Pauline Anderson

TOPLINE:

High-dose vitamin D supplementation may prevent atrial fibrillation (AFib) in healthy elderly men and women, a post hoc analysis from a randomized trial conducted in Finland suggests.

METHODOLOGY:

• Observational studies have suggested that vitamin D deficiency is associated with increased risk for AFib, but few randomized trials have looked at the effect of vitamin D supplementation on AFib incidence in healthy people.
• The study, a post hoc analysis from a trial that explored the effects of vitamin D3 supplementation on incidence of cardiovascular diseases and cancer, included 2,495 vitamin D–sufficient healthy older adults, mean age 68.2 years, of whom 43% were women.
• Participants had been randomized to one of three groups in which they received vitamin D3 at either 1,600 IU/day or 3,200 IU/day, or placebo.
• Serum 25(OH)D3 concentrations were measured and data on incident AFib were gathered from national health records.

TAKEAWAY:

• Atrial fibrillation was diagnosed in 190 participants.
• Over a follow-up averaging 4.1 years, risk for incident AFib was reduced by 27% for participants who received the 1,600 IU/day dose, compared with placebo; hazard ratio, 0.73 (95% confidence interval, 0.52-1.02; P = .07), and by 32% for those in the 3,200 IU/day arm; HR, 0.68 (95% CI, 0.48-0.96; P = .03).
• The incident-AFib risk was reduced by 30% in a comparison of the two vitamin D groups combined versus the placebo group; HR, 0.70 (95% CI, 0.53-0.94; P = .02).
• After exclusion of 122 participants who reported being on antiarrhythmic medications at baseline, the 1,600 IU/day group showed a significant 27% reduction in risk for AF (95% CI, 4%-58%; P = .03) and the 3,200 IU/day group a nonsignificant 30% (95% CI, 5%-53%; P = .08) reduction in risk.

IN PRACTICE:

High-dose vitamin D3 supplementation may reduce incidence of AFib in a generally healthy, largely vitamin D–sufficient elderly population, the authors proposed. Additional controlled trials are needed, especially in diverse populations.

STUDY DETAILS:

The study was conducted by Jyrki K. Virtanen, PhD, University of Eastern Finland, Institute of Public Health and Clinical Nutrition, Kuopio, and colleagues. It was published in the American Heart Journal.

LIMITATIONS:

Atrial fibrillation was not prespecified as a primary outcome, and the results differ from those of other randomized controlled trials. Information on type of AFib (whether paroxysmal or nonparoxysmal, for example) wasn’t available nor were participants’ history of AFib. All participants were White and from Finland, limiting generalizability of the results.

DISCLOSURES:

The study was supported by the Academy of Finland, University of Eastern Finland, the Juho Vainio Foundation, Medicinska Understödsföreningen Liv och Hälsa, Finnish Foundation for Cardiovascular Research, Finnish Diabetes Research Foundation, and the Finnish Cultural Foundation. One coauthor disclosed receiving grants from the National Institutes of Health and Mars Edge. Another coauthor disclosed receipt of a grant from Orion. The other authors disclosed no relevant financial relationships.

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

TOPLINE:

High-dose vitamin D supplementation may prevent atrial fibrillation (AFib) in healthy elderly men and women, a post hoc analysis from a randomized trial conducted in Finland suggests.

METHODOLOGY:

• Observational studies have suggested that vitamin D deficiency is associated with increased risk for AFib, but few randomized trials have looked at the effect of vitamin D supplementation on AFib incidence in healthy people.
• The study, a post hoc analysis from a trial that explored the effects of vitamin D3 supplementation on incidence of cardiovascular diseases and cancer, included 2,495 vitamin D–sufficient healthy older adults, mean age 68.2 years, of whom 43% were women.
• Participants had been randomized to one of three groups in which they received vitamin D3 at either 1,600 IU/day or 3,200 IU/day, or placebo.
• Serum 25(OH)D3 concentrations were measured and data on incident AFib were gathered from national health records.

TAKEAWAY:

• Atrial fibrillation was diagnosed in 190 participants.
• Over a follow-up averaging 4.1 years, risk for incident AFib was reduced by 27% for participants who received the 1,600 IU/day dose, compared with placebo; hazard ratio, 0.73 (95% confidence interval, 0.52-1.02; P = .07), and by 32% for those in the 3,200 IU/day arm; HR, 0.68 (95% CI, 0.48-0.96; P = .03).
• The incident-AFib risk was reduced by 30% in a comparison of the two vitamin D groups combined versus the placebo group; HR, 0.70 (95% CI, 0.53-0.94; P = .02).
• After exclusion of 122 participants who reported being on antiarrhythmic medications at baseline, the 1,600 IU/day group showed a significant 27% reduction in risk for AF (95% CI, 4%-58%; P = .03) and the 3,200 IU/day group a nonsignificant 30% (95% CI, 5%-53%; P = .08) reduction in risk.

IN PRACTICE:

High-dose vitamin D3 supplementation may reduce incidence of AFib in a generally healthy, largely vitamin D–sufficient elderly population, the authors proposed. Additional controlled trials are needed, especially in diverse populations.

STUDY DETAILS:

The study was conducted by Jyrki K. Virtanen, PhD, University of Eastern Finland, Institute of Public Health and Clinical Nutrition, Kuopio, and colleagues. It was published in the American Heart Journal.

LIMITATIONS:

Atrial fibrillation was not prespecified as a primary outcome, and the results differ from those of other randomized controlled trials. Information on type of AFib (whether paroxysmal or nonparoxysmal, for example) wasn’t available nor were participants’ history of AFib. All participants were White and from Finland, limiting generalizability of the results.

DISCLOSURES:

The study was supported by the Academy of Finland, University of Eastern Finland, the Juho Vainio Foundation, Medicinska Understödsföreningen Liv och Hälsa, Finnish Foundation for Cardiovascular Research, Finnish Diabetes Research Foundation, and the Finnish Cultural Foundation. One coauthor disclosed receiving grants from the National Institutes of Health and Mars Edge. Another coauthor disclosed receipt of a grant from Orion. The other authors disclosed no relevant financial relationships.

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

TOPLINE:

High-dose vitamin D supplementation may prevent atrial fibrillation (AFib) in healthy elderly men and women, a post hoc analysis from a randomized trial conducted in Finland suggests.

METHODOLOGY:

• Observational studies have suggested that vitamin D deficiency is associated with increased risk for AFib, but few randomized trials have looked at the effect of vitamin D supplementation on AFib incidence in healthy people.
• The study, a post hoc analysis from a trial that explored the effects of vitamin D3 supplementation on incidence of cardiovascular diseases and cancer, included 2,495 vitamin D–sufficient healthy older adults, mean age 68.2 years, of whom 43% were women.
• Participants had been randomized to one of three groups in which they received vitamin D3 at either 1,600 IU/day or 3,200 IU/day, or placebo.
• Serum 25(OH)D3 concentrations were measured and data on incident AFib were gathered from national health records.

TAKEAWAY:

• Atrial fibrillation was diagnosed in 190 participants.
• Over a follow-up averaging 4.1 years, risk for incident AFib was reduced by 27% for participants who received the 1,600 IU/day dose, compared with placebo; hazard ratio, 0.73 (95% confidence interval, 0.52-1.02; P = .07), and by 32% for those in the 3,200 IU/day arm; HR, 0.68 (95% CI, 0.48-0.96; P = .03).
• The incident-AFib risk was reduced by 30% in a comparison of the two vitamin D groups combined versus the placebo group; HR, 0.70 (95% CI, 0.53-0.94; P = .02).
• After exclusion of 122 participants who reported being on antiarrhythmic medications at baseline, the 1,600 IU/day group showed a significant 27% reduction in risk for AF (95% CI, 4%-58%; P = .03) and the 3,200 IU/day group a nonsignificant 30% (95% CI, 5%-53%; P = .08) reduction in risk.

IN PRACTICE:

High-dose vitamin D3 supplementation may reduce incidence of AFib in a generally healthy, largely vitamin D–sufficient elderly population, the authors proposed. Additional controlled trials are needed, especially in diverse populations.

STUDY DETAILS:

The study was conducted by Jyrki K. Virtanen, PhD, University of Eastern Finland, Institute of Public Health and Clinical Nutrition, Kuopio, and colleagues. It was published in the American Heart Journal.

LIMITATIONS:

Atrial fibrillation was not prespecified as a primary outcome, and the results differ from those of other randomized controlled trials. Information on type of AFib (whether paroxysmal or nonparoxysmal, for example) wasn’t available nor were participants’ history of AFib. All participants were White and from Finland, limiting generalizability of the results.

DISCLOSURES:

The study was supported by the Academy of Finland, University of Eastern Finland, the Juho Vainio Foundation, Medicinska Understödsföreningen Liv och Hälsa, Finnish Foundation for Cardiovascular Research, Finnish Diabetes Research Foundation, and the Finnish Cultural Foundation. One coauthor disclosed receiving grants from the National Institutes of Health and Mars Edge. Another coauthor disclosed receipt of a grant from Orion. The other authors disclosed no relevant financial relationships.

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

A group of more than 30 academics and researchers in psychiatry and psychopharmacology is challenging the conclusions of an umbrella review published last year that concluded there is no convincing evidence that serotonin deficiency is the primary cause of depression. The authors of the article, however, stand by their conclusion.

“The methodology doesn’t conform to a conventional umbrella review,” said the commentary’s lead author, Sameer Jauhar, MD, PhD, first author of the commentary criticizing the review, which was published online in Molecular Psychiatry.

In addition, preeminent psychiatrist David J. Nutt, MD, PhD, Edmond J. Safra Professor of Neuropsychopharmacology, Imperial College London, is calling for the review to be retracted. In an interview with The Daily Mail, he said the article is “full of flaws and it should never have been published in the first place. Yet it has been frequently cited and people believe it is true. It’s essentially misinformation. That’s why I’m calling on the journal to retract it.” Dr. Nutt is one of the authors of the published commentary.
 

‘No convincing evidence’

Led by Joanna Moncrieff, MD, professor of clinical and social psychiatry, University College London, the authors analyzed systematic reviews and meta-analyses to determine whether low serotonin levels are, in fact, associated with depression.

Of 361 potential studies, 17 were selected for the review, including meta-analyses, systematic reviews, and a genetic association study.

The review included examinations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in “body fluids,” 5HT_1A receptor and serotonin transporter protein (SERT) availability in imaging and postmortem studies, investigations of SERT gene polymorphisms, interactions between SERT and stress in depression, and effects of tryptophan depletion on mood.

The tryptophan hypothesis suggests depression occurs through tryptophan depletion, which lowers available serotonin. According to the review, two crossover studies of patients with depression who were currently receiving or had recently received antidepressant treatment did not show substantial effects of depletion, and data from studies involving volunteers largely showed no effect.

Ultimately, Dr. Moncrieff and colleagues concluded that “there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity.”
 

‘Unconventional, odd’ methodology

However, Dr. Jauhar and the commentary’s coauthors disagree with the study’s conclusion. The researchers claim that “we don’t see depression symptoms in healthy volunteers when given tryptophan depletion; everyone knows that and agrees with that; it’s only in people vulnerable to depression who will have it.”

Furthermore, he said, the study’s conclusion does not consider that experimental medicine studies of tryptophan depletion are difficult to conduct. “You’re not going to have huge sample sizes as you would in a genetic study or big epidemiological studies.

Dr. Jauhar said he found it “unconventional” and “odd” that the review included individual tryptophan depletion studies that were not in the prespecified protocol.

For studies involving molecular imaging, Dr. Jauhar said the review’s inferences were “simplistic” and the review authors are “basically shaping the argument” to fit their desired narrative.

He also noted factual errors in the review. “They make a mistake when they talk about serotonin transporter imaging; they say there are no consistent findings across studies when, in fact, there are.”

With both tryptophan depletion and molecular imaging studies, the review “glosses over findings” from the original studies, said Dr. Jauhar.

For tryptophan depletion, “a more accurate, constructive conclusion would be that acute tryptophan depletion and decreased plasma tryptophan in depression indicate a role for 5-HT in those vulnerable to or suffering from depression, and that molecular imaging suggests the system is perturbed,” the commentators wrote.

“The proven efficacy of SSRIs in a proportion of people with depression lends credibility to this position,” they added.

Dr. Jauhar also took issue with criteria for certainty of finding of these and other studies used in the review. “If you’re setting the criteria yourself, it’s arbitrary.”
 

No new data

An umbrella review is supposed to be of the highest quality and should entail “taking out the studies and analysing them yourself,” but here, “all they have done is put a synthesis forward of other people’s reviews, so essentially there’s no new data there,” said Dr. Jauhar.

And sometimes the review’s findings differ from the original research. “When you have people who haven’t conducted original research themselves quoting someone else’s work and ignoring what those people say, we’re all in trouble,” said Dr. Jauhar.

In an additional commentary also published in Molecular Psychiatry, Jacob Pade Ramsøe Jacobsen, Evecxia Therapeutics, Durham, N.C., also criticized the review by Dr. Moncrieff and colleagues.

Its authors appear unfamiliar with serotonin biology and pharmacology, Dr. Jacobsen wrote.

“The review contains factual errors, makes conclusions serotonin neurobiology may not support, and quotes the cited literature in a selective manner,” he added.

“Most troubling, they misinterpret some data reviewed and intimate that serotonin reuptake inhibitor antidepressants, e.g., SSRIs, may decrease, rather than increase, serotonin function.”

If accepted by general practitioners and the public, the review’s conclusions “could lead to reduced use of antidepressants among patients in need and increased morbidity related to depression.”
 

Dr. Moncrieff pushes back

Responding to the torrent of criticism of her study, Dr. Moncrieff told this news organization via email that they stand by the review, adding that Dr. Jauhar and others “don’t want to let the cat out of the bag” that there’s no good evidence to support the hypothesis that low serotonin causes depression because it challenges antidepressant use.

“The idea that antidepressants work by correcting an underlying chemical imbalance or serotonin abnormality has led research up a blind alley and meant scientists have not taken the harmful effects of these drugs seriously enough.”

These critics, she added, “want business as usual – which means people will continue to be misinformed and exposed to harmful effects of drugs that have minimal and uncertain benefits.”

In a letter to the editor of Molecular Psychiatry, Dr. Moncrieff and her fellow authors maintain that they used approved and well-accepted methods for the umbrella review, including preregistering the protocol and using recommended search methods and quality assessments, and that they did not miss certain studies, as has been claimed.

In her blog, Dr. Moncrieff wrote that the “marginal differences between antidepressants and placebo that are apparent in clinical trials are likely to be produced by alternative, more plausible mechanisms like the emotional blunting effects of the drugs or by amplified placebo effects, rather than by targeting underlying biological mechanisms (since these have not been demonstrated).”

It also highlights “how we don’t know what antidepressants do to the brain exactly, which is a cause for concern,” she adds.

Dr. Jauhar has received honoraria for nonpromotional educational talks on antipsychotics from Janssen, Sunovion, and Lundbeck and on causes of schizophrenia for Boehringer-Ingelheim. He has also received honoraria for consulting on antipsychotics for LB Pharmaceuticals. He sits on Council for the British Association for Psychopharmacology and was a recent panel member for the Wellcome Trust.

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

A group of more than 30 academics and researchers in psychiatry and psychopharmacology is challenging the conclusions of an umbrella review published last year that concluded there is no convincing evidence that serotonin deficiency is the primary cause of depression. The authors of the article, however, stand by their conclusion.

“The methodology doesn’t conform to a conventional umbrella review,” said the commentary’s lead author, Sameer Jauhar, MD, PhD, first author of the commentary criticizing the review, which was published online in Molecular Psychiatry.

In addition, preeminent psychiatrist David J. Nutt, MD, PhD, Edmond J. Safra Professor of Neuropsychopharmacology, Imperial College London, is calling for the review to be retracted. In an interview with The Daily Mail, he said the article is “full of flaws and it should never have been published in the first place. Yet it has been frequently cited and people believe it is true. It’s essentially misinformation. That’s why I’m calling on the journal to retract it.” Dr. Nutt is one of the authors of the published commentary.
 

‘No convincing evidence’

Led by Joanna Moncrieff, MD, professor of clinical and social psychiatry, University College London, the authors analyzed systematic reviews and meta-analyses to determine whether low serotonin levels are, in fact, associated with depression.

Of 361 potential studies, 17 were selected for the review, including meta-analyses, systematic reviews, and a genetic association study.

The review included examinations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in “body fluids,” 5HT_1A receptor and serotonin transporter protein (SERT) availability in imaging and postmortem studies, investigations of SERT gene polymorphisms, interactions between SERT and stress in depression, and effects of tryptophan depletion on mood.

The tryptophan hypothesis suggests depression occurs through tryptophan depletion, which lowers available serotonin. According to the review, two crossover studies of patients with depression who were currently receiving or had recently received antidepressant treatment did not show substantial effects of depletion, and data from studies involving volunteers largely showed no effect.

Ultimately, Dr. Moncrieff and colleagues concluded that “there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity.”
 

‘Unconventional, odd’ methodology

However, Dr. Jauhar and the commentary’s coauthors disagree with the study’s conclusion. The researchers claim that “we don’t see depression symptoms in healthy volunteers when given tryptophan depletion; everyone knows that and agrees with that; it’s only in people vulnerable to depression who will have it.”

Furthermore, he said, the study’s conclusion does not consider that experimental medicine studies of tryptophan depletion are difficult to conduct. “You’re not going to have huge sample sizes as you would in a genetic study or big epidemiological studies.

Dr. Jauhar said he found it “unconventional” and “odd” that the review included individual tryptophan depletion studies that were not in the prespecified protocol.

For studies involving molecular imaging, Dr. Jauhar said the review’s inferences were “simplistic” and the review authors are “basically shaping the argument” to fit their desired narrative.

He also noted factual errors in the review. “They make a mistake when they talk about serotonin transporter imaging; they say there are no consistent findings across studies when, in fact, there are.”

With both tryptophan depletion and molecular imaging studies, the review “glosses over findings” from the original studies, said Dr. Jauhar.

For tryptophan depletion, “a more accurate, constructive conclusion would be that acute tryptophan depletion and decreased plasma tryptophan in depression indicate a role for 5-HT in those vulnerable to or suffering from depression, and that molecular imaging suggests the system is perturbed,” the commentators wrote.

“The proven efficacy of SSRIs in a proportion of people with depression lends credibility to this position,” they added.

Dr. Jauhar also took issue with criteria for certainty of finding of these and other studies used in the review. “If you’re setting the criteria yourself, it’s arbitrary.”
 

No new data

An umbrella review is supposed to be of the highest quality and should entail “taking out the studies and analysing them yourself,” but here, “all they have done is put a synthesis forward of other people’s reviews, so essentially there’s no new data there,” said Dr. Jauhar.

And sometimes the review’s findings differ from the original research. “When you have people who haven’t conducted original research themselves quoting someone else’s work and ignoring what those people say, we’re all in trouble,” said Dr. Jauhar.

In an additional commentary also published in Molecular Psychiatry, Jacob Pade Ramsøe Jacobsen, Evecxia Therapeutics, Durham, N.C., also criticized the review by Dr. Moncrieff and colleagues.

Its authors appear unfamiliar with serotonin biology and pharmacology, Dr. Jacobsen wrote.

“The review contains factual errors, makes conclusions serotonin neurobiology may not support, and quotes the cited literature in a selective manner,” he added.

“Most troubling, they misinterpret some data reviewed and intimate that serotonin reuptake inhibitor antidepressants, e.g., SSRIs, may decrease, rather than increase, serotonin function.”

If accepted by general practitioners and the public, the review’s conclusions “could lead to reduced use of antidepressants among patients in need and increased morbidity related to depression.”
 

Dr. Moncrieff pushes back

Responding to the torrent of criticism of her study, Dr. Moncrieff told this news organization via email that they stand by the review, adding that Dr. Jauhar and others “don’t want to let the cat out of the bag” that there’s no good evidence to support the hypothesis that low serotonin causes depression because it challenges antidepressant use.

“The idea that antidepressants work by correcting an underlying chemical imbalance or serotonin abnormality has led research up a blind alley and meant scientists have not taken the harmful effects of these drugs seriously enough.”

These critics, she added, “want business as usual – which means people will continue to be misinformed and exposed to harmful effects of drugs that have minimal and uncertain benefits.”

In a letter to the editor of Molecular Psychiatry, Dr. Moncrieff and her fellow authors maintain that they used approved and well-accepted methods for the umbrella review, including preregistering the protocol and using recommended search methods and quality assessments, and that they did not miss certain studies, as has been claimed.

In her blog, Dr. Moncrieff wrote that the “marginal differences between antidepressants and placebo that are apparent in clinical trials are likely to be produced by alternative, more plausible mechanisms like the emotional blunting effects of the drugs or by amplified placebo effects, rather than by targeting underlying biological mechanisms (since these have not been demonstrated).”

It also highlights “how we don’t know what antidepressants do to the brain exactly, which is a cause for concern,” she adds.

Dr. Jauhar has received honoraria for nonpromotional educational talks on antipsychotics from Janssen, Sunovion, and Lundbeck and on causes of schizophrenia for Boehringer-Ingelheim. He has also received honoraria for consulting on antipsychotics for LB Pharmaceuticals. He sits on Council for the British Association for Psychopharmacology and was a recent panel member for the Wellcome Trust.

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

A group of more than 30 academics and researchers in psychiatry and psychopharmacology is challenging the conclusions of an umbrella review published last year that concluded there is no convincing evidence that serotonin deficiency is the primary cause of depression. The authors of the article, however, stand by their conclusion.

“The methodology doesn’t conform to a conventional umbrella review,” said the commentary’s lead author, Sameer Jauhar, MD, PhD, first author of the commentary criticizing the review, which was published online in Molecular Psychiatry.

In addition, preeminent psychiatrist David J. Nutt, MD, PhD, Edmond J. Safra Professor of Neuropsychopharmacology, Imperial College London, is calling for the review to be retracted. In an interview with The Daily Mail, he said the article is “full of flaws and it should never have been published in the first place. Yet it has been frequently cited and people believe it is true. It’s essentially misinformation. That’s why I’m calling on the journal to retract it.” Dr. Nutt is one of the authors of the published commentary.
 

‘No convincing evidence’

Led by Joanna Moncrieff, MD, professor of clinical and social psychiatry, University College London, the authors analyzed systematic reviews and meta-analyses to determine whether low serotonin levels are, in fact, associated with depression.

Of 361 potential studies, 17 were selected for the review, including meta-analyses, systematic reviews, and a genetic association study.

The review included examinations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in “body fluids,” 5HT_1A receptor and serotonin transporter protein (SERT) availability in imaging and postmortem studies, investigations of SERT gene polymorphisms, interactions between SERT and stress in depression, and effects of tryptophan depletion on mood.

The tryptophan hypothesis suggests depression occurs through tryptophan depletion, which lowers available serotonin. According to the review, two crossover studies of patients with depression who were currently receiving or had recently received antidepressant treatment did not show substantial effects of depletion, and data from studies involving volunteers largely showed no effect.

Ultimately, Dr. Moncrieff and colleagues concluded that “there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity.”
 

‘Unconventional, odd’ methodology

However, Dr. Jauhar and the commentary’s coauthors disagree with the study’s conclusion. The researchers claim that “we don’t see depression symptoms in healthy volunteers when given tryptophan depletion; everyone knows that and agrees with that; it’s only in people vulnerable to depression who will have it.”

Furthermore, he said, the study’s conclusion does not consider that experimental medicine studies of tryptophan depletion are difficult to conduct. “You’re not going to have huge sample sizes as you would in a genetic study or big epidemiological studies.

Dr. Jauhar said he found it “unconventional” and “odd” that the review included individual tryptophan depletion studies that were not in the prespecified protocol.

For studies involving molecular imaging, Dr. Jauhar said the review’s inferences were “simplistic” and the review authors are “basically shaping the argument” to fit their desired narrative.

He also noted factual errors in the review. “They make a mistake when they talk about serotonin transporter imaging; they say there are no consistent findings across studies when, in fact, there are.”

With both tryptophan depletion and molecular imaging studies, the review “glosses over findings” from the original studies, said Dr. Jauhar.

For tryptophan depletion, “a more accurate, constructive conclusion would be that acute tryptophan depletion and decreased plasma tryptophan in depression indicate a role for 5-HT in those vulnerable to or suffering from depression, and that molecular imaging suggests the system is perturbed,” the commentators wrote.

“The proven efficacy of SSRIs in a proportion of people with depression lends credibility to this position,” they added.

Dr. Jauhar also took issue with criteria for certainty of finding of these and other studies used in the review. “If you’re setting the criteria yourself, it’s arbitrary.”
 

No new data

An umbrella review is supposed to be of the highest quality and should entail “taking out the studies and analysing them yourself,” but here, “all they have done is put a synthesis forward of other people’s reviews, so essentially there’s no new data there,” said Dr. Jauhar.

And sometimes the review’s findings differ from the original research. “When you have people who haven’t conducted original research themselves quoting someone else’s work and ignoring what those people say, we’re all in trouble,” said Dr. Jauhar.

In an additional commentary also published in Molecular Psychiatry, Jacob Pade Ramsøe Jacobsen, Evecxia Therapeutics, Durham, N.C., also criticized the review by Dr. Moncrieff and colleagues.

Its authors appear unfamiliar with serotonin biology and pharmacology, Dr. Jacobsen wrote.

“The review contains factual errors, makes conclusions serotonin neurobiology may not support, and quotes the cited literature in a selective manner,” he added.

“Most troubling, they misinterpret some data reviewed and intimate that serotonin reuptake inhibitor antidepressants, e.g., SSRIs, may decrease, rather than increase, serotonin function.”

If accepted by general practitioners and the public, the review’s conclusions “could lead to reduced use of antidepressants among patients in need and increased morbidity related to depression.”
 

Dr. Moncrieff pushes back

Responding to the torrent of criticism of her study, Dr. Moncrieff told this news organization via email that they stand by the review, adding that Dr. Jauhar and others “don’t want to let the cat out of the bag” that there’s no good evidence to support the hypothesis that low serotonin causes depression because it challenges antidepressant use.

“The idea that antidepressants work by correcting an underlying chemical imbalance or serotonin abnormality has led research up a blind alley and meant scientists have not taken the harmful effects of these drugs seriously enough.”

These critics, she added, “want business as usual – which means people will continue to be misinformed and exposed to harmful effects of drugs that have minimal and uncertain benefits.”

In a letter to the editor of Molecular Psychiatry, Dr. Moncrieff and her fellow authors maintain that they used approved and well-accepted methods for the umbrella review, including preregistering the protocol and using recommended search methods and quality assessments, and that they did not miss certain studies, as has been claimed.

In her blog, Dr. Moncrieff wrote that the “marginal differences between antidepressants and placebo that are apparent in clinical trials are likely to be produced by alternative, more plausible mechanisms like the emotional blunting effects of the drugs or by amplified placebo effects, rather than by targeting underlying biological mechanisms (since these have not been demonstrated).”

It also highlights “how we don’t know what antidepressants do to the brain exactly, which is a cause for concern,” she adds.

Dr. Jauhar has received honoraria for nonpromotional educational talks on antipsychotics from Janssen, Sunovion, and Lundbeck and on causes of schizophrenia for Boehringer-Ingelheim. He has also received honoraria for consulting on antipsychotics for LB Pharmaceuticals. He sits on Council for the British Association for Psychopharmacology and was a recent panel member for the Wellcome Trust.

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

TOPLINE:

After passage of state laws that allow recreational cannabis use, binge drinking declined among those younger than 21 but increased among those aged 31 and older.

METHODOLOGY:

Among adolescents, binge drinking, defined as having five or more drinks for men and four or more drinks for women at one time, is associated with poor academic performance, sexual risk, and injury in the short term, as well as the development of alcohol use disorder and academic disengagement in the long term.

Current evidence regarding the association between recreational cannabis laws (RCLs) and binge drinking is limited.

States in which RCLs have been implemented include Colorado, Washington, Alaska, Oregon, Nevada, California, Massachusetts, and Vermont, as well as the District of Columbia.

The study included 817,359 people aged 12 and older who participated in the 2008-2019 National Survey on Drug Use and Health (NSDUH), a nationally representative survey of the U.S. population.
 

TAKEAWAY:

Overall, states that have not enacted cannabis laws showed consistently lower rates of binge drinking over time among all age groups.

In all states, there were substantial declines in reporting of past-month binge drinking in some age groups – from 17.5% (95% confidence interval, 16.9-18.2) in 2008 to 11.1% (10.4-11.8) in 2019 among those aged 12-20 and a drop from 43.7% (42.4-44.9) to 40.2% (39.1-41.1) among those aged 21-30.

There were overall increases in binge drinking in all states regardless of cannabis laws among individuals aged 31 and older. The most extensive increases were among people aged 31-40 (from 28.1% [95% CI, 26.6-29.6] to 33.3% [32.1-34.6]), followed by participants aged 51 and over (from 13.3% [95% CI, 12.2-14.4] to 16.8% [15.8-17.7]).
 

IN PRACTICE:

“Our findings support calls to reinforce health care providers’ discussions about alcohol use with older adults,” particularly in RCL states, the researchers write.

STUDY DETAILS:

The study was conducted out by Priscila Dib Gonçalves, PhD, department of epidemiology, Columbia University School of Public Health, New York, and colleagues. It was published in the International Journal of Drug Policy.

LIMITATIONS:

Alcohol-related measures, including binge drinking, were self-reported, which may introduce recall bias and underreporting. NSDUH binge drinking measures were not adjusted for sex differences from 2008 to 2014, which may result in underreporting of binge drinking in females before 2015. The researchers did not examine cannabis policy provisions, such as cultivation restrictions, pricing control, the tax imposed, and consumption restrictions.

DISCLOSURES:

The study received support from the National Institutes of Health, the National Institute on Drug Abuse, the National Center for Injury Prevention and Control, and the Centers for Disease Control and Prevention. The authors report no relevant conflicts of interest.

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

TOPLINE:

After passage of state laws that allow recreational cannabis use, binge drinking declined among those younger than 21 but increased among those aged 31 and older.

METHODOLOGY:

Among adolescents, binge drinking, defined as having five or more drinks for men and four or more drinks for women at one time, is associated with poor academic performance, sexual risk, and injury in the short term, as well as the development of alcohol use disorder and academic disengagement in the long term.

Current evidence regarding the association between recreational cannabis laws (RCLs) and binge drinking is limited.

States in which RCLs have been implemented include Colorado, Washington, Alaska, Oregon, Nevada, California, Massachusetts, and Vermont, as well as the District of Columbia.

The study included 817,359 people aged 12 and older who participated in the 2008-2019 National Survey on Drug Use and Health (NSDUH), a nationally representative survey of the U.S. population.
 

TAKEAWAY:

Overall, states that have not enacted cannabis laws showed consistently lower rates of binge drinking over time among all age groups.

In all states, there were substantial declines in reporting of past-month binge drinking in some age groups – from 17.5% (95% confidence interval, 16.9-18.2) in 2008 to 11.1% (10.4-11.8) in 2019 among those aged 12-20 and a drop from 43.7% (42.4-44.9) to 40.2% (39.1-41.1) among those aged 21-30.

There were overall increases in binge drinking in all states regardless of cannabis laws among individuals aged 31 and older. The most extensive increases were among people aged 31-40 (from 28.1% [95% CI, 26.6-29.6] to 33.3% [32.1-34.6]), followed by participants aged 51 and over (from 13.3% [95% CI, 12.2-14.4] to 16.8% [15.8-17.7]).
 

IN PRACTICE:

“Our findings support calls to reinforce health care providers’ discussions about alcohol use with older adults,” particularly in RCL states, the researchers write.

STUDY DETAILS:

The study was conducted out by Priscila Dib Gonçalves, PhD, department of epidemiology, Columbia University School of Public Health, New York, and colleagues. It was published in the International Journal of Drug Policy.

LIMITATIONS:

Alcohol-related measures, including binge drinking, were self-reported, which may introduce recall bias and underreporting. NSDUH binge drinking measures were not adjusted for sex differences from 2008 to 2014, which may result in underreporting of binge drinking in females before 2015. The researchers did not examine cannabis policy provisions, such as cultivation restrictions, pricing control, the tax imposed, and consumption restrictions.

DISCLOSURES:

The study received support from the National Institutes of Health, the National Institute on Drug Abuse, the National Center for Injury Prevention and Control, and the Centers for Disease Control and Prevention. The authors report no relevant conflicts of interest.

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

TOPLINE:

After passage of state laws that allow recreational cannabis use, binge drinking declined among those younger than 21 but increased among those aged 31 and older.

METHODOLOGY:

Among adolescents, binge drinking, defined as having five or more drinks for men and four or more drinks for women at one time, is associated with poor academic performance, sexual risk, and injury in the short term, as well as the development of alcohol use disorder and academic disengagement in the long term.

Current evidence regarding the association between recreational cannabis laws (RCLs) and binge drinking is limited.

States in which RCLs have been implemented include Colorado, Washington, Alaska, Oregon, Nevada, California, Massachusetts, and Vermont, as well as the District of Columbia.

The study included 817,359 people aged 12 and older who participated in the 2008-2019 National Survey on Drug Use and Health (NSDUH), a nationally representative survey of the U.S. population.
 

TAKEAWAY:

Overall, states that have not enacted cannabis laws showed consistently lower rates of binge drinking over time among all age groups.

In all states, there were substantial declines in reporting of past-month binge drinking in some age groups – from 17.5% (95% confidence interval, 16.9-18.2) in 2008 to 11.1% (10.4-11.8) in 2019 among those aged 12-20 and a drop from 43.7% (42.4-44.9) to 40.2% (39.1-41.1) among those aged 21-30.

There were overall increases in binge drinking in all states regardless of cannabis laws among individuals aged 31 and older. The most extensive increases were among people aged 31-40 (from 28.1% [95% CI, 26.6-29.6] to 33.3% [32.1-34.6]), followed by participants aged 51 and over (from 13.3% [95% CI, 12.2-14.4] to 16.8% [15.8-17.7]).
 

IN PRACTICE:

“Our findings support calls to reinforce health care providers’ discussions about alcohol use with older adults,” particularly in RCL states, the researchers write.

STUDY DETAILS:

The study was conducted out by Priscila Dib Gonçalves, PhD, department of epidemiology, Columbia University School of Public Health, New York, and colleagues. It was published in the International Journal of Drug Policy.

LIMITATIONS:

Alcohol-related measures, including binge drinking, were self-reported, which may introduce recall bias and underreporting. NSDUH binge drinking measures were not adjusted for sex differences from 2008 to 2014, which may result in underreporting of binge drinking in females before 2015. The researchers did not examine cannabis policy provisions, such as cultivation restrictions, pricing control, the tax imposed, and consumption restrictions.

DISCLOSURES:

The study received support from the National Institutes of Health, the National Institute on Drug Abuse, the National Center for Injury Prevention and Control, and the Centers for Disease Control and Prevention. The authors report no relevant conflicts of interest.

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

TOPLINE:

Therapists’ oxytocin levels significantly affect the association between patients’ negative emotions and reduction in their depressive symptoms.

METHODOLOGY:

• Evidence suggests patient experiences of negative emotions predict outcomes of psychotherapy for major depressive disorder (MDD), but mechanisms remain unclear.
• Researchers used a mediation model based on the role of oxytocin (OT) in attachment relationships, such as between parent and infant.
• They collected 435 oxytocin samples pre- and post-session from therapists of 62 patients receiving psychotherapy for MDD.
• Hamilton Rating Scale for Depression (HRSD) was administered to patients before sessions, and patients reported their in-session emotions.

TAKEAWAY:

• Higher negative emotion levels of patients predicted higher therapist oxytocin levels on the post-session assessment, when controlling for the pre-session oxytocin (“a” path [same-session path between negative affect and OT levels]: 0.11; standard error, 0.05; P = 03; 95% confidence interval, 0.003-0.20)
• Higher therapist oxytocin levels predicted lower depression severity in the next session (“b” path [time-lagged association between post-session OT levels and depression severity]: –0.97; SE, 0.34; P = .005; 95 % CI, –1.57 to –0.22)
• An increase in therapists’ oxytocin in response to patients’ negative emotions may represent activation of the therapists’ caregiving system signaling the emergence of a healthy therapeutic interaction.

IN PRACTICE:

“The findings suggest that therapists’ oxytocin responses could potentially serve as a biomarker of an effective therapeutic process,” the researchers write.

STUDY DETAILS:

The study was conducted by Hadar Fisher, department of psychology, University of Haifa, Israel, and colleagues. It was published online in the Journal of Affective Disorders.

LIMITATIONS:

The sample size, while one of the largest in studies looking at oxytocin in psychotherapy, still has limited statistical power. The study used post-session retrospective self-reports to measure negative emotions, which focused on patients’ experiences rather than expression of these emotions.

DISCLOSURES:

The study was supported by a grant from the Israeli Science Foundation. The authors report no competing interests.

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

TOPLINE:

Therapists’ oxytocin levels significantly affect the association between patients’ negative emotions and reduction in their depressive symptoms.

METHODOLOGY:

• Evidence suggests patient experiences of negative emotions predict outcomes of psychotherapy for major depressive disorder (MDD), but mechanisms remain unclear.
• Researchers used a mediation model based on the role of oxytocin (OT) in attachment relationships, such as between parent and infant.
• They collected 435 oxytocin samples pre- and post-session from therapists of 62 patients receiving psychotherapy for MDD.
• Hamilton Rating Scale for Depression (HRSD) was administered to patients before sessions, and patients reported their in-session emotions.

TAKEAWAY:

• Higher negative emotion levels of patients predicted higher therapist oxytocin levels on the post-session assessment, when controlling for the pre-session oxytocin (“a” path [same-session path between negative affect and OT levels]: 0.11; standard error, 0.05; P = 03; 95% confidence interval, 0.003-0.20)
• Higher therapist oxytocin levels predicted lower depression severity in the next session (“b” path [time-lagged association between post-session OT levels and depression severity]: –0.97; SE, 0.34; P = .005; 95 % CI, –1.57 to –0.22)
• An increase in therapists’ oxytocin in response to patients’ negative emotions may represent activation of the therapists’ caregiving system signaling the emergence of a healthy therapeutic interaction.

IN PRACTICE:

“The findings suggest that therapists’ oxytocin responses could potentially serve as a biomarker of an effective therapeutic process,” the researchers write.

STUDY DETAILS:

The study was conducted by Hadar Fisher, department of psychology, University of Haifa, Israel, and colleagues. It was published online in the Journal of Affective Disorders.

LIMITATIONS:

The sample size, while one of the largest in studies looking at oxytocin in psychotherapy, still has limited statistical power. The study used post-session retrospective self-reports to measure negative emotions, which focused on patients’ experiences rather than expression of these emotions.

DISCLOSURES:

The study was supported by a grant from the Israeli Science Foundation. The authors report no competing interests.

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

TOPLINE:

Therapists’ oxytocin levels significantly affect the association between patients’ negative emotions and reduction in their depressive symptoms.

METHODOLOGY:

• Evidence suggests patient experiences of negative emotions predict outcomes of psychotherapy for major depressive disorder (MDD), but mechanisms remain unclear.
• Researchers used a mediation model based on the role of oxytocin (OT) in attachment relationships, such as between parent and infant.
• They collected 435 oxytocin samples pre- and post-session from therapists of 62 patients receiving psychotherapy for MDD.
• Hamilton Rating Scale for Depression (HRSD) was administered to patients before sessions, and patients reported their in-session emotions.

TAKEAWAY:

• Higher negative emotion levels of patients predicted higher therapist oxytocin levels on the post-session assessment, when controlling for the pre-session oxytocin (“a” path [same-session path between negative affect and OT levels]: 0.11; standard error, 0.05; P = 03; 95% confidence interval, 0.003-0.20)
• Higher therapist oxytocin levels predicted lower depression severity in the next session (“b” path [time-lagged association between post-session OT levels and depression severity]: –0.97; SE, 0.34; P = .005; 95 % CI, –1.57 to –0.22)
• An increase in therapists’ oxytocin in response to patients’ negative emotions may represent activation of the therapists’ caregiving system signaling the emergence of a healthy therapeutic interaction.

IN PRACTICE:

“The findings suggest that therapists’ oxytocin responses could potentially serve as a biomarker of an effective therapeutic process,” the researchers write.

STUDY DETAILS:

The study was conducted by Hadar Fisher, department of psychology, University of Haifa, Israel, and colleagues. It was published online in the Journal of Affective Disorders.

LIMITATIONS:

The sample size, while one of the largest in studies looking at oxytocin in psychotherapy, still has limited statistical power. The study used post-session retrospective self-reports to measure negative emotions, which focused on patients’ experiences rather than expression of these emotions.

DISCLOSURES:

The study was supported by a grant from the Israeli Science Foundation. The authors report no competing interests.

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

TOPLINE

Mean lipid levels are similar among adolescents with and without major depressive disorder (MDD), as is the proportion of adolescents with borderline-high lipid levels.

METHODOLOGY

Teen depression is associated with an increased likelihood of experiencing cardiovascular (CV) events, with dyslipidemia being a potentially modifiable risk factor.

Only a few studies have examined the association between depression and lipids during adolescence, when confounding comorbidities such as obesity and diabetes are less common.

The study included 243 adolescents (186 with MDD and 57 healthy controls [HCs]) who were mostly female and had a mean age of 15 years.

Researchers assessed CV risk factors including body mass index (BMI), blood pressure, smoking status, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride (TG), which were classified as acceptable or borderline high.

Dyslipidemia was defined as having concentration of at least one lipid outside the acceptable range.
 

TAKEAWAY

Most participants in both groups had lipid concentrations within the acceptable range.

There were no differences between study groups in mean lipid levels after adjusting for age, sex, and standardized BMI.

There were also no differences in the proportion of adolescents with borderline-high lipid concentrations.

Among youth with MDD, greater depressive symptoms were associated with higher HDL levels and a lower TG:HDL ratio after adjusting for sex, age, and standardized BMI.
 

IN PRACTICE

“Taken together, results of the current study support the need for further examination of the relationship between gender, depression, and cholesterol,” the authors write.

STUDY DETAILS

The study was conducted by Anisa F. Khalfan, Neurosciences and Mental Health research program, SickKids Research Institute, Toronto, Canada, and colleagues. It was published online in the Journal of Affective Disorders.

LIMITATIONS

The HC group was relatively small, which might have contributed to the null findings. The mean Center for Epidemiologic Studies Depression Scale for Children (CES-DC) score was 8.3 among healthy youth, compared with 37.5 among MDD youth, limiting detection of an association related to depression severity.

DISCLOSURES

The study was supported by the Lunenfeld Summer Studentship. The authors report no relevant financial relationships.

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

TOPLINE

Mean lipid levels are similar among adolescents with and without major depressive disorder (MDD), as is the proportion of adolescents with borderline-high lipid levels.

METHODOLOGY

Teen depression is associated with an increased likelihood of experiencing cardiovascular (CV) events, with dyslipidemia being a potentially modifiable risk factor.

Only a few studies have examined the association between depression and lipids during adolescence, when confounding comorbidities such as obesity and diabetes are less common.

The study included 243 adolescents (186 with MDD and 57 healthy controls [HCs]) who were mostly female and had a mean age of 15 years.

Researchers assessed CV risk factors including body mass index (BMI), blood pressure, smoking status, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride (TG), which were classified as acceptable or borderline high.

Dyslipidemia was defined as having concentration of at least one lipid outside the acceptable range.
 

TAKEAWAY

Most participants in both groups had lipid concentrations within the acceptable range.

There were no differences between study groups in mean lipid levels after adjusting for age, sex, and standardized BMI.

There were also no differences in the proportion of adolescents with borderline-high lipid concentrations.

Among youth with MDD, greater depressive symptoms were associated with higher HDL levels and a lower TG:HDL ratio after adjusting for sex, age, and standardized BMI.
 

IN PRACTICE

“Taken together, results of the current study support the need for further examination of the relationship between gender, depression, and cholesterol,” the authors write.

STUDY DETAILS

The study was conducted by Anisa F. Khalfan, Neurosciences and Mental Health research program, SickKids Research Institute, Toronto, Canada, and colleagues. It was published online in the Journal of Affective Disorders.

LIMITATIONS

The HC group was relatively small, which might have contributed to the null findings. The mean Center for Epidemiologic Studies Depression Scale for Children (CES-DC) score was 8.3 among healthy youth, compared with 37.5 among MDD youth, limiting detection of an association related to depression severity.

DISCLOSURES

The study was supported by the Lunenfeld Summer Studentship. The authors report no relevant financial relationships.

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

TOPLINE

Mean lipid levels are similar among adolescents with and without major depressive disorder (MDD), as is the proportion of adolescents with borderline-high lipid levels.

METHODOLOGY

Teen depression is associated with an increased likelihood of experiencing cardiovascular (CV) events, with dyslipidemia being a potentially modifiable risk factor.

Only a few studies have examined the association between depression and lipids during adolescence, when confounding comorbidities such as obesity and diabetes are less common.

The study included 243 adolescents (186 with MDD and 57 healthy controls [HCs]) who were mostly female and had a mean age of 15 years.

Researchers assessed CV risk factors including body mass index (BMI), blood pressure, smoking status, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride (TG), which were classified as acceptable or borderline high.

Dyslipidemia was defined as having concentration of at least one lipid outside the acceptable range.
 

TAKEAWAY

Most participants in both groups had lipid concentrations within the acceptable range.

There were no differences between study groups in mean lipid levels after adjusting for age, sex, and standardized BMI.

There were also no differences in the proportion of adolescents with borderline-high lipid concentrations.

Among youth with MDD, greater depressive symptoms were associated with higher HDL levels and a lower TG:HDL ratio after adjusting for sex, age, and standardized BMI.
 

IN PRACTICE

“Taken together, results of the current study support the need for further examination of the relationship between gender, depression, and cholesterol,” the authors write.

STUDY DETAILS

The study was conducted by Anisa F. Khalfan, Neurosciences and Mental Health research program, SickKids Research Institute, Toronto, Canada, and colleagues. It was published online in the Journal of Affective Disorders.

LIMITATIONS

The HC group was relatively small, which might have contributed to the null findings. The mean Center for Epidemiologic Studies Depression Scale for Children (CES-DC) score was 8.3 among healthy youth, compared with 37.5 among MDD youth, limiting detection of an association related to depression severity.

DISCLOSURES

The study was supported by the Lunenfeld Summer Studentship. The authors report no relevant financial relationships.

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

TOPLINE:

Prepandemic cortisol response to stress and amygdala emotion-evoked activation predicted persistent teen engagement in nonsuicidal self-injury (NSSI) among teensduring the COVID-19 pandemic.

METHODOLOGY:

The analysis included 64 mostly White and middle class or upper middle class female patients in Minneapolis, Minnesota (mean age, 16.2 years) who were part of a larger study of the neurobiology of NSSI.

Before the pandemic, researchers assessed the presence of NSSI and measured cortisol levels in saliva while the participant was experiencing stress, such as when giving a speech (less cortisol in response to stress is a sign of HPA axis hyporeactivity); adolescents were assessed for depression and underwent neuroimaging.

In the early stages of the pandemic, adolescents were assessed for recent engagement in NSSI.

Researchers classified adolescents into three NSSI groups: never (n = 17), desist (a history of NSSI but did not report it during the pandemic; n = 26), or persist (a history of NSSI and reported it during the pandemic; n = 21).
 

TAKEAWAY:

Lower prepandemic levels of under the curve ground (AUCg), an index of overall activation of cortisol levels (B = −0.250; standard error, 0.109; P = .022) and lower prepandemic amygdala activation (B = −0.789; SE = 0.352; P = .025) predicted desistance of NSSI, compared to persistence of NSSI, during the pandemic.

This remained significant after controlling for pandemic-related stressors that could exacerbate underlying risk factors

When depression was included as a covariate, decreased cortisol AUCg and amygdala activation remained significantly predictive of desistance. Decreased medial prefrontal cortex resting state functional connectivity and decreased depressive symptoms were also predictive of desistance of NSSI.
 

IN PRACTICE:

The results “may give insight into predictors of maladaptive patterns of coping with negative emotions” for those with a history of NSSI, the authors noted.

STUDY DETAILS:

The study was conducted by Katherine A. Carosella, department of psychology, University of Minnesota, Minneapolis, and colleagues. It was published online in Psychoneuroendocrinology.

LIMITATIONS:

The study was relatively small, and the investigators could not make causal inferences or rule out the possibility that different stages of development affected the data. Measures employed during COVID were not identical to those used in the prepandemic assessment.

DISCLOSURES:

The study received support from the National Institute of Mental Health and the University of Minnesota. The authors have disclosed no relevant financial relationships.

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

TOPLINE:

Prepandemic cortisol response to stress and amygdala emotion-evoked activation predicted persistent teen engagement in nonsuicidal self-injury (NSSI) among teensduring the COVID-19 pandemic.

METHODOLOGY:

The analysis included 64 mostly White and middle class or upper middle class female patients in Minneapolis, Minnesota (mean age, 16.2 years) who were part of a larger study of the neurobiology of NSSI.

Before the pandemic, researchers assessed the presence of NSSI and measured cortisol levels in saliva while the participant was experiencing stress, such as when giving a speech (less cortisol in response to stress is a sign of HPA axis hyporeactivity); adolescents were assessed for depression and underwent neuroimaging.

In the early stages of the pandemic, adolescents were assessed for recent engagement in NSSI.

Researchers classified adolescents into three NSSI groups: never (n = 17), desist (a history of NSSI but did not report it during the pandemic; n = 26), or persist (a history of NSSI and reported it during the pandemic; n = 21).
 

TAKEAWAY:

Lower prepandemic levels of under the curve ground (AUCg), an index of overall activation of cortisol levels (B = −0.250; standard error, 0.109; P = .022) and lower prepandemic amygdala activation (B = −0.789; SE = 0.352; P = .025) predicted desistance of NSSI, compared to persistence of NSSI, during the pandemic.

This remained significant after controlling for pandemic-related stressors that could exacerbate underlying risk factors

When depression was included as a covariate, decreased cortisol AUCg and amygdala activation remained significantly predictive of desistance. Decreased medial prefrontal cortex resting state functional connectivity and decreased depressive symptoms were also predictive of desistance of NSSI.
 

IN PRACTICE:

The results “may give insight into predictors of maladaptive patterns of coping with negative emotions” for those with a history of NSSI, the authors noted.

STUDY DETAILS:

The study was conducted by Katherine A. Carosella, department of psychology, University of Minnesota, Minneapolis, and colleagues. It was published online in Psychoneuroendocrinology.

LIMITATIONS:

The study was relatively small, and the investigators could not make causal inferences or rule out the possibility that different stages of development affected the data. Measures employed during COVID were not identical to those used in the prepandemic assessment.

DISCLOSURES:

The study received support from the National Institute of Mental Health and the University of Minnesota. The authors have disclosed no relevant financial relationships.

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

TOPLINE:

Prepandemic cortisol response to stress and amygdala emotion-evoked activation predicted persistent teen engagement in nonsuicidal self-injury (NSSI) among teensduring the COVID-19 pandemic.

METHODOLOGY:

The analysis included 64 mostly White and middle class or upper middle class female patients in Minneapolis, Minnesota (mean age, 16.2 years) who were part of a larger study of the neurobiology of NSSI.

Before the pandemic, researchers assessed the presence of NSSI and measured cortisol levels in saliva while the participant was experiencing stress, such as when giving a speech (less cortisol in response to stress is a sign of HPA axis hyporeactivity); adolescents were assessed for depression and underwent neuroimaging.

In the early stages of the pandemic, adolescents were assessed for recent engagement in NSSI.

Researchers classified adolescents into three NSSI groups: never (n = 17), desist (a history of NSSI but did not report it during the pandemic; n = 26), or persist (a history of NSSI and reported it during the pandemic; n = 21).
 

TAKEAWAY:

Lower prepandemic levels of under the curve ground (AUCg), an index of overall activation of cortisol levels (B = −0.250; standard error, 0.109; P = .022) and lower prepandemic amygdala activation (B = −0.789; SE = 0.352; P = .025) predicted desistance of NSSI, compared to persistence of NSSI, during the pandemic.

This remained significant after controlling for pandemic-related stressors that could exacerbate underlying risk factors

When depression was included as a covariate, decreased cortisol AUCg and amygdala activation remained significantly predictive of desistance. Decreased medial prefrontal cortex resting state functional connectivity and decreased depressive symptoms were also predictive of desistance of NSSI.
 

IN PRACTICE:

The results “may give insight into predictors of maladaptive patterns of coping with negative emotions” for those with a history of NSSI, the authors noted.

STUDY DETAILS:

The study was conducted by Katherine A. Carosella, department of psychology, University of Minnesota, Minneapolis, and colleagues. It was published online in Psychoneuroendocrinology.

LIMITATIONS:

The study was relatively small, and the investigators could not make causal inferences or rule out the possibility that different stages of development affected the data. Measures employed during COVID were not identical to those used in the prepandemic assessment.

DISCLOSURES:

The study received support from the National Institute of Mental Health and the University of Minnesota. The authors have disclosed no relevant financial relationships.

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

TOPLINE

Patients who received zuranolone 50 mg/d demonstrated significantly greater improvement in depressive symptoms than those who received placebo, with a rapid onset of effect.

METHODOLOGY

The Food and Drug Administration has accepted filing of a new drug application for zuranolone, a neuroactive steroid that targets g-aminobutyric acid type A receptors (GABAAR), for the treatment of major depressive disorder (MDD) and postpartum depression.

The study included 543 mostly White female patients with MDD. The mean age of the patients was 40 years. Participants were randomly assigned to receive oral zuranolone 50 mg or placebo once daily for 14 days.

About 30% of patients were taking an antidepressant.

The primary endpoint was change in Hamilton Depression Rating Scale (HAM-D) score at day 15.
 

TAKEAWAY

The zuranolone group showed significantly greater improvement in depressive symptoms at 15 days compared with the placebo group (least square mean [LSM] change on HAM-D, –14.1, vs. –12.3; P = .01; Cohen’s d = 0.23).

Improvements were observed on day 3, the earliest assessment, and were sustained at all subsequent visits during the treatment and follow-up period (through day 42).

Results favored zuranolone regardless of the use of antidepressant therapies.

Patients with anxiety who received the active drug experienced improvement in anxiety symptoms compared to the patients who received placebo.

The drug was well tolerated, and there were no new safety findings. The most common treatment-emergent adverse events were somnolence and headache. There was no weight gain, sexual dysfunction, withdrawal symptoms, or increased suicidal ideation or behavior.
 

IN PRACTICE

The study adds to evidence suggesting zuranolone is a promising novel therapy for treating MDD, the authors noted.

STUDY DETAILS

The study was conducted by Anita H. Clayton, MD, department of psychiatry and neurobehavioral sciences, University of Virginia, Charlottesville, and colleagues. It was published online May 3 in The American Journal of Psychiatry.

LIMITATIONS

The study was short term, and the patient population was severely depressed at study entry, which may limit application to those with mild or moderate symptoms. There was a robust placebo response, possibly partly due to the COVID-19 pandemic, when there was an increase in depressive symptoms in the U.S. population, and so frequent in-person visits may have led to an improvement in symptoms even if the patient was receiving placebo.

DISCLOSURES

The study was funded by Sage Therapeutics and Biogen.

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

TOPLINE

Patients who received zuranolone 50 mg/d demonstrated significantly greater improvement in depressive symptoms than those who received placebo, with a rapid onset of effect.

METHODOLOGY

The Food and Drug Administration has accepted filing of a new drug application for zuranolone, a neuroactive steroid that targets g-aminobutyric acid type A receptors (GABAAR), for the treatment of major depressive disorder (MDD) and postpartum depression.

The study included 543 mostly White female patients with MDD. The mean age of the patients was 40 years. Participants were randomly assigned to receive oral zuranolone 50 mg or placebo once daily for 14 days.

About 30% of patients were taking an antidepressant.

The primary endpoint was change in Hamilton Depression Rating Scale (HAM-D) score at day 15.
 

TAKEAWAY

The zuranolone group showed significantly greater improvement in depressive symptoms at 15 days compared with the placebo group (least square mean [LSM] change on HAM-D, –14.1, vs. –12.3; P = .01; Cohen’s d = 0.23).

Improvements were observed on day 3, the earliest assessment, and were sustained at all subsequent visits during the treatment and follow-up period (through day 42).

Results favored zuranolone regardless of the use of antidepressant therapies.

Patients with anxiety who received the active drug experienced improvement in anxiety symptoms compared to the patients who received placebo.

The drug was well tolerated, and there were no new safety findings. The most common treatment-emergent adverse events were somnolence and headache. There was no weight gain, sexual dysfunction, withdrawal symptoms, or increased suicidal ideation or behavior.
 

IN PRACTICE

The study adds to evidence suggesting zuranolone is a promising novel therapy for treating MDD, the authors noted.

STUDY DETAILS

The study was conducted by Anita H. Clayton, MD, department of psychiatry and neurobehavioral sciences, University of Virginia, Charlottesville, and colleagues. It was published online May 3 in The American Journal of Psychiatry.

LIMITATIONS

The study was short term, and the patient population was severely depressed at study entry, which may limit application to those with mild or moderate symptoms. There was a robust placebo response, possibly partly due to the COVID-19 pandemic, when there was an increase in depressive symptoms in the U.S. population, and so frequent in-person visits may have led to an improvement in symptoms even if the patient was receiving placebo.

DISCLOSURES

The study was funded by Sage Therapeutics and Biogen.

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

TOPLINE

Patients who received zuranolone 50 mg/d demonstrated significantly greater improvement in depressive symptoms than those who received placebo, with a rapid onset of effect.

METHODOLOGY

The Food and Drug Administration has accepted filing of a new drug application for zuranolone, a neuroactive steroid that targets g-aminobutyric acid type A receptors (GABAAR), for the treatment of major depressive disorder (MDD) and postpartum depression.

The study included 543 mostly White female patients with MDD. The mean age of the patients was 40 years. Participants were randomly assigned to receive oral zuranolone 50 mg or placebo once daily for 14 days.

About 30% of patients were taking an antidepressant.

The primary endpoint was change in Hamilton Depression Rating Scale (HAM-D) score at day 15.
 

TAKEAWAY

The zuranolone group showed significantly greater improvement in depressive symptoms at 15 days compared with the placebo group (least square mean [LSM] change on HAM-D, –14.1, vs. –12.3; P = .01; Cohen’s d = 0.23).

Improvements were observed on day 3, the earliest assessment, and were sustained at all subsequent visits during the treatment and follow-up period (through day 42).

Results favored zuranolone regardless of the use of antidepressant therapies.

Patients with anxiety who received the active drug experienced improvement in anxiety symptoms compared to the patients who received placebo.

The drug was well tolerated, and there were no new safety findings. The most common treatment-emergent adverse events were somnolence and headache. There was no weight gain, sexual dysfunction, withdrawal symptoms, or increased suicidal ideation or behavior.
 

IN PRACTICE

The study adds to evidence suggesting zuranolone is a promising novel therapy for treating MDD, the authors noted.

STUDY DETAILS

The study was conducted by Anita H. Clayton, MD, department of psychiatry and neurobehavioral sciences, University of Virginia, Charlottesville, and colleagues. It was published online May 3 in The American Journal of Psychiatry.

LIMITATIONS

The study was short term, and the patient population was severely depressed at study entry, which may limit application to those with mild or moderate symptoms. There was a robust placebo response, possibly partly due to the COVID-19 pandemic, when there was an increase in depressive symptoms in the U.S. population, and so frequent in-person visits may have led to an improvement in symptoms even if the patient was receiving placebo.

DISCLOSURES

The study was funded by Sage Therapeutics and Biogen.

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

TOPLINE:

Among Korean women younger than 50 years, hysterectomy is associated with an increased risk of cardiovascular disease (CVD), especially stroke, a new cohort study shows.

METHODOLOGY:

• Risk of CVD rapidly increases after menopause, possibly owing to loss of protective effects of female sex hormones and hemorheologic changes.
• Results of previous studies of the association between hysterectomy and CVD were mixed.
• Using national health insurance data, this cohort study included 55,539 South Korean women (median age, 45 years) who underwent a hysterectomy and a propensity-matched group of women.
• The primary outcome was CVD, including myocardial infarction (MI), coronary artery revascularization, and stroke.

TAKEAWAY:

• During follow-up of just under 8 years, the hysterectomy group had an increased risk of CVD compared with the non-hysterectomy group (hazard ratio [HR] 1.25; 95% confidence interval [CI], 1.09-1.44; P = .002)
• The incidence of MI and coronary revascularization was comparable between groups, but the risk of stroke was significantly higher among those who had had a hysterectomy (HR, 1.31; 95% CI, 1.12-1.53; P < .001)
• This increase in risk was similar after excluding patients who also underwent adnexal surgery.

IN PRACTICE:

Early hysterectomy was linked to higher CVD risk, especially stroke, but since the CVD incidence wasn’t high, a change in clinical practice may not be needed, said the authors.

STUDY DETAILS:

The study was conducted by Jin-Sung Yuk, MD, PhD, Department of Obstetrics and Gynecology, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Republic of Korea, and colleagues. It was published online June 12 in JAMA Network Open.

LIMITATIONS:

The study was retrospective and observational and used administrative databases that may be prone to inaccurate coding. The findings may not be generalizable outside Korea.

DISCLOSURES:

The study was supported by a National Research Foundation of Korea grant funded by the Korea government. The authors report no conflicts of interest.

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

TOPLINE:

Among Korean women younger than 50 years, hysterectomy is associated with an increased risk of cardiovascular disease (CVD), especially stroke, a new cohort study shows.

METHODOLOGY:

• Risk of CVD rapidly increases after menopause, possibly owing to loss of protective effects of female sex hormones and hemorheologic changes.
• Results of previous studies of the association between hysterectomy and CVD were mixed.
• Using national health insurance data, this cohort study included 55,539 South Korean women (median age, 45 years) who underwent a hysterectomy and a propensity-matched group of women.
• The primary outcome was CVD, including myocardial infarction (MI), coronary artery revascularization, and stroke.

TAKEAWAY:

• During follow-up of just under 8 years, the hysterectomy group had an increased risk of CVD compared with the non-hysterectomy group (hazard ratio [HR] 1.25; 95% confidence interval [CI], 1.09-1.44; P = .002)
• The incidence of MI and coronary revascularization was comparable between groups, but the risk of stroke was significantly higher among those who had had a hysterectomy (HR, 1.31; 95% CI, 1.12-1.53; P < .001)
• This increase in risk was similar after excluding patients who also underwent adnexal surgery.

IN PRACTICE:

Early hysterectomy was linked to higher CVD risk, especially stroke, but since the CVD incidence wasn’t high, a change in clinical practice may not be needed, said the authors.

STUDY DETAILS:

The study was conducted by Jin-Sung Yuk, MD, PhD, Department of Obstetrics and Gynecology, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Republic of Korea, and colleagues. It was published online June 12 in JAMA Network Open.

LIMITATIONS:

The study was retrospective and observational and used administrative databases that may be prone to inaccurate coding. The findings may not be generalizable outside Korea.

DISCLOSURES:

The study was supported by a National Research Foundation of Korea grant funded by the Korea government. The authors report no conflicts of interest.

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

TOPLINE:

Among Korean women younger than 50 years, hysterectomy is associated with an increased risk of cardiovascular disease (CVD), especially stroke, a new cohort study shows.

METHODOLOGY:

• Risk of CVD rapidly increases after menopause, possibly owing to loss of protective effects of female sex hormones and hemorheologic changes.
• Results of previous studies of the association between hysterectomy and CVD were mixed.
• Using national health insurance data, this cohort study included 55,539 South Korean women (median age, 45 years) who underwent a hysterectomy and a propensity-matched group of women.
• The primary outcome was CVD, including myocardial infarction (MI), coronary artery revascularization, and stroke.

TAKEAWAY:

• During follow-up of just under 8 years, the hysterectomy group had an increased risk of CVD compared with the non-hysterectomy group (hazard ratio [HR] 1.25; 95% confidence interval [CI], 1.09-1.44; P = .002)
• The incidence of MI and coronary revascularization was comparable between groups, but the risk of stroke was significantly higher among those who had had a hysterectomy (HR, 1.31; 95% CI, 1.12-1.53; P < .001)
• This increase in risk was similar after excluding patients who also underwent adnexal surgery.

IN PRACTICE:

Early hysterectomy was linked to higher CVD risk, especially stroke, but since the CVD incidence wasn’t high, a change in clinical practice may not be needed, said the authors.

STUDY DETAILS:

The study was conducted by Jin-Sung Yuk, MD, PhD, Department of Obstetrics and Gynecology, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Republic of Korea, and colleagues. It was published online June 12 in JAMA Network Open.

LIMITATIONS:

The study was retrospective and observational and used administrative databases that may be prone to inaccurate coding. The findings may not be generalizable outside Korea.

DISCLOSURES:

The study was supported by a National Research Foundation of Korea grant funded by the Korea government. The authors report no conflicts of interest.

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

Members of a Food and Drug Administration advisory committee have unanimously concluded that a postmarketing study confirms the benefit of the Alzheimer’s drug lecanemab (Leqembi, Eisai), paving the way for traditional approval.

“Overall, the study demonstrated clearly that this is an effective treatment,” said acting chair Robert C. Alexander, MD, chief scientific officer, Alzheimer’s Prevention Initiative, Banner Alzheimer’s Institute, and research professor, department of psychiatry, University of Arizona, Phoenix, during the meeting.

An intravenous infusion targeting amyloid-beta, lecanemab received accelerated FDA approved earlier in 2023 for the treatment of early Alzheimer’s disease (AD). The company was required to complete a confirmatory study to verify and describe the product’s clinical benefit.

The Peripheral and Central Nervous System Drugs Advisory Committee met to discuss this phase 3 study (CLARITY-AD). The multicenter, double-blind study included 1,795 patients (mean age, 71 years) who had mild cognitive impairment caused by AD or mild AD dementia.
 

Delayed progression

Study participants had a broad range of comorbidities, and many were concomitantly receiving other medications. Black people were underrepresented in the study at just 3% of the total cohort.

Patients were randomly assigned to receive placebo or lecanemab 10 mg/kg biweekly. In addition to a placebo-controlled period and safety follow-up, the study has an ongoing extension phase of up to 4 years.

The study met its primary endpoint, showing a highly statistically significant 27% less decline on the Clinical Dementia Rating-Sum of Boxes at 18 months (difference in adjusted mean, –0.45; 95% CI, –0.67 to –0.23; P = .00005).

This was supported by a significant 26% difference on the AD Assessment Scale–Cognitive Subscale with 14 tasks (ADAS-Cog 14).

The drug also affected function, with a 37% decrease, compared with placebo, on the AD Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment.

Committee members heard that the results signal delays in disease progression by about 5 months, giving patients more time to live independently and participate in hobbies and interests.

Patients who received the active drug also experienced quality of life benefits. Compared with patients who received placebo, those who took lecanemab had 49% less decline as measured with the European Quality of Life–5 Dimensions scale and 56% less decline as measured by the Quality of Life in AD scale, and caregivers reported less burden.

Lecanemab also affected biomarkers of amyloid, tau, and neurodegeneration, providing a biological basis for the treatment effects consistent with slowing of disease progression.
 

Unanimous support

All six committee members agreed by vote that the study provides evidence of clinical benefit. They variously descried the study and results as “robust,” “compelling,” “well conducted,” “clear and consistent,” and “clinically meaningful.”

In the active treatment group, there was a higher incidence of amyloid-related imaging abnormalities (ARIAs), which can be serious and life-threatening but are usually asymptomatic. In this study, most ARIAs had resolved by 3 months.

Deaths occurred in 0.8% of the placebo and 0.7% of the treatment group. Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., noted that the numbers of deaths and serious adverse events were “quite similar” in the two groups.

“And for serious ARIA, there was an imbalance favoring placebo, but overall, these were pretty rare,” he said.
 

Subgroup concerns

Committee members discussed the risk/benefit profile for three subgroups of patients – those with apolipoprotein E4 (apo E4) allele, patients taking an anticoagulant, and those with cerebral amyloid angiopathy (CAA).

In the apo E4 group, the study’s primary endpoint did not favor the drug, but secondary endpoints did.

“I think the general feeling [for apo E4 status] is that the risk/benefit still remains favorable, especially when looking across multiple endpoints,” said Dr. Alexander.

However, some members supported recommending genetic testing before initiating the drug.

The views were more diverse for the use of lecanemab in the presence of an anticoagulant, which may increase the risk for cerebral hemorrhage. Some committee members strongly recommended that these patients not receive lecanemab, while others highlighted the need for more information, owing to uncertainties about the risks.

With respect to CAA, most members supported the idea of considering use of the drug in the presence of this condition, but only after discussing the risks with patients and their families and in the presence of a robust reporting system.

An Alzheimer’s Association representative was in attendance during the public hearing portion of the meeting to express support for traditional approval of lecanemab for people with early AD.

The association strongly favors full Medicare coverage for FDA-approved AD treatments. The Centers for Medicare & Medicaid Services has determined that AD treatments receiving traditional FDA approval will be covered if clinicians register and enter data in a registry.

“While this is an important signal that CMS wants to improve access to FDA-approved treatments, registry as a condition of coverage is an unnecessary and potentially harmful barrier,” said the Alzheimer’s Association in a press release following the meeting.

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

Members of a Food and Drug Administration advisory committee have unanimously concluded that a postmarketing study confirms the benefit of the Alzheimer’s drug lecanemab (Leqembi, Eisai), paving the way for traditional approval.

“Overall, the study demonstrated clearly that this is an effective treatment,” said acting chair Robert C. Alexander, MD, chief scientific officer, Alzheimer’s Prevention Initiative, Banner Alzheimer’s Institute, and research professor, department of psychiatry, University of Arizona, Phoenix, during the meeting.

An intravenous infusion targeting amyloid-beta, lecanemab received accelerated FDA approved earlier in 2023 for the treatment of early Alzheimer’s disease (AD). The company was required to complete a confirmatory study to verify and describe the product’s clinical benefit.

The Peripheral and Central Nervous System Drugs Advisory Committee met to discuss this phase 3 study (CLARITY-AD). The multicenter, double-blind study included 1,795 patients (mean age, 71 years) who had mild cognitive impairment caused by AD or mild AD dementia.
 

Delayed progression

Study participants had a broad range of comorbidities, and many were concomitantly receiving other medications. Black people were underrepresented in the study at just 3% of the total cohort.

Patients were randomly assigned to receive placebo or lecanemab 10 mg/kg biweekly. In addition to a placebo-controlled period and safety follow-up, the study has an ongoing extension phase of up to 4 years.

The study met its primary endpoint, showing a highly statistically significant 27% less decline on the Clinical Dementia Rating-Sum of Boxes at 18 months (difference in adjusted mean, –0.45; 95% CI, –0.67 to –0.23; P = .00005).

This was supported by a significant 26% difference on the AD Assessment Scale–Cognitive Subscale with 14 tasks (ADAS-Cog 14).

The drug also affected function, with a 37% decrease, compared with placebo, on the AD Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment.

Committee members heard that the results signal delays in disease progression by about 5 months, giving patients more time to live independently and participate in hobbies and interests.

Patients who received the active drug also experienced quality of life benefits. Compared with patients who received placebo, those who took lecanemab had 49% less decline as measured with the European Quality of Life–5 Dimensions scale and 56% less decline as measured by the Quality of Life in AD scale, and caregivers reported less burden.

Lecanemab also affected biomarkers of amyloid, tau, and neurodegeneration, providing a biological basis for the treatment effects consistent with slowing of disease progression.
 

Unanimous support

All six committee members agreed by vote that the study provides evidence of clinical benefit. They variously descried the study and results as “robust,” “compelling,” “well conducted,” “clear and consistent,” and “clinically meaningful.”

In the active treatment group, there was a higher incidence of amyloid-related imaging abnormalities (ARIAs), which can be serious and life-threatening but are usually asymptomatic. In this study, most ARIAs had resolved by 3 months.

Deaths occurred in 0.8% of the placebo and 0.7% of the treatment group. Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., noted that the numbers of deaths and serious adverse events were “quite similar” in the two groups.

“And for serious ARIA, there was an imbalance favoring placebo, but overall, these were pretty rare,” he said.
 

Subgroup concerns

Committee members discussed the risk/benefit profile for three subgroups of patients – those with apolipoprotein E4 (apo E4) allele, patients taking an anticoagulant, and those with cerebral amyloid angiopathy (CAA).

In the apo E4 group, the study’s primary endpoint did not favor the drug, but secondary endpoints did.

“I think the general feeling [for apo E4 status] is that the risk/benefit still remains favorable, especially when looking across multiple endpoints,” said Dr. Alexander.

However, some members supported recommending genetic testing before initiating the drug.

The views were more diverse for the use of lecanemab in the presence of an anticoagulant, which may increase the risk for cerebral hemorrhage. Some committee members strongly recommended that these patients not receive lecanemab, while others highlighted the need for more information, owing to uncertainties about the risks.

With respect to CAA, most members supported the idea of considering use of the drug in the presence of this condition, but only after discussing the risks with patients and their families and in the presence of a robust reporting system.

An Alzheimer’s Association representative was in attendance during the public hearing portion of the meeting to express support for traditional approval of lecanemab for people with early AD.

The association strongly favors full Medicare coverage for FDA-approved AD treatments. The Centers for Medicare & Medicaid Services has determined that AD treatments receiving traditional FDA approval will be covered if clinicians register and enter data in a registry.

“While this is an important signal that CMS wants to improve access to FDA-approved treatments, registry as a condition of coverage is an unnecessary and potentially harmful barrier,” said the Alzheimer’s Association in a press release following the meeting.

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

Members of a Food and Drug Administration advisory committee have unanimously concluded that a postmarketing study confirms the benefit of the Alzheimer’s drug lecanemab (Leqembi, Eisai), paving the way for traditional approval.

“Overall, the study demonstrated clearly that this is an effective treatment,” said acting chair Robert C. Alexander, MD, chief scientific officer, Alzheimer’s Prevention Initiative, Banner Alzheimer’s Institute, and research professor, department of psychiatry, University of Arizona, Phoenix, during the meeting.

An intravenous infusion targeting amyloid-beta, lecanemab received accelerated FDA approved earlier in 2023 for the treatment of early Alzheimer’s disease (AD). The company was required to complete a confirmatory study to verify and describe the product’s clinical benefit.

The Peripheral and Central Nervous System Drugs Advisory Committee met to discuss this phase 3 study (CLARITY-AD). The multicenter, double-blind study included 1,795 patients (mean age, 71 years) who had mild cognitive impairment caused by AD or mild AD dementia.
 

Delayed progression

Study participants had a broad range of comorbidities, and many were concomitantly receiving other medications. Black people were underrepresented in the study at just 3% of the total cohort.

Patients were randomly assigned to receive placebo or lecanemab 10 mg/kg biweekly. In addition to a placebo-controlled period and safety follow-up, the study has an ongoing extension phase of up to 4 years.

The study met its primary endpoint, showing a highly statistically significant 27% less decline on the Clinical Dementia Rating-Sum of Boxes at 18 months (difference in adjusted mean, –0.45; 95% CI, –0.67 to –0.23; P = .00005).

This was supported by a significant 26% difference on the AD Assessment Scale–Cognitive Subscale with 14 tasks (ADAS-Cog 14).

The drug also affected function, with a 37% decrease, compared with placebo, on the AD Cooperative Study–Activities of Daily Living Scale for Mild Cognitive Impairment.

Committee members heard that the results signal delays in disease progression by about 5 months, giving patients more time to live independently and participate in hobbies and interests.

Patients who received the active drug also experienced quality of life benefits. Compared with patients who received placebo, those who took lecanemab had 49% less decline as measured with the European Quality of Life–5 Dimensions scale and 56% less decline as measured by the Quality of Life in AD scale, and caregivers reported less burden.

Lecanemab also affected biomarkers of amyloid, tau, and neurodegeneration, providing a biological basis for the treatment effects consistent with slowing of disease progression.
 

Unanimous support

All six committee members agreed by vote that the study provides evidence of clinical benefit. They variously descried the study and results as “robust,” “compelling,” “well conducted,” “clear and consistent,” and “clinically meaningful.”

In the active treatment group, there was a higher incidence of amyloid-related imaging abnormalities (ARIAs), which can be serious and life-threatening but are usually asymptomatic. In this study, most ARIAs had resolved by 3 months.

Deaths occurred in 0.8% of the placebo and 0.7% of the treatment group. Dean Follmann, PhD, assistant director for biostatistics, National Institute of Allergy and Infectious Diseases, Bethesda, Md., noted that the numbers of deaths and serious adverse events were “quite similar” in the two groups.

“And for serious ARIA, there was an imbalance favoring placebo, but overall, these were pretty rare,” he said.
 

Subgroup concerns

Committee members discussed the risk/benefit profile for three subgroups of patients – those with apolipoprotein E4 (apo E4) allele, patients taking an anticoagulant, and those with cerebral amyloid angiopathy (CAA).

In the apo E4 group, the study’s primary endpoint did not favor the drug, but secondary endpoints did.

“I think the general feeling [for apo E4 status] is that the risk/benefit still remains favorable, especially when looking across multiple endpoints,” said Dr. Alexander.

However, some members supported recommending genetic testing before initiating the drug.

The views were more diverse for the use of lecanemab in the presence of an anticoagulant, which may increase the risk for cerebral hemorrhage. Some committee members strongly recommended that these patients not receive lecanemab, while others highlighted the need for more information, owing to uncertainties about the risks.

With respect to CAA, most members supported the idea of considering use of the drug in the presence of this condition, but only after discussing the risks with patients and their families and in the presence of a robust reporting system.

An Alzheimer’s Association representative was in attendance during the public hearing portion of the meeting to express support for traditional approval of lecanemab for people with early AD.

The association strongly favors full Medicare coverage for FDA-approved AD treatments. The Centers for Medicare & Medicaid Services has determined that AD treatments receiving traditional FDA approval will be covered if clinicians register and enter data in a registry.

“While this is an important signal that CMS wants to improve access to FDA-approved treatments, registry as a condition of coverage is an unnecessary and potentially harmful barrier,” said the Alzheimer’s Association in a press release following the meeting.

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

TOPLINE

Alcohol dependence, but not consumption, at age 18 years increases the risk for depression at age 24 years.

METHODOLOGY

• The study included 3,902 mostly White adolescents, about 58% female, born in England from April 1991 to December 1992, who were part of the Avon Longitudinal Study of Parents and Children (ALSPAC) that examined genetic and environmental determinants of health and development.
• Participants completed the self-report Alcohol Use Disorders Identification Test (AUDIT) between the ages of 16 and 23 years, a period when average alcohol use increases rapidly.
• The primary outcome was probability for depression at age 24 years, using the Clinical Interview Schedule Revised (CIS-R), a self-administered computerized clinical assessment of common mental disorder symptoms during the past week.
• Researchers assessed frequency and quantity of alcohol consumption as well as alcohol dependence.
• Confounders included sex, housing type, maternal education and depressive symptoms, parents’ alcohol use, conduct problems at age 4 years, being bullied, and smoking status.

TAKEAWAYS

• After adjustments, alcohol dependence at age 18 years was associated with depression at age 24 years (unstandardized probit coefficient 0.13; 95% confidence interval, 0.02-0.25; P = .019)
• The relationship appeared to persist for alcohol dependence at each age of the growth curve (17-22 years).
• There was no evidence that frequency or quantity of alcohol consumption at age 18 was significantly associated with depression at age 24, suggesting these factors may not increase the risk for later depression unless there are also features of dependency.

IN PRACTICE

“Our findings suggest that preventing alcohol dependence during adolescence, or treating it early, could reduce the risk of depression,” which could have important public health implications, the researchers write.

STUDY DETAILS

The study was carried out by researchers at the University of Bristol; University College London; Critical Thinking Unit, Public Health Directorate, NHS; University of Nottingham, all in the United Kingdom. It was published online in Lancet Psychiatry

LIMITATIONS

There was substantial attrition in the ALSPAC cohort from birth to age 24 years. The sample was recruited from one U.K. region and most participants were White. Measures of alcohol consumption and dependence excluded some features of abuse. And as this is an observational study, the possibility of residual confounding can’t be excluded.

DISCLOSURES

The investigators report no relevant disclosures. The study received support from the UK Medical Research Council and Alcohol Research UK.

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

TOPLINE

Alcohol dependence, but not consumption, at age 18 years increases the risk for depression at age 24 years.

METHODOLOGY

• The study included 3,902 mostly White adolescents, about 58% female, born in England from April 1991 to December 1992, who were part of the Avon Longitudinal Study of Parents and Children (ALSPAC) that examined genetic and environmental determinants of health and development.
• Participants completed the self-report Alcohol Use Disorders Identification Test (AUDIT) between the ages of 16 and 23 years, a period when average alcohol use increases rapidly.
• The primary outcome was probability for depression at age 24 years, using the Clinical Interview Schedule Revised (CIS-R), a self-administered computerized clinical assessment of common mental disorder symptoms during the past week.
• Researchers assessed frequency and quantity of alcohol consumption as well as alcohol dependence.
• Confounders included sex, housing type, maternal education and depressive symptoms, parents’ alcohol use, conduct problems at age 4 years, being bullied, and smoking status.

TAKEAWAYS

• After adjustments, alcohol dependence at age 18 years was associated with depression at age 24 years (unstandardized probit coefficient 0.13; 95% confidence interval, 0.02-0.25; P = .019)
• The relationship appeared to persist for alcohol dependence at each age of the growth curve (17-22 years).
• There was no evidence that frequency or quantity of alcohol consumption at age 18 was significantly associated with depression at age 24, suggesting these factors may not increase the risk for later depression unless there are also features of dependency.

IN PRACTICE

“Our findings suggest that preventing alcohol dependence during adolescence, or treating it early, could reduce the risk of depression,” which could have important public health implications, the researchers write.

STUDY DETAILS

The study was carried out by researchers at the University of Bristol; University College London; Critical Thinking Unit, Public Health Directorate, NHS; University of Nottingham, all in the United Kingdom. It was published online in Lancet Psychiatry

LIMITATIONS

There was substantial attrition in the ALSPAC cohort from birth to age 24 years. The sample was recruited from one U.K. region and most participants were White. Measures of alcohol consumption and dependence excluded some features of abuse. And as this is an observational study, the possibility of residual confounding can’t be excluded.

DISCLOSURES

The investigators report no relevant disclosures. The study received support from the UK Medical Research Council and Alcohol Research UK.

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

TOPLINE

Alcohol dependence, but not consumption, at age 18 years increases the risk for depression at age 24 years.

METHODOLOGY

• The study included 3,902 mostly White adolescents, about 58% female, born in England from April 1991 to December 1992, who were part of the Avon Longitudinal Study of Parents and Children (ALSPAC) that examined genetic and environmental determinants of health and development.
• Participants completed the self-report Alcohol Use Disorders Identification Test (AUDIT) between the ages of 16 and 23 years, a period when average alcohol use increases rapidly.
• The primary outcome was probability for depression at age 24 years, using the Clinical Interview Schedule Revised (CIS-R), a self-administered computerized clinical assessment of common mental disorder symptoms during the past week.
• Researchers assessed frequency and quantity of alcohol consumption as well as alcohol dependence.
• Confounders included sex, housing type, maternal education and depressive symptoms, parents’ alcohol use, conduct problems at age 4 years, being bullied, and smoking status.

TAKEAWAYS

• After adjustments, alcohol dependence at age 18 years was associated with depression at age 24 years (unstandardized probit coefficient 0.13; 95% confidence interval, 0.02-0.25; P = .019)
• The relationship appeared to persist for alcohol dependence at each age of the growth curve (17-22 years).
• There was no evidence that frequency or quantity of alcohol consumption at age 18 was significantly associated with depression at age 24, suggesting these factors may not increase the risk for later depression unless there are also features of dependency.

IN PRACTICE

“Our findings suggest that preventing alcohol dependence during adolescence, or treating it early, could reduce the risk of depression,” which could have important public health implications, the researchers write.

STUDY DETAILS

The study was carried out by researchers at the University of Bristol; University College London; Critical Thinking Unit, Public Health Directorate, NHS; University of Nottingham, all in the United Kingdom. It was published online in Lancet Psychiatry

LIMITATIONS

There was substantial attrition in the ALSPAC cohort from birth to age 24 years. The sample was recruited from one U.K. region and most participants were White. Measures of alcohol consumption and dependence excluded some features of abuse. And as this is an observational study, the possibility of residual confounding can’t be excluded.

DISCLOSURES

The investigators report no relevant disclosures. The study received support from the UK Medical Research Council and Alcohol Research UK.

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