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Does vitamin D benefit only those who are deficient?
, suggests a new large-scale analysis.
Data on more than 380,000 participants gathered from 35 studies showed that, overall, there is no significant relationship between 25(OH)D concentrations, a clinical indicator of vitamin D status, and the incidence of coronary heart disease (CHD), stroke, or all-cause death, in a Mendelian randomization analysis.
However, Stephen Burgess, PhD, and colleagues showed that, in vitamin D–deficient individuals, each 10 nmol/L increase in 25(OH)D concentrations reduced the risk of all-cause mortality by 31%.
The research, published in The Lancet Diabetes & Endocrinology, also suggests there was a nonsignificant link between 25(OH)D concentrations and stroke and CHD, but again, only in vitamin D deficient individuals.
In an accompanying editorial, Guillaume Butler-Laporte, MD, and J. Brent Richards, MD, praise the researchers on their study methodology.
They add that the results “could have important public health and clinical consequences” and will “allow clinicians to better weigh the potential benefits of supplementation against its risk,” such as financial cost, “for better patient care – particularly among those with frank vitamin D deficiency.”
They continue: “Given that vitamin D deficiency is relatively common and vitamin D supplementation is safe, the rationale exists to test the effect of vitamin D supplementation in those with deficiency in large-scale randomized controlled trials.”
However, Dr. Butler-Laporte and Dr. Richards, of the Lady Davis Institute, Jewish General Hospital, Montreal, also note the study has several limitations, including the fact that the lifetime exposure to lower vitamin D levels captured by Mendelian randomization may result in larger effect sizes than in conventional trials.
Prior RCTS underpowered to detect effects of vitamin D supplements
“There are several potential mechanisms by which vitamin D could be protective for cardiovascular mortality, including mechanisms linking low vitamin D status with hyperparathyroidism and low serum calcium and phosphate,” write Dr. Burgess of the MRC Biostatistics Unit, University of Cambridge (England), and coauthors.
They also highlight that vitamin D is “further implicated in endothelial cell function” and affects the transcription of genes linked to cell division and apoptosis, providing “potential mechanisms implicating vitamin D for cancer.”
The researchers note that, while epidemiologic studies have “consistently” found a link between 25(OH)D levels and increased risk of cardiovascular disease, all-cause mortality, and other chronic diseases, several large trials of vitamin D supplementation have reported “null results.”
They argue, however, that many of these trials have recruited individuals “irrespective of baseline 25(OH)D concentration” and have been underpowered to detect the effects of supplementation.
To overcome these limitations, the team gathered data from the UK Biobank, the European Prospective Investigation Into Cancer and Nutrition Cardiovascular Disease (EPIC-CVD) study, 31 studies from the Vitamin D Studies Collaboration (VitDSC), and two Copenhagen population-based studies.
They first performed an observational study that included 384,721 individuals from the UK Biobank and 26,336 from EPIC-CVD who had a valid 25(OH)D measurement and no previously known cardiovascular disease at baseline.
Researchers also included 67,992 participants from the VitDSC studies who did not have previously known cardiovascular disease. They analyzed 25(OH)D concentrations, conventional cardiovascular risk factors, and major incident cardiovascular morbidity and mortality using individual participant data.
The results showed that, at low 25(OH)D concentrations, there was an inverse association between 25(OH)D and incident CHD, stroke, and all-cause mortality.
Next, the team conducted a Mendelian randomization analysis on 333,002 individuals from the UK Biobank and 26,336 from EPIC-CVD who were of European ancestry and had both a valid 25(OH)D measurement and genetic data that passed quality-control steps.
Information on 31,362 participants in the Copenhagen population-based studies was also included, giving a total of 386,406 individuals, of whom 33,546 had CHD, 18,166 had a stroke, and 27,885 died.
The mean age of participants ranged from 54.8 to 57.5 years, and between 53.4% and 55.4% were female.
Up to 7% of study participants were vitamin D deficient
The 25(OH)D analysis indicated that 3.9% of UK Biobank and 3.7% of Copenhagen study participants were deficient, compared with 6.9% in EPIC-CVD.
Across the full range of 25(OH)D concentrations, there was no significant association between genetically predicted 25(OH)D levels and CHD, stroke, or all-cause mortality.
However, restricting the analysis to individuals deemed vitamin D deficient (25[OH]D concentration < 25 nmol/L) revealed there was “strong evidence” for an inverse association with all-cause mortality, at an odds ratio per 10 nmol/L increase in genetically predicted 25(OH)D concentration of 0.69 (P < .0001), the team notes.
There were also nonsignificant associations between being in the deficient stratum and CHD, at an odds ratio of 0.89 (P = .14), and stroke, at an odds ratio of 0.85 (P = .09).
Further analysis suggests the association between 25(OH)D concentrations and all-cause mortality has a “clear threshold shape,” the researchers say, with evidence of an inverse association at concentrations below 40 nmol/L and null associations above that threshold.
They acknowledge, however, that their study has several potential limitations, including the assumption in their Mendelian randomization that the “only causal pathway from the genetic variants to the outcome is via 25(OH)D concentrations.”
Moreover, the genetic variants may affect 25(OH)D concentrations in a different way from “dietary supplementation or other clinical interventions.”
They also concede that their study was limited to middle-aged participants of European ancestries, which means the findings “might not be applicable to other populations.”
The study was funded by the British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer. Dr. Burgess has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.
A version of this article first appeared on Medscape.com.
, suggests a new large-scale analysis.
Data on more than 380,000 participants gathered from 35 studies showed that, overall, there is no significant relationship between 25(OH)D concentrations, a clinical indicator of vitamin D status, and the incidence of coronary heart disease (CHD), stroke, or all-cause death, in a Mendelian randomization analysis.
However, Stephen Burgess, PhD, and colleagues showed that, in vitamin D–deficient individuals, each 10 nmol/L increase in 25(OH)D concentrations reduced the risk of all-cause mortality by 31%.
The research, published in The Lancet Diabetes & Endocrinology, also suggests there was a nonsignificant link between 25(OH)D concentrations and stroke and CHD, but again, only in vitamin D deficient individuals.
In an accompanying editorial, Guillaume Butler-Laporte, MD, and J. Brent Richards, MD, praise the researchers on their study methodology.
They add that the results “could have important public health and clinical consequences” and will “allow clinicians to better weigh the potential benefits of supplementation against its risk,” such as financial cost, “for better patient care – particularly among those with frank vitamin D deficiency.”
They continue: “Given that vitamin D deficiency is relatively common and vitamin D supplementation is safe, the rationale exists to test the effect of vitamin D supplementation in those with deficiency in large-scale randomized controlled trials.”
However, Dr. Butler-Laporte and Dr. Richards, of the Lady Davis Institute, Jewish General Hospital, Montreal, also note the study has several limitations, including the fact that the lifetime exposure to lower vitamin D levels captured by Mendelian randomization may result in larger effect sizes than in conventional trials.
Prior RCTS underpowered to detect effects of vitamin D supplements
“There are several potential mechanisms by which vitamin D could be protective for cardiovascular mortality, including mechanisms linking low vitamin D status with hyperparathyroidism and low serum calcium and phosphate,” write Dr. Burgess of the MRC Biostatistics Unit, University of Cambridge (England), and coauthors.
They also highlight that vitamin D is “further implicated in endothelial cell function” and affects the transcription of genes linked to cell division and apoptosis, providing “potential mechanisms implicating vitamin D for cancer.”
The researchers note that, while epidemiologic studies have “consistently” found a link between 25(OH)D levels and increased risk of cardiovascular disease, all-cause mortality, and other chronic diseases, several large trials of vitamin D supplementation have reported “null results.”
They argue, however, that many of these trials have recruited individuals “irrespective of baseline 25(OH)D concentration” and have been underpowered to detect the effects of supplementation.
To overcome these limitations, the team gathered data from the UK Biobank, the European Prospective Investigation Into Cancer and Nutrition Cardiovascular Disease (EPIC-CVD) study, 31 studies from the Vitamin D Studies Collaboration (VitDSC), and two Copenhagen population-based studies.
They first performed an observational study that included 384,721 individuals from the UK Biobank and 26,336 from EPIC-CVD who had a valid 25(OH)D measurement and no previously known cardiovascular disease at baseline.
Researchers also included 67,992 participants from the VitDSC studies who did not have previously known cardiovascular disease. They analyzed 25(OH)D concentrations, conventional cardiovascular risk factors, and major incident cardiovascular morbidity and mortality using individual participant data.
The results showed that, at low 25(OH)D concentrations, there was an inverse association between 25(OH)D and incident CHD, stroke, and all-cause mortality.
Next, the team conducted a Mendelian randomization analysis on 333,002 individuals from the UK Biobank and 26,336 from EPIC-CVD who were of European ancestry and had both a valid 25(OH)D measurement and genetic data that passed quality-control steps.
Information on 31,362 participants in the Copenhagen population-based studies was also included, giving a total of 386,406 individuals, of whom 33,546 had CHD, 18,166 had a stroke, and 27,885 died.
The mean age of participants ranged from 54.8 to 57.5 years, and between 53.4% and 55.4% were female.
Up to 7% of study participants were vitamin D deficient
The 25(OH)D analysis indicated that 3.9% of UK Biobank and 3.7% of Copenhagen study participants were deficient, compared with 6.9% in EPIC-CVD.
Across the full range of 25(OH)D concentrations, there was no significant association between genetically predicted 25(OH)D levels and CHD, stroke, or all-cause mortality.
However, restricting the analysis to individuals deemed vitamin D deficient (25[OH]D concentration < 25 nmol/L) revealed there was “strong evidence” for an inverse association with all-cause mortality, at an odds ratio per 10 nmol/L increase in genetically predicted 25(OH)D concentration of 0.69 (P < .0001), the team notes.
There were also nonsignificant associations between being in the deficient stratum and CHD, at an odds ratio of 0.89 (P = .14), and stroke, at an odds ratio of 0.85 (P = .09).
Further analysis suggests the association between 25(OH)D concentrations and all-cause mortality has a “clear threshold shape,” the researchers say, with evidence of an inverse association at concentrations below 40 nmol/L and null associations above that threshold.
They acknowledge, however, that their study has several potential limitations, including the assumption in their Mendelian randomization that the “only causal pathway from the genetic variants to the outcome is via 25(OH)D concentrations.”
Moreover, the genetic variants may affect 25(OH)D concentrations in a different way from “dietary supplementation or other clinical interventions.”
They also concede that their study was limited to middle-aged participants of European ancestries, which means the findings “might not be applicable to other populations.”
The study was funded by the British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer. Dr. Burgess has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.
A version of this article first appeared on Medscape.com.
, suggests a new large-scale analysis.
Data on more than 380,000 participants gathered from 35 studies showed that, overall, there is no significant relationship between 25(OH)D concentrations, a clinical indicator of vitamin D status, and the incidence of coronary heart disease (CHD), stroke, or all-cause death, in a Mendelian randomization analysis.
However, Stephen Burgess, PhD, and colleagues showed that, in vitamin D–deficient individuals, each 10 nmol/L increase in 25(OH)D concentrations reduced the risk of all-cause mortality by 31%.
The research, published in The Lancet Diabetes & Endocrinology, also suggests there was a nonsignificant link between 25(OH)D concentrations and stroke and CHD, but again, only in vitamin D deficient individuals.
In an accompanying editorial, Guillaume Butler-Laporte, MD, and J. Brent Richards, MD, praise the researchers on their study methodology.
They add that the results “could have important public health and clinical consequences” and will “allow clinicians to better weigh the potential benefits of supplementation against its risk,” such as financial cost, “for better patient care – particularly among those with frank vitamin D deficiency.”
They continue: “Given that vitamin D deficiency is relatively common and vitamin D supplementation is safe, the rationale exists to test the effect of vitamin D supplementation in those with deficiency in large-scale randomized controlled trials.”
However, Dr. Butler-Laporte and Dr. Richards, of the Lady Davis Institute, Jewish General Hospital, Montreal, also note the study has several limitations, including the fact that the lifetime exposure to lower vitamin D levels captured by Mendelian randomization may result in larger effect sizes than in conventional trials.
Prior RCTS underpowered to detect effects of vitamin D supplements
“There are several potential mechanisms by which vitamin D could be protective for cardiovascular mortality, including mechanisms linking low vitamin D status with hyperparathyroidism and low serum calcium and phosphate,” write Dr. Burgess of the MRC Biostatistics Unit, University of Cambridge (England), and coauthors.
They also highlight that vitamin D is “further implicated in endothelial cell function” and affects the transcription of genes linked to cell division and apoptosis, providing “potential mechanisms implicating vitamin D for cancer.”
The researchers note that, while epidemiologic studies have “consistently” found a link between 25(OH)D levels and increased risk of cardiovascular disease, all-cause mortality, and other chronic diseases, several large trials of vitamin D supplementation have reported “null results.”
They argue, however, that many of these trials have recruited individuals “irrespective of baseline 25(OH)D concentration” and have been underpowered to detect the effects of supplementation.
To overcome these limitations, the team gathered data from the UK Biobank, the European Prospective Investigation Into Cancer and Nutrition Cardiovascular Disease (EPIC-CVD) study, 31 studies from the Vitamin D Studies Collaboration (VitDSC), and two Copenhagen population-based studies.
They first performed an observational study that included 384,721 individuals from the UK Biobank and 26,336 from EPIC-CVD who had a valid 25(OH)D measurement and no previously known cardiovascular disease at baseline.
Researchers also included 67,992 participants from the VitDSC studies who did not have previously known cardiovascular disease. They analyzed 25(OH)D concentrations, conventional cardiovascular risk factors, and major incident cardiovascular morbidity and mortality using individual participant data.
The results showed that, at low 25(OH)D concentrations, there was an inverse association between 25(OH)D and incident CHD, stroke, and all-cause mortality.
Next, the team conducted a Mendelian randomization analysis on 333,002 individuals from the UK Biobank and 26,336 from EPIC-CVD who were of European ancestry and had both a valid 25(OH)D measurement and genetic data that passed quality-control steps.
Information on 31,362 participants in the Copenhagen population-based studies was also included, giving a total of 386,406 individuals, of whom 33,546 had CHD, 18,166 had a stroke, and 27,885 died.
The mean age of participants ranged from 54.8 to 57.5 years, and between 53.4% and 55.4% were female.
Up to 7% of study participants were vitamin D deficient
The 25(OH)D analysis indicated that 3.9% of UK Biobank and 3.7% of Copenhagen study participants were deficient, compared with 6.9% in EPIC-CVD.
Across the full range of 25(OH)D concentrations, there was no significant association between genetically predicted 25(OH)D levels and CHD, stroke, or all-cause mortality.
However, restricting the analysis to individuals deemed vitamin D deficient (25[OH]D concentration < 25 nmol/L) revealed there was “strong evidence” for an inverse association with all-cause mortality, at an odds ratio per 10 nmol/L increase in genetically predicted 25(OH)D concentration of 0.69 (P < .0001), the team notes.
There were also nonsignificant associations between being in the deficient stratum and CHD, at an odds ratio of 0.89 (P = .14), and stroke, at an odds ratio of 0.85 (P = .09).
Further analysis suggests the association between 25(OH)D concentrations and all-cause mortality has a “clear threshold shape,” the researchers say, with evidence of an inverse association at concentrations below 40 nmol/L and null associations above that threshold.
They acknowledge, however, that their study has several potential limitations, including the assumption in their Mendelian randomization that the “only causal pathway from the genetic variants to the outcome is via 25(OH)D concentrations.”
Moreover, the genetic variants may affect 25(OH)D concentrations in a different way from “dietary supplementation or other clinical interventions.”
They also concede that their study was limited to middle-aged participants of European ancestries, which means the findings “might not be applicable to other populations.”
The study was funded by the British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer. Dr. Burgess has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.
A version of this article first appeared on Medscape.com.
Surgery offers best chance in cancer but needs more ‘support’
warns a European expert.
In addition, there are many obstacles to the delivery of optimal cancer surgery, says Domenico M. D’Ugo, MD, professor of surgery at the Catholic University of Rome – A. Gemelli Medical School, Rome, Italy.
Dr. D’Ugo, who is president of the European Society of Surgical Oncology (ESSO), calls for a range of measures to improve the quality of cancer surgery and patient access in Europe.
These measures include recognition of surgical oncology as a specialist discipline, greater support for surgical research and innovation, and a greater role for surgery in multidisciplinary care.
The demands were made in open letter that was published by ESSO on Nov. 9 to coincide with the society’s annual meeting, held in Lisbon, Portugal.
The theme of this year’s meeting was the future of cancer surgery in Europe – a future that “holds many promises to make surgical oncology safer, more efficient and minimally invasive,” writes Dr. D’Ugo.
However, ESSO needs the support of European leaders to bring the recommendations to life and, ultimately, to help provide high-quality cancer treatment, he adds. This is particularly important given the upcoming implementation of Europe’s Beating Cancer Plan.
The open letter is addressed to Stella Kyriakides, European commissioner for health and food safety, and Bartosz Arłukowicz, chair of the European Parliament Special Committee on Beating Cancer, among others.
Best chance of cure
“High-quality surgery remains the best chance to cure solid cancer when diagnosed early,” Dr. D’Ugo notes in his letter. It is also the most cost-effective treatment for the majority of nonmetastasized tumors, he writes.
In addition, surgery is “fundamental” to the prevention of cancer in patients with inherited susceptibility and to the diagnosis and staging of cancer, as well as to the treatment of metastatic disease, the preservation of quality of life, and the alleviation of cancer symptoms, he writes.
There is thus a substantial and steadily growing demand for surgical oncology.
It is estimated that approximately 80% of cancer patients will require surgical intervention at some point during the course of their disease, and 45 million surgical procedures will be needed worldwide by 2030.
Dr. D’Ugo says that at present, fewer than a quarter of cancer patients receive safe, affordable, or timely surgery.
It is time to give surgical oncology the political and financial attention it deserves, he argues. He outlines a four-point plan to achieve this.
The first point is to enhance recognition of surgical oncology as a specialist discipline through, for example, the global curriculum proposed by ESSO and the Society of Surgical Oncology in 2016.
At present, only eight countries in Europe recognize surgical oncology as a specialty, and the lack of harmonization is “causing disparities in training, qualifications and practices,” as well as in patient access, Dr. D’Ugo says.
Next is a call to support research and innovation. Despite recent advances, research in cancer surgery “remains highly underfunded in Europe when compared with pharmaceutical research,” he says.
Improved screening and early detection of cancer are the next key area, because when the disease is diagnosed at an early stage, curative surgery has “a greater chance to be successful.”
At present, screening programs in Europe address only colorectal, breast, and cervical cancers, and the uptake remains “low,” he writes.
Lastly, he emphasizes that surgery is “integral” to multidisciplinary care and that outcomes for patients are better in comprehensive cancer centers that support patients throughout the disease pathway.
Dr. D’Ugo suggests that surgical oncologists take on a “bigger role” in multidisciplinary care, and he calls for the certification and accreditation of cancer units to increase and unify standards of care across the region.
D’Ugo has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
warns a European expert.
In addition, there are many obstacles to the delivery of optimal cancer surgery, says Domenico M. D’Ugo, MD, professor of surgery at the Catholic University of Rome – A. Gemelli Medical School, Rome, Italy.
Dr. D’Ugo, who is president of the European Society of Surgical Oncology (ESSO), calls for a range of measures to improve the quality of cancer surgery and patient access in Europe.
These measures include recognition of surgical oncology as a specialist discipline, greater support for surgical research and innovation, and a greater role for surgery in multidisciplinary care.
The demands were made in open letter that was published by ESSO on Nov. 9 to coincide with the society’s annual meeting, held in Lisbon, Portugal.
The theme of this year’s meeting was the future of cancer surgery in Europe – a future that “holds many promises to make surgical oncology safer, more efficient and minimally invasive,” writes Dr. D’Ugo.
However, ESSO needs the support of European leaders to bring the recommendations to life and, ultimately, to help provide high-quality cancer treatment, he adds. This is particularly important given the upcoming implementation of Europe’s Beating Cancer Plan.
The open letter is addressed to Stella Kyriakides, European commissioner for health and food safety, and Bartosz Arłukowicz, chair of the European Parliament Special Committee on Beating Cancer, among others.
Best chance of cure
“High-quality surgery remains the best chance to cure solid cancer when diagnosed early,” Dr. D’Ugo notes in his letter. It is also the most cost-effective treatment for the majority of nonmetastasized tumors, he writes.
In addition, surgery is “fundamental” to the prevention of cancer in patients with inherited susceptibility and to the diagnosis and staging of cancer, as well as to the treatment of metastatic disease, the preservation of quality of life, and the alleviation of cancer symptoms, he writes.
There is thus a substantial and steadily growing demand for surgical oncology.
It is estimated that approximately 80% of cancer patients will require surgical intervention at some point during the course of their disease, and 45 million surgical procedures will be needed worldwide by 2030.
Dr. D’Ugo says that at present, fewer than a quarter of cancer patients receive safe, affordable, or timely surgery.
It is time to give surgical oncology the political and financial attention it deserves, he argues. He outlines a four-point plan to achieve this.
The first point is to enhance recognition of surgical oncology as a specialist discipline through, for example, the global curriculum proposed by ESSO and the Society of Surgical Oncology in 2016.
At present, only eight countries in Europe recognize surgical oncology as a specialty, and the lack of harmonization is “causing disparities in training, qualifications and practices,” as well as in patient access, Dr. D’Ugo says.
Next is a call to support research and innovation. Despite recent advances, research in cancer surgery “remains highly underfunded in Europe when compared with pharmaceutical research,” he says.
Improved screening and early detection of cancer are the next key area, because when the disease is diagnosed at an early stage, curative surgery has “a greater chance to be successful.”
At present, screening programs in Europe address only colorectal, breast, and cervical cancers, and the uptake remains “low,” he writes.
Lastly, he emphasizes that surgery is “integral” to multidisciplinary care and that outcomes for patients are better in comprehensive cancer centers that support patients throughout the disease pathway.
Dr. D’Ugo suggests that surgical oncologists take on a “bigger role” in multidisciplinary care, and he calls for the certification and accreditation of cancer units to increase and unify standards of care across the region.
D’Ugo has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
warns a European expert.
In addition, there are many obstacles to the delivery of optimal cancer surgery, says Domenico M. D’Ugo, MD, professor of surgery at the Catholic University of Rome – A. Gemelli Medical School, Rome, Italy.
Dr. D’Ugo, who is president of the European Society of Surgical Oncology (ESSO), calls for a range of measures to improve the quality of cancer surgery and patient access in Europe.
These measures include recognition of surgical oncology as a specialist discipline, greater support for surgical research and innovation, and a greater role for surgery in multidisciplinary care.
The demands were made in open letter that was published by ESSO on Nov. 9 to coincide with the society’s annual meeting, held in Lisbon, Portugal.
The theme of this year’s meeting was the future of cancer surgery in Europe – a future that “holds many promises to make surgical oncology safer, more efficient and minimally invasive,” writes Dr. D’Ugo.
However, ESSO needs the support of European leaders to bring the recommendations to life and, ultimately, to help provide high-quality cancer treatment, he adds. This is particularly important given the upcoming implementation of Europe’s Beating Cancer Plan.
The open letter is addressed to Stella Kyriakides, European commissioner for health and food safety, and Bartosz Arłukowicz, chair of the European Parliament Special Committee on Beating Cancer, among others.
Best chance of cure
“High-quality surgery remains the best chance to cure solid cancer when diagnosed early,” Dr. D’Ugo notes in his letter. It is also the most cost-effective treatment for the majority of nonmetastasized tumors, he writes.
In addition, surgery is “fundamental” to the prevention of cancer in patients with inherited susceptibility and to the diagnosis and staging of cancer, as well as to the treatment of metastatic disease, the preservation of quality of life, and the alleviation of cancer symptoms, he writes.
There is thus a substantial and steadily growing demand for surgical oncology.
It is estimated that approximately 80% of cancer patients will require surgical intervention at some point during the course of their disease, and 45 million surgical procedures will be needed worldwide by 2030.
Dr. D’Ugo says that at present, fewer than a quarter of cancer patients receive safe, affordable, or timely surgery.
It is time to give surgical oncology the political and financial attention it deserves, he argues. He outlines a four-point plan to achieve this.
The first point is to enhance recognition of surgical oncology as a specialist discipline through, for example, the global curriculum proposed by ESSO and the Society of Surgical Oncology in 2016.
At present, only eight countries in Europe recognize surgical oncology as a specialty, and the lack of harmonization is “causing disparities in training, qualifications and practices,” as well as in patient access, Dr. D’Ugo says.
Next is a call to support research and innovation. Despite recent advances, research in cancer surgery “remains highly underfunded in Europe when compared with pharmaceutical research,” he says.
Improved screening and early detection of cancer are the next key area, because when the disease is diagnosed at an early stage, curative surgery has “a greater chance to be successful.”
At present, screening programs in Europe address only colorectal, breast, and cervical cancers, and the uptake remains “low,” he writes.
Lastly, he emphasizes that surgery is “integral” to multidisciplinary care and that outcomes for patients are better in comprehensive cancer centers that support patients throughout the disease pathway.
Dr. D’Ugo suggests that surgical oncologists take on a “bigger role” in multidisciplinary care, and he calls for the certification and accreditation of cancer units to increase and unify standards of care across the region.
D’Ugo has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Antiepileptic medications linked to increased priapism risk
Several antiepileptic drugs (AEDs) are associated with an increased risk for priapism, new research suggests.
After analyzing U.S. adverse event reporting data, investigators found that among nearly 200 cases of priapism, a persistent, often painful erection unrelated to sexual interest or stimulation that lasts more than 4 hours, eight AEDs were associated with a positive “safety signal” for priapism.
These included valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine. Of these, valpromide had the largest association.
“Based on our results, we would recommend to clinicians to be cautious about the possibility of encountering priapism” in patients receiving the eight AEDs identified, lead researcher Ana Pejcic, PhD, department of pharmacology and toxicology, University of Kragujevac, Serbia, told meeting attendees.
If clinicians encounter such cases, they should be “reported to the regulatory authorities,” Dr. Pejcic added.
The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
Noteworthy limitations
Dr. Pejcic told this news organization that the safety signal with AEDs “does not directly mean that a medicine has caused the reported adverse event” because an illness or other drug taken by the patient could be responsible instead.
She also noted that the U.S. Food and Drug Administration’s Adverse Event Reporting System relies on “spontaneous reports of adverse events,” which have multiple limitations.
These limitations include that the FDA “does not require that a causal relationship between a drug and event be proven, and reports do not always have enough information to properly evaluate an event.”
Nevertheless, Dr. Pejcic added that if a causal relationship was to be shown, the underlying mechanism could be linked to the pharmacological properties of the individual antiepileptic, such as altered alpha-1 adrenergic receptor expression or increased dopamine release.
Still, that would require “further evaluation in larger pharmacoepidemiological studies, with adjustment for potential confounding variables,” she said.
Replication needed
Priapism has recently been observed in case reports in association with the use of some AEDs. In addition, use of the drugs has been associated with hypo- and hypersexuality, as well as erectile and ejaculatory dysfunction.
Because the relationship between priapism and AED use “has not been well characterized,” the researchers mined data from the FDA’s Adverse Event Reporting System.
They examined entries from the first quarter of 2004 and the third quarter of 2020, focusing on 47 AEDs from the N03A subgroup of the Anatomical Therapeutic Chemical Classification System.
The researchers identified 8,122,037 cases for data analysis, of which 1,936 involved priapism as an adverse event. In total, 16 antiepileptic medications had at least one case of an adverse event involving priapism.
A positive safety signal was defined as a Proportional Reporting Ratio (PRR) of at least two, a chi-squared of at least four, or three or more cases. The signal was detected for valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine.
The largest association with priapism was with valpromide, at a PRR of 61.79. That was followed by PRR of 9.61 for brivaracetam, 7.28 for valproic acid, and 3.23 for topiramate.
“Considering that the proportionality analysis we applied in our study is used for hypothesis generation, our results will need to confirm in large cohorts and case-control studies,” said Dr. Pejcic.
New and important hypothesis?
Commenting on the study, Daniel Goldenholz, MD, PhD, instructor in the Division of Epilepsy, Beth Israel Deaconess Medical Center, Boston, said priapism is not something that practicing epileptologists are instructed “to look for.”
He noted that “the idea of looking for a hidden signal in a massive database like this is very appealing” because it could reveal patterns that were previously undetected.
However, the event rate in the study suggests priapism, which “in the right context would be considered a medical emergency, [is] relatively uncommon,” said Dr. Goldenholz, who was not involved with the research.
He noted that medications that could cause priapism, “such as antidepressants, blood pressure meds, and anticoagulants,” are commonly used by many people – including those with epilepsy.
It is consequently possible that “the finding from this study can be explained by comorbid medical problems,” Dr. Goldenholz said. This is particularly likely because many of the AEDs in question “have been on the market for decades,” he added.
“If a seemingly dangerous symptom would be happening as a result of one of these medications, ,” he said.
Still, Dr. Goldenholz noted that it is “possible that these authors have a new and important hypothesis which must now be tested: Does priapism occur in patients with antiseizure medications when other causes are already ruled out?”
The investigators and Dr. Goldenholz have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Several antiepileptic drugs (AEDs) are associated with an increased risk for priapism, new research suggests.
After analyzing U.S. adverse event reporting data, investigators found that among nearly 200 cases of priapism, a persistent, often painful erection unrelated to sexual interest or stimulation that lasts more than 4 hours, eight AEDs were associated with a positive “safety signal” for priapism.
These included valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine. Of these, valpromide had the largest association.
“Based on our results, we would recommend to clinicians to be cautious about the possibility of encountering priapism” in patients receiving the eight AEDs identified, lead researcher Ana Pejcic, PhD, department of pharmacology and toxicology, University of Kragujevac, Serbia, told meeting attendees.
If clinicians encounter such cases, they should be “reported to the regulatory authorities,” Dr. Pejcic added.
The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
Noteworthy limitations
Dr. Pejcic told this news organization that the safety signal with AEDs “does not directly mean that a medicine has caused the reported adverse event” because an illness or other drug taken by the patient could be responsible instead.
She also noted that the U.S. Food and Drug Administration’s Adverse Event Reporting System relies on “spontaneous reports of adverse events,” which have multiple limitations.
These limitations include that the FDA “does not require that a causal relationship between a drug and event be proven, and reports do not always have enough information to properly evaluate an event.”
Nevertheless, Dr. Pejcic added that if a causal relationship was to be shown, the underlying mechanism could be linked to the pharmacological properties of the individual antiepileptic, such as altered alpha-1 adrenergic receptor expression or increased dopamine release.
Still, that would require “further evaluation in larger pharmacoepidemiological studies, with adjustment for potential confounding variables,” she said.
Replication needed
Priapism has recently been observed in case reports in association with the use of some AEDs. In addition, use of the drugs has been associated with hypo- and hypersexuality, as well as erectile and ejaculatory dysfunction.
Because the relationship between priapism and AED use “has not been well characterized,” the researchers mined data from the FDA’s Adverse Event Reporting System.
They examined entries from the first quarter of 2004 and the third quarter of 2020, focusing on 47 AEDs from the N03A subgroup of the Anatomical Therapeutic Chemical Classification System.
The researchers identified 8,122,037 cases for data analysis, of which 1,936 involved priapism as an adverse event. In total, 16 antiepileptic medications had at least one case of an adverse event involving priapism.
A positive safety signal was defined as a Proportional Reporting Ratio (PRR) of at least two, a chi-squared of at least four, or three or more cases. The signal was detected for valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine.
The largest association with priapism was with valpromide, at a PRR of 61.79. That was followed by PRR of 9.61 for brivaracetam, 7.28 for valproic acid, and 3.23 for topiramate.
“Considering that the proportionality analysis we applied in our study is used for hypothesis generation, our results will need to confirm in large cohorts and case-control studies,” said Dr. Pejcic.
New and important hypothesis?
Commenting on the study, Daniel Goldenholz, MD, PhD, instructor in the Division of Epilepsy, Beth Israel Deaconess Medical Center, Boston, said priapism is not something that practicing epileptologists are instructed “to look for.”
He noted that “the idea of looking for a hidden signal in a massive database like this is very appealing” because it could reveal patterns that were previously undetected.
However, the event rate in the study suggests priapism, which “in the right context would be considered a medical emergency, [is] relatively uncommon,” said Dr. Goldenholz, who was not involved with the research.
He noted that medications that could cause priapism, “such as antidepressants, blood pressure meds, and anticoagulants,” are commonly used by many people – including those with epilepsy.
It is consequently possible that “the finding from this study can be explained by comorbid medical problems,” Dr. Goldenholz said. This is particularly likely because many of the AEDs in question “have been on the market for decades,” he added.
“If a seemingly dangerous symptom would be happening as a result of one of these medications, ,” he said.
Still, Dr. Goldenholz noted that it is “possible that these authors have a new and important hypothesis which must now be tested: Does priapism occur in patients with antiseizure medications when other causes are already ruled out?”
The investigators and Dr. Goldenholz have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Several antiepileptic drugs (AEDs) are associated with an increased risk for priapism, new research suggests.
After analyzing U.S. adverse event reporting data, investigators found that among nearly 200 cases of priapism, a persistent, often painful erection unrelated to sexual interest or stimulation that lasts more than 4 hours, eight AEDs were associated with a positive “safety signal” for priapism.
These included valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine. Of these, valpromide had the largest association.
“Based on our results, we would recommend to clinicians to be cautious about the possibility of encountering priapism” in patients receiving the eight AEDs identified, lead researcher Ana Pejcic, PhD, department of pharmacology and toxicology, University of Kragujevac, Serbia, told meeting attendees.
If clinicians encounter such cases, they should be “reported to the regulatory authorities,” Dr. Pejcic added.
The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
Noteworthy limitations
Dr. Pejcic told this news organization that the safety signal with AEDs “does not directly mean that a medicine has caused the reported adverse event” because an illness or other drug taken by the patient could be responsible instead.
She also noted that the U.S. Food and Drug Administration’s Adverse Event Reporting System relies on “spontaneous reports of adverse events,” which have multiple limitations.
These limitations include that the FDA “does not require that a causal relationship between a drug and event be proven, and reports do not always have enough information to properly evaluate an event.”
Nevertheless, Dr. Pejcic added that if a causal relationship was to be shown, the underlying mechanism could be linked to the pharmacological properties of the individual antiepileptic, such as altered alpha-1 adrenergic receptor expression or increased dopamine release.
Still, that would require “further evaluation in larger pharmacoepidemiological studies, with adjustment for potential confounding variables,” she said.
Replication needed
Priapism has recently been observed in case reports in association with the use of some AEDs. In addition, use of the drugs has been associated with hypo- and hypersexuality, as well as erectile and ejaculatory dysfunction.
Because the relationship between priapism and AED use “has not been well characterized,” the researchers mined data from the FDA’s Adverse Event Reporting System.
They examined entries from the first quarter of 2004 and the third quarter of 2020, focusing on 47 AEDs from the N03A subgroup of the Anatomical Therapeutic Chemical Classification System.
The researchers identified 8,122,037 cases for data analysis, of which 1,936 involved priapism as an adverse event. In total, 16 antiepileptic medications had at least one case of an adverse event involving priapism.
A positive safety signal was defined as a Proportional Reporting Ratio (PRR) of at least two, a chi-squared of at least four, or three or more cases. The signal was detected for valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine.
The largest association with priapism was with valpromide, at a PRR of 61.79. That was followed by PRR of 9.61 for brivaracetam, 7.28 for valproic acid, and 3.23 for topiramate.
“Considering that the proportionality analysis we applied in our study is used for hypothesis generation, our results will need to confirm in large cohorts and case-control studies,” said Dr. Pejcic.
New and important hypothesis?
Commenting on the study, Daniel Goldenholz, MD, PhD, instructor in the Division of Epilepsy, Beth Israel Deaconess Medical Center, Boston, said priapism is not something that practicing epileptologists are instructed “to look for.”
He noted that “the idea of looking for a hidden signal in a massive database like this is very appealing” because it could reveal patterns that were previously undetected.
However, the event rate in the study suggests priapism, which “in the right context would be considered a medical emergency, [is] relatively uncommon,” said Dr. Goldenholz, who was not involved with the research.
He noted that medications that could cause priapism, “such as antidepressants, blood pressure meds, and anticoagulants,” are commonly used by many people – including those with epilepsy.
It is consequently possible that “the finding from this study can be explained by comorbid medical problems,” Dr. Goldenholz said. This is particularly likely because many of the AEDs in question “have been on the market for decades,” he added.
“If a seemingly dangerous symptom would be happening as a result of one of these medications, ,” he said.
Still, Dr. Goldenholz noted that it is “possible that these authors have a new and important hypothesis which must now be tested: Does priapism occur in patients with antiseizure medications when other causes are already ruled out?”
The investigators and Dr. Goldenholz have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ECNP 2021
Art therapy linked to slowed Parkinson’s progression
Adding art therapy to standard drug treatment in Parkinson’s disease (PD) not only improves severity of both motor and nonmotor symptoms, but also slows rates of disease progression, new research suggests.
Fifty PD patients were randomly assigned to receive either art therapy, including sculpting and drawing, plus drug therapy or drug therapy alone, and followed up over 12 months.
Patients receiving combined therapy experienced improvements in symptoms, depression, and cognitive scores, and had reduced tremor and daytime sleepiness. They were also substantially less likely to experience disease progression.
“The use of art therapy can reduce the severity of motor and nonmotor manifestations of Parkinson’s disease,” said study investigator Iryna Khubetova, MD, PhD, head of the neurology department, Odessa (Ukraine) Regional Clinical Hospital.
she added.
The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
A promising approach
Dr. Khubetova told this news organization that offering art therapy to PD patients was “very affordable,” especially as professional artists “provided materials for painting and other art supplies free of charge.”
“We hope this approach is very promising and would be widely adopted.”
She suggested the positive effect of art therapy could be related to “activating the brain’s reward neural network.”
This may be via improved visual attention acting on visuospatial mechanisms and emotional drive, with “activation of the medial orbitofrontal cortex, ventral striatum, and other structures.”
The researchers note PD, a “multisystem progressive neurodegenerative disease,” is among the three most common neurological disorders, with an incidence of 100-150 cases per 100,000 people.
They also note that nonpharmacologic approaches are “widely used” as an adjunct to drug therapy and as part of an “integrated approach” to disease management.
To examine the clinical efficacy of art therapy, the team recruited patients with PD who had preserved facility for independent movement, defined as stages 1-2.5 on the Hoehn and Yahr scale.
Patients were randomly assigned to art therapy sessions alongside standard drug therapy or to standard drug therapy alone. The art therapy included sculpting, free drawing, and coloring patterns.
Multiple benefits
Participants were assessed at baseline and at 6 and 12 months with the Unified Parkinson Disease Rating Scale (UPDRS), the Beck Depression Inventory, the Montreal Cognitive Assessment, and the Pegboard Test of finger dexterity.
Fifty patients were included in the study, with 30 assigned to standard drug therapy alone and 20 to the combined intervention. Participants had a mean age of 57.8 years, and 46% were women.
Over the study period, investigators found patients assigned to art therapy plus drug treatment had improved mood, as well as decreased daytime sleeping, reduced tremor, and a decrease in anxiety and fear intensity.
Between baseline and the 6- and 12-month assessments, patients in the combined therapy group showed improvements in scores on all of the questionnaires, and on the Pegboard Test. In contrast, scores were either stable or worsened in the standard drug therapy–alone group.
The team notes that there was also a marked difference in rates of disease progression, defined as a change on the Hoehn and Yahr scale of at least 0.5 points, between the two groups.
Only two (10%) patients in the combined drug and art therapy progressed over the study period, compared with 10 (33%) in the control group (P = .05).
The findings complement those of a recent study conducted by Alberto Cucca, MD, of the Fresco Institute for Parkinson’s and Movement Disorders, New York University, and colleagues.
Eighteen patients took part in the prospective, open-label trial. They were assessed before and after 20 sessions of art therapy on a range of measures.
Results revealed that following the art therapy, patients had improvements in the Navon Test (which assesses visual neglect, eye tracking, and UPDRS scores), as well as significantly increased functional connectivity levels in the visual cortex on resting-state functional MRI.
Many benefits, no side effects
Rebecca Gilbert, MD, PhD, vice president and chief scientific officer of the American Parkinson Disease Association, who was not involved in either study, told this news organization that the idea of art therapy for patients with Parkinson’s is “very reasonable.”
She highlighted that “people with Parkinson’s have many issues with their visuospatial abilities,” as well as their depth and distance perception, and so “enhancing that aspect could potentially be very beneficial.”
“So I’m hopeful that it’s a really good avenue to explore, and the preliminary data are very exciting.”
Dr. Gilbert also highlighted that the “wonderful” aspect of art therapy is that there are “so many benefits and not really any side effects.” Patients can “take the meds … and then enhance that with various therapies, and this would be an additional option.”
Another notable aspect of art therapy is the “social element” and the sense of “camaraderie,” although that has “to be teased out from the benefits you would get from the actual art therapy.”
Finally, Dr. Gilbert pointed out that the difference between the current trial and Dr. Cucca’s trial is the presence of a control group.
“Of course, it’s not blinded, because you know whether you got therapy or not … but that extra element of being able to compare with a group that didn’t get the treatment gives it a little more weight in terms of the field.”
No funding was declared. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Adding art therapy to standard drug treatment in Parkinson’s disease (PD) not only improves severity of both motor and nonmotor symptoms, but also slows rates of disease progression, new research suggests.
Fifty PD patients were randomly assigned to receive either art therapy, including sculpting and drawing, plus drug therapy or drug therapy alone, and followed up over 12 months.
Patients receiving combined therapy experienced improvements in symptoms, depression, and cognitive scores, and had reduced tremor and daytime sleepiness. They were also substantially less likely to experience disease progression.
“The use of art therapy can reduce the severity of motor and nonmotor manifestations of Parkinson’s disease,” said study investigator Iryna Khubetova, MD, PhD, head of the neurology department, Odessa (Ukraine) Regional Clinical Hospital.
she added.
The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
A promising approach
Dr. Khubetova told this news organization that offering art therapy to PD patients was “very affordable,” especially as professional artists “provided materials for painting and other art supplies free of charge.”
“We hope this approach is very promising and would be widely adopted.”
She suggested the positive effect of art therapy could be related to “activating the brain’s reward neural network.”
This may be via improved visual attention acting on visuospatial mechanisms and emotional drive, with “activation of the medial orbitofrontal cortex, ventral striatum, and other structures.”
The researchers note PD, a “multisystem progressive neurodegenerative disease,” is among the three most common neurological disorders, with an incidence of 100-150 cases per 100,000 people.
They also note that nonpharmacologic approaches are “widely used” as an adjunct to drug therapy and as part of an “integrated approach” to disease management.
To examine the clinical efficacy of art therapy, the team recruited patients with PD who had preserved facility for independent movement, defined as stages 1-2.5 on the Hoehn and Yahr scale.
Patients were randomly assigned to art therapy sessions alongside standard drug therapy or to standard drug therapy alone. The art therapy included sculpting, free drawing, and coloring patterns.
Multiple benefits
Participants were assessed at baseline and at 6 and 12 months with the Unified Parkinson Disease Rating Scale (UPDRS), the Beck Depression Inventory, the Montreal Cognitive Assessment, and the Pegboard Test of finger dexterity.
Fifty patients were included in the study, with 30 assigned to standard drug therapy alone and 20 to the combined intervention. Participants had a mean age of 57.8 years, and 46% were women.
Over the study period, investigators found patients assigned to art therapy plus drug treatment had improved mood, as well as decreased daytime sleeping, reduced tremor, and a decrease in anxiety and fear intensity.
Between baseline and the 6- and 12-month assessments, patients in the combined therapy group showed improvements in scores on all of the questionnaires, and on the Pegboard Test. In contrast, scores were either stable or worsened in the standard drug therapy–alone group.
The team notes that there was also a marked difference in rates of disease progression, defined as a change on the Hoehn and Yahr scale of at least 0.5 points, between the two groups.
Only two (10%) patients in the combined drug and art therapy progressed over the study period, compared with 10 (33%) in the control group (P = .05).
The findings complement those of a recent study conducted by Alberto Cucca, MD, of the Fresco Institute for Parkinson’s and Movement Disorders, New York University, and colleagues.
Eighteen patients took part in the prospective, open-label trial. They were assessed before and after 20 sessions of art therapy on a range of measures.
Results revealed that following the art therapy, patients had improvements in the Navon Test (which assesses visual neglect, eye tracking, and UPDRS scores), as well as significantly increased functional connectivity levels in the visual cortex on resting-state functional MRI.
Many benefits, no side effects
Rebecca Gilbert, MD, PhD, vice president and chief scientific officer of the American Parkinson Disease Association, who was not involved in either study, told this news organization that the idea of art therapy for patients with Parkinson’s is “very reasonable.”
She highlighted that “people with Parkinson’s have many issues with their visuospatial abilities,” as well as their depth and distance perception, and so “enhancing that aspect could potentially be very beneficial.”
“So I’m hopeful that it’s a really good avenue to explore, and the preliminary data are very exciting.”
Dr. Gilbert also highlighted that the “wonderful” aspect of art therapy is that there are “so many benefits and not really any side effects.” Patients can “take the meds … and then enhance that with various therapies, and this would be an additional option.”
Another notable aspect of art therapy is the “social element” and the sense of “camaraderie,” although that has “to be teased out from the benefits you would get from the actual art therapy.”
Finally, Dr. Gilbert pointed out that the difference between the current trial and Dr. Cucca’s trial is the presence of a control group.
“Of course, it’s not blinded, because you know whether you got therapy or not … but that extra element of being able to compare with a group that didn’t get the treatment gives it a little more weight in terms of the field.”
No funding was declared. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Adding art therapy to standard drug treatment in Parkinson’s disease (PD) not only improves severity of both motor and nonmotor symptoms, but also slows rates of disease progression, new research suggests.
Fifty PD patients were randomly assigned to receive either art therapy, including sculpting and drawing, plus drug therapy or drug therapy alone, and followed up over 12 months.
Patients receiving combined therapy experienced improvements in symptoms, depression, and cognitive scores, and had reduced tremor and daytime sleepiness. They were also substantially less likely to experience disease progression.
“The use of art therapy can reduce the severity of motor and nonmotor manifestations of Parkinson’s disease,” said study investigator Iryna Khubetova, MD, PhD, head of the neurology department, Odessa (Ukraine) Regional Clinical Hospital.
she added.
The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
A promising approach
Dr. Khubetova told this news organization that offering art therapy to PD patients was “very affordable,” especially as professional artists “provided materials for painting and other art supplies free of charge.”
“We hope this approach is very promising and would be widely adopted.”
She suggested the positive effect of art therapy could be related to “activating the brain’s reward neural network.”
This may be via improved visual attention acting on visuospatial mechanisms and emotional drive, with “activation of the medial orbitofrontal cortex, ventral striatum, and other structures.”
The researchers note PD, a “multisystem progressive neurodegenerative disease,” is among the three most common neurological disorders, with an incidence of 100-150 cases per 100,000 people.
They also note that nonpharmacologic approaches are “widely used” as an adjunct to drug therapy and as part of an “integrated approach” to disease management.
To examine the clinical efficacy of art therapy, the team recruited patients with PD who had preserved facility for independent movement, defined as stages 1-2.5 on the Hoehn and Yahr scale.
Patients were randomly assigned to art therapy sessions alongside standard drug therapy or to standard drug therapy alone. The art therapy included sculpting, free drawing, and coloring patterns.
Multiple benefits
Participants were assessed at baseline and at 6 and 12 months with the Unified Parkinson Disease Rating Scale (UPDRS), the Beck Depression Inventory, the Montreal Cognitive Assessment, and the Pegboard Test of finger dexterity.
Fifty patients were included in the study, with 30 assigned to standard drug therapy alone and 20 to the combined intervention. Participants had a mean age of 57.8 years, and 46% were women.
Over the study period, investigators found patients assigned to art therapy plus drug treatment had improved mood, as well as decreased daytime sleeping, reduced tremor, and a decrease in anxiety and fear intensity.
Between baseline and the 6- and 12-month assessments, patients in the combined therapy group showed improvements in scores on all of the questionnaires, and on the Pegboard Test. In contrast, scores were either stable or worsened in the standard drug therapy–alone group.
The team notes that there was also a marked difference in rates of disease progression, defined as a change on the Hoehn and Yahr scale of at least 0.5 points, between the two groups.
Only two (10%) patients in the combined drug and art therapy progressed over the study period, compared with 10 (33%) in the control group (P = .05).
The findings complement those of a recent study conducted by Alberto Cucca, MD, of the Fresco Institute for Parkinson’s and Movement Disorders, New York University, and colleagues.
Eighteen patients took part in the prospective, open-label trial. They were assessed before and after 20 sessions of art therapy on a range of measures.
Results revealed that following the art therapy, patients had improvements in the Navon Test (which assesses visual neglect, eye tracking, and UPDRS scores), as well as significantly increased functional connectivity levels in the visual cortex on resting-state functional MRI.
Many benefits, no side effects
Rebecca Gilbert, MD, PhD, vice president and chief scientific officer of the American Parkinson Disease Association, who was not involved in either study, told this news organization that the idea of art therapy for patients with Parkinson’s is “very reasonable.”
She highlighted that “people with Parkinson’s have many issues with their visuospatial abilities,” as well as their depth and distance perception, and so “enhancing that aspect could potentially be very beneficial.”
“So I’m hopeful that it’s a really good avenue to explore, and the preliminary data are very exciting.”
Dr. Gilbert also highlighted that the “wonderful” aspect of art therapy is that there are “so many benefits and not really any side effects.” Patients can “take the meds … and then enhance that with various therapies, and this would be an additional option.”
Another notable aspect of art therapy is the “social element” and the sense of “camaraderie,” although that has “to be teased out from the benefits you would get from the actual art therapy.”
Finally, Dr. Gilbert pointed out that the difference between the current trial and Dr. Cucca’s trial is the presence of a control group.
“Of course, it’s not blinded, because you know whether you got therapy or not … but that extra element of being able to compare with a group that didn’t get the treatment gives it a little more weight in terms of the field.”
No funding was declared. The authors have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ECNP 2021
‘Impressive’ results for novel antidepressant, so why the FDA delay?
A novel antidepressant (AXS-05, Axsome Therapeutics) appears to have a rapid and durable effect in patients with major depressive disorder (MDD), results of an open label, phase 3 trial, show. Yet, its new drug application (NDA) remains in limbo with the U.S. Food and Drug Administration for reasons that are unclear.
In the study, which included 876 patients with MDD, results showed the drug, a combination of dextromethorphan and bupropion, had a clinical response rate of 80% and a remission rate of almost 70%. In addition, functional improvements were “substantial” and AXS-05 was determined to be “generally safe and well-tolerated.”
The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
The study
The COMET trial was a phase 3, multicenter, U.S. trial, in which patients with MDD were treated with AXS-05 twice daily for up to 12 months. Patients had to have a Montgomery-Åsberg Depression Rating Scale (MADRS) score of at least 25. They could have completed a prior AXS-05 study or be newly enrolled.
Of 876 patients included in the study, 611 were newly enrolled. The mean age was 42.4 years, and 62.4% were women. Just over half (58.1%) were White, with 35.6% Black, and 2.0% Asian. The mean body mass index was 31.4 kg/m2.
The mean MADRS total score at baseline was 32.7 and the Sheehan Disability Scale (SDS) score was 20.0.
Presenting efficacy data in 609 newly enrolled patients, the team showed that MADRS total scores fell sharply on starting AXS-05, by 9.1 points at week 1, 14.0 points at week 2, and 21.2 points at week 6.
By 6 months, the reduction over baseline was 23.9 points, which was maintained out to 12 months, at a mean reduction of 23.0 points.
The proportion of patients achieving a clinical response, defined as a greater than or equal to 50% improvement in MADRS scores, was 18.8% at week 1, 39.7% at week 2, and 73.2% at week 6. There was a clinical response in 84.6% of patients at 6 months and in 82.8% at 12 months.
Clinical remission, defined as a MADRS score less than or equal to 10, was achieved in 8.3% of patients at week 1, rising to 21.5% at week 2, and 52.5% at week 6. At 6 months, 68.7% of patients were in clinical remission, reaching 69.0% at 12 months.
These benefits were accompanied by substantial improvements in depressive symptoms on the Clinical Global Impression of Improvement scale, with a marked or moderate improvement seen in 86.7% of patients at 6 months and 93.1% at 12 months.
Moreover, a clinical response in functioning on the SDS was achieved by 80.6% of patients at 6 months and 75.9% at 12 months.
The safety analysis of AXS-05 in the entire cohort suggested it was well-tolerated, with dizziness seen in 12.7% of patients, along with nausea in 11.9%, headache in 8.8%, dry mouth in 7.1%, and decreased appetite in 6.1%.
The rate of discontinuation due to adverse events was 8.4%, and there were no signs of psychotomimetic effects, cognitive impairment, weight gain, or increased sexual dysfunction.
and increased rates of suicidal ideation resolution, and was also effective for treatment-resistant depression.
Results from an analysis of the ASCEND phase 2 and GEMINI phase 3 trials also suggested that AXS-05 was superior to both bupropion and placebo in achieving rapid and sustained improvements in depression symptoms.
FDA delay
Yet despite these seemingly positive findings, the FDA appears to have issues with the agent’s new drug application.
As reported in August, the agency reviewed the NDA for AXS-05 for the treatment of MDD, but at that time the drug’s manufacturer revealed that the agency had identified “deficiencies that preclude labeling discussions at this time.”
With the latest results presented at ECNP 2021, this news organization asked Axsome about the status of the NDA and whether there had been any further discussions and/or movement with the FDA.
Instead of a direct reply from the drug company, this news organization was directed to a statement released by Axsome in August announcing that the FDA had informed the company that its NDA review “would not be completed by the Prescription Drug User Fee Act target action date of August 22, 2021.”
“The FDA did not request additional information from the company, and the review of the application is ongoing,” the statement said. Axsome did not respond to further questions.
‘Impressive’ remission rate
Commenting on the research, Marin Jukic, PhD, department of physiology and pharmacology, Karolinska Institutet, Stockholm, who was not involved in the research, said AXS-05 “looks promising in relation to the efficacy and tolerability results” with a remission rate that is “truly impressive.”
However, Dr. Jukic cautioned that it was an open-label trial and therefore had no placebo or active comparator arms.
He noted that it would be “interesting to compare the efficacy with placebo and escitalopram, for example, to evaluate the potential for the benefits and efficacy better.”
The research was funded by Axsome Therapeutics, and, except for one, the researchers for the four studies are employees of Axsome Therapeutics.
A version of this article first appeared on Medscape.com.
A novel antidepressant (AXS-05, Axsome Therapeutics) appears to have a rapid and durable effect in patients with major depressive disorder (MDD), results of an open label, phase 3 trial, show. Yet, its new drug application (NDA) remains in limbo with the U.S. Food and Drug Administration for reasons that are unclear.
In the study, which included 876 patients with MDD, results showed the drug, a combination of dextromethorphan and bupropion, had a clinical response rate of 80% and a remission rate of almost 70%. In addition, functional improvements were “substantial” and AXS-05 was determined to be “generally safe and well-tolerated.”
The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
The study
The COMET trial was a phase 3, multicenter, U.S. trial, in which patients with MDD were treated with AXS-05 twice daily for up to 12 months. Patients had to have a Montgomery-Åsberg Depression Rating Scale (MADRS) score of at least 25. They could have completed a prior AXS-05 study or be newly enrolled.
Of 876 patients included in the study, 611 were newly enrolled. The mean age was 42.4 years, and 62.4% were women. Just over half (58.1%) were White, with 35.6% Black, and 2.0% Asian. The mean body mass index was 31.4 kg/m2.
The mean MADRS total score at baseline was 32.7 and the Sheehan Disability Scale (SDS) score was 20.0.
Presenting efficacy data in 609 newly enrolled patients, the team showed that MADRS total scores fell sharply on starting AXS-05, by 9.1 points at week 1, 14.0 points at week 2, and 21.2 points at week 6.
By 6 months, the reduction over baseline was 23.9 points, which was maintained out to 12 months, at a mean reduction of 23.0 points.
The proportion of patients achieving a clinical response, defined as a greater than or equal to 50% improvement in MADRS scores, was 18.8% at week 1, 39.7% at week 2, and 73.2% at week 6. There was a clinical response in 84.6% of patients at 6 months and in 82.8% at 12 months.
Clinical remission, defined as a MADRS score less than or equal to 10, was achieved in 8.3% of patients at week 1, rising to 21.5% at week 2, and 52.5% at week 6. At 6 months, 68.7% of patients were in clinical remission, reaching 69.0% at 12 months.
These benefits were accompanied by substantial improvements in depressive symptoms on the Clinical Global Impression of Improvement scale, with a marked or moderate improvement seen in 86.7% of patients at 6 months and 93.1% at 12 months.
Moreover, a clinical response in functioning on the SDS was achieved by 80.6% of patients at 6 months and 75.9% at 12 months.
The safety analysis of AXS-05 in the entire cohort suggested it was well-tolerated, with dizziness seen in 12.7% of patients, along with nausea in 11.9%, headache in 8.8%, dry mouth in 7.1%, and decreased appetite in 6.1%.
The rate of discontinuation due to adverse events was 8.4%, and there were no signs of psychotomimetic effects, cognitive impairment, weight gain, or increased sexual dysfunction.
and increased rates of suicidal ideation resolution, and was also effective for treatment-resistant depression.
Results from an analysis of the ASCEND phase 2 and GEMINI phase 3 trials also suggested that AXS-05 was superior to both bupropion and placebo in achieving rapid and sustained improvements in depression symptoms.
FDA delay
Yet despite these seemingly positive findings, the FDA appears to have issues with the agent’s new drug application.
As reported in August, the agency reviewed the NDA for AXS-05 for the treatment of MDD, but at that time the drug’s manufacturer revealed that the agency had identified “deficiencies that preclude labeling discussions at this time.”
With the latest results presented at ECNP 2021, this news organization asked Axsome about the status of the NDA and whether there had been any further discussions and/or movement with the FDA.
Instead of a direct reply from the drug company, this news organization was directed to a statement released by Axsome in August announcing that the FDA had informed the company that its NDA review “would not be completed by the Prescription Drug User Fee Act target action date of August 22, 2021.”
“The FDA did not request additional information from the company, and the review of the application is ongoing,” the statement said. Axsome did not respond to further questions.
‘Impressive’ remission rate
Commenting on the research, Marin Jukic, PhD, department of physiology and pharmacology, Karolinska Institutet, Stockholm, who was not involved in the research, said AXS-05 “looks promising in relation to the efficacy and tolerability results” with a remission rate that is “truly impressive.”
However, Dr. Jukic cautioned that it was an open-label trial and therefore had no placebo or active comparator arms.
He noted that it would be “interesting to compare the efficacy with placebo and escitalopram, for example, to evaluate the potential for the benefits and efficacy better.”
The research was funded by Axsome Therapeutics, and, except for one, the researchers for the four studies are employees of Axsome Therapeutics.
A version of this article first appeared on Medscape.com.
A novel antidepressant (AXS-05, Axsome Therapeutics) appears to have a rapid and durable effect in patients with major depressive disorder (MDD), results of an open label, phase 3 trial, show. Yet, its new drug application (NDA) remains in limbo with the U.S. Food and Drug Administration for reasons that are unclear.
In the study, which included 876 patients with MDD, results showed the drug, a combination of dextromethorphan and bupropion, had a clinical response rate of 80% and a remission rate of almost 70%. In addition, functional improvements were “substantial” and AXS-05 was determined to be “generally safe and well-tolerated.”
The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
The study
The COMET trial was a phase 3, multicenter, U.S. trial, in which patients with MDD were treated with AXS-05 twice daily for up to 12 months. Patients had to have a Montgomery-Åsberg Depression Rating Scale (MADRS) score of at least 25. They could have completed a prior AXS-05 study or be newly enrolled.
Of 876 patients included in the study, 611 were newly enrolled. The mean age was 42.4 years, and 62.4% were women. Just over half (58.1%) were White, with 35.6% Black, and 2.0% Asian. The mean body mass index was 31.4 kg/m2.
The mean MADRS total score at baseline was 32.7 and the Sheehan Disability Scale (SDS) score was 20.0.
Presenting efficacy data in 609 newly enrolled patients, the team showed that MADRS total scores fell sharply on starting AXS-05, by 9.1 points at week 1, 14.0 points at week 2, and 21.2 points at week 6.
By 6 months, the reduction over baseline was 23.9 points, which was maintained out to 12 months, at a mean reduction of 23.0 points.
The proportion of patients achieving a clinical response, defined as a greater than or equal to 50% improvement in MADRS scores, was 18.8% at week 1, 39.7% at week 2, and 73.2% at week 6. There was a clinical response in 84.6% of patients at 6 months and in 82.8% at 12 months.
Clinical remission, defined as a MADRS score less than or equal to 10, was achieved in 8.3% of patients at week 1, rising to 21.5% at week 2, and 52.5% at week 6. At 6 months, 68.7% of patients were in clinical remission, reaching 69.0% at 12 months.
These benefits were accompanied by substantial improvements in depressive symptoms on the Clinical Global Impression of Improvement scale, with a marked or moderate improvement seen in 86.7% of patients at 6 months and 93.1% at 12 months.
Moreover, a clinical response in functioning on the SDS was achieved by 80.6% of patients at 6 months and 75.9% at 12 months.
The safety analysis of AXS-05 in the entire cohort suggested it was well-tolerated, with dizziness seen in 12.7% of patients, along with nausea in 11.9%, headache in 8.8%, dry mouth in 7.1%, and decreased appetite in 6.1%.
The rate of discontinuation due to adverse events was 8.4%, and there were no signs of psychotomimetic effects, cognitive impairment, weight gain, or increased sexual dysfunction.
and increased rates of suicidal ideation resolution, and was also effective for treatment-resistant depression.
Results from an analysis of the ASCEND phase 2 and GEMINI phase 3 trials also suggested that AXS-05 was superior to both bupropion and placebo in achieving rapid and sustained improvements in depression symptoms.
FDA delay
Yet despite these seemingly positive findings, the FDA appears to have issues with the agent’s new drug application.
As reported in August, the agency reviewed the NDA for AXS-05 for the treatment of MDD, but at that time the drug’s manufacturer revealed that the agency had identified “deficiencies that preclude labeling discussions at this time.”
With the latest results presented at ECNP 2021, this news organization asked Axsome about the status of the NDA and whether there had been any further discussions and/or movement with the FDA.
Instead of a direct reply from the drug company, this news organization was directed to a statement released by Axsome in August announcing that the FDA had informed the company that its NDA review “would not be completed by the Prescription Drug User Fee Act target action date of August 22, 2021.”
“The FDA did not request additional information from the company, and the review of the application is ongoing,” the statement said. Axsome did not respond to further questions.
‘Impressive’ remission rate
Commenting on the research, Marin Jukic, PhD, department of physiology and pharmacology, Karolinska Institutet, Stockholm, who was not involved in the research, said AXS-05 “looks promising in relation to the efficacy and tolerability results” with a remission rate that is “truly impressive.”
However, Dr. Jukic cautioned that it was an open-label trial and therefore had no placebo or active comparator arms.
He noted that it would be “interesting to compare the efficacy with placebo and escitalopram, for example, to evaluate the potential for the benefits and efficacy better.”
The research was funded by Axsome Therapeutics, and, except for one, the researchers for the four studies are employees of Axsome Therapeutics.
A version of this article first appeared on Medscape.com.
FROM ECNP 2021
Lower thyroid hormone levels a red flag for elevated suicide risk?
Patients with comorbid anxiety and mood disorders who have reduced, albeit “normal” serum levels of thyroid-stimulating hormone (TSH) may be at increased risk for suicidal ideation, new research suggests.
In a cross-sectional study, clinical data on diagnosis, medication use, and symptom scores were gathered, along with assessments of blood levels of thyroid axis hormones, in patients with both anxiety and mood disorders.
After investigators accounted for age, gender, symptoms, medication use, and other potential confounders, patients with suicidal ideation were 54% less likely to have higher TSH levels. There was no association found with other thyroid hormones.
Based on the results, the assessment of thyroid hormone levels “may be important for suicide prevention and might allow clinicians to evaluate the potential of the suicidal ideation risk in individuals with [anxiety and mood disorders],” co-investigator Vilma Liaugaudaite, PhD student, Neuroscience Institute of the Lithuanian University of Health Sciences, Palanga, and colleagues note.
The findings were presented at the 34th European College of Neuropsychopharmacology (ECNP) Congress.
‘Complex mechanism’
Ms. Liaugaudaite told this news organization that thyroid hormones are known to have a “profound” effect on mood and behavior.
Recent studies show “various degrees of hypothalamic-pituitary-thyroid axis dysregulation are associated with suicidal behavior” in patients with depression, she added.
Noting that disturbances in the serotonin system “constitute the most common biochemical abnormality associated with suicidal behavior,” Ms. Liaugaudaite said it is thought thyroid hormones “are involved in a complex compensatory mechanism to correct reduced central 5-hydroxytryptamine activity” via lower TSH levels.
In addition, hypersecretion of thyrotropin-releasing hormone, which stimulates the release of TSH, “has been considered a compensatory mechanism to maintain normal thyroid hormone secretion and normalize serotonin activity in depressed patients,” she said.
To investigate associations between thyroid axis hormones and suicidality in individuals with comorbid anxiety and mood disorders, the researchers assessed consecutive patients attending a stress disorders clinic.
Sociodemographic and clinical information was gathered, and patients completed the Mini International Neuropsychiatric Interview, the Patient Health Questionnaire-9 (PHQ-9), and the General Anxiety Disorder-7 (GAD-7) scale.
Fasting blood samples were also tested for free thyroxine (FT4), free triiodothyronine (FT3), and TSH levels.
Significant association
Suicidal ideation was identified in 42 participants. Serum FT4, FT3, and TSH levels were within the normal range.
There were no significant differences between patients with and without suicidal ideation in terms of age, gender, education, obesity, smoking, and medication use.
Suicidal ideation was associated with higher scores on the PHQ-9 (15.5 vs. 13.3; P = .085), and with lower TSH levels (1.54 IU/L vs. 2.04 IU/L; P = .092).
The association between serum TSH levels and suicidal ideation was significant after multivariate logistic regression analysis accounted for age, gender, PHQ-9 and GAD-7 scores, education, body mass index, smoking, and use of antidepressants, tranquilizers, mood stabilizers, and neuroleptics.
Specifically, patients with suicidal ideation were significantly less likely to have higher TSH levels than those without, at an odds ratio of 0.46 (P = .027).
There were no significant associations between serum FT4 and FT3 levels and suicidal ideation.
Interesting, but preliminary
Commenting on the findings, Sanjeev Sockalingam, MD, vice chair and professor of psychiatry at the University of Toronto, said it is an “interesting study” because the literature on trying to identify individuals at risk for suicidal ideation or behaviors is “quite mixed, in terms of the results.”
However, it was a cross-sectional study with a relatively small sample size, and studies of this nature typically include patients with hypothyroidism “who end up having suicidal thoughts,” said Dr. Sockalingam, who was not involved with the research.
“I do wonder, given the sample size and patient population, if there may be other factors that may have been related to this,” he added.
Dr. Sockalingam noted that he would like to see more data on the medications the patients were taking, and he underlined that the thyroid levels were in the normal range, “so it’s a bit difficult to untangle what that means in terms of these subtle changes in thyroid levels.”
Robert Levitan, MD, Cameron Wilson Chair in Depression Research at the Centre for Addiction and Mental Health, Toronto, also emphasized that the thyroid levels were in the normal range.
He commented that it therefore “seems unlikely that there’s going to be some biological effect that’s going to affect the brain in a significant enough way” to influence suicidal ideation.
Dr. Levitan continued, “What’s probably happening is there’s some other clinical issue here that they just haven’t picked up on that’s leading in one direction to the suicidal ideation and perhaps affecting the TSH to some extent.”
Although the study is, therefore, “preliminary,” the findings are nevertheless “interesting,” he concluded.
The study received no funding. Ms. Liaugaudaite, Dr. Sockalingam, and Dr. Levitan have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Patients with comorbid anxiety and mood disorders who have reduced, albeit “normal” serum levels of thyroid-stimulating hormone (TSH) may be at increased risk for suicidal ideation, new research suggests.
In a cross-sectional study, clinical data on diagnosis, medication use, and symptom scores were gathered, along with assessments of blood levels of thyroid axis hormones, in patients with both anxiety and mood disorders.
After investigators accounted for age, gender, symptoms, medication use, and other potential confounders, patients with suicidal ideation were 54% less likely to have higher TSH levels. There was no association found with other thyroid hormones.
Based on the results, the assessment of thyroid hormone levels “may be important for suicide prevention and might allow clinicians to evaluate the potential of the suicidal ideation risk in individuals with [anxiety and mood disorders],” co-investigator Vilma Liaugaudaite, PhD student, Neuroscience Institute of the Lithuanian University of Health Sciences, Palanga, and colleagues note.
The findings were presented at the 34th European College of Neuropsychopharmacology (ECNP) Congress.
‘Complex mechanism’
Ms. Liaugaudaite told this news organization that thyroid hormones are known to have a “profound” effect on mood and behavior.
Recent studies show “various degrees of hypothalamic-pituitary-thyroid axis dysregulation are associated with suicidal behavior” in patients with depression, she added.
Noting that disturbances in the serotonin system “constitute the most common biochemical abnormality associated with suicidal behavior,” Ms. Liaugaudaite said it is thought thyroid hormones “are involved in a complex compensatory mechanism to correct reduced central 5-hydroxytryptamine activity” via lower TSH levels.
In addition, hypersecretion of thyrotropin-releasing hormone, which stimulates the release of TSH, “has been considered a compensatory mechanism to maintain normal thyroid hormone secretion and normalize serotonin activity in depressed patients,” she said.
To investigate associations between thyroid axis hormones and suicidality in individuals with comorbid anxiety and mood disorders, the researchers assessed consecutive patients attending a stress disorders clinic.
Sociodemographic and clinical information was gathered, and patients completed the Mini International Neuropsychiatric Interview, the Patient Health Questionnaire-9 (PHQ-9), and the General Anxiety Disorder-7 (GAD-7) scale.
Fasting blood samples were also tested for free thyroxine (FT4), free triiodothyronine (FT3), and TSH levels.
Significant association
Suicidal ideation was identified in 42 participants. Serum FT4, FT3, and TSH levels were within the normal range.
There were no significant differences between patients with and without suicidal ideation in terms of age, gender, education, obesity, smoking, and medication use.
Suicidal ideation was associated with higher scores on the PHQ-9 (15.5 vs. 13.3; P = .085), and with lower TSH levels (1.54 IU/L vs. 2.04 IU/L; P = .092).
The association between serum TSH levels and suicidal ideation was significant after multivariate logistic regression analysis accounted for age, gender, PHQ-9 and GAD-7 scores, education, body mass index, smoking, and use of antidepressants, tranquilizers, mood stabilizers, and neuroleptics.
Specifically, patients with suicidal ideation were significantly less likely to have higher TSH levels than those without, at an odds ratio of 0.46 (P = .027).
There were no significant associations between serum FT4 and FT3 levels and suicidal ideation.
Interesting, but preliminary
Commenting on the findings, Sanjeev Sockalingam, MD, vice chair and professor of psychiatry at the University of Toronto, said it is an “interesting study” because the literature on trying to identify individuals at risk for suicidal ideation or behaviors is “quite mixed, in terms of the results.”
However, it was a cross-sectional study with a relatively small sample size, and studies of this nature typically include patients with hypothyroidism “who end up having suicidal thoughts,” said Dr. Sockalingam, who was not involved with the research.
“I do wonder, given the sample size and patient population, if there may be other factors that may have been related to this,” he added.
Dr. Sockalingam noted that he would like to see more data on the medications the patients were taking, and he underlined that the thyroid levels were in the normal range, “so it’s a bit difficult to untangle what that means in terms of these subtle changes in thyroid levels.”
Robert Levitan, MD, Cameron Wilson Chair in Depression Research at the Centre for Addiction and Mental Health, Toronto, also emphasized that the thyroid levels were in the normal range.
He commented that it therefore “seems unlikely that there’s going to be some biological effect that’s going to affect the brain in a significant enough way” to influence suicidal ideation.
Dr. Levitan continued, “What’s probably happening is there’s some other clinical issue here that they just haven’t picked up on that’s leading in one direction to the suicidal ideation and perhaps affecting the TSH to some extent.”
Although the study is, therefore, “preliminary,” the findings are nevertheless “interesting,” he concluded.
The study received no funding. Ms. Liaugaudaite, Dr. Sockalingam, and Dr. Levitan have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Patients with comorbid anxiety and mood disorders who have reduced, albeit “normal” serum levels of thyroid-stimulating hormone (TSH) may be at increased risk for suicidal ideation, new research suggests.
In a cross-sectional study, clinical data on diagnosis, medication use, and symptom scores were gathered, along with assessments of blood levels of thyroid axis hormones, in patients with both anxiety and mood disorders.
After investigators accounted for age, gender, symptoms, medication use, and other potential confounders, patients with suicidal ideation were 54% less likely to have higher TSH levels. There was no association found with other thyroid hormones.
Based on the results, the assessment of thyroid hormone levels “may be important for suicide prevention and might allow clinicians to evaluate the potential of the suicidal ideation risk in individuals with [anxiety and mood disorders],” co-investigator Vilma Liaugaudaite, PhD student, Neuroscience Institute of the Lithuanian University of Health Sciences, Palanga, and colleagues note.
The findings were presented at the 34th European College of Neuropsychopharmacology (ECNP) Congress.
‘Complex mechanism’
Ms. Liaugaudaite told this news organization that thyroid hormones are known to have a “profound” effect on mood and behavior.
Recent studies show “various degrees of hypothalamic-pituitary-thyroid axis dysregulation are associated with suicidal behavior” in patients with depression, she added.
Noting that disturbances in the serotonin system “constitute the most common biochemical abnormality associated with suicidal behavior,” Ms. Liaugaudaite said it is thought thyroid hormones “are involved in a complex compensatory mechanism to correct reduced central 5-hydroxytryptamine activity” via lower TSH levels.
In addition, hypersecretion of thyrotropin-releasing hormone, which stimulates the release of TSH, “has been considered a compensatory mechanism to maintain normal thyroid hormone secretion and normalize serotonin activity in depressed patients,” she said.
To investigate associations between thyroid axis hormones and suicidality in individuals with comorbid anxiety and mood disorders, the researchers assessed consecutive patients attending a stress disorders clinic.
Sociodemographic and clinical information was gathered, and patients completed the Mini International Neuropsychiatric Interview, the Patient Health Questionnaire-9 (PHQ-9), and the General Anxiety Disorder-7 (GAD-7) scale.
Fasting blood samples were also tested for free thyroxine (FT4), free triiodothyronine (FT3), and TSH levels.
Significant association
Suicidal ideation was identified in 42 participants. Serum FT4, FT3, and TSH levels were within the normal range.
There were no significant differences between patients with and without suicidal ideation in terms of age, gender, education, obesity, smoking, and medication use.
Suicidal ideation was associated with higher scores on the PHQ-9 (15.5 vs. 13.3; P = .085), and with lower TSH levels (1.54 IU/L vs. 2.04 IU/L; P = .092).
The association between serum TSH levels and suicidal ideation was significant after multivariate logistic regression analysis accounted for age, gender, PHQ-9 and GAD-7 scores, education, body mass index, smoking, and use of antidepressants, tranquilizers, mood stabilizers, and neuroleptics.
Specifically, patients with suicidal ideation were significantly less likely to have higher TSH levels than those without, at an odds ratio of 0.46 (P = .027).
There were no significant associations between serum FT4 and FT3 levels and suicidal ideation.
Interesting, but preliminary
Commenting on the findings, Sanjeev Sockalingam, MD, vice chair and professor of psychiatry at the University of Toronto, said it is an “interesting study” because the literature on trying to identify individuals at risk for suicidal ideation or behaviors is “quite mixed, in terms of the results.”
However, it was a cross-sectional study with a relatively small sample size, and studies of this nature typically include patients with hypothyroidism “who end up having suicidal thoughts,” said Dr. Sockalingam, who was not involved with the research.
“I do wonder, given the sample size and patient population, if there may be other factors that may have been related to this,” he added.
Dr. Sockalingam noted that he would like to see more data on the medications the patients were taking, and he underlined that the thyroid levels were in the normal range, “so it’s a bit difficult to untangle what that means in terms of these subtle changes in thyroid levels.”
Robert Levitan, MD, Cameron Wilson Chair in Depression Research at the Centre for Addiction and Mental Health, Toronto, also emphasized that the thyroid levels were in the normal range.
He commented that it therefore “seems unlikely that there’s going to be some biological effect that’s going to affect the brain in a significant enough way” to influence suicidal ideation.
Dr. Levitan continued, “What’s probably happening is there’s some other clinical issue here that they just haven’t picked up on that’s leading in one direction to the suicidal ideation and perhaps affecting the TSH to some extent.”
Although the study is, therefore, “preliminary,” the findings are nevertheless “interesting,” he concluded.
The study received no funding. Ms. Liaugaudaite, Dr. Sockalingam, and Dr. Levitan have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ECNP 2021
Steroid a promising short-term treatment option for major depression?
Study results of an experimental agent that improves symptoms of major depression and boosts quality of life in as little as 3 days suggest it may be an effective short-term treatment option.
Phase 3 results of a randomized, placebo-controlled trial compared zuranolone, an neuroactive steroid that binds to both synaptic and extra-synaptic GABA-A receptors, to placebo in patients with major depressive disorder (MDD). Overall, 30% of participants were already taking antidepressants.
Investigators found the drug was associated with a significant improvement in depression scores versus placebo, with benefit observed as early as day 3. This was accompanied by improved function and well-being.
, said study presenter Colville Brown, MD, Sage Therapeutics, Cambridge, Mass.
“These data continue to support the development of zuranolone as a potential 14-day short course treatment for major depressive disorder episodes.”
The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
High placebo response
However, despite being significant, the drug’s benefit was only slightly higher than that of placebo, raising questions about the study design and the true performance of the drug.
Dr. Brown explained that patients with MDD were randomized to oral zuranolone 50 mg or placebo once daily for 14 days, with dose reductions to 40 mg or matching placebo permitted in case of perceived intolerance.
Patients were assessed at baseline and day 15 via the 17-item Hamilton Rating Scale for Depression (HAMD-17) before entering a 28-day follow-up period off the study drug.
Among the 268 participants who received zuranolone, 90.3% completed the study, compared with 87.4% of 269 patients in the placebo group.
The mean age of participants was 40 years. Women made up 69.4% of those who received zuranolone and 61.7% assigned to placebo.
The mean HAMD-17 score at baseline was 26.8 and 26.9 in the zuranolone and placebo groups, respectively. Dr. Brown noted that 29.5% of patients in the zuranolone group and 30.1% of those assigned to placebo were taking antidepressants at baseline.
The study’s primary endpoint was met, with patients taking the study drug experiencing a significantly greater reduction in HAMD-17 scores from baseline to day 15 versus those given placebo, at 14.1 versus 12.3 points (P = .0141).
Dr. Brown highlighted that the difference in reduction in HAMD-17 scores between the zuranolone and placebo groups was already significant at day 3 (P < .0001), and again at day 8 (P < .0001) and day 12 (P < .001).
At day 3, response rates on the HAMD-17 were significantly higher among zuranolone-treated patients than among those given placebo, at 29.3% versus 16.3% (P < .001). However, the differences on day 15 and on day 42 were no longer significant.
A similar effect was seen for HAMD-17 remissions, which were seen in 7.6% of zuranolone-treated patients and 2.3% of those given placebo at day 3 (P < .01), rising to 29.8% versus 27.1% at day 15, and 30.8% versus 29.6% at day 42, and neither difference was significant.
Dr. Brown also showed that, at all time points during the treatment and follow-up periods, improvements in response rates in Global Improvement on the Clinical Global Impression scale favored zuranolone.
On the SF-36v2 quality of life questionnaire, improvements again favored zuranolone on all domains, although the difference between active treatment and placebo was significant only for vitality on day 15, at 12.8 versus 9.7 points (P < .05).
Treatment-emergent adverse events were more common with zuranolone, with 60.1% of patients experiencing at least one event of any grade versus 44.6% with placebo. However, severe events were seen in only 3.0% versus 1.1% of patients, and serious adverse events were recorded in only two patients (0.7%) in both groups.
The most common adverse events were somnolence, dizziness, headache, sedation, and diarrhea, with no increase in suicidal ideation or withdrawal. Dr. Brown noted that there was “no change in the safety signal” between patients with or without prior antidepressant therapy.
From the audience, Marie-Josée Filteau, MD, department of psychiatry, Laval University, Quebec, drew attention to the similarity in the improvement in HAMD-17 scores between the zuranolone and placebo groups, asking: “How is that compelling?”
Dr. Brown replied that “what they are excited about is that change from baseline with zuranolone,” adding: “You do see it in the placebo group as well, and ... this isn’t new to psychiatry.
“This is a heterogeneous disease, and remember this [study] was conducted during COVID, so patients were being seen with clinic visits during COVID.
“What impact did that have? The placebo is not really placebo” in this case.
More effective than results suggest?
Approached for comment by this news organization, Maurizio Fava, MD, executive vice chair, department of psychiatry, and executive director, Clinical Trials Network and Institute, Massachusetts General Hospital, Boston, noted there are several issues with the trial.
Because of those, the drug “is likely to be much more efficacious than it looks because it achieved statistical significance despite an extremely high placebo response,” he said
“Whenever your change on placebo is greater than 10 points on the HAMD, you have an excessive response ... and a very, very low chance of detecting a signal,” he said.
Dr. Fava said that another issue was including patients who were either on or off antidepressants, which meant the population was not sufficiently homogenous.
Another “flaw” was to assume that the placebo effect would be “transient” and deteriorate over time, whereas the results showed the opposite.
Nevertheless, “it’s a positive study because of the sample size ... that provides further evidence for the antidepressant activity of zuranolone” and the drug was “well tolerated.”
Dr. Fava expects zuranolone “will make it to the market,” as an indication from the Food and Drug Administration is likely, “but if you’re asking me: Is the drug as effective as shown in their studies? It’s probably much more effective.”
The study was funded by Sage Therapeutics and Biogen. Dr. Brown is an employee of Sage Therapeutics. Lead investigator Anita Clayton, MD, University of Virginia, Charlottesville, has reported relationships with Dario Bioscience, Janssen, Praxis Precision Medicines, Relmada Therapeutics, Sage Therapeutics, Fabre-Kramer, MindCure, Ovoca Bio, PureTech Health, S1 Biopharma, Vella Bioscience, WCG MedAvante-ProPhase, Ballantine Books/Random House, Guilford Publications, Euthymics, and Mediflix.
A version of this article first appeared on Medscape.com.
Study results of an experimental agent that improves symptoms of major depression and boosts quality of life in as little as 3 days suggest it may be an effective short-term treatment option.
Phase 3 results of a randomized, placebo-controlled trial compared zuranolone, an neuroactive steroid that binds to both synaptic and extra-synaptic GABA-A receptors, to placebo in patients with major depressive disorder (MDD). Overall, 30% of participants were already taking antidepressants.
Investigators found the drug was associated with a significant improvement in depression scores versus placebo, with benefit observed as early as day 3. This was accompanied by improved function and well-being.
, said study presenter Colville Brown, MD, Sage Therapeutics, Cambridge, Mass.
“These data continue to support the development of zuranolone as a potential 14-day short course treatment for major depressive disorder episodes.”
The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
High placebo response
However, despite being significant, the drug’s benefit was only slightly higher than that of placebo, raising questions about the study design and the true performance of the drug.
Dr. Brown explained that patients with MDD were randomized to oral zuranolone 50 mg or placebo once daily for 14 days, with dose reductions to 40 mg or matching placebo permitted in case of perceived intolerance.
Patients were assessed at baseline and day 15 via the 17-item Hamilton Rating Scale for Depression (HAMD-17) before entering a 28-day follow-up period off the study drug.
Among the 268 participants who received zuranolone, 90.3% completed the study, compared with 87.4% of 269 patients in the placebo group.
The mean age of participants was 40 years. Women made up 69.4% of those who received zuranolone and 61.7% assigned to placebo.
The mean HAMD-17 score at baseline was 26.8 and 26.9 in the zuranolone and placebo groups, respectively. Dr. Brown noted that 29.5% of patients in the zuranolone group and 30.1% of those assigned to placebo were taking antidepressants at baseline.
The study’s primary endpoint was met, with patients taking the study drug experiencing a significantly greater reduction in HAMD-17 scores from baseline to day 15 versus those given placebo, at 14.1 versus 12.3 points (P = .0141).
Dr. Brown highlighted that the difference in reduction in HAMD-17 scores between the zuranolone and placebo groups was already significant at day 3 (P < .0001), and again at day 8 (P < .0001) and day 12 (P < .001).
At day 3, response rates on the HAMD-17 were significantly higher among zuranolone-treated patients than among those given placebo, at 29.3% versus 16.3% (P < .001). However, the differences on day 15 and on day 42 were no longer significant.
A similar effect was seen for HAMD-17 remissions, which were seen in 7.6% of zuranolone-treated patients and 2.3% of those given placebo at day 3 (P < .01), rising to 29.8% versus 27.1% at day 15, and 30.8% versus 29.6% at day 42, and neither difference was significant.
Dr. Brown also showed that, at all time points during the treatment and follow-up periods, improvements in response rates in Global Improvement on the Clinical Global Impression scale favored zuranolone.
On the SF-36v2 quality of life questionnaire, improvements again favored zuranolone on all domains, although the difference between active treatment and placebo was significant only for vitality on day 15, at 12.8 versus 9.7 points (P < .05).
Treatment-emergent adverse events were more common with zuranolone, with 60.1% of patients experiencing at least one event of any grade versus 44.6% with placebo. However, severe events were seen in only 3.0% versus 1.1% of patients, and serious adverse events were recorded in only two patients (0.7%) in both groups.
The most common adverse events were somnolence, dizziness, headache, sedation, and diarrhea, with no increase in suicidal ideation or withdrawal. Dr. Brown noted that there was “no change in the safety signal” between patients with or without prior antidepressant therapy.
From the audience, Marie-Josée Filteau, MD, department of psychiatry, Laval University, Quebec, drew attention to the similarity in the improvement in HAMD-17 scores between the zuranolone and placebo groups, asking: “How is that compelling?”
Dr. Brown replied that “what they are excited about is that change from baseline with zuranolone,” adding: “You do see it in the placebo group as well, and ... this isn’t new to psychiatry.
“This is a heterogeneous disease, and remember this [study] was conducted during COVID, so patients were being seen with clinic visits during COVID.
“What impact did that have? The placebo is not really placebo” in this case.
More effective than results suggest?
Approached for comment by this news organization, Maurizio Fava, MD, executive vice chair, department of psychiatry, and executive director, Clinical Trials Network and Institute, Massachusetts General Hospital, Boston, noted there are several issues with the trial.
Because of those, the drug “is likely to be much more efficacious than it looks because it achieved statistical significance despite an extremely high placebo response,” he said
“Whenever your change on placebo is greater than 10 points on the HAMD, you have an excessive response ... and a very, very low chance of detecting a signal,” he said.
Dr. Fava said that another issue was including patients who were either on or off antidepressants, which meant the population was not sufficiently homogenous.
Another “flaw” was to assume that the placebo effect would be “transient” and deteriorate over time, whereas the results showed the opposite.
Nevertheless, “it’s a positive study because of the sample size ... that provides further evidence for the antidepressant activity of zuranolone” and the drug was “well tolerated.”
Dr. Fava expects zuranolone “will make it to the market,” as an indication from the Food and Drug Administration is likely, “but if you’re asking me: Is the drug as effective as shown in their studies? It’s probably much more effective.”
The study was funded by Sage Therapeutics and Biogen. Dr. Brown is an employee of Sage Therapeutics. Lead investigator Anita Clayton, MD, University of Virginia, Charlottesville, has reported relationships with Dario Bioscience, Janssen, Praxis Precision Medicines, Relmada Therapeutics, Sage Therapeutics, Fabre-Kramer, MindCure, Ovoca Bio, PureTech Health, S1 Biopharma, Vella Bioscience, WCG MedAvante-ProPhase, Ballantine Books/Random House, Guilford Publications, Euthymics, and Mediflix.
A version of this article first appeared on Medscape.com.
Study results of an experimental agent that improves symptoms of major depression and boosts quality of life in as little as 3 days suggest it may be an effective short-term treatment option.
Phase 3 results of a randomized, placebo-controlled trial compared zuranolone, an neuroactive steroid that binds to both synaptic and extra-synaptic GABA-A receptors, to placebo in patients with major depressive disorder (MDD). Overall, 30% of participants were already taking antidepressants.
Investigators found the drug was associated with a significant improvement in depression scores versus placebo, with benefit observed as early as day 3. This was accompanied by improved function and well-being.
, said study presenter Colville Brown, MD, Sage Therapeutics, Cambridge, Mass.
“These data continue to support the development of zuranolone as a potential 14-day short course treatment for major depressive disorder episodes.”
The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
High placebo response
However, despite being significant, the drug’s benefit was only slightly higher than that of placebo, raising questions about the study design and the true performance of the drug.
Dr. Brown explained that patients with MDD were randomized to oral zuranolone 50 mg or placebo once daily for 14 days, with dose reductions to 40 mg or matching placebo permitted in case of perceived intolerance.
Patients were assessed at baseline and day 15 via the 17-item Hamilton Rating Scale for Depression (HAMD-17) before entering a 28-day follow-up period off the study drug.
Among the 268 participants who received zuranolone, 90.3% completed the study, compared with 87.4% of 269 patients in the placebo group.
The mean age of participants was 40 years. Women made up 69.4% of those who received zuranolone and 61.7% assigned to placebo.
The mean HAMD-17 score at baseline was 26.8 and 26.9 in the zuranolone and placebo groups, respectively. Dr. Brown noted that 29.5% of patients in the zuranolone group and 30.1% of those assigned to placebo were taking antidepressants at baseline.
The study’s primary endpoint was met, with patients taking the study drug experiencing a significantly greater reduction in HAMD-17 scores from baseline to day 15 versus those given placebo, at 14.1 versus 12.3 points (P = .0141).
Dr. Brown highlighted that the difference in reduction in HAMD-17 scores between the zuranolone and placebo groups was already significant at day 3 (P < .0001), and again at day 8 (P < .0001) and day 12 (P < .001).
At day 3, response rates on the HAMD-17 were significantly higher among zuranolone-treated patients than among those given placebo, at 29.3% versus 16.3% (P < .001). However, the differences on day 15 and on day 42 were no longer significant.
A similar effect was seen for HAMD-17 remissions, which were seen in 7.6% of zuranolone-treated patients and 2.3% of those given placebo at day 3 (P < .01), rising to 29.8% versus 27.1% at day 15, and 30.8% versus 29.6% at day 42, and neither difference was significant.
Dr. Brown also showed that, at all time points during the treatment and follow-up periods, improvements in response rates in Global Improvement on the Clinical Global Impression scale favored zuranolone.
On the SF-36v2 quality of life questionnaire, improvements again favored zuranolone on all domains, although the difference between active treatment and placebo was significant only for vitality on day 15, at 12.8 versus 9.7 points (P < .05).
Treatment-emergent adverse events were more common with zuranolone, with 60.1% of patients experiencing at least one event of any grade versus 44.6% with placebo. However, severe events were seen in only 3.0% versus 1.1% of patients, and serious adverse events were recorded in only two patients (0.7%) in both groups.
The most common adverse events were somnolence, dizziness, headache, sedation, and diarrhea, with no increase in suicidal ideation or withdrawal. Dr. Brown noted that there was “no change in the safety signal” between patients with or without prior antidepressant therapy.
From the audience, Marie-Josée Filteau, MD, department of psychiatry, Laval University, Quebec, drew attention to the similarity in the improvement in HAMD-17 scores between the zuranolone and placebo groups, asking: “How is that compelling?”
Dr. Brown replied that “what they are excited about is that change from baseline with zuranolone,” adding: “You do see it in the placebo group as well, and ... this isn’t new to psychiatry.
“This is a heterogeneous disease, and remember this [study] was conducted during COVID, so patients were being seen with clinic visits during COVID.
“What impact did that have? The placebo is not really placebo” in this case.
More effective than results suggest?
Approached for comment by this news organization, Maurizio Fava, MD, executive vice chair, department of psychiatry, and executive director, Clinical Trials Network and Institute, Massachusetts General Hospital, Boston, noted there are several issues with the trial.
Because of those, the drug “is likely to be much more efficacious than it looks because it achieved statistical significance despite an extremely high placebo response,” he said
“Whenever your change on placebo is greater than 10 points on the HAMD, you have an excessive response ... and a very, very low chance of detecting a signal,” he said.
Dr. Fava said that another issue was including patients who were either on or off antidepressants, which meant the population was not sufficiently homogenous.
Another “flaw” was to assume that the placebo effect would be “transient” and deteriorate over time, whereas the results showed the opposite.
Nevertheless, “it’s a positive study because of the sample size ... that provides further evidence for the antidepressant activity of zuranolone” and the drug was “well tolerated.”
Dr. Fava expects zuranolone “will make it to the market,” as an indication from the Food and Drug Administration is likely, “but if you’re asking me: Is the drug as effective as shown in their studies? It’s probably much more effective.”
The study was funded by Sage Therapeutics and Biogen. Dr. Brown is an employee of Sage Therapeutics. Lead investigator Anita Clayton, MD, University of Virginia, Charlottesville, has reported relationships with Dario Bioscience, Janssen, Praxis Precision Medicines, Relmada Therapeutics, Sage Therapeutics, Fabre-Kramer, MindCure, Ovoca Bio, PureTech Health, S1 Biopharma, Vella Bioscience, WCG MedAvante-ProPhase, Ballantine Books/Random House, Guilford Publications, Euthymics, and Mediflix.
A version of this article first appeared on Medscape.com.
FROM ECNP 2021
Constipation med boosts cognitive performance in mental illness
, new research suggests.
In a randomized controlled trial, 44 healthy individuals were assigned to receive the selective serotonin-4 (5-HT4) receptor agonist prucalopride (Motegrity) or placebo for 1 week.
After 6 days, the active-treatment group performed significantly better on memory tests than the participants who received placebo. In addition, the drug increased activity in brain areas related to cognition.
“What we’re hoping is...these agents may be able to help those with cognitive impairment as part of their mental illness,” lead author Angharad N. de Cates, a clinical DPhil student in the department of psychiatry, University of Oxford, Oxford, United Kingdom, told meeting attendees.
“Currently, we’re looking to see if we can translate our finding a step further and do a similar study in those with depression,” Ms. de Cates added.
The findings were presented at the 34th European College of Neuropsychopharmacology (ECNP) Congress and were simultaneously published in Translational Psychiatry.
“Exciting early evidence”
“Even when the low mood associated with depression is well-treated with conventional antidepressants, many patients continue to experience problems with their memory,” co-investigator Susannah Murphy, PhD, a senior research fellow at the University of Oxford, said in a release.
“Our study provides exciting early evidence in humans of a new approach that might be a helpful way to treat these residual cognitive symptoms,” Dr. Murphy added.
Preclinical and animal studies suggest that the 5-HT4 receptor is a promising treatment target for cognitive impairment in individuals with psychiatric disorders, although studies in humans have been limited by the adverse effects of early agents.
“We’ve had our eye on this receptor for a while,” explained de Cates, inasmuch as the animal data “have been so good.”
However, she said in an interview that “a lack of safe human agents made translation tricky.”
As previously reported, prucalopride, a selective high-affinity 5-HT4 partial agonist, was approved in 2018 by the U.S. Food and Drug Administration for the treatment of chronic idiopathic constipation.
The current researchers note that the drug has “good brain penetration,” which “allowed us to investigate 5-HT4-receptor agonism in humans.”
Having previously shown that a single dose of the drug has “pro-cognitive effects,” the investigators conducted the new trial in 44 healthy participants. All were randomly assigned in a 1:1 ratio to receive either prucalopride 1 mg for 7 days or placebo.
In accordance with enrollment criteria, patients were 18 to 36 years of age, right-handed, and were not pregnant or breastfeeding. Participants’ body mass index was 18 to 30 kg/m2, and they had no contraindications to the study drug. The two treatment groups were well balanced; the participants who received placebo were significantly more likely to be nonnative English speakers (P = .02).
On day 6 of treatment administration, all participants underwent 3T MRI.
Before undergoing imaging, the participants were presented with eight emotionally neutral images of animals or landscapes and were asked to indicate whether or not the images were of animals. The task was then repeated with the eight familiar images and eight novel ones.
During the scan, participants were shown the same images or eight novel images and were again asked whether or not the images contained an animal. They were also instructed to try to remember the images for a subsequent memory task. In that task, the eight original images, 48 novel images, and 27 “distractor” images were presented.
Better memory
In the pre-scan assessment, results showed no significant differences in the ability of members of the prucalopride and placebo groups to identify images as being familiar or different.
However, taking prucalopride was associated with significantly improved memory performance in the post-scan recall task.
Compared to the placebo group, participants in the prucalopride group were more accurate in selecting images as familiar vs distractors (P = .029) and in distinguishing images as familiar, novel, or distractors (P = .035).
Functional MRI revealed increased activity in the left and right hippocampus in response to both novel and familiar images among the participants in the prucalopride group in comparison with those in the placebo group.
There was also increased activity in the right angular gyrus in the prucalopride group in comparison with the placebo group in response to familiar images (P < .005).
“Clinically, angular gyri lesions cause language dysfunction, low mood, and poor memory and can mimic dementia or pseudodementia,” the investigators write. They note that the right angular gyrus “shows significantly decreased activity” in mild cognitive impairment.
“Therefore, the increased activity seen in the right angular gyrus following prucalopride administration in our study is consistent with the pro-cognitive behavioural effects we observed,” they add.
Ms. De Cates noted that the dose used in their study was lower than the 2 mg given for constipation.
“At the low dose, there were no differences in side effects between groups and no withdrawals from the prucalopride group for side effects. We are going to try increasing the dose in our next study actually, as we don’t have PET data to tell us what the optimal dose for binding at the receptor should be,” said Ms. de Cates.
“In safety studies, the dose was trialled in healthy volunteers at 4 mg, which was found to be safe, although perhaps less well tolerated than 2 mg,” she said.
Generalizable findings?
Commenting on the research, Vibe G. Frøkjær, MD, adjunct professor, department of psychology, Copenhagen University, Denmark, said the study “highlights a very interesting and much needed potential for repurposing drugs to help cognitive dysfunction.”
He noted that cognitive dysfunction is often associated with psychiatric disorders -- even in states of remission.
“Importantly, as the authors also state, it will be vital to translate these findings from healthy populations into clinical populations,” said Dr. Frøkjær, who was not involved in the research.
“It will also be important to understand if prucalopride adds to the effects of existing antidepressant treatments or can be used as a stand-alone therapy,” he added.
The study was funded by the NIHR Oxford Health Biomedical Research Center and by the Wellcome Center for Integrative Neuroscience. Ms. De Cates has received a travel grant from the Royal College of Psychiatrists/Gatsby Foundation and support from Wellcome. The other authors have relationships with P1vital Ltd, Janssen Pharmaceuticals, Sage Therapeutics, Pfizer, Zogenix, Compass Pathways, and Lundbeck.
A version of this article first appeared on Medscape.com.
, new research suggests.
In a randomized controlled trial, 44 healthy individuals were assigned to receive the selective serotonin-4 (5-HT4) receptor agonist prucalopride (Motegrity) or placebo for 1 week.
After 6 days, the active-treatment group performed significantly better on memory tests than the participants who received placebo. In addition, the drug increased activity in brain areas related to cognition.
“What we’re hoping is...these agents may be able to help those with cognitive impairment as part of their mental illness,” lead author Angharad N. de Cates, a clinical DPhil student in the department of psychiatry, University of Oxford, Oxford, United Kingdom, told meeting attendees.
“Currently, we’re looking to see if we can translate our finding a step further and do a similar study in those with depression,” Ms. de Cates added.
The findings were presented at the 34th European College of Neuropsychopharmacology (ECNP) Congress and were simultaneously published in Translational Psychiatry.
“Exciting early evidence”
“Even when the low mood associated with depression is well-treated with conventional antidepressants, many patients continue to experience problems with their memory,” co-investigator Susannah Murphy, PhD, a senior research fellow at the University of Oxford, said in a release.
“Our study provides exciting early evidence in humans of a new approach that might be a helpful way to treat these residual cognitive symptoms,” Dr. Murphy added.
Preclinical and animal studies suggest that the 5-HT4 receptor is a promising treatment target for cognitive impairment in individuals with psychiatric disorders, although studies in humans have been limited by the adverse effects of early agents.
“We’ve had our eye on this receptor for a while,” explained de Cates, inasmuch as the animal data “have been so good.”
However, she said in an interview that “a lack of safe human agents made translation tricky.”
As previously reported, prucalopride, a selective high-affinity 5-HT4 partial agonist, was approved in 2018 by the U.S. Food and Drug Administration for the treatment of chronic idiopathic constipation.
The current researchers note that the drug has “good brain penetration,” which “allowed us to investigate 5-HT4-receptor agonism in humans.”
Having previously shown that a single dose of the drug has “pro-cognitive effects,” the investigators conducted the new trial in 44 healthy participants. All were randomly assigned in a 1:1 ratio to receive either prucalopride 1 mg for 7 days or placebo.
In accordance with enrollment criteria, patients were 18 to 36 years of age, right-handed, and were not pregnant or breastfeeding. Participants’ body mass index was 18 to 30 kg/m2, and they had no contraindications to the study drug. The two treatment groups were well balanced; the participants who received placebo were significantly more likely to be nonnative English speakers (P = .02).
On day 6 of treatment administration, all participants underwent 3T MRI.
Before undergoing imaging, the participants were presented with eight emotionally neutral images of animals or landscapes and were asked to indicate whether or not the images were of animals. The task was then repeated with the eight familiar images and eight novel ones.
During the scan, participants were shown the same images or eight novel images and were again asked whether or not the images contained an animal. They were also instructed to try to remember the images for a subsequent memory task. In that task, the eight original images, 48 novel images, and 27 “distractor” images were presented.
Better memory
In the pre-scan assessment, results showed no significant differences in the ability of members of the prucalopride and placebo groups to identify images as being familiar or different.
However, taking prucalopride was associated with significantly improved memory performance in the post-scan recall task.
Compared to the placebo group, participants in the prucalopride group were more accurate in selecting images as familiar vs distractors (P = .029) and in distinguishing images as familiar, novel, or distractors (P = .035).
Functional MRI revealed increased activity in the left and right hippocampus in response to both novel and familiar images among the participants in the prucalopride group in comparison with those in the placebo group.
There was also increased activity in the right angular gyrus in the prucalopride group in comparison with the placebo group in response to familiar images (P < .005).
“Clinically, angular gyri lesions cause language dysfunction, low mood, and poor memory and can mimic dementia or pseudodementia,” the investigators write. They note that the right angular gyrus “shows significantly decreased activity” in mild cognitive impairment.
“Therefore, the increased activity seen in the right angular gyrus following prucalopride administration in our study is consistent with the pro-cognitive behavioural effects we observed,” they add.
Ms. De Cates noted that the dose used in their study was lower than the 2 mg given for constipation.
“At the low dose, there were no differences in side effects between groups and no withdrawals from the prucalopride group for side effects. We are going to try increasing the dose in our next study actually, as we don’t have PET data to tell us what the optimal dose for binding at the receptor should be,” said Ms. de Cates.
“In safety studies, the dose was trialled in healthy volunteers at 4 mg, which was found to be safe, although perhaps less well tolerated than 2 mg,” she said.
Generalizable findings?
Commenting on the research, Vibe G. Frøkjær, MD, adjunct professor, department of psychology, Copenhagen University, Denmark, said the study “highlights a very interesting and much needed potential for repurposing drugs to help cognitive dysfunction.”
He noted that cognitive dysfunction is often associated with psychiatric disorders -- even in states of remission.
“Importantly, as the authors also state, it will be vital to translate these findings from healthy populations into clinical populations,” said Dr. Frøkjær, who was not involved in the research.
“It will also be important to understand if prucalopride adds to the effects of existing antidepressant treatments or can be used as a stand-alone therapy,” he added.
The study was funded by the NIHR Oxford Health Biomedical Research Center and by the Wellcome Center for Integrative Neuroscience. Ms. De Cates has received a travel grant from the Royal College of Psychiatrists/Gatsby Foundation and support from Wellcome. The other authors have relationships with P1vital Ltd, Janssen Pharmaceuticals, Sage Therapeutics, Pfizer, Zogenix, Compass Pathways, and Lundbeck.
A version of this article first appeared on Medscape.com.
, new research suggests.
In a randomized controlled trial, 44 healthy individuals were assigned to receive the selective serotonin-4 (5-HT4) receptor agonist prucalopride (Motegrity) or placebo for 1 week.
After 6 days, the active-treatment group performed significantly better on memory tests than the participants who received placebo. In addition, the drug increased activity in brain areas related to cognition.
“What we’re hoping is...these agents may be able to help those with cognitive impairment as part of their mental illness,” lead author Angharad N. de Cates, a clinical DPhil student in the department of psychiatry, University of Oxford, Oxford, United Kingdom, told meeting attendees.
“Currently, we’re looking to see if we can translate our finding a step further and do a similar study in those with depression,” Ms. de Cates added.
The findings were presented at the 34th European College of Neuropsychopharmacology (ECNP) Congress and were simultaneously published in Translational Psychiatry.
“Exciting early evidence”
“Even when the low mood associated with depression is well-treated with conventional antidepressants, many patients continue to experience problems with their memory,” co-investigator Susannah Murphy, PhD, a senior research fellow at the University of Oxford, said in a release.
“Our study provides exciting early evidence in humans of a new approach that might be a helpful way to treat these residual cognitive symptoms,” Dr. Murphy added.
Preclinical and animal studies suggest that the 5-HT4 receptor is a promising treatment target for cognitive impairment in individuals with psychiatric disorders, although studies in humans have been limited by the adverse effects of early agents.
“We’ve had our eye on this receptor for a while,” explained de Cates, inasmuch as the animal data “have been so good.”
However, she said in an interview that “a lack of safe human agents made translation tricky.”
As previously reported, prucalopride, a selective high-affinity 5-HT4 partial agonist, was approved in 2018 by the U.S. Food and Drug Administration for the treatment of chronic idiopathic constipation.
The current researchers note that the drug has “good brain penetration,” which “allowed us to investigate 5-HT4-receptor agonism in humans.”
Having previously shown that a single dose of the drug has “pro-cognitive effects,” the investigators conducted the new trial in 44 healthy participants. All were randomly assigned in a 1:1 ratio to receive either prucalopride 1 mg for 7 days or placebo.
In accordance with enrollment criteria, patients were 18 to 36 years of age, right-handed, and were not pregnant or breastfeeding. Participants’ body mass index was 18 to 30 kg/m2, and they had no contraindications to the study drug. The two treatment groups were well balanced; the participants who received placebo were significantly more likely to be nonnative English speakers (P = .02).
On day 6 of treatment administration, all participants underwent 3T MRI.
Before undergoing imaging, the participants were presented with eight emotionally neutral images of animals or landscapes and were asked to indicate whether or not the images were of animals. The task was then repeated with the eight familiar images and eight novel ones.
During the scan, participants were shown the same images or eight novel images and were again asked whether or not the images contained an animal. They were also instructed to try to remember the images for a subsequent memory task. In that task, the eight original images, 48 novel images, and 27 “distractor” images were presented.
Better memory
In the pre-scan assessment, results showed no significant differences in the ability of members of the prucalopride and placebo groups to identify images as being familiar or different.
However, taking prucalopride was associated with significantly improved memory performance in the post-scan recall task.
Compared to the placebo group, participants in the prucalopride group were more accurate in selecting images as familiar vs distractors (P = .029) and in distinguishing images as familiar, novel, or distractors (P = .035).
Functional MRI revealed increased activity in the left and right hippocampus in response to both novel and familiar images among the participants in the prucalopride group in comparison with those in the placebo group.
There was also increased activity in the right angular gyrus in the prucalopride group in comparison with the placebo group in response to familiar images (P < .005).
“Clinically, angular gyri lesions cause language dysfunction, low mood, and poor memory and can mimic dementia or pseudodementia,” the investigators write. They note that the right angular gyrus “shows significantly decreased activity” in mild cognitive impairment.
“Therefore, the increased activity seen in the right angular gyrus following prucalopride administration in our study is consistent with the pro-cognitive behavioural effects we observed,” they add.
Ms. De Cates noted that the dose used in their study was lower than the 2 mg given for constipation.
“At the low dose, there were no differences in side effects between groups and no withdrawals from the prucalopride group for side effects. We are going to try increasing the dose in our next study actually, as we don’t have PET data to tell us what the optimal dose for binding at the receptor should be,” said Ms. de Cates.
“In safety studies, the dose was trialled in healthy volunteers at 4 mg, which was found to be safe, although perhaps less well tolerated than 2 mg,” she said.
Generalizable findings?
Commenting on the research, Vibe G. Frøkjær, MD, adjunct professor, department of psychology, Copenhagen University, Denmark, said the study “highlights a very interesting and much needed potential for repurposing drugs to help cognitive dysfunction.”
He noted that cognitive dysfunction is often associated with psychiatric disorders -- even in states of remission.
“Importantly, as the authors also state, it will be vital to translate these findings from healthy populations into clinical populations,” said Dr. Frøkjær, who was not involved in the research.
“It will also be important to understand if prucalopride adds to the effects of existing antidepressant treatments or can be used as a stand-alone therapy,” he added.
The study was funded by the NIHR Oxford Health Biomedical Research Center and by the Wellcome Center for Integrative Neuroscience. Ms. De Cates has received a travel grant from the Royal College of Psychiatrists/Gatsby Foundation and support from Wellcome. The other authors have relationships with P1vital Ltd, Janssen Pharmaceuticals, Sage Therapeutics, Pfizer, Zogenix, Compass Pathways, and Lundbeck.
A version of this article first appeared on Medscape.com.
Long COVID appears to ‘impair’ survival in cancer patients
More than one in six cancer patients experience long-term sequelae following SARS-CoV-2 infection, placing them at increased risk of discontinuing their cancer treatment or dying, according to European registry data.
Given the “high lethality” of COVID-19 in cancer patients and the risk for long-term complications following infection in the general population, Alessio Cortellini, MD, a consultant medical oncologist at Hammersmith Hospital and Imperial College London, and colleagues wanted to explore the “prevalence and clinical significance of COVID-19 sequelae in cancer patients and their oncological continuity of care.”
Dr. Cortellini presented the OnCovid registry research on Sept. 21 at the 2021 European Society for Medical Oncology Congress. He reported that overall, the data suggest that post–COVID-19 complications may “impair” patients’ cancer survival as well as their cancer care.
The OnCovid registry data showed that the 15% of cancer patients who had long-term COVID-19 complications were 76% more likely to die than those without sequelae. Cancer patients with COVID-19 sequelae were significantly more likely to permanently stop taking their systemic anticancer therapy, and they were more than 3.5 times more likely to die than those who continued their treatment as planned. In terms of long-term complications, almost half of patients experienced dyspnea, and two-fifths reported chronic fatigue.
“This data confirms the need to continue to prioritize cancer patients,” Antonio Passaro, MD, PhD, division of thoracic oncology, European Institute of Oncology IRCCS, Milan, commented in a press release. “In the fight against the pandemic, it is of the utmost importance that we do not neglect to study and understand the curves of cancer incidence and mortality.”
Invited to discuss the results, Anne-Marie C. Dingemans, MD, PhD, a pulmonologist and professor of thoracic oncology at Erasmus Medical Center, Rotterdam, the Netherlands, said COVID-19 remains a “very important” issue for cancer patients.
Interestingly, Dr. Dingemans noted that COVID-19 sequelae in patients with cancer appear to occur slightly less frequently, compared with estimates in the general population – which range from 13% to 60% – though patients with cancer tend to have more respiratory problems.
However, Dr. Dingemans added, the difficulty with comparing sequelae rates between cancer patients and the general population is that cancer patients “probably already have a lot of symptoms” associated with long COVID, such as dyspnea and fatigue, and may not be aware that they are experiencing COVID sequelae.
The registry results
To investigate the long-term impact of COVID-19 on survival and continuity of care, the team examined data from the OnCovid registry, which was established at the beginning of the pandemic to study consecutive patients aged 18 years and older with confirmed SARS-CoV-2 infection and a history of solid or hematologic malignancies.
At the data cutoff on March 1, 2021, the registry included 35 institutions in six European countries. The institutions collected information on patient demographics and comorbidities, cancer history, anticancer therapy, COVID-19 investigations, and COVID-19–specific therapies.
For the current analysis, the team included 1,557 of 2,634 patients who had undergone a clinical reassessment after recovering from COVID-19. Information sufficient to conduct multivariate analysis was available for 840 of these patients.
About half of the patients were younger than 60 years, and just over half were women. The most common cancer diagnoses were breast cancer (23.4%), gastrointestinal tumors (16.5%), gynecologic/genitourinary tumors (19.3%), and hematologic cancers (14.1%), with even distribution between local/locoregional and advanced disease.
The median interval between COVID-19 recovery and reassessment was 44 days, and the mean post–COVID-19 follow-up period was 128 days.
About 15% of patients experienced at least one long-term sequela from COVID-19. The most common were dyspnea/shortness of breath (49.6%), fatigue (41.0%), chronic cough (33.8%), and other respiratory complications (10.7%).
Dr. Cortellini noted that cancer patients who experienced sequelae were more likely to be male, aged 65 years or older, to have at least two comorbidities, and to have a history of smoking. In addition, cancer patients who experienced long-term complications were significantly more likely to have had COVID-19 complications, to have required COVID-19 therapy, and to have been hospitalized for the disease.
Factoring in gender, age, comorbidity burden, primary tumor, stage, receipt of anticancer and anti–COVID-19 therapy, COVID-19 complications, and hospitalization, the team found that COVID-19 sequelae were independently associated with an increased risk for death (hazard ratio, 1.76).
Further analysis of patterns of systemic anticancer therapy in 471 patients revealed that 14.8% of COVID-19 survivors permanently discontinued therapy and that a dose or regimen adjustment occurred for 37.8%.
Patients who permanently discontinued anticancer therapy were more likely to be former or current smokers, to have had COVID-19 complications or been hospitalized for COVID-19, and to have had COVID-19 sequelae at reassessment. The investigators found no association between permanent discontinuation of therapy and cancer disease stage.
Dr. Cortellini and colleagues reported that permanent cessation of systemic anticancer therapy was associated with an increased risk for death. A change in dose or regimen did not affect survival.
The most common reason for stopping therapy permanently was deterioration of the patient’s performance status (61.3%), followed by disease progression (29.0%). Dose or regimen adjustments typically occurred to avoid immune suppression (50.0%), hospitalization (25.8%), and intravenous drug administration (19.1%).
Dr. Cortellini concluded his presentation by highlighting the importance of increasing awareness of long COVID in patients with cancer as well as early treatment of COVID-19 sequelae to improve patient outcomes.
The study was funded by the Imperial College Biomedical Research Center. Dr. Cortellini has relationships with MSD, Bristol-Myers Squibb, Roche, Novartis, AstraZeneca, Astellas, and Sun Pharma. Dr. Dingemans has relationships with Roche, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Jansen, Chiesi, Amgen, Pfizer, Bayer, Takeda, Pharmamar, and Sanofi.
A version of this article first appeared on Medscape.com.
More than one in six cancer patients experience long-term sequelae following SARS-CoV-2 infection, placing them at increased risk of discontinuing their cancer treatment or dying, according to European registry data.
Given the “high lethality” of COVID-19 in cancer patients and the risk for long-term complications following infection in the general population, Alessio Cortellini, MD, a consultant medical oncologist at Hammersmith Hospital and Imperial College London, and colleagues wanted to explore the “prevalence and clinical significance of COVID-19 sequelae in cancer patients and their oncological continuity of care.”
Dr. Cortellini presented the OnCovid registry research on Sept. 21 at the 2021 European Society for Medical Oncology Congress. He reported that overall, the data suggest that post–COVID-19 complications may “impair” patients’ cancer survival as well as their cancer care.
The OnCovid registry data showed that the 15% of cancer patients who had long-term COVID-19 complications were 76% more likely to die than those without sequelae. Cancer patients with COVID-19 sequelae were significantly more likely to permanently stop taking their systemic anticancer therapy, and they were more than 3.5 times more likely to die than those who continued their treatment as planned. In terms of long-term complications, almost half of patients experienced dyspnea, and two-fifths reported chronic fatigue.
“This data confirms the need to continue to prioritize cancer patients,” Antonio Passaro, MD, PhD, division of thoracic oncology, European Institute of Oncology IRCCS, Milan, commented in a press release. “In the fight against the pandemic, it is of the utmost importance that we do not neglect to study and understand the curves of cancer incidence and mortality.”
Invited to discuss the results, Anne-Marie C. Dingemans, MD, PhD, a pulmonologist and professor of thoracic oncology at Erasmus Medical Center, Rotterdam, the Netherlands, said COVID-19 remains a “very important” issue for cancer patients.
Interestingly, Dr. Dingemans noted that COVID-19 sequelae in patients with cancer appear to occur slightly less frequently, compared with estimates in the general population – which range from 13% to 60% – though patients with cancer tend to have more respiratory problems.
However, Dr. Dingemans added, the difficulty with comparing sequelae rates between cancer patients and the general population is that cancer patients “probably already have a lot of symptoms” associated with long COVID, such as dyspnea and fatigue, and may not be aware that they are experiencing COVID sequelae.
The registry results
To investigate the long-term impact of COVID-19 on survival and continuity of care, the team examined data from the OnCovid registry, which was established at the beginning of the pandemic to study consecutive patients aged 18 years and older with confirmed SARS-CoV-2 infection and a history of solid or hematologic malignancies.
At the data cutoff on March 1, 2021, the registry included 35 institutions in six European countries. The institutions collected information on patient demographics and comorbidities, cancer history, anticancer therapy, COVID-19 investigations, and COVID-19–specific therapies.
For the current analysis, the team included 1,557 of 2,634 patients who had undergone a clinical reassessment after recovering from COVID-19. Information sufficient to conduct multivariate analysis was available for 840 of these patients.
About half of the patients were younger than 60 years, and just over half were women. The most common cancer diagnoses were breast cancer (23.4%), gastrointestinal tumors (16.5%), gynecologic/genitourinary tumors (19.3%), and hematologic cancers (14.1%), with even distribution between local/locoregional and advanced disease.
The median interval between COVID-19 recovery and reassessment was 44 days, and the mean post–COVID-19 follow-up period was 128 days.
About 15% of patients experienced at least one long-term sequela from COVID-19. The most common were dyspnea/shortness of breath (49.6%), fatigue (41.0%), chronic cough (33.8%), and other respiratory complications (10.7%).
Dr. Cortellini noted that cancer patients who experienced sequelae were more likely to be male, aged 65 years or older, to have at least two comorbidities, and to have a history of smoking. In addition, cancer patients who experienced long-term complications were significantly more likely to have had COVID-19 complications, to have required COVID-19 therapy, and to have been hospitalized for the disease.
Factoring in gender, age, comorbidity burden, primary tumor, stage, receipt of anticancer and anti–COVID-19 therapy, COVID-19 complications, and hospitalization, the team found that COVID-19 sequelae were independently associated with an increased risk for death (hazard ratio, 1.76).
Further analysis of patterns of systemic anticancer therapy in 471 patients revealed that 14.8% of COVID-19 survivors permanently discontinued therapy and that a dose or regimen adjustment occurred for 37.8%.
Patients who permanently discontinued anticancer therapy were more likely to be former or current smokers, to have had COVID-19 complications or been hospitalized for COVID-19, and to have had COVID-19 sequelae at reassessment. The investigators found no association between permanent discontinuation of therapy and cancer disease stage.
Dr. Cortellini and colleagues reported that permanent cessation of systemic anticancer therapy was associated with an increased risk for death. A change in dose or regimen did not affect survival.
The most common reason for stopping therapy permanently was deterioration of the patient’s performance status (61.3%), followed by disease progression (29.0%). Dose or regimen adjustments typically occurred to avoid immune suppression (50.0%), hospitalization (25.8%), and intravenous drug administration (19.1%).
Dr. Cortellini concluded his presentation by highlighting the importance of increasing awareness of long COVID in patients with cancer as well as early treatment of COVID-19 sequelae to improve patient outcomes.
The study was funded by the Imperial College Biomedical Research Center. Dr. Cortellini has relationships with MSD, Bristol-Myers Squibb, Roche, Novartis, AstraZeneca, Astellas, and Sun Pharma. Dr. Dingemans has relationships with Roche, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Jansen, Chiesi, Amgen, Pfizer, Bayer, Takeda, Pharmamar, and Sanofi.
A version of this article first appeared on Medscape.com.
More than one in six cancer patients experience long-term sequelae following SARS-CoV-2 infection, placing them at increased risk of discontinuing their cancer treatment or dying, according to European registry data.
Given the “high lethality” of COVID-19 in cancer patients and the risk for long-term complications following infection in the general population, Alessio Cortellini, MD, a consultant medical oncologist at Hammersmith Hospital and Imperial College London, and colleagues wanted to explore the “prevalence and clinical significance of COVID-19 sequelae in cancer patients and their oncological continuity of care.”
Dr. Cortellini presented the OnCovid registry research on Sept. 21 at the 2021 European Society for Medical Oncology Congress. He reported that overall, the data suggest that post–COVID-19 complications may “impair” patients’ cancer survival as well as their cancer care.
The OnCovid registry data showed that the 15% of cancer patients who had long-term COVID-19 complications were 76% more likely to die than those without sequelae. Cancer patients with COVID-19 sequelae were significantly more likely to permanently stop taking their systemic anticancer therapy, and they were more than 3.5 times more likely to die than those who continued their treatment as planned. In terms of long-term complications, almost half of patients experienced dyspnea, and two-fifths reported chronic fatigue.
“This data confirms the need to continue to prioritize cancer patients,” Antonio Passaro, MD, PhD, division of thoracic oncology, European Institute of Oncology IRCCS, Milan, commented in a press release. “In the fight against the pandemic, it is of the utmost importance that we do not neglect to study and understand the curves of cancer incidence and mortality.”
Invited to discuss the results, Anne-Marie C. Dingemans, MD, PhD, a pulmonologist and professor of thoracic oncology at Erasmus Medical Center, Rotterdam, the Netherlands, said COVID-19 remains a “very important” issue for cancer patients.
Interestingly, Dr. Dingemans noted that COVID-19 sequelae in patients with cancer appear to occur slightly less frequently, compared with estimates in the general population – which range from 13% to 60% – though patients with cancer tend to have more respiratory problems.
However, Dr. Dingemans added, the difficulty with comparing sequelae rates between cancer patients and the general population is that cancer patients “probably already have a lot of symptoms” associated with long COVID, such as dyspnea and fatigue, and may not be aware that they are experiencing COVID sequelae.
The registry results
To investigate the long-term impact of COVID-19 on survival and continuity of care, the team examined data from the OnCovid registry, which was established at the beginning of the pandemic to study consecutive patients aged 18 years and older with confirmed SARS-CoV-2 infection and a history of solid or hematologic malignancies.
At the data cutoff on March 1, 2021, the registry included 35 institutions in six European countries. The institutions collected information on patient demographics and comorbidities, cancer history, anticancer therapy, COVID-19 investigations, and COVID-19–specific therapies.
For the current analysis, the team included 1,557 of 2,634 patients who had undergone a clinical reassessment after recovering from COVID-19. Information sufficient to conduct multivariate analysis was available for 840 of these patients.
About half of the patients were younger than 60 years, and just over half were women. The most common cancer diagnoses were breast cancer (23.4%), gastrointestinal tumors (16.5%), gynecologic/genitourinary tumors (19.3%), and hematologic cancers (14.1%), with even distribution between local/locoregional and advanced disease.
The median interval between COVID-19 recovery and reassessment was 44 days, and the mean post–COVID-19 follow-up period was 128 days.
About 15% of patients experienced at least one long-term sequela from COVID-19. The most common were dyspnea/shortness of breath (49.6%), fatigue (41.0%), chronic cough (33.8%), and other respiratory complications (10.7%).
Dr. Cortellini noted that cancer patients who experienced sequelae were more likely to be male, aged 65 years or older, to have at least two comorbidities, and to have a history of smoking. In addition, cancer patients who experienced long-term complications were significantly more likely to have had COVID-19 complications, to have required COVID-19 therapy, and to have been hospitalized for the disease.
Factoring in gender, age, comorbidity burden, primary tumor, stage, receipt of anticancer and anti–COVID-19 therapy, COVID-19 complications, and hospitalization, the team found that COVID-19 sequelae were independently associated with an increased risk for death (hazard ratio, 1.76).
Further analysis of patterns of systemic anticancer therapy in 471 patients revealed that 14.8% of COVID-19 survivors permanently discontinued therapy and that a dose or regimen adjustment occurred for 37.8%.
Patients who permanently discontinued anticancer therapy were more likely to be former or current smokers, to have had COVID-19 complications or been hospitalized for COVID-19, and to have had COVID-19 sequelae at reassessment. The investigators found no association between permanent discontinuation of therapy and cancer disease stage.
Dr. Cortellini and colleagues reported that permanent cessation of systemic anticancer therapy was associated with an increased risk for death. A change in dose or regimen did not affect survival.
The most common reason for stopping therapy permanently was deterioration of the patient’s performance status (61.3%), followed by disease progression (29.0%). Dose or regimen adjustments typically occurred to avoid immune suppression (50.0%), hospitalization (25.8%), and intravenous drug administration (19.1%).
Dr. Cortellini concluded his presentation by highlighting the importance of increasing awareness of long COVID in patients with cancer as well as early treatment of COVID-19 sequelae to improve patient outcomes.
The study was funded by the Imperial College Biomedical Research Center. Dr. Cortellini has relationships with MSD, Bristol-Myers Squibb, Roche, Novartis, AstraZeneca, Astellas, and Sun Pharma. Dr. Dingemans has relationships with Roche, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Jansen, Chiesi, Amgen, Pfizer, Bayer, Takeda, Pharmamar, and Sanofi.
A version of this article first appeared on Medscape.com.
Nivo/ipi combo now ‘standard of care’ in mesothelioma
After 3 years, 23% of patients who received combination immunotherapy were still alive, in comparison with 15% of patients in the chemotherapy arm.
Combination immunotherapy continued to provide a “durable and long-term benefit” compared with chemotherapy, commented Solange Peters, MD, from the Oncology Department, Center Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
The new data from the additional 12 months of follow-up “confirm nivolumab plus ipilimumab as a standard of care for unresectable MPM, regardless of histology,” she commented.
She presented the update on September 17 at the annual meeting of the European Society of Medical Oncology (ESMO). She is the current president of the organization.
Previously, 2-year data from this study showed that the combination yielded a median overall survival of 18.1 months, compared to 14.1 months with standard-of-care chemotherapy.
As reported by this news organization, this translated into a 26% improvement in overall survival; 41% of patients in the immunotherapy arm were still alive at 2 years, versus 27% in the chemotherapy group.
On the basis of these data, the combination was subsequently approved in the United States, the European Union, and elsewhere for the first-line treatment of adults with unresectable MPM.
The new data come from a 3-year update, as well as an exploratory biomarker analysis. The new data show significantly improved overall survival with the combination immunotherapy. Among those who responded to immunotherapy, response was ongoing for 28% of patients at 3 years.
Benefit was seen even for patients who discontinued the treatment because of treatment-related adverse events, indicating that discontinuance does not appear to have a negative impact on the long-term benefits, Dr. Peters commented.
In addition, the new analysis suggested that patients with a high score on a four-gene inflammatory signature did particularly well with nivolumab plus ipilimumab, whereas chemotherapy patients did worse if they had nonepithelioid disease, a finding not seen with immunotherapy.
The discussant for this abstract, Pilar Garrido, MD, PhD, associate professor of medicine at the Universidad de Alcalá, Madrid, said that despite the impressive findings, there is a “critical need” to establish predictive biomarkers in MPM.
This is particularly pressing in cases involving early progression, inasmuch as median progression-free survival (PFS) in CheckMate 743 was similar overall, and chemotherapy performed better than immunotherapy in the first 8 months.
There is also a need to be able to identify patients who will have an ongoing response at 3 years, as well as to clarify the impact of toxicity, given that the median duration of response was 20 months following discontinuation of treatment after just 4 months.
Dr. Garrido cautioned that the exploratory analyses were of “limited value,” because RNA data for the gene signature analysis were available for only 54% of patients, and the study was not powered to detect differences on the basis of programmed cell death–ligand-1 (PD-L1) expression.
Summarizing, Dr. Garrido said that although the current results showed that combination immunotherapy “continued to provide” a survival benefit in “a subgroup of patients,” the “better characterization of predictive biomarkers” will be “crucial” to improving these results.
Study details
Dr. Peters reminded the audience that the CheckMate 743 trial involved patients with unresectable MPM who had not previously received any systemic therapy and who had a good performance status.
A total of 605 patients were enrolled. They were randomly assigned in a 1:1 ratio to receive either nivolumab plus ipilimumab for up to 2 years or six cycles of pemetrexed plus cisplatin or carboplatin.
The median age of the patients was 69 years, and 77% were men. The baseline characteristics were well balanced between the two treatment groups; 75% to 76% had epithelioid disease, and for 74% to 80% of patients, baseline PD-L1 expression was greater than or equal to 1%.
Subgroup analysis indicated that combination immunotherapy was beneficial regardless of patient age, sex, performance status, and smoking status.
However, the new analysis suggested that the improvement in overall survival depended on PD-L1 expression, at a hazard ratio for combination immunotherapy versus chemotherapy of 0.71 in patients with expression of greater than or equal to 1%, compared with 0.99 for patients with expression of less than 1%.
Dr. Peters explained that the performance of nivolumab plus ipilimumab was identical in both PD-L1 expression groups, but it was the chemotherapy arm that performed markedly better for patients with expression of less than 1%.
An inverse finding was observed when patients were stratified by tumor histology.
In those with epithelioid disease, the median overall survival with combination immunotherapy was 18.2 months, versus 16.7 with chemotherapy, at a hazard ratio of 0.85.
At 36 months, 24% of immunotherapy patients were still alive, as were 19% of those given standard-of-care chemotherapy.
Among patients with nonepithelioid disease, however, median overall survival was 18.1 months with nivolumab plus ipilimumab, versus just 8.8 months with chemotherapy, at a hazard ratio of 0.48. At 3 years, 22% of patients who received combination immunotherapy were still alive, compared with 4% of those who received chemotherapy.
Other results showed that PFS was only slightly longer with combination immunotherapy, at 6.8 months versus 7.2 months, for a hazard ratio of 0.92.
Yet at 36 months, 14% of patients who received nivolumab plus ipilimumab had not experienced disease progression, versus just 1% of those in the chemotherapy arm.
This difference was even more pronounced when the researchers assessed objective response rates: 28% of patients who received combination immunotherapy were still responding at 36 months, versus 0% among patients given chemotherapy.
This translated into a median duration of response of 11.6 months for nivolumab plus ipilimumab, versus 6.7 months with chemotherapy.
The safety assessment showed that rates of treatment-related adverse events of any grade and of grade 3-4 were similar between the combination immunotherapy and chemotherapy arms.
However, rates of treatment-related adverse events that led to discontinuation of all components of the regimen were higher with immunotherapy, at 17% for events of any grade and 13% for events of grade 3-4, compared with 8% and 5%, respectively, with chemotherapy.
Serious treatment-related adverse events were more common with nivolumab plus ipilimumab. Events of grade 3-4 occurred in 13% of patients with nivolumab plus ipilimumab, versus 5% with chemotherapy.
Dr. Peters showed that this did not severely affect overall survival, however. Among patients who discontinued combination immunotherapy, the median duration of response was 20.0 months.
Median overall survival in these patients was 25.4 months, and the 3-year overall survival rate was 37%.
The study was funded by Bristol-Myers Squibb. Dr. Peters and Dr. Garrido reported relationships with numerous sources in industry.
A version of this article first appeared on Medscape.com.
After 3 years, 23% of patients who received combination immunotherapy were still alive, in comparison with 15% of patients in the chemotherapy arm.
Combination immunotherapy continued to provide a “durable and long-term benefit” compared with chemotherapy, commented Solange Peters, MD, from the Oncology Department, Center Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
The new data from the additional 12 months of follow-up “confirm nivolumab plus ipilimumab as a standard of care for unresectable MPM, regardless of histology,” she commented.
She presented the update on September 17 at the annual meeting of the European Society of Medical Oncology (ESMO). She is the current president of the organization.
Previously, 2-year data from this study showed that the combination yielded a median overall survival of 18.1 months, compared to 14.1 months with standard-of-care chemotherapy.
As reported by this news organization, this translated into a 26% improvement in overall survival; 41% of patients in the immunotherapy arm were still alive at 2 years, versus 27% in the chemotherapy group.
On the basis of these data, the combination was subsequently approved in the United States, the European Union, and elsewhere for the first-line treatment of adults with unresectable MPM.
The new data come from a 3-year update, as well as an exploratory biomarker analysis. The new data show significantly improved overall survival with the combination immunotherapy. Among those who responded to immunotherapy, response was ongoing for 28% of patients at 3 years.
Benefit was seen even for patients who discontinued the treatment because of treatment-related adverse events, indicating that discontinuance does not appear to have a negative impact on the long-term benefits, Dr. Peters commented.
In addition, the new analysis suggested that patients with a high score on a four-gene inflammatory signature did particularly well with nivolumab plus ipilimumab, whereas chemotherapy patients did worse if they had nonepithelioid disease, a finding not seen with immunotherapy.
The discussant for this abstract, Pilar Garrido, MD, PhD, associate professor of medicine at the Universidad de Alcalá, Madrid, said that despite the impressive findings, there is a “critical need” to establish predictive biomarkers in MPM.
This is particularly pressing in cases involving early progression, inasmuch as median progression-free survival (PFS) in CheckMate 743 was similar overall, and chemotherapy performed better than immunotherapy in the first 8 months.
There is also a need to be able to identify patients who will have an ongoing response at 3 years, as well as to clarify the impact of toxicity, given that the median duration of response was 20 months following discontinuation of treatment after just 4 months.
Dr. Garrido cautioned that the exploratory analyses were of “limited value,” because RNA data for the gene signature analysis were available for only 54% of patients, and the study was not powered to detect differences on the basis of programmed cell death–ligand-1 (PD-L1) expression.
Summarizing, Dr. Garrido said that although the current results showed that combination immunotherapy “continued to provide” a survival benefit in “a subgroup of patients,” the “better characterization of predictive biomarkers” will be “crucial” to improving these results.
Study details
Dr. Peters reminded the audience that the CheckMate 743 trial involved patients with unresectable MPM who had not previously received any systemic therapy and who had a good performance status.
A total of 605 patients were enrolled. They were randomly assigned in a 1:1 ratio to receive either nivolumab plus ipilimumab for up to 2 years or six cycles of pemetrexed plus cisplatin or carboplatin.
The median age of the patients was 69 years, and 77% were men. The baseline characteristics were well balanced between the two treatment groups; 75% to 76% had epithelioid disease, and for 74% to 80% of patients, baseline PD-L1 expression was greater than or equal to 1%.
Subgroup analysis indicated that combination immunotherapy was beneficial regardless of patient age, sex, performance status, and smoking status.
However, the new analysis suggested that the improvement in overall survival depended on PD-L1 expression, at a hazard ratio for combination immunotherapy versus chemotherapy of 0.71 in patients with expression of greater than or equal to 1%, compared with 0.99 for patients with expression of less than 1%.
Dr. Peters explained that the performance of nivolumab plus ipilimumab was identical in both PD-L1 expression groups, but it was the chemotherapy arm that performed markedly better for patients with expression of less than 1%.
An inverse finding was observed when patients were stratified by tumor histology.
In those with epithelioid disease, the median overall survival with combination immunotherapy was 18.2 months, versus 16.7 with chemotherapy, at a hazard ratio of 0.85.
At 36 months, 24% of immunotherapy patients were still alive, as were 19% of those given standard-of-care chemotherapy.
Among patients with nonepithelioid disease, however, median overall survival was 18.1 months with nivolumab plus ipilimumab, versus just 8.8 months with chemotherapy, at a hazard ratio of 0.48. At 3 years, 22% of patients who received combination immunotherapy were still alive, compared with 4% of those who received chemotherapy.
Other results showed that PFS was only slightly longer with combination immunotherapy, at 6.8 months versus 7.2 months, for a hazard ratio of 0.92.
Yet at 36 months, 14% of patients who received nivolumab plus ipilimumab had not experienced disease progression, versus just 1% of those in the chemotherapy arm.
This difference was even more pronounced when the researchers assessed objective response rates: 28% of patients who received combination immunotherapy were still responding at 36 months, versus 0% among patients given chemotherapy.
This translated into a median duration of response of 11.6 months for nivolumab plus ipilimumab, versus 6.7 months with chemotherapy.
The safety assessment showed that rates of treatment-related adverse events of any grade and of grade 3-4 were similar between the combination immunotherapy and chemotherapy arms.
However, rates of treatment-related adverse events that led to discontinuation of all components of the regimen were higher with immunotherapy, at 17% for events of any grade and 13% for events of grade 3-4, compared with 8% and 5%, respectively, with chemotherapy.
Serious treatment-related adverse events were more common with nivolumab plus ipilimumab. Events of grade 3-4 occurred in 13% of patients with nivolumab plus ipilimumab, versus 5% with chemotherapy.
Dr. Peters showed that this did not severely affect overall survival, however. Among patients who discontinued combination immunotherapy, the median duration of response was 20.0 months.
Median overall survival in these patients was 25.4 months, and the 3-year overall survival rate was 37%.
The study was funded by Bristol-Myers Squibb. Dr. Peters and Dr. Garrido reported relationships with numerous sources in industry.
A version of this article first appeared on Medscape.com.
After 3 years, 23% of patients who received combination immunotherapy were still alive, in comparison with 15% of patients in the chemotherapy arm.
Combination immunotherapy continued to provide a “durable and long-term benefit” compared with chemotherapy, commented Solange Peters, MD, from the Oncology Department, Center Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
The new data from the additional 12 months of follow-up “confirm nivolumab plus ipilimumab as a standard of care for unresectable MPM, regardless of histology,” she commented.
She presented the update on September 17 at the annual meeting of the European Society of Medical Oncology (ESMO). She is the current president of the organization.
Previously, 2-year data from this study showed that the combination yielded a median overall survival of 18.1 months, compared to 14.1 months with standard-of-care chemotherapy.
As reported by this news organization, this translated into a 26% improvement in overall survival; 41% of patients in the immunotherapy arm were still alive at 2 years, versus 27% in the chemotherapy group.
On the basis of these data, the combination was subsequently approved in the United States, the European Union, and elsewhere for the first-line treatment of adults with unresectable MPM.
The new data come from a 3-year update, as well as an exploratory biomarker analysis. The new data show significantly improved overall survival with the combination immunotherapy. Among those who responded to immunotherapy, response was ongoing for 28% of patients at 3 years.
Benefit was seen even for patients who discontinued the treatment because of treatment-related adverse events, indicating that discontinuance does not appear to have a negative impact on the long-term benefits, Dr. Peters commented.
In addition, the new analysis suggested that patients with a high score on a four-gene inflammatory signature did particularly well with nivolumab plus ipilimumab, whereas chemotherapy patients did worse if they had nonepithelioid disease, a finding not seen with immunotherapy.
The discussant for this abstract, Pilar Garrido, MD, PhD, associate professor of medicine at the Universidad de Alcalá, Madrid, said that despite the impressive findings, there is a “critical need” to establish predictive biomarkers in MPM.
This is particularly pressing in cases involving early progression, inasmuch as median progression-free survival (PFS) in CheckMate 743 was similar overall, and chemotherapy performed better than immunotherapy in the first 8 months.
There is also a need to be able to identify patients who will have an ongoing response at 3 years, as well as to clarify the impact of toxicity, given that the median duration of response was 20 months following discontinuation of treatment after just 4 months.
Dr. Garrido cautioned that the exploratory analyses were of “limited value,” because RNA data for the gene signature analysis were available for only 54% of patients, and the study was not powered to detect differences on the basis of programmed cell death–ligand-1 (PD-L1) expression.
Summarizing, Dr. Garrido said that although the current results showed that combination immunotherapy “continued to provide” a survival benefit in “a subgroup of patients,” the “better characterization of predictive biomarkers” will be “crucial” to improving these results.
Study details
Dr. Peters reminded the audience that the CheckMate 743 trial involved patients with unresectable MPM who had not previously received any systemic therapy and who had a good performance status.
A total of 605 patients were enrolled. They were randomly assigned in a 1:1 ratio to receive either nivolumab plus ipilimumab for up to 2 years or six cycles of pemetrexed plus cisplatin or carboplatin.
The median age of the patients was 69 years, and 77% were men. The baseline characteristics were well balanced between the two treatment groups; 75% to 76% had epithelioid disease, and for 74% to 80% of patients, baseline PD-L1 expression was greater than or equal to 1%.
Subgroup analysis indicated that combination immunotherapy was beneficial regardless of patient age, sex, performance status, and smoking status.
However, the new analysis suggested that the improvement in overall survival depended on PD-L1 expression, at a hazard ratio for combination immunotherapy versus chemotherapy of 0.71 in patients with expression of greater than or equal to 1%, compared with 0.99 for patients with expression of less than 1%.
Dr. Peters explained that the performance of nivolumab plus ipilimumab was identical in both PD-L1 expression groups, but it was the chemotherapy arm that performed markedly better for patients with expression of less than 1%.
An inverse finding was observed when patients were stratified by tumor histology.
In those with epithelioid disease, the median overall survival with combination immunotherapy was 18.2 months, versus 16.7 with chemotherapy, at a hazard ratio of 0.85.
At 36 months, 24% of immunotherapy patients were still alive, as were 19% of those given standard-of-care chemotherapy.
Among patients with nonepithelioid disease, however, median overall survival was 18.1 months with nivolumab plus ipilimumab, versus just 8.8 months with chemotherapy, at a hazard ratio of 0.48. At 3 years, 22% of patients who received combination immunotherapy were still alive, compared with 4% of those who received chemotherapy.
Other results showed that PFS was only slightly longer with combination immunotherapy, at 6.8 months versus 7.2 months, for a hazard ratio of 0.92.
Yet at 36 months, 14% of patients who received nivolumab plus ipilimumab had not experienced disease progression, versus just 1% of those in the chemotherapy arm.
This difference was even more pronounced when the researchers assessed objective response rates: 28% of patients who received combination immunotherapy were still responding at 36 months, versus 0% among patients given chemotherapy.
This translated into a median duration of response of 11.6 months for nivolumab plus ipilimumab, versus 6.7 months with chemotherapy.
The safety assessment showed that rates of treatment-related adverse events of any grade and of grade 3-4 were similar between the combination immunotherapy and chemotherapy arms.
However, rates of treatment-related adverse events that led to discontinuation of all components of the regimen were higher with immunotherapy, at 17% for events of any grade and 13% for events of grade 3-4, compared with 8% and 5%, respectively, with chemotherapy.
Serious treatment-related adverse events were more common with nivolumab plus ipilimumab. Events of grade 3-4 occurred in 13% of patients with nivolumab plus ipilimumab, versus 5% with chemotherapy.
Dr. Peters showed that this did not severely affect overall survival, however. Among patients who discontinued combination immunotherapy, the median duration of response was 20.0 months.
Median overall survival in these patients was 25.4 months, and the 3-year overall survival rate was 37%.
The study was funded by Bristol-Myers Squibb. Dr. Peters and Dr. Garrido reported relationships with numerous sources in industry.
A version of this article first appeared on Medscape.com.