravenously every 4 weeks for up to 72 weeks.
Participants also underwent F-florbetapir and F-flortaucipir PET scans at various timepoints and completed a slew of cognitive tests.
The study’s primary outcome measure was change between baseline and 76 weeks post treatment on composite score for cognition, as measured by the iADRS. The iADRS combines the ADAS-Cog13 and the ADCS-iADL.
This measure ranges from 0 to 144, with lower scores associated with greater cognitive impairment. Both treatment groups had an iADRS score of 106 at baseline.
More research needed
Results showed that the score change from baseline on the iADRS was –6.86 for the active treatment group vs –10.06 for the placebo group (group difference, 3.2; 95% confidence interval [CI], 0.12-6.27; P = .04). Although significant, “the trial was powered to show a 6-point difference,” which was not met, the investigators note.
Differences in score changes from baseline to 76 weeks for the treatment vs. placebo groups on the following secondary outcome measures were:
- CDR-SB: –0.36 (95% CI, –0.83 to –0.12).
- ADAS-Cog13: –1.86 (95% CI, –3.63 to –0.09).
- ADCS-iADL: 1.21 (95% CI, –0.77 to 3.2).
- MMSE: 0.64 (95% CI, –0.4 to 1.67).
The CDR-SB was designated as the first secondary outcome, and because it did not show a significant between-group difference, “the hierarchy failed and no definite conclusions can be drawn from data regarding the differences between groups in the change in the ADAS-Cog13,” the investigators wrote.
In addition, the differences in scores on the latter two secondary outcomes were not “substantial,” they reported.
However, at 76 weeks, the donanemab group showed a reduction of 84.13 centiloids in amyloid plaque level vs. an increase of 0.93 centiloids in the placebo group (between-group difference, 85.06 centiloids). At 24 weeks, the active-treatment group had a 67.83-centiloids greater reduction vs. the placebo group.
In addition, 40%, 59.8%, and 67.8% of the donanemab group achieved “amyloid-negative status” at 24, 52, and 76 weeks, respectively. Amyloid-negative status was defined as an amyloid plaque level of less than 24.1 centiloids.
Total incidence of death or serious adverse events did not differ significantly between the groups. However, the donanemab group had significantly more reports of ARIA-E compared with the placebo group (26.7% vs. 0.8%).
Overall, the researchers noted that more trials of longer duration with larger patient numbers are warranted “to further determine the efficacy and safety of donanemab” in AD.
Positive signal?
In a statement, Maria Carrillo, PhD, chief science officer for the Alzheimer’s Association, said the organization “is encouraged by this promising data.
“It is the first phase 2 Alzheimer’s trial to show positive results on a primary outcome measure related to memory and thinking,” Dr. Carrillo said. However, “more work needs to be done on this experimental drug therapy.”
Dr. Carrillo noted that because the trial was moderately sized and only 180 participants completed the study, “we look forward to the results of a second, larger phase 2 trial of this drug.”
Still, she added, there were several “novel and innovative aspects” in the way the study was conducted noting that it showcases the evolution of AD research.
“I’m hopeful for the future,” Dr. Carrillo said.
Also commenting on the results, Howard Fillit, MD, neuroscientist and founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation, said the study showed “the pharmacology works” and that the drug did what it was supposed to do in terms of removing A-beta plaque.
“It also gave us a signal in a relatively small phase 2 study that there might be a modest cognitive benefit,” said Dr. Fillit, who was not involved with the research.
He noted that although the rate of decline slowing was statistically significant it remains to be seen whether this is clinically meaningful, particularly in light of the fact that the secondary outcome results were mixed.
“Basically, it was a positive study that probably needs to be followed by another, much larger study to get us to really see the benefit,” Dr. Fillit said.
Dr. Mintun is an employee of Eli Lilly, which funded the study. Dr. Carrillo and Dr. Fillit have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Results from the TRAILBLAZER-ALZ trial were presented at the 2021 International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD) and were simultaneously published online March 13 in the New England Journal of Medicine.
As previously reported by Medscape Medical News, topline results showed that donanemab slowed cognitive decline by 32% on the Integrated AD Rating Scale (iADRS) from baseline to 76 weeks relative to placebo.
The newly released detailed findings showed that “the use of donanemab resulted in a better composite score for cognition and for the ability to perform activities of daily living than placebo at 76 weeks, although results for secondary outcomes were mixed,” the investigators, with first author Mark A. Mintun, MD, an employee of Eli Lilly, reported.
Results revealed improvement in scores on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) and the 13-item cognitive subscale of the AD Assessment Scale (ADAS-Cog13), but the differences between the two treatment groups were not significant. In addition, score changes on the AD Cooperative Study–Instrumental Activities of Daily Inventory (ADCS-iADL) and the Mini-Mental State Examination (MMSE) were not “substantial.”
However, the donanemab group did show an 85-centiloid greater reduction in amyloid plaque level at 76 weeks, as shown on PET, compared with the placebo group.
Proof of concept?
The humanized antibody donanemab, which was previously known as LY3002813, targets a modified form of deposited amyloid-beta (A-beta) peptide called N3pG.
The randomized, placebo-controlled, double-blind TRAILBLAZER-ALZ trial, which was described as a “phase 2 proof of concept trial” in the AD/PD program, was conducted at 56 sites in the United States and Canada and included 257 patients between the ages of 60 and 85 years (52% were women). PET confirmed tau and amyloid deposition in all participants.
The active treatment group (n = 131) was randomly assigned to receive donanemab 700 mg for three doses; after that, treatment was bumped up to 1,400 mg. Both the donanemab and placebo groups (n = 126) received treatment intravenously every 4 weeks for up to 72 weeks.
Participants also underwent F-florbetapir and F-flortaucipir PET scans at various timepoints and completed a slew of cognitive tests.
The study’s primary outcome measure was change between baseline and 76 weeks post treatment on composite score for cognition, as measured by the iADRS. The iADRS combines the ADAS-Cog13 and the ADCS-iADL.
This measure ranges from 0 to 144, with lower scores associated with greater cognitive impairment. Both treatment groups had an iADRS score of 106 at baseline.
More research needed
Results showed that the score change from baseline on the iADRS was –6.86 for the active treatment group vs –10.06 for the placebo group (group difference, 3.2; 95% confidence interval [CI], 0.12-6.27; P = .04). Although significant, “the trial was powered to show a 6-point difference,” which was not met, the investigators note.
Differences in score changes from baseline to 76 weeks for the treatment vs. placebo groups on the following secondary outcome measures were:
- CDR-SB: –0.36 (95% CI, –0.83 to –0.12).
- ADAS-Cog13: –1.86 (95% CI, –3.63 to –0.09).
- ADCS-iADL: 1.21 (95% CI, –0.77 to 3.2).
- MMSE: 0.64 (95% CI, –0.4 to 1.67).
The CDR-SB was designated as the first secondary outcome, and because it did not show a significant between-group difference, “the hierarchy failed and no definite conclusions can be drawn from data regarding the differences between groups in the change in the ADAS-Cog13,” the investigators wrote.
In addition, the differences in scores on the latter two secondary outcomes were not “substantial,” they reported.
However, at 76 weeks, the donanemab group showed a reduction of 84.13 centiloids in amyloid plaque level vs. an increase of 0.93 centiloids in the placebo group (between-group difference, 85.06 centiloids). At 24 weeks, the active-treatment group had a 67.83-centiloids greater reduction vs. the placebo group.
In addition, 40%, 59.8%, and 67.8% of the donanemab group achieved “amyloid-negative status” at 24, 52, and 76 weeks, respectively. Amyloid-negative status was defined as an amyloid plaque level of less than 24.1 centiloids.
Total incidence of death or serious adverse events did not differ significantly between the groups. However, the donanemab group had significantly more reports of ARIA-E compared with the placebo group (26.7% vs. 0.8%).
Overall, the researchers noted that more trials of longer duration with larger patient numbers are warranted “to further determine the efficacy and safety of donanemab” in AD.
Positive signal?
In a statement, Maria Carrillo, PhD, chief science officer for the Alzheimer’s Association, said the organization “is encouraged by this promising data.
“It is the first phase 2 Alzheimer’s trial to show positive results on a primary outcome measure related to memory and thinking,” Dr. Carrillo said. However, “more work needs to be done on this experimental drug therapy.”
Dr. Carrillo noted that because the trial was moderately sized and only 180 participants completed the study, “we look forward to the results of a second, larger phase 2 trial of this drug.”
Still, she added, there were several “novel and innovative aspects” in the way the study was conducted noting that it showcases the evolution of AD research.
“I’m hopeful for the future,” Dr. Carrillo said.
Also commenting on the results, Howard Fillit, MD, neuroscientist and founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation, said the study showed “the pharmacology works” and that the drug did what it was supposed to do in terms of removing A-beta plaque.
“It also gave us a signal in a relatively small phase 2 study that there might be a modest cognitive benefit,” said Dr. Fillit, who was not involved with the research.
He noted that although the rate of decline slowing was statistically significant it remains to be seen whether this is clinically meaningful, particularly in light of the fact that the secondary outcome results were mixed.
“Basically, it was a positive study that probably needs to be followed by another, much larger study to get us to really see the benefit,” Dr. Fillit said.
Dr. Mintun is an employee of Eli Lilly, which funded the study. Dr. Carrillo and Dr. Fillit have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Results from the TRAILBLAZER-ALZ trial were presented at the 2021 International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD) and were simultaneously published online March 13 in the New England Journal of Medicine.
As previously reported by Medscape Medical News, topline results showed that donanemab slowed cognitive decline by 32% on the Integrated AD Rating Scale (iADRS) from baseline to 76 weeks relative to placebo.
The newly released detailed findings showed that “the use of donanemab resulted in a better composite score for cognition and for the ability to perform activities of daily living than placebo at 76 weeks, although results for secondary outcomes were mixed,” the investigators, with first author Mark A. Mintun, MD, an employee of Eli Lilly, reported.
Results revealed improvement in scores on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) and the 13-item cognitive subscale of the AD Assessment Scale (ADAS-Cog13), but the differences between the two treatment groups were not significant. In addition, score changes on the AD Cooperative Study–Instrumental Activities of Daily Inventory (ADCS-iADL) and the Mini-Mental State Examination (MMSE) were not “substantial.”
However, the donanemab group did show an 85-centiloid greater reduction in amyloid plaque level at 76 weeks, as shown on PET, compared with the placebo group.
Proof of concept?
The humanized antibody donanemab, which was previously known as LY3002813, targets a modified form of deposited amyloid-beta (A-beta) peptide called N3pG.
The randomized, placebo-controlled, double-blind TRAILBLAZER-ALZ trial, which was described as a “phase 2 proof of concept trial” in the AD/PD program, was conducted at 56 sites in the United States and Canada and included 257 patients between the ages of 60 and 85 years (52% were women). PET confirmed tau and amyloid deposition in all participants.
The active treatment group (n = 131) was randomly assigned to receive donanemab 700 mg for three doses; after that, treatment was bumped up to 1,400 mg. Both the donanemab and placebo groups (n = 126) received treatment intravenously every 4 weeks for up to 72 weeks.
Participants also underwent F-florbetapir and F-flortaucipir PET scans at various timepoints and completed a slew of cognitive tests.
The study’s primary outcome measure was change between baseline and 76 weeks post treatment on composite score for cognition, as measured by the iADRS. The iADRS combines the ADAS-Cog13 and the ADCS-iADL.
This measure ranges from 0 to 144, with lower scores associated with greater cognitive impairment. Both treatment groups had an iADRS score of 106 at baseline.
More research needed
Results showed that the score change from baseline on the iADRS was –6.86 for the active treatment group vs –10.06 for the placebo group (group difference, 3.2; 95% confidence interval [CI], 0.12-6.27; P = .04). Although significant, “the trial was powered to show a 6-point difference,” which was not met, the investigators note.
Differences in score changes from baseline to 76 weeks for the treatment vs. placebo groups on the following secondary outcome measures were:
- CDR-SB: –0.36 (95% CI, –0.83 to –0.12).
- ADAS-Cog13: –1.86 (95% CI, –3.63 to –0.09).
- ADCS-iADL: 1.21 (95% CI, –0.77 to 3.2).
- MMSE: 0.64 (95% CI, –0.4 to 1.67).
The CDR-SB was designated as the first secondary outcome, and because it did not show a significant between-group difference, “the hierarchy failed and no definite conclusions can be drawn from data regarding the differences between groups in the change in the ADAS-Cog13,” the investigators wrote.
In addition, the differences in scores on the latter two secondary outcomes were not “substantial,” they reported.
However, at 76 weeks, the donanemab group showed a reduction of 84.13 centiloids in amyloid plaque level vs. an increase of 0.93 centiloids in the placebo group (between-group difference, 85.06 centiloids). At 24 weeks, the active-treatment group had a 67.83-centiloids greater reduction vs. the placebo group.
In addition, 40%, 59.8%, and 67.8% of the donanemab group achieved “amyloid-negative status” at 24, 52, and 76 weeks, respectively. Amyloid-negative status was defined as an amyloid plaque level of less than 24.1 centiloids.
Total incidence of death or serious adverse events did not differ significantly between the groups. However, the donanemab group had significantly more reports of ARIA-E compared with the placebo group (26.7% vs. 0.8%).
Overall, the researchers noted that more trials of longer duration with larger patient numbers are warranted “to further determine the efficacy and safety of donanemab” in AD.
Positive signal?
In a statement, Maria Carrillo, PhD, chief science officer for the Alzheimer’s Association, said the organization “is encouraged by this promising data.
“It is the first phase 2 Alzheimer’s trial to show positive results on a primary outcome measure related to memory and thinking,” Dr. Carrillo said. However, “more work needs to be done on this experimental drug therapy.”
Dr. Carrillo noted that because the trial was moderately sized and only 180 participants completed the study, “we look forward to the results of a second, larger phase 2 trial of this drug.”
Still, she added, there were several “novel and innovative aspects” in the way the study was conducted noting that it showcases the evolution of AD research.
“I’m hopeful for the future,” Dr. Carrillo said.
Also commenting on the results, Howard Fillit, MD, neuroscientist and founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation, said the study showed “the pharmacology works” and that the drug did what it was supposed to do in terms of removing A-beta plaque.
“It also gave us a signal in a relatively small phase 2 study that there might be a modest cognitive benefit,” said Dr. Fillit, who was not involved with the research.
He noted that although the rate of decline slowing was statistically significant it remains to be seen whether this is clinically meaningful, particularly in light of the fact that the secondary outcome results were mixed.
“Basically, it was a positive study that probably needs to be followed by another, much larger study to get us to really see the benefit,” Dr. Fillit said.
Dr. Mintun is an employee of Eli Lilly, which funded the study. Dr. Carrillo and Dr. Fillit have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Meghan Markle interview resurfaces suicidality screening debate
An eye-opening moment during March 7’s Meghan Markle/Prince Harry interview with Oprah Winfrey was Markle’s admission that, before the royal couple moved from the U.K., she was suicidal and had nowhere to turn for help.
For health care practitioners, this has resurfaced the debate over universal suicidality screening and discussion about what should happen when patients screen positive.
The American Psychiatric Association reports suicide is the 10th leading cause of death in the United States, but the second leading cause of death in people age 10-34 years old.
The latest data from the Centers for Disease Control and Prevention show that, in 2019, suicide rates dropped for the first time in 14 years. However, it is widely expected that, in the face of the COVID-19 pandemic and its associated isolation, loneliness, and stress, the next round of data will show a surge in suicide deaths.
, chair of the APA’s Committee on Women’s Mental Health.
“I can see it in my office. People who didn’t necessarily complain about anxiety and depression before or who had been stable for many years are decompensating now,” Dr. De Faria said in an interview.
Although other parts of the interview may have been controversial, said Dr. De Faria, Markle’s disclosure has opened up a much-needed discussion.
“I’m all for people talking about mental health, and I commend [Markle] for sharing her struggle and putting it out there,” she added.
In a perfect world, she noted, there would be universal suicide screening by all medical professionals.
However, Dr. De Faria, associate clinical professor of psychiatry, University of Florida, Gainesville, acknowledged that from a resource standpoint this is not a pragmatic solution.
Primary care physicians are often the frontline defense for suicide prevention, noted Mona Masood, DO, a Philadelphia-area psychiatrist and founder and chief organizer of the Physician Support Line, a free mental health hotline exclusively for doctors staffed by volunteer psychiatrists. 
“I believe our general practitioner colleagues, our family medicine colleagues are the ones who are going to be seeing the majority of mental health concerns or illnesses because of the stigma that is often there from seeing a psychiatrist,” Dr. Masood said in an interview.
Dr. De Faria noted that the Patient Health Questionnaire-2 (PHQ-2) for mental health offers a simple screen that includes two key questions. It asks: Over the last 2 weeks, how often have you been bothered by the following problems?
- Little interest or pleasure in doing things.
- Feeling down, depressed, or hopeless.
However, both Dr. De Faria and Dr. Masood emphasized that individualized follow-up questions and follow-up care are equally important.
Unlike Dr. De Faria, who prefers universal screening but understands the challenges of implementing it, Dr. Masood favors targeted screening.
“For physicians, the whole point of what we do is to save lives. To talk to somebody about the complete opposite and to ask, ‘Are you planning on ending your life?’ is very jarring. But for the patient, that may be their only outlet. A primary care provider may be the only professional that they talk to about their mental health,” said Dr. Masood.
Patients can easily say “no” to suicidal ideation questions from a general screen, but targeted, probing questions let patients know that they’re being heard and seen beyond their physical examination, she added.
She also suggested that clinicians ask open-ended questions of those patients who are struggling.
Dr. Masood noted that having a plan in place before screening a patient is especially key.
“I’d argue that one of the subconscious reasons why so many doctors do not ask the question [about suicidality] is because if you ask it, you have to be ready for the answer and to know what you’d do,” she said.
All primary care physicians should have “mental health professionals as resources in your back pocket” in order to have a referral ready to give to patients in need, she said.
“Outside of your clinic time, have a rapport with your local psychiatrist or therapist and know where to send someone who is suicidal,” Dr. Masood said. “Know what is in your local area so you’ll already know how to implement your plan.”
Dr. Masood also recommended:
- Informing staff about protocols for patients with suicidal thoughts who need to go to the hospital for evaluation.
- Creating a safe space in the clinic/office, such as an unused exam room, where patients can wait for next steps.
- Having staff inform a patient’s emergency contact about the situation.
- Trying for a “warm handoff,” where the emergency contact takes the patient to the nearest crisis center and having staff call ahead to let them know to expect the patient.
- If the patient has no emergency contact, following your state’s involuntary crisis response protocol, which involves calling 911 for emergency services.
In addition, the APA’s suicide prevention page includes a long list of helpful resources for patients, families, and physicians.
A version of this article first appeared on Medscape.com.
An eye-opening moment during March 7’s Meghan Markle/Prince Harry interview with Oprah Winfrey was Markle’s admission that, before the royal couple moved from the U.K., she was suicidal and had nowhere to turn for help.
For health care practitioners, this has resurfaced the debate over universal suicidality screening and discussion about what should happen when patients screen positive.
The American Psychiatric Association reports suicide is the 10th leading cause of death in the United States, but the second leading cause of death in people age 10-34 years old.
The latest data from the Centers for Disease Control and Prevention show that, in 2019, suicide rates dropped for the first time in 14 years. However, it is widely expected that, in the face of the COVID-19 pandemic and its associated isolation, loneliness, and stress, the next round of data will show a surge in suicide deaths.
, chair of the APA’s Committee on Women’s Mental Health.
“I can see it in my office. People who didn’t necessarily complain about anxiety and depression before or who had been stable for many years are decompensating now,” Dr. De Faria said in an interview.
Although other parts of the interview may have been controversial, said Dr. De Faria, Markle’s disclosure has opened up a much-needed discussion.
“I’m all for people talking about mental health, and I commend [Markle] for sharing her struggle and putting it out there,” she added.
In a perfect world, she noted, there would be universal suicide screening by all medical professionals.
However, Dr. De Faria, associate clinical professor of psychiatry, University of Florida, Gainesville, acknowledged that from a resource standpoint this is not a pragmatic solution.
Primary care physicians are often the frontline defense for suicide prevention, noted Mona Masood, DO, a Philadelphia-area psychiatrist and founder and chief organizer of the Physician Support Line, a free mental health hotline exclusively for doctors staffed by volunteer psychiatrists.
“I believe our general practitioner colleagues, our family medicine colleagues are the ones who are going to be seeing the majority of mental health concerns or illnesses because of the stigma that is often there from seeing a psychiatrist,” Dr. Masood said in an interview.
Dr. De Faria noted that the Patient Health Questionnaire-2 (PHQ-2) for mental health offers a simple screen that includes two key questions. It asks: Over the last 2 weeks, how often have you been bothered by the following problems?
- Little interest or pleasure in doing things.
- Feeling down, depressed, or hopeless.
However, both Dr. De Faria and Dr. Masood emphasized that individualized follow-up questions and follow-up care are equally important.
Unlike Dr. De Faria, who prefers universal screening but understands the challenges of implementing it, Dr. Masood favors targeted screening.
“For physicians, the whole point of what we do is to save lives. To talk to somebody about the complete opposite and to ask, ‘Are you planning on ending your life?’ is very jarring. But for the patient, that may be their only outlet. A primary care provider may be the only professional that they talk to about their mental health,” said Dr. Masood.
Patients can easily say “no” to suicidal ideation questions from a general screen, but targeted, probing questions let patients know that they’re being heard and seen beyond their physical examination, she added.
She also suggested that clinicians ask open-ended questions of those patients who are struggling.
Dr. Masood noted that having a plan in place before screening a patient is especially key.
“I’d argue that one of the subconscious reasons why so many doctors do not ask the question [about suicidality] is because if you ask it, you have to be ready for the answer and to know what you’d do,” she said.
All primary care physicians should have “mental health professionals as resources in your back pocket” in order to have a referral ready to give to patients in need, she said.
“Outside of your clinic time, have a rapport with your local psychiatrist or therapist and know where to send someone who is suicidal,” Dr. Masood said. “Know what is in your local area so you’ll already know how to implement your plan.”
Dr. Masood also recommended:
- Informing staff about protocols for patients with suicidal thoughts who need to go to the hospital for evaluation.
- Creating a safe space in the clinic/office, such as an unused exam room, where patients can wait for next steps.
- Having staff inform a patient’s emergency contact about the situation.
- Trying for a “warm handoff,” where the emergency contact takes the patient to the nearest crisis center and having staff call ahead to let them know to expect the patient.
- If the patient has no emergency contact, following your state’s involuntary crisis response protocol, which involves calling 911 for emergency services.
In addition, the APA’s suicide prevention page includes a long list of helpful resources for patients, families, and physicians.
A version of this article first appeared on Medscape.com.
An eye-opening moment during March 7’s Meghan Markle/Prince Harry interview with Oprah Winfrey was Markle’s admission that, before the royal couple moved from the U.K., she was suicidal and had nowhere to turn for help.
For health care practitioners, this has resurfaced the debate over universal suicidality screening and discussion about what should happen when patients screen positive.
The American Psychiatric Association reports suicide is the 10th leading cause of death in the United States, but the second leading cause of death in people age 10-34 years old.
The latest data from the Centers for Disease Control and Prevention show that, in 2019, suicide rates dropped for the first time in 14 years. However, it is widely expected that, in the face of the COVID-19 pandemic and its associated isolation, loneliness, and stress, the next round of data will show a surge in suicide deaths.
, chair of the APA’s Committee on Women’s Mental Health.
“I can see it in my office. People who didn’t necessarily complain about anxiety and depression before or who had been stable for many years are decompensating now,” Dr. De Faria said in an interview.
Although other parts of the interview may have been controversial, said Dr. De Faria, Markle’s disclosure has opened up a much-needed discussion.
“I’m all for people talking about mental health, and I commend [Markle] for sharing her struggle and putting it out there,” she added.
In a perfect world, she noted, there would be universal suicide screening by all medical professionals.
However, Dr. De Faria, associate clinical professor of psychiatry, University of Florida, Gainesville, acknowledged that from a resource standpoint this is not a pragmatic solution.
Primary care physicians are often the frontline defense for suicide prevention, noted Mona Masood, DO, a Philadelphia-area psychiatrist and founder and chief organizer of the Physician Support Line, a free mental health hotline exclusively for doctors staffed by volunteer psychiatrists.
“I believe our general practitioner colleagues, our family medicine colleagues are the ones who are going to be seeing the majority of mental health concerns or illnesses because of the stigma that is often there from seeing a psychiatrist,” Dr. Masood said in an interview.
Dr. De Faria noted that the Patient Health Questionnaire-2 (PHQ-2) for mental health offers a simple screen that includes two key questions. It asks: Over the last 2 weeks, how often have you been bothered by the following problems?
- Little interest or pleasure in doing things.
- Feeling down, depressed, or hopeless.
However, both Dr. De Faria and Dr. Masood emphasized that individualized follow-up questions and follow-up care are equally important.
Unlike Dr. De Faria, who prefers universal screening but understands the challenges of implementing it, Dr. Masood favors targeted screening.
“For physicians, the whole point of what we do is to save lives. To talk to somebody about the complete opposite and to ask, ‘Are you planning on ending your life?’ is very jarring. But for the patient, that may be their only outlet. A primary care provider may be the only professional that they talk to about their mental health,” said Dr. Masood.
Patients can easily say “no” to suicidal ideation questions from a general screen, but targeted, probing questions let patients know that they’re being heard and seen beyond their physical examination, she added.
She also suggested that clinicians ask open-ended questions of those patients who are struggling.
Dr. Masood noted that having a plan in place before screening a patient is especially key.
“I’d argue that one of the subconscious reasons why so many doctors do not ask the question [about suicidality] is because if you ask it, you have to be ready for the answer and to know what you’d do,” she said.
All primary care physicians should have “mental health professionals as resources in your back pocket” in order to have a referral ready to give to patients in need, she said.
“Outside of your clinic time, have a rapport with your local psychiatrist or therapist and know where to send someone who is suicidal,” Dr. Masood said. “Know what is in your local area so you’ll already know how to implement your plan.”
Dr. Masood also recommended:
- Informing staff about protocols for patients with suicidal thoughts who need to go to the hospital for evaluation.
- Creating a safe space in the clinic/office, such as an unused exam room, where patients can wait for next steps.
- Having staff inform a patient’s emergency contact about the situation.
- Trying for a “warm handoff,” where the emergency contact takes the patient to the nearest crisis center and having staff call ahead to let them know to expect the patient.
- If the patient has no emergency contact, following your state’s involuntary crisis response protocol, which involves calling 911 for emergency services.
In addition, the APA’s suicide prevention page includes a long list of helpful resources for patients, families, and physicians.
A version of this article first appeared on Medscape.com.
PTSD prevalent in survivors of severe COVID-19
Posttraumatic stress disorder may occur in up to a third of patients who recover from severe COVID-19 infection, new research suggests.
A study of more than 300 patients who presented to the emergency department with the virus showed a 30.2% prevalence for PTSD 30-120 days after COVID recovery.
or having persistent medical symptoms after hospitalization.
Additional diagnoses, such as depressive and hypomanic episodes and generalized anxiety disorder (GAD), were also present in some of the survivors.
“Previous coronavirus epidemics were associated with PTSD diagnoses in postillness stages, with meta-analytic findings indicating a prevalence of 32.2%,” write the investigators, led by Delfina Janiri, MD, department of psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome.
However, data focused specifically on COVID-19 have been “piecemeal,” they add.
The findings were published online Feb. 18 in a research letter in JAMA Psychiatry.
A traumatic event
From April to October 2020, the researchers assessed 381 consecutive patients (100% white; 56.4% men; mean age, 55.3 years) who presented to the ED and subsequently participated in a health check at the Fondazione Policlinico Universitario Agostino Gemelli.
The mean length of stay for the 309 patients hospitalized with severe COVID-19 was 18.4 days.
Results showed that 115 participants (30.2%) had PTSD, based on DSM-5 criteria, and 55.7% of the women had the disorder. Additional diagnoses found in the full patient population included:
- Depressive episodes (17.3%).
- GAD (7%).
- Hypomanic episodes (0.7%).
- Psychotic disorders (0.2%).
Patients with PTSD had higher rates than those without PTSD of a previous history of psychiatric disorders (34.8% vs. 20.7%; P = .003) and of delirium or agitation during hospitalization, as assessed with the Confusion Assessment Method (16.5% vs. 6.4%; P = .002).
In addition, 62.6% of those with PTSD had three or more persistent COVID-19 symptoms vs. 37.2% of their counterparts without PTSD (P < .001).
After logistic regression analyses, significant factors associated with a PTSD diagnosis were persistent medical symptoms (P = .002), delirium or agitation (P = .02), and being female (P = .02).
The investigators note that their results are “in line” with findings reported in research examining other traumatic events. This includes about 30% of Hurricane Katrina survivors who experienced PTSD, as did around 25% of survivors of the 2011 “Great Japan Earthquake and Tsunami.”
Study limitations cited include the “relatively small” size of the patient population, that it focused on only one participating center, and that it didn’t include a control group of non-COVID patients who reported to the ED.
“Further longitudinal studies are needed to tailor therapeutic interventions and prevention strategies,” the researchers write.
Dr. Janiri and four of the five other authors have disclosed no relevant financial relationships. The other author, Gabriele Sani, MD, reported having received personal fees from Angelini Spa, Janssen, and Lundbeck outside the submitted work.
A version of this article first appeared on Medscape.com.
Posttraumatic stress disorder may occur in up to a third of patients who recover from severe COVID-19 infection, new research suggests.
A study of more than 300 patients who presented to the emergency department with the virus showed a 30.2% prevalence for PTSD 30-120 days after COVID recovery.
or having persistent medical symptoms after hospitalization.
Additional diagnoses, such as depressive and hypomanic episodes and generalized anxiety disorder (GAD), were also present in some of the survivors.
“Previous coronavirus epidemics were associated with PTSD diagnoses in postillness stages, with meta-analytic findings indicating a prevalence of 32.2%,” write the investigators, led by Delfina Janiri, MD, department of psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome.
However, data focused specifically on COVID-19 have been “piecemeal,” they add.
The findings were published online Feb. 18 in a research letter in JAMA Psychiatry.
A traumatic event
From April to October 2020, the researchers assessed 381 consecutive patients (100% white; 56.4% men; mean age, 55.3 years) who presented to the ED and subsequently participated in a health check at the Fondazione Policlinico Universitario Agostino Gemelli.
The mean length of stay for the 309 patients hospitalized with severe COVID-19 was 18.4 days.
Results showed that 115 participants (30.2%) had PTSD, based on DSM-5 criteria, and 55.7% of the women had the disorder. Additional diagnoses found in the full patient population included:
- Depressive episodes (17.3%).
- GAD (7%).
- Hypomanic episodes (0.7%).
- Psychotic disorders (0.2%).
Patients with PTSD had higher rates than those without PTSD of a previous history of psychiatric disorders (34.8% vs. 20.7%; P = .003) and of delirium or agitation during hospitalization, as assessed with the Confusion Assessment Method (16.5% vs. 6.4%; P = .002).
In addition, 62.6% of those with PTSD had three or more persistent COVID-19 symptoms vs. 37.2% of their counterparts without PTSD (P < .001).
After logistic regression analyses, significant factors associated with a PTSD diagnosis were persistent medical symptoms (P = .002), delirium or agitation (P = .02), and being female (P = .02).
The investigators note that their results are “in line” with findings reported in research examining other traumatic events. This includes about 30% of Hurricane Katrina survivors who experienced PTSD, as did around 25% of survivors of the 2011 “Great Japan Earthquake and Tsunami.”
Study limitations cited include the “relatively small” size of the patient population, that it focused on only one participating center, and that it didn’t include a control group of non-COVID patients who reported to the ED.
“Further longitudinal studies are needed to tailor therapeutic interventions and prevention strategies,” the researchers write.
Dr. Janiri and four of the five other authors have disclosed no relevant financial relationships. The other author, Gabriele Sani, MD, reported having received personal fees from Angelini Spa, Janssen, and Lundbeck outside the submitted work.
A version of this article first appeared on Medscape.com.
Posttraumatic stress disorder may occur in up to a third of patients who recover from severe COVID-19 infection, new research suggests.
A study of more than 300 patients who presented to the emergency department with the virus showed a 30.2% prevalence for PTSD 30-120 days after COVID recovery.
or having persistent medical symptoms after hospitalization.
Additional diagnoses, such as depressive and hypomanic episodes and generalized anxiety disorder (GAD), were also present in some of the survivors.
“Previous coronavirus epidemics were associated with PTSD diagnoses in postillness stages, with meta-analytic findings indicating a prevalence of 32.2%,” write the investigators, led by Delfina Janiri, MD, department of psychiatry, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome.
However, data focused specifically on COVID-19 have been “piecemeal,” they add.
The findings were published online Feb. 18 in a research letter in JAMA Psychiatry.
A traumatic event
From April to October 2020, the researchers assessed 381 consecutive patients (100% white; 56.4% men; mean age, 55.3 years) who presented to the ED and subsequently participated in a health check at the Fondazione Policlinico Universitario Agostino Gemelli.
The mean length of stay for the 309 patients hospitalized with severe COVID-19 was 18.4 days.
Results showed that 115 participants (30.2%) had PTSD, based on DSM-5 criteria, and 55.7% of the women had the disorder. Additional diagnoses found in the full patient population included:
- Depressive episodes (17.3%).
- GAD (7%).
- Hypomanic episodes (0.7%).
- Psychotic disorders (0.2%).
Patients with PTSD had higher rates than those without PTSD of a previous history of psychiatric disorders (34.8% vs. 20.7%; P = .003) and of delirium or agitation during hospitalization, as assessed with the Confusion Assessment Method (16.5% vs. 6.4%; P = .002).
In addition, 62.6% of those with PTSD had three or more persistent COVID-19 symptoms vs. 37.2% of their counterparts without PTSD (P < .001).
After logistic regression analyses, significant factors associated with a PTSD diagnosis were persistent medical symptoms (P = .002), delirium or agitation (P = .02), and being female (P = .02).
The investigators note that their results are “in line” with findings reported in research examining other traumatic events. This includes about 30% of Hurricane Katrina survivors who experienced PTSD, as did around 25% of survivors of the 2011 “Great Japan Earthquake and Tsunami.”
Study limitations cited include the “relatively small” size of the patient population, that it focused on only one participating center, and that it didn’t include a control group of non-COVID patients who reported to the ED.
“Further longitudinal studies are needed to tailor therapeutic interventions and prevention strategies,” the researchers write.
Dr. Janiri and four of the five other authors have disclosed no relevant financial relationships. The other author, Gabriele Sani, MD, reported having received personal fees from Angelini Spa, Janssen, and Lundbeck outside the submitted work.
A version of this article first appeared on Medscape.com.