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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
Lie down for orthostatic hypotension assessment
New research shows that supine orthostatic hypotension is more common and better predicts falls and orthostatic symptoms than seated OH, supporting a supine OH protocol in clinical practice, the researchers say.
“Older adults at risk for falls undergoing assessment for OH should lie supine rather than sitting prior to standing to get the most informative OH assessment,” study author Stephen Juraschek, MD, PhD, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, said in an interview.
“The findings call for a change in current practice,” Dr. Juraschek said.
He presented the study Sept. 29 at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.
The seated position for detecting OH is “commonly used for convenience. Since many clinics already perform a seated blood pressure, it saves time for people to stand shortly afterward,” he explained.
“It has also been thought that the two are interchangeable [i.e., the change in blood pressure from seated to standing was just a lower magnitude than the change from supine to standing]. However, we showed that the physiology is on average quite different, questioning prior perspectives on the interchangeability of the two protocols,” he added.
The researchers studied 522 adults (mean age, 76 years; 42% women) at high risk for falls and with vitamin D levels in the insufficient/deficient range participating in the Study to Understand Fall Reduction and Vitamin D (STURDY).
The study showed that vitamin D supplementation was not associated with OH or the main study outcome of falls.
The study used two different OH assessment protocols – seated to standing and supine to standing – and Dr. Juraschek’s team used the data to gauge the impact of supine and seated positions on OH prevalence and its relation with fall risk and orthostatic symptoms.
OH was defined as a drop in systolic BP of at least 20 mm Hg or diastolic BP of at least 10 mm Hg.
At baseline, mean BP was 129/68 mm Hg. Mean BP increased 3.4/2.6 mm Hg after sitting, but decreased 3.7/0.7 mm Hg after lying supine.
Of the 953 OH assessments (supine and seated), OH was detected in 14.8% of the supine measurements but in only 2.2% of the seated measures.
Supine OH better predicted falls (hazard ratio, 1.60; 95% CI, 0.98-2.61; P = .06) than seated OH (HR, 0.70; 95% CI, 0.30-1.60; P = .39).
Although both were nonsignificant, “potentially due to power,” the association with falls was stronger for supine OH than for seated OH, Dr. Juraschek said.
In addition, seated OH was not associated with orthostatic symptoms, whereas supine OH was significantly associated with a greater risk of fainting, blacking out, seeing spots, room spinning, and headache in the previous month (P = .048-.002).
Useful study confirms anecdotal evidence
This is a “useful study” from a “reputable” group, “and the results reveal what I would have expected,” Robert Carey, MD, University of Virginia, Charlottesville, who wasn’t involved in the study, said in an interview.
The findings, Dr. Carey said, show that measuring supine, compared with standing, “actually correlates much better with the untoward effects of orthostatic hypotension which are falls and symptoms such as dizziness and spots before your eyes.”
“Seated BP is mostly used for convenience and a little bit shorter protocol. Most clinical trials do seated orthostatic hypotension measurements. I’ve always taught my medical students and others to use the supine to standing because I’ve just anecdotally felt that this was a much better way of detecting true orthostatic hypotension and that’s how we do it at the University of Virginia Hospital,” Dr. Carey said.
The study had no funding. Dr. Juraschek and Dr. Carey have no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
New research shows that supine orthostatic hypotension is more common and better predicts falls and orthostatic symptoms than seated OH, supporting a supine OH protocol in clinical practice, the researchers say.
“Older adults at risk for falls undergoing assessment for OH should lie supine rather than sitting prior to standing to get the most informative OH assessment,” study author Stephen Juraschek, MD, PhD, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, said in an interview.
“The findings call for a change in current practice,” Dr. Juraschek said.
He presented the study Sept. 29 at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.
The seated position for detecting OH is “commonly used for convenience. Since many clinics already perform a seated blood pressure, it saves time for people to stand shortly afterward,” he explained.
“It has also been thought that the two are interchangeable [i.e., the change in blood pressure from seated to standing was just a lower magnitude than the change from supine to standing]. However, we showed that the physiology is on average quite different, questioning prior perspectives on the interchangeability of the two protocols,” he added.
The researchers studied 522 adults (mean age, 76 years; 42% women) at high risk for falls and with vitamin D levels in the insufficient/deficient range participating in the Study to Understand Fall Reduction and Vitamin D (STURDY).
The study showed that vitamin D supplementation was not associated with OH or the main study outcome of falls.
The study used two different OH assessment protocols – seated to standing and supine to standing – and Dr. Juraschek’s team used the data to gauge the impact of supine and seated positions on OH prevalence and its relation with fall risk and orthostatic symptoms.
OH was defined as a drop in systolic BP of at least 20 mm Hg or diastolic BP of at least 10 mm Hg.
At baseline, mean BP was 129/68 mm Hg. Mean BP increased 3.4/2.6 mm Hg after sitting, but decreased 3.7/0.7 mm Hg after lying supine.
Of the 953 OH assessments (supine and seated), OH was detected in 14.8% of the supine measurements but in only 2.2% of the seated measures.
Supine OH better predicted falls (hazard ratio, 1.60; 95% CI, 0.98-2.61; P = .06) than seated OH (HR, 0.70; 95% CI, 0.30-1.60; P = .39).
Although both were nonsignificant, “potentially due to power,” the association with falls was stronger for supine OH than for seated OH, Dr. Juraschek said.
In addition, seated OH was not associated with orthostatic symptoms, whereas supine OH was significantly associated with a greater risk of fainting, blacking out, seeing spots, room spinning, and headache in the previous month (P = .048-.002).
Useful study confirms anecdotal evidence
This is a “useful study” from a “reputable” group, “and the results reveal what I would have expected,” Robert Carey, MD, University of Virginia, Charlottesville, who wasn’t involved in the study, said in an interview.
The findings, Dr. Carey said, show that measuring supine, compared with standing, “actually correlates much better with the untoward effects of orthostatic hypotension which are falls and symptoms such as dizziness and spots before your eyes.”
“Seated BP is mostly used for convenience and a little bit shorter protocol. Most clinical trials do seated orthostatic hypotension measurements. I’ve always taught my medical students and others to use the supine to standing because I’ve just anecdotally felt that this was a much better way of detecting true orthostatic hypotension and that’s how we do it at the University of Virginia Hospital,” Dr. Carey said.
The study had no funding. Dr. Juraschek and Dr. Carey have no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
New research shows that supine orthostatic hypotension is more common and better predicts falls and orthostatic symptoms than seated OH, supporting a supine OH protocol in clinical practice, the researchers say.
“Older adults at risk for falls undergoing assessment for OH should lie supine rather than sitting prior to standing to get the most informative OH assessment,” study author Stephen Juraschek, MD, PhD, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, said in an interview.
“The findings call for a change in current practice,” Dr. Juraschek said.
He presented the study Sept. 29 at the joint scientific sessions of the American Heart Association Council on Hypertension, AHA Council on Kidney in Cardiovascular Disease, and American Society of Hypertension.
The seated position for detecting OH is “commonly used for convenience. Since many clinics already perform a seated blood pressure, it saves time for people to stand shortly afterward,” he explained.
“It has also been thought that the two are interchangeable [i.e., the change in blood pressure from seated to standing was just a lower magnitude than the change from supine to standing]. However, we showed that the physiology is on average quite different, questioning prior perspectives on the interchangeability of the two protocols,” he added.
The researchers studied 522 adults (mean age, 76 years; 42% women) at high risk for falls and with vitamin D levels in the insufficient/deficient range participating in the Study to Understand Fall Reduction and Vitamin D (STURDY).
The study showed that vitamin D supplementation was not associated with OH or the main study outcome of falls.
The study used two different OH assessment protocols – seated to standing and supine to standing – and Dr. Juraschek’s team used the data to gauge the impact of supine and seated positions on OH prevalence and its relation with fall risk and orthostatic symptoms.
OH was defined as a drop in systolic BP of at least 20 mm Hg or diastolic BP of at least 10 mm Hg.
At baseline, mean BP was 129/68 mm Hg. Mean BP increased 3.4/2.6 mm Hg after sitting, but decreased 3.7/0.7 mm Hg after lying supine.
Of the 953 OH assessments (supine and seated), OH was detected in 14.8% of the supine measurements but in only 2.2% of the seated measures.
Supine OH better predicted falls (hazard ratio, 1.60; 95% CI, 0.98-2.61; P = .06) than seated OH (HR, 0.70; 95% CI, 0.30-1.60; P = .39).
Although both were nonsignificant, “potentially due to power,” the association with falls was stronger for supine OH than for seated OH, Dr. Juraschek said.
In addition, seated OH was not associated with orthostatic symptoms, whereas supine OH was significantly associated with a greater risk of fainting, blacking out, seeing spots, room spinning, and headache in the previous month (P = .048-.002).
Useful study confirms anecdotal evidence
This is a “useful study” from a “reputable” group, “and the results reveal what I would have expected,” Robert Carey, MD, University of Virginia, Charlottesville, who wasn’t involved in the study, said in an interview.
The findings, Dr. Carey said, show that measuring supine, compared with standing, “actually correlates much better with the untoward effects of orthostatic hypotension which are falls and symptoms such as dizziness and spots before your eyes.”
“Seated BP is mostly used for convenience and a little bit shorter protocol. Most clinical trials do seated orthostatic hypotension measurements. I’ve always taught my medical students and others to use the supine to standing because I’ve just anecdotally felt that this was a much better way of detecting true orthostatic hypotension and that’s how we do it at the University of Virginia Hospital,” Dr. Carey said.
The study had no funding. Dr. Juraschek and Dr. Carey have no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
New nonhormonal therapies for hot flashes on the horizon
Hot flashes affect three out of four women and can last 7-10 years, but the current standard of care treatment isn’t necessarily appropriate for all women who experience vasomotor symptoms, according to Stephanie Faubion, MD, MBA, director of the Mayo Clinic Women’s Health Clinic in Jacksonville, Fla.
For the majority of women under age 60 who are within 10 years of menopause, hormone therapy currently remains the most effective management option for hot flashes where the benefits outweigh the risks, Dr. Faubion told attendees Sept. 25 during a plenary at the annual meeting of the North American Menopause Society. “But really, individualizing treatment is the goal, and there are some women who are going to need some other options.”
Contraindications for hormone therapy include having a history of breast cancer, coronary heart disease, active liver disease, unexplained vaginal bleeding, high-risk endometrial cancer, transient ischemic attack, and a previous venous thromboembolic event or stroke.
“Fortunately, we have things in development,” Dr. Faubion said. She reviewed a wide range of therapies that are not currently Food and Drug Administration approved for vasomotor symptoms but are either available off label or are in clinical trials.
One of these is oxybutynin, an antimuscarinic, anticholinergic agent currently used to treat overactive bladder and overactive sweating. In a 2016 trial, 73% of women taking 15 mg extended-release oxybutynin once daily rated their symptoms as “much better,” compared with 26% who received placebo. The women experienced reduced frequency and severity of hot flashes and better sleep.
Subsequent research found a 60% reduction in hot flash frequency with 2.5 mg twice a day and a 77% reduction with 5 mg twice a day, compared with a 27% reduction with placebo. The only reported side effect that occurred more often with oxybutynin was dry mouth, but there were no significant differences in reasons for discontinuation between the treatment and placebo groups.
There are, however, some potential long-term cognitive effects from oxybutynin, Dr. Faubion said. Some research has shown an increased risk of dementia from oxybutynin and from an overall higher cumulative use of anticholinergics.
“There’s some concern about that for long-term use,” she said, but it’s effective, it’s “probably not harmful [when] used short term in women with significant, bothersome hot flashes who are unwilling or unable to use hormone therapy, and the adverse effects are tolerable for most women.” Women with bladder symptoms would be especially ideal candidates since the drug already treats those.
Dr. Faubion then discussed a new estrogen called estetrol (E4), a naturally occurring estrogen with selection action in tissues that is produced by the fetal liver and crosses the placenta. It has a long half-life of 28-32 hours, and its potential mechanism may give it a different safety profile than estradiol (E2). “There may be a lower risk of drug-drug interactions; lower breast stimulation, pain or carcinogenic impact; lower impact on triglycerides; and a neutral impact on markers of coagulation,” she said.
Though estetrol was recently approved as an oral contraceptive under the name Estelle, it’s also under investigation as a postmenopausal regimen. Preliminary findings suggest it reduces vasomotor symptom severity by 44%, compared with 30% with placebo, at 15 mg, the apparent minimum effective dose. The safety profile showed no endometrial hyperplasia and no unexpected adverse events. In those taking 15 mg of estetrol, mean endometrial thickness increased from 2 to 6 mm but returned to baseline after progestin therapy.
“The 15-mg dose also positively influenced markers of bone turnover, increased HDL [cholesterol], improved glucose tolerance,” and had no effects on coagulation parameters or triglycerides, Dr. Faubion added.
Another group of potential agents being studied for hot flashes are NK3 antagonists, which aim to exploit the recent discovery that kisspeptin, neurokinin B, and dynorphin (KNDy) neurons may play an important role in the etiology of vasomotor symptoms. Development of one of these, MLE 4901, was halted despite a 45% reduction in hot flashes because 3 of 28 women developed transiently elevated liver function tests, about four to six times the upper limit of normal.
Two others, fezolinetant and NT-814, are in phase 2 trials and have shown a significant reduction in symptoms, compared with placebo. The most commonly reported adverse effect in the phase 2a trial was gastrointestinal effects, but none of the participants stopped the drug because of these, and no elevated liver tests occurred. In the larger phase 2b trial, the most commonly reported treatment-emergent adverse events included nausea, diarrhea, fatigue, urinary tract infection, sinusitis, upper respiratory infection, headache, and cough. Five women discontinued the drug because of elevated liver enzymes.
“Overall, NK3 inhibitors appear to be generally well tolerated,” Dr. Faubion said. “There does seem to be mild transaminase elevation,” though it’s not yet known if this is an effect from this class of drugs as a whole. She noted that follicle-stimulating hormone does not significantly increase, which is important because elevated FSH is associated with poor bone health, nor does estradiol significantly increase, which is clinically relevant for women at high risk of breast cancer.
“We don’t know the effects on the heart, the brain, the bone, mood, weight, or sexual health, so there’s a lot that is still not known,” Dr. Faubion said. “We still don’t know about long-term safety and efficacy with these chemical compounds,” but clinical trials of them are ongoing.
They “would be a welcome alternative to hormone therapy for those who can’t or prefer not to use a hormonal option,” Dr. Faubion said. “However, we may need broad education of clinicians to caution against widespread abandonment of hormone therapy, particularly in women with premature or early menopause.”
Donna Klassen, LCSW, the cofounder of Let’s Talk Menopause, asked whether any of these new therapies were being tested in women with breast cancer and whether anything was known about taking oxybutynin at the same time as letrozole.
“I suspect that most women with chronic diseases would have been excluded from these initial studies, but I can’t speak to that,” Dr. Faubion said, and she wasn’t aware of any data related to taking oxybutynin and letrozole concurrently.
James Simon, MD, medical director and founder of IntimMedicine and one of those who led the research on oxybutynin, responded that his trials excluded breast cancer survivors and anyone taking aromatase inhibitors.
“It will be unlikely that, in the very near future, that data will be available because all the clinical developments on these NK3s or KNDy neuron-modulating drugs exclude cancer patients,” Dr. Simon said.
However, another attendee, Lisa Larkin, MD, of Cincinnati, introduced herself as a breast cancer survivor who takes tamoxifen and said she feels “completely comfortable” prescribing oxybutynin to breast cancer survivors.
“In terms of side effects and effectiveness in patients on tamoxifen and aromatase inhibitors, I’ve had incredibly good luck with it, and I think it’s underutilized,” Dr. Larkin said. “The clinical pearl I would tell you is you can start really low, and the dry mouth really seems to improve with time.” She added that patients should be informed that it takes 2 weeks before it begins working, but the side effects eventually go away. “It becomes very tolerable, so I just encourage all of you to consider it as another great option.”
Dr. Faubion had no disclosures. Disclosure information was unavailable for Dr. Simon, Dr. Larkin, and Ms. Klassen.
Hot flashes affect three out of four women and can last 7-10 years, but the current standard of care treatment isn’t necessarily appropriate for all women who experience vasomotor symptoms, according to Stephanie Faubion, MD, MBA, director of the Mayo Clinic Women’s Health Clinic in Jacksonville, Fla.
For the majority of women under age 60 who are within 10 years of menopause, hormone therapy currently remains the most effective management option for hot flashes where the benefits outweigh the risks, Dr. Faubion told attendees Sept. 25 during a plenary at the annual meeting of the North American Menopause Society. “But really, individualizing treatment is the goal, and there are some women who are going to need some other options.”
Contraindications for hormone therapy include having a history of breast cancer, coronary heart disease, active liver disease, unexplained vaginal bleeding, high-risk endometrial cancer, transient ischemic attack, and a previous venous thromboembolic event or stroke.
“Fortunately, we have things in development,” Dr. Faubion said. She reviewed a wide range of therapies that are not currently Food and Drug Administration approved for vasomotor symptoms but are either available off label or are in clinical trials.
One of these is oxybutynin, an antimuscarinic, anticholinergic agent currently used to treat overactive bladder and overactive sweating. In a 2016 trial, 73% of women taking 15 mg extended-release oxybutynin once daily rated their symptoms as “much better,” compared with 26% who received placebo. The women experienced reduced frequency and severity of hot flashes and better sleep.
Subsequent research found a 60% reduction in hot flash frequency with 2.5 mg twice a day and a 77% reduction with 5 mg twice a day, compared with a 27% reduction with placebo. The only reported side effect that occurred more often with oxybutynin was dry mouth, but there were no significant differences in reasons for discontinuation between the treatment and placebo groups.
There are, however, some potential long-term cognitive effects from oxybutynin, Dr. Faubion said. Some research has shown an increased risk of dementia from oxybutynin and from an overall higher cumulative use of anticholinergics.
“There’s some concern about that for long-term use,” she said, but it’s effective, it’s “probably not harmful [when] used short term in women with significant, bothersome hot flashes who are unwilling or unable to use hormone therapy, and the adverse effects are tolerable for most women.” Women with bladder symptoms would be especially ideal candidates since the drug already treats those.
Dr. Faubion then discussed a new estrogen called estetrol (E4), a naturally occurring estrogen with selection action in tissues that is produced by the fetal liver and crosses the placenta. It has a long half-life of 28-32 hours, and its potential mechanism may give it a different safety profile than estradiol (E2). “There may be a lower risk of drug-drug interactions; lower breast stimulation, pain or carcinogenic impact; lower impact on triglycerides; and a neutral impact on markers of coagulation,” she said.
Though estetrol was recently approved as an oral contraceptive under the name Estelle, it’s also under investigation as a postmenopausal regimen. Preliminary findings suggest it reduces vasomotor symptom severity by 44%, compared with 30% with placebo, at 15 mg, the apparent minimum effective dose. The safety profile showed no endometrial hyperplasia and no unexpected adverse events. In those taking 15 mg of estetrol, mean endometrial thickness increased from 2 to 6 mm but returned to baseline after progestin therapy.
“The 15-mg dose also positively influenced markers of bone turnover, increased HDL [cholesterol], improved glucose tolerance,” and had no effects on coagulation parameters or triglycerides, Dr. Faubion added.
Another group of potential agents being studied for hot flashes are NK3 antagonists, which aim to exploit the recent discovery that kisspeptin, neurokinin B, and dynorphin (KNDy) neurons may play an important role in the etiology of vasomotor symptoms. Development of one of these, MLE 4901, was halted despite a 45% reduction in hot flashes because 3 of 28 women developed transiently elevated liver function tests, about four to six times the upper limit of normal.
Two others, fezolinetant and NT-814, are in phase 2 trials and have shown a significant reduction in symptoms, compared with placebo. The most commonly reported adverse effect in the phase 2a trial was gastrointestinal effects, but none of the participants stopped the drug because of these, and no elevated liver tests occurred. In the larger phase 2b trial, the most commonly reported treatment-emergent adverse events included nausea, diarrhea, fatigue, urinary tract infection, sinusitis, upper respiratory infection, headache, and cough. Five women discontinued the drug because of elevated liver enzymes.
“Overall, NK3 inhibitors appear to be generally well tolerated,” Dr. Faubion said. “There does seem to be mild transaminase elevation,” though it’s not yet known if this is an effect from this class of drugs as a whole. She noted that follicle-stimulating hormone does not significantly increase, which is important because elevated FSH is associated with poor bone health, nor does estradiol significantly increase, which is clinically relevant for women at high risk of breast cancer.
“We don’t know the effects on the heart, the brain, the bone, mood, weight, or sexual health, so there’s a lot that is still not known,” Dr. Faubion said. “We still don’t know about long-term safety and efficacy with these chemical compounds,” but clinical trials of them are ongoing.
They “would be a welcome alternative to hormone therapy for those who can’t or prefer not to use a hormonal option,” Dr. Faubion said. “However, we may need broad education of clinicians to caution against widespread abandonment of hormone therapy, particularly in women with premature or early menopause.”
Donna Klassen, LCSW, the cofounder of Let’s Talk Menopause, asked whether any of these new therapies were being tested in women with breast cancer and whether anything was known about taking oxybutynin at the same time as letrozole.
“I suspect that most women with chronic diseases would have been excluded from these initial studies, but I can’t speak to that,” Dr. Faubion said, and she wasn’t aware of any data related to taking oxybutynin and letrozole concurrently.
James Simon, MD, medical director and founder of IntimMedicine and one of those who led the research on oxybutynin, responded that his trials excluded breast cancer survivors and anyone taking aromatase inhibitors.
“It will be unlikely that, in the very near future, that data will be available because all the clinical developments on these NK3s or KNDy neuron-modulating drugs exclude cancer patients,” Dr. Simon said.
However, another attendee, Lisa Larkin, MD, of Cincinnati, introduced herself as a breast cancer survivor who takes tamoxifen and said she feels “completely comfortable” prescribing oxybutynin to breast cancer survivors.
“In terms of side effects and effectiveness in patients on tamoxifen and aromatase inhibitors, I’ve had incredibly good luck with it, and I think it’s underutilized,” Dr. Larkin said. “The clinical pearl I would tell you is you can start really low, and the dry mouth really seems to improve with time.” She added that patients should be informed that it takes 2 weeks before it begins working, but the side effects eventually go away. “It becomes very tolerable, so I just encourage all of you to consider it as another great option.”
Dr. Faubion had no disclosures. Disclosure information was unavailable for Dr. Simon, Dr. Larkin, and Ms. Klassen.
Hot flashes affect three out of four women and can last 7-10 years, but the current standard of care treatment isn’t necessarily appropriate for all women who experience vasomotor symptoms, according to Stephanie Faubion, MD, MBA, director of the Mayo Clinic Women’s Health Clinic in Jacksonville, Fla.
For the majority of women under age 60 who are within 10 years of menopause, hormone therapy currently remains the most effective management option for hot flashes where the benefits outweigh the risks, Dr. Faubion told attendees Sept. 25 during a plenary at the annual meeting of the North American Menopause Society. “But really, individualizing treatment is the goal, and there are some women who are going to need some other options.”
Contraindications for hormone therapy include having a history of breast cancer, coronary heart disease, active liver disease, unexplained vaginal bleeding, high-risk endometrial cancer, transient ischemic attack, and a previous venous thromboembolic event or stroke.
“Fortunately, we have things in development,” Dr. Faubion said. She reviewed a wide range of therapies that are not currently Food and Drug Administration approved for vasomotor symptoms but are either available off label or are in clinical trials.
One of these is oxybutynin, an antimuscarinic, anticholinergic agent currently used to treat overactive bladder and overactive sweating. In a 2016 trial, 73% of women taking 15 mg extended-release oxybutynin once daily rated their symptoms as “much better,” compared with 26% who received placebo. The women experienced reduced frequency and severity of hot flashes and better sleep.
Subsequent research found a 60% reduction in hot flash frequency with 2.5 mg twice a day and a 77% reduction with 5 mg twice a day, compared with a 27% reduction with placebo. The only reported side effect that occurred more often with oxybutynin was dry mouth, but there were no significant differences in reasons for discontinuation between the treatment and placebo groups.
There are, however, some potential long-term cognitive effects from oxybutynin, Dr. Faubion said. Some research has shown an increased risk of dementia from oxybutynin and from an overall higher cumulative use of anticholinergics.
“There’s some concern about that for long-term use,” she said, but it’s effective, it’s “probably not harmful [when] used short term in women with significant, bothersome hot flashes who are unwilling or unable to use hormone therapy, and the adverse effects are tolerable for most women.” Women with bladder symptoms would be especially ideal candidates since the drug already treats those.
Dr. Faubion then discussed a new estrogen called estetrol (E4), a naturally occurring estrogen with selection action in tissues that is produced by the fetal liver and crosses the placenta. It has a long half-life of 28-32 hours, and its potential mechanism may give it a different safety profile than estradiol (E2). “There may be a lower risk of drug-drug interactions; lower breast stimulation, pain or carcinogenic impact; lower impact on triglycerides; and a neutral impact on markers of coagulation,” she said.
Though estetrol was recently approved as an oral contraceptive under the name Estelle, it’s also under investigation as a postmenopausal regimen. Preliminary findings suggest it reduces vasomotor symptom severity by 44%, compared with 30% with placebo, at 15 mg, the apparent minimum effective dose. The safety profile showed no endometrial hyperplasia and no unexpected adverse events. In those taking 15 mg of estetrol, mean endometrial thickness increased from 2 to 6 mm but returned to baseline after progestin therapy.
“The 15-mg dose also positively influenced markers of bone turnover, increased HDL [cholesterol], improved glucose tolerance,” and had no effects on coagulation parameters or triglycerides, Dr. Faubion added.
Another group of potential agents being studied for hot flashes are NK3 antagonists, which aim to exploit the recent discovery that kisspeptin, neurokinin B, and dynorphin (KNDy) neurons may play an important role in the etiology of vasomotor symptoms. Development of one of these, MLE 4901, was halted despite a 45% reduction in hot flashes because 3 of 28 women developed transiently elevated liver function tests, about four to six times the upper limit of normal.
Two others, fezolinetant and NT-814, are in phase 2 trials and have shown a significant reduction in symptoms, compared with placebo. The most commonly reported adverse effect in the phase 2a trial was gastrointestinal effects, but none of the participants stopped the drug because of these, and no elevated liver tests occurred. In the larger phase 2b trial, the most commonly reported treatment-emergent adverse events included nausea, diarrhea, fatigue, urinary tract infection, sinusitis, upper respiratory infection, headache, and cough. Five women discontinued the drug because of elevated liver enzymes.
“Overall, NK3 inhibitors appear to be generally well tolerated,” Dr. Faubion said. “There does seem to be mild transaminase elevation,” though it’s not yet known if this is an effect from this class of drugs as a whole. She noted that follicle-stimulating hormone does not significantly increase, which is important because elevated FSH is associated with poor bone health, nor does estradiol significantly increase, which is clinically relevant for women at high risk of breast cancer.
“We don’t know the effects on the heart, the brain, the bone, mood, weight, or sexual health, so there’s a lot that is still not known,” Dr. Faubion said. “We still don’t know about long-term safety and efficacy with these chemical compounds,” but clinical trials of them are ongoing.
They “would be a welcome alternative to hormone therapy for those who can’t or prefer not to use a hormonal option,” Dr. Faubion said. “However, we may need broad education of clinicians to caution against widespread abandonment of hormone therapy, particularly in women with premature or early menopause.”
Donna Klassen, LCSW, the cofounder of Let’s Talk Menopause, asked whether any of these new therapies were being tested in women with breast cancer and whether anything was known about taking oxybutynin at the same time as letrozole.
“I suspect that most women with chronic diseases would have been excluded from these initial studies, but I can’t speak to that,” Dr. Faubion said, and she wasn’t aware of any data related to taking oxybutynin and letrozole concurrently.
James Simon, MD, medical director and founder of IntimMedicine and one of those who led the research on oxybutynin, responded that his trials excluded breast cancer survivors and anyone taking aromatase inhibitors.
“It will be unlikely that, in the very near future, that data will be available because all the clinical developments on these NK3s or KNDy neuron-modulating drugs exclude cancer patients,” Dr. Simon said.
However, another attendee, Lisa Larkin, MD, of Cincinnati, introduced herself as a breast cancer survivor who takes tamoxifen and said she feels “completely comfortable” prescribing oxybutynin to breast cancer survivors.
“In terms of side effects and effectiveness in patients on tamoxifen and aromatase inhibitors, I’ve had incredibly good luck with it, and I think it’s underutilized,” Dr. Larkin said. “The clinical pearl I would tell you is you can start really low, and the dry mouth really seems to improve with time.” She added that patients should be informed that it takes 2 weeks before it begins working, but the side effects eventually go away. “It becomes very tolerable, so I just encourage all of you to consider it as another great option.”
Dr. Faubion had no disclosures. Disclosure information was unavailable for Dr. Simon, Dr. Larkin, and Ms. Klassen.
FROM NAMS 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.
In atopic dermatitis trial, abrocitinib offers faster itch relief than dupilumab
), in a multicenter randomized trial presented as a late breaker at the annual meeting of the European Academy of Dermatology and Venereology.
The earlier onset of action with the JAK inhibitor was achieved even though most patients in both arms were on topical corticosteroids, a design element that “is clinically relevant” for a practical comparison of these two agents, according to Kristian Reich, MD, PhD, Center for Translational Research in Inflammatory Skin Diseases, University Medical Center, Hamburg-Eppendorf, Germany.
The goal of this phase 3b trial, called JADE DARE, was to compare relative safety and efficacy of these strategies over the early course of treatment, he said.
Over 700 patients randomized
JADE DARE enrolled 727 patients over age 18 years who previously had an inadequate response to conventional topical therapies. All had moderate to severe AD defined by criteria such as body surface area greater than or equal to 10% and Eczema Area Severity Index (EASI) greater than or equal to 16. They were randomly assigned to 200 mg oral abrocitinib once daily or 300 mg subcutaneous dupilumab (after a loading dose of 600 mg) every 2 weeks. A double-dummy design preserved blinding.
The coprimary endpoints were at least a 4-point improvement in pruritus as measured with the Peak Pruritus Numerical Rating Scale (PP-NRS) score at week 2 and at least a 90% improvement in the EASI (EASI 90) at week 4.
The primary endpoint for pruritus at 2 weeks was reached by nearly twice as many patients randomly assigned to abrocitinib (46.2% vs. 25.5%; P < .001). The proportion of those meeting the EASI 90 endpoint at week 4 was also superior on abrocitinib (28.5% vs. 14.6%; P < .001)
Advantage for pruritus control dissipates
For the pruritus endpoint, the advantage of abrocitinib slowly diminished over time after the peak difference observed at 2 weeks. Although the advantage at week 4 (58.1% vs. 40.8%) and week 8 (65.8% vs. 52.7%) remained sizable, there were very small differences thereafter. However, Dr. Reich pointed out that the percentages continued to favor abrocitinib at least numerically through the 26 weeks of follow-up completed so far.
The pattern of response on EASI 90 was not the same. After demonstrating superiority at the 4-week timepoint, the advantage of abrocitinib persisted. When compared at week 16, which was a secondary endpoint of the JADE DARE trial, the advantage of abrocitinib remained significant (54.3% vs. 41.9%; P < .001). The advantage of abrocitinib narrowed but remained numerically superior at 26 weeks (54.6% vs. 47.6%).
Based on the data collected to date, “abrocitinib is clearly superior early on,” Dr. Reich said. Moreover, he reiterated that topical corticosteroids were allowed as background therapy in both arms.
“It is difficult to show an advantage for one active therapy over the other in patients on background corticosteroids,” Dr. Reich maintained.
Both drugs are well tolerated
The drugs were similarly well tolerated. Serious adverse events were uncommon in either arm. The rate of study dropouts due to an adverse event potentially related to treatment assignment was 3% in each group.
Nausea (19% vs. 2%), acne (13.5% vs. 2%), and headache (13% vs. 7.5%) were all more common in patients randomly assigned to abrocitinib. Conjunctivitis was more common in the group randomly assigned to dupilumab (10% vs. 2%).
The two deaths that occurred during this study were in the abrocitinib arm, but one was the result of COVID-19 infection and the other was a cardiovascular event in a patient with risk factors. Neither was considered to be treatment-related.
Abrocitinib’s relative selectivity for the JAK1 inhibitor is a potential differentiator from other currently available JAK inhibitors, although direct comparisons of these therapies for clinical activity in AD as well as most other diseases remains limited.
The relatively rapid relief of pruritus with the JAK inhibitor relative to the monoclonal antibody in the JADE DARE trial is likely to be perceived as clinically significant by patients with AD, according to Sonja Ständer, MD, professor of dermatology and neurodermatology at the University Hospital Münster, Germany.
“One of the highest needs of patients with atopic dermatitis is a rapid and profound relief of itch,” Dr. Ständer, who wrote a review article on AD earlier this year, said in an interview.
Although several current therapies are effective against pruritus, Dr. Ständer believes that the higher proportion of patients achieving itch control at 2 weeks on abrocitinib “will attract the attention of affected patients.”
However, she added that patients need to take both benefits and risks into account, indicating that clinical utility cannot be judged on a single outcome. In selecting one drug over the others, she advised “a balanced use of therapies.”
Abrocitinib was first approved in the United Kingdom in early September, followed by Japan last Thursday, for the treatment of moderate to severe AD in patients ages 12 and older. It is under review elsewhere, including in the United States and the European Union for AD.
In September, the FDA approved the first JAK inhibitor for treating AD – a topical JAK inhibitor, ruxolitinib.
Dr. Reich reports financial relationships with 20 pharmaceutical companies, including Pfizer, which provided funding for the JADE DARE trial. Dr. Ständer reports financial relationships with Beiersdorf AG, Galderma, Kliniska, Lilly, Pfizer, and Sanofi.
A version of this article first appeared on Medscape.com.
), in a multicenter randomized trial presented as a late breaker at the annual meeting of the European Academy of Dermatology and Venereology.
The earlier onset of action with the JAK inhibitor was achieved even though most patients in both arms were on topical corticosteroids, a design element that “is clinically relevant” for a practical comparison of these two agents, according to Kristian Reich, MD, PhD, Center for Translational Research in Inflammatory Skin Diseases, University Medical Center, Hamburg-Eppendorf, Germany.
The goal of this phase 3b trial, called JADE DARE, was to compare relative safety and efficacy of these strategies over the early course of treatment, he said.
Over 700 patients randomized
JADE DARE enrolled 727 patients over age 18 years who previously had an inadequate response to conventional topical therapies. All had moderate to severe AD defined by criteria such as body surface area greater than or equal to 10% and Eczema Area Severity Index (EASI) greater than or equal to 16. They were randomly assigned to 200 mg oral abrocitinib once daily or 300 mg subcutaneous dupilumab (after a loading dose of 600 mg) every 2 weeks. A double-dummy design preserved blinding.
The coprimary endpoints were at least a 4-point improvement in pruritus as measured with the Peak Pruritus Numerical Rating Scale (PP-NRS) score at week 2 and at least a 90% improvement in the EASI (EASI 90) at week 4.
The primary endpoint for pruritus at 2 weeks was reached by nearly twice as many patients randomly assigned to abrocitinib (46.2% vs. 25.5%; P < .001). The proportion of those meeting the EASI 90 endpoint at week 4 was also superior on abrocitinib (28.5% vs. 14.6%; P < .001)
Advantage for pruritus control dissipates
For the pruritus endpoint, the advantage of abrocitinib slowly diminished over time after the peak difference observed at 2 weeks. Although the advantage at week 4 (58.1% vs. 40.8%) and week 8 (65.8% vs. 52.7%) remained sizable, there were very small differences thereafter. However, Dr. Reich pointed out that the percentages continued to favor abrocitinib at least numerically through the 26 weeks of follow-up completed so far.
The pattern of response on EASI 90 was not the same. After demonstrating superiority at the 4-week timepoint, the advantage of abrocitinib persisted. When compared at week 16, which was a secondary endpoint of the JADE DARE trial, the advantage of abrocitinib remained significant (54.3% vs. 41.9%; P < .001). The advantage of abrocitinib narrowed but remained numerically superior at 26 weeks (54.6% vs. 47.6%).
Based on the data collected to date, “abrocitinib is clearly superior early on,” Dr. Reich said. Moreover, he reiterated that topical corticosteroids were allowed as background therapy in both arms.
“It is difficult to show an advantage for one active therapy over the other in patients on background corticosteroids,” Dr. Reich maintained.
Both drugs are well tolerated
The drugs were similarly well tolerated. Serious adverse events were uncommon in either arm. The rate of study dropouts due to an adverse event potentially related to treatment assignment was 3% in each group.
Nausea (19% vs. 2%), acne (13.5% vs. 2%), and headache (13% vs. 7.5%) were all more common in patients randomly assigned to abrocitinib. Conjunctivitis was more common in the group randomly assigned to dupilumab (10% vs. 2%).
The two deaths that occurred during this study were in the abrocitinib arm, but one was the result of COVID-19 infection and the other was a cardiovascular event in a patient with risk factors. Neither was considered to be treatment-related.
Abrocitinib’s relative selectivity for the JAK1 inhibitor is a potential differentiator from other currently available JAK inhibitors, although direct comparisons of these therapies for clinical activity in AD as well as most other diseases remains limited.
The relatively rapid relief of pruritus with the JAK inhibitor relative to the monoclonal antibody in the JADE DARE trial is likely to be perceived as clinically significant by patients with AD, according to Sonja Ständer, MD, professor of dermatology and neurodermatology at the University Hospital Münster, Germany.
“One of the highest needs of patients with atopic dermatitis is a rapid and profound relief of itch,” Dr. Ständer, who wrote a review article on AD earlier this year, said in an interview.
Although several current therapies are effective against pruritus, Dr. Ständer believes that the higher proportion of patients achieving itch control at 2 weeks on abrocitinib “will attract the attention of affected patients.”
However, she added that patients need to take both benefits and risks into account, indicating that clinical utility cannot be judged on a single outcome. In selecting one drug over the others, she advised “a balanced use of therapies.”
Abrocitinib was first approved in the United Kingdom in early September, followed by Japan last Thursday, for the treatment of moderate to severe AD in patients ages 12 and older. It is under review elsewhere, including in the United States and the European Union for AD.
In September, the FDA approved the first JAK inhibitor for treating AD – a topical JAK inhibitor, ruxolitinib.
Dr. Reich reports financial relationships with 20 pharmaceutical companies, including Pfizer, which provided funding for the JADE DARE trial. Dr. Ständer reports financial relationships with Beiersdorf AG, Galderma, Kliniska, Lilly, Pfizer, and Sanofi.
A version of this article first appeared on Medscape.com.
), in a multicenter randomized trial presented as a late breaker at the annual meeting of the European Academy of Dermatology and Venereology.
The earlier onset of action with the JAK inhibitor was achieved even though most patients in both arms were on topical corticosteroids, a design element that “is clinically relevant” for a practical comparison of these two agents, according to Kristian Reich, MD, PhD, Center for Translational Research in Inflammatory Skin Diseases, University Medical Center, Hamburg-Eppendorf, Germany.
The goal of this phase 3b trial, called JADE DARE, was to compare relative safety and efficacy of these strategies over the early course of treatment, he said.
Over 700 patients randomized
JADE DARE enrolled 727 patients over age 18 years who previously had an inadequate response to conventional topical therapies. All had moderate to severe AD defined by criteria such as body surface area greater than or equal to 10% and Eczema Area Severity Index (EASI) greater than or equal to 16. They were randomly assigned to 200 mg oral abrocitinib once daily or 300 mg subcutaneous dupilumab (after a loading dose of 600 mg) every 2 weeks. A double-dummy design preserved blinding.
The coprimary endpoints were at least a 4-point improvement in pruritus as measured with the Peak Pruritus Numerical Rating Scale (PP-NRS) score at week 2 and at least a 90% improvement in the EASI (EASI 90) at week 4.
The primary endpoint for pruritus at 2 weeks was reached by nearly twice as many patients randomly assigned to abrocitinib (46.2% vs. 25.5%; P < .001). The proportion of those meeting the EASI 90 endpoint at week 4 was also superior on abrocitinib (28.5% vs. 14.6%; P < .001)
Advantage for pruritus control dissipates
For the pruritus endpoint, the advantage of abrocitinib slowly diminished over time after the peak difference observed at 2 weeks. Although the advantage at week 4 (58.1% vs. 40.8%) and week 8 (65.8% vs. 52.7%) remained sizable, there were very small differences thereafter. However, Dr. Reich pointed out that the percentages continued to favor abrocitinib at least numerically through the 26 weeks of follow-up completed so far.
The pattern of response on EASI 90 was not the same. After demonstrating superiority at the 4-week timepoint, the advantage of abrocitinib persisted. When compared at week 16, which was a secondary endpoint of the JADE DARE trial, the advantage of abrocitinib remained significant (54.3% vs. 41.9%; P < .001). The advantage of abrocitinib narrowed but remained numerically superior at 26 weeks (54.6% vs. 47.6%).
Based on the data collected to date, “abrocitinib is clearly superior early on,” Dr. Reich said. Moreover, he reiterated that topical corticosteroids were allowed as background therapy in both arms.
“It is difficult to show an advantage for one active therapy over the other in patients on background corticosteroids,” Dr. Reich maintained.
Both drugs are well tolerated
The drugs were similarly well tolerated. Serious adverse events were uncommon in either arm. The rate of study dropouts due to an adverse event potentially related to treatment assignment was 3% in each group.
Nausea (19% vs. 2%), acne (13.5% vs. 2%), and headache (13% vs. 7.5%) were all more common in patients randomly assigned to abrocitinib. Conjunctivitis was more common in the group randomly assigned to dupilumab (10% vs. 2%).
The two deaths that occurred during this study were in the abrocitinib arm, but one was the result of COVID-19 infection and the other was a cardiovascular event in a patient with risk factors. Neither was considered to be treatment-related.
Abrocitinib’s relative selectivity for the JAK1 inhibitor is a potential differentiator from other currently available JAK inhibitors, although direct comparisons of these therapies for clinical activity in AD as well as most other diseases remains limited.
The relatively rapid relief of pruritus with the JAK inhibitor relative to the monoclonal antibody in the JADE DARE trial is likely to be perceived as clinically significant by patients with AD, according to Sonja Ständer, MD, professor of dermatology and neurodermatology at the University Hospital Münster, Germany.
“One of the highest needs of patients with atopic dermatitis is a rapid and profound relief of itch,” Dr. Ständer, who wrote a review article on AD earlier this year, said in an interview.
Although several current therapies are effective against pruritus, Dr. Ständer believes that the higher proportion of patients achieving itch control at 2 weeks on abrocitinib “will attract the attention of affected patients.”
However, she added that patients need to take both benefits and risks into account, indicating that clinical utility cannot be judged on a single outcome. In selecting one drug over the others, she advised “a balanced use of therapies.”
Abrocitinib was first approved in the United Kingdom in early September, followed by Japan last Thursday, for the treatment of moderate to severe AD in patients ages 12 and older. It is under review elsewhere, including in the United States and the European Union for AD.
In September, the FDA approved the first JAK inhibitor for treating AD – a topical JAK inhibitor, ruxolitinib.
Dr. Reich reports financial relationships with 20 pharmaceutical companies, including Pfizer, which provided funding for the JADE DARE trial. Dr. Ständer reports financial relationships with Beiersdorf AG, Galderma, Kliniska, Lilly, Pfizer, and Sanofi.
A version of this article first appeared on Medscape.com.
Case reports underscore risk of cerebral edema, AFCE in children with COVID-19
according to pediatric neurologists who are urging colleagues to watch out for similar cases.
At least one other child in the United States has died after becoming infected with the virus and developing cerebral edema. “The rapid and devastating clinical course in both of these cases highlights the need for early recognition of a cerebral edema and AFCE as potential complications of COVID-19 in pediatric patients,” the neurologists wrote.
The case was highlighted in a poster presented at the annual meeting of the Child Neurology Society and in a report published earlier this year in Child Neurology Open.
According to pediatric neurologist Timothy Gershon, MD, PhD , of the University of North Carolina at Chapel Hill, the child appeared in clinic in July 2020. She had been healthy but was suffering from 1 day of fever, seizure-like activity (generalized convulsions and drooling), anorexia, and lethargy.
The girl, who was subsequently diagnosed with COVID-19, deteriorated in the hospital. “She received IV dexamethasone in attempts to reduce cerebral edema,” the neurologists wrote. “Regarding immunomodulatory therapy, she received intravenous immunoglobulin (2 g/kg), anakinra, and hydrocortisone; despite approval for remdesivir and COVID-19 convalescent plasma, these were ultimately withheld due to poor prognosis.”
Brain death examinations at 24 and 48 hours after cardiac arrest were consistent with brain death, they reported.
Neurologists believe the patient suffered from AFCE, “an often fatal pediatric clinical entity consisting of fever, encephalopathy, and new-onset seizures followed by rapid, diffuse, and medically-refractory cerebral edema.” They add that “AFCE occurs as a rare complication of a variety of common pediatric infections, and a CNS [central nervous system] pathogen is identified in only a minority of cases, suggesting a para-infectious mechanism of edema.”
Neurologists offered a case definition of the “recently recognized” AFCE earlier this year.
“This was an extremely rare rapid progression to cerebral edema. I think it was related to the patient’s COVID infection, but why this patient got it and others don’t is unknown,” Dr. Gershon said in an interview. “The full spectrum of neurological complications of COVID were not yet known [at the time]. We didn’t know, and still don’t know, what the causative links are between COVID and suddenly having seizures and brain swelling.”
He said he’d treat a similar patient differently now and give dexamethasone earlier in the clinical course, although “there is no data to tell us if any therapy could have reversed it.” Specifically, he said, “I’d give dexamethasone at the first sign of brain involvement, using the dosing recommended for cerebral edema, and try to get the MRI earlier in the course.”
Dr. Gershon and colleagues noted another case of fatal cerebral edema in a child, a 7-year-old boy who was treated in New York state. That case “shows that fatal cerebral edema may complicate pediatric multisystem inflammatory syndrome,” they wrote.
Pediatric critical care specialist Preetha Krishnan, MD, of Randall Children’s Hospital at Legacy Emanuel in Portland, Ore., helped develop the new definition of AFCE. In an interview, she said AFCE is difficult to diagnose because the signs/symptoms – such as fever, altered sensorium, and seizures – are found in other conditions such as febrile status epilepticus with a viral illness.
“The key to recognition of AFCE is that unlike other disease processes, these children have rapid neurologic progression,” she said. “In addition, many of our AFCE patients also had vomiting and/or headache, which in retrospect was likely an indication of elevated ICP [intracranial pressure] rather than viral infection.”
She added that “if a child with fever, seizures, and encephalopathy has cerebral edema on imaging and/or has neurologic progression, AFCE should be considered. Most of our cases of AFCE had fulminant progression within the first 3 days of their head imaging noting cerebral edema. There are other neurologic diseases, such as acute necrotizing encephalopathy of childhood, that also have progressive signs/symptoms, but head imaging and lab work should help differentiate many of these etiologies.”
In regard to treatment, she said, “our unit would likely err on the side of providing as much neuroprotective measures as is reasonable, such as maintaining normothermia, consideration of hyperosmolar therapy, maintaining normocarbia and normoxemia, managing seizures, etc. I would recommend getting the entire neurocritical care team involved in the management discussion. This varies by center, but will likely include neurology, ID [infectious disease], possibly neurosurgery, and PICU.”
As for the new case report, Krishnan said COVID-19 has been linked to neurologic complications, “so it does not surprise me that AFCE is part of the neurologic spectrum of disease.”
No funding was reported, and the authors report no relevant disclosures. Dr. Krishnan has no disclosures.
according to pediatric neurologists who are urging colleagues to watch out for similar cases.
At least one other child in the United States has died after becoming infected with the virus and developing cerebral edema. “The rapid and devastating clinical course in both of these cases highlights the need for early recognition of a cerebral edema and AFCE as potential complications of COVID-19 in pediatric patients,” the neurologists wrote.
The case was highlighted in a poster presented at the annual meeting of the Child Neurology Society and in a report published earlier this year in Child Neurology Open.
According to pediatric neurologist Timothy Gershon, MD, PhD , of the University of North Carolina at Chapel Hill, the child appeared in clinic in July 2020. She had been healthy but was suffering from 1 day of fever, seizure-like activity (generalized convulsions and drooling), anorexia, and lethargy.
The girl, who was subsequently diagnosed with COVID-19, deteriorated in the hospital. “She received IV dexamethasone in attempts to reduce cerebral edema,” the neurologists wrote. “Regarding immunomodulatory therapy, she received intravenous immunoglobulin (2 g/kg), anakinra, and hydrocortisone; despite approval for remdesivir and COVID-19 convalescent plasma, these were ultimately withheld due to poor prognosis.”
Brain death examinations at 24 and 48 hours after cardiac arrest were consistent with brain death, they reported.
Neurologists believe the patient suffered from AFCE, “an often fatal pediatric clinical entity consisting of fever, encephalopathy, and new-onset seizures followed by rapid, diffuse, and medically-refractory cerebral edema.” They add that “AFCE occurs as a rare complication of a variety of common pediatric infections, and a CNS [central nervous system] pathogen is identified in only a minority of cases, suggesting a para-infectious mechanism of edema.”
Neurologists offered a case definition of the “recently recognized” AFCE earlier this year.
“This was an extremely rare rapid progression to cerebral edema. I think it was related to the patient’s COVID infection, but why this patient got it and others don’t is unknown,” Dr. Gershon said in an interview. “The full spectrum of neurological complications of COVID were not yet known [at the time]. We didn’t know, and still don’t know, what the causative links are between COVID and suddenly having seizures and brain swelling.”
He said he’d treat a similar patient differently now and give dexamethasone earlier in the clinical course, although “there is no data to tell us if any therapy could have reversed it.” Specifically, he said, “I’d give dexamethasone at the first sign of brain involvement, using the dosing recommended for cerebral edema, and try to get the MRI earlier in the course.”
Dr. Gershon and colleagues noted another case of fatal cerebral edema in a child, a 7-year-old boy who was treated in New York state. That case “shows that fatal cerebral edema may complicate pediatric multisystem inflammatory syndrome,” they wrote.
Pediatric critical care specialist Preetha Krishnan, MD, of Randall Children’s Hospital at Legacy Emanuel in Portland, Ore., helped develop the new definition of AFCE. In an interview, she said AFCE is difficult to diagnose because the signs/symptoms – such as fever, altered sensorium, and seizures – are found in other conditions such as febrile status epilepticus with a viral illness.
“The key to recognition of AFCE is that unlike other disease processes, these children have rapid neurologic progression,” she said. “In addition, many of our AFCE patients also had vomiting and/or headache, which in retrospect was likely an indication of elevated ICP [intracranial pressure] rather than viral infection.”
She added that “if a child with fever, seizures, and encephalopathy has cerebral edema on imaging and/or has neurologic progression, AFCE should be considered. Most of our cases of AFCE had fulminant progression within the first 3 days of their head imaging noting cerebral edema. There are other neurologic diseases, such as acute necrotizing encephalopathy of childhood, that also have progressive signs/symptoms, but head imaging and lab work should help differentiate many of these etiologies.”
In regard to treatment, she said, “our unit would likely err on the side of providing as much neuroprotective measures as is reasonable, such as maintaining normothermia, consideration of hyperosmolar therapy, maintaining normocarbia and normoxemia, managing seizures, etc. I would recommend getting the entire neurocritical care team involved in the management discussion. This varies by center, but will likely include neurology, ID [infectious disease], possibly neurosurgery, and PICU.”
As for the new case report, Krishnan said COVID-19 has been linked to neurologic complications, “so it does not surprise me that AFCE is part of the neurologic spectrum of disease.”
No funding was reported, and the authors report no relevant disclosures. Dr. Krishnan has no disclosures.
according to pediatric neurologists who are urging colleagues to watch out for similar cases.
At least one other child in the United States has died after becoming infected with the virus and developing cerebral edema. “The rapid and devastating clinical course in both of these cases highlights the need for early recognition of a cerebral edema and AFCE as potential complications of COVID-19 in pediatric patients,” the neurologists wrote.
The case was highlighted in a poster presented at the annual meeting of the Child Neurology Society and in a report published earlier this year in Child Neurology Open.
According to pediatric neurologist Timothy Gershon, MD, PhD , of the University of North Carolina at Chapel Hill, the child appeared in clinic in July 2020. She had been healthy but was suffering from 1 day of fever, seizure-like activity (generalized convulsions and drooling), anorexia, and lethargy.
The girl, who was subsequently diagnosed with COVID-19, deteriorated in the hospital. “She received IV dexamethasone in attempts to reduce cerebral edema,” the neurologists wrote. “Regarding immunomodulatory therapy, she received intravenous immunoglobulin (2 g/kg), anakinra, and hydrocortisone; despite approval for remdesivir and COVID-19 convalescent plasma, these were ultimately withheld due to poor prognosis.”
Brain death examinations at 24 and 48 hours after cardiac arrest were consistent with brain death, they reported.
Neurologists believe the patient suffered from AFCE, “an often fatal pediatric clinical entity consisting of fever, encephalopathy, and new-onset seizures followed by rapid, diffuse, and medically-refractory cerebral edema.” They add that “AFCE occurs as a rare complication of a variety of common pediatric infections, and a CNS [central nervous system] pathogen is identified in only a minority of cases, suggesting a para-infectious mechanism of edema.”
Neurologists offered a case definition of the “recently recognized” AFCE earlier this year.
“This was an extremely rare rapid progression to cerebral edema. I think it was related to the patient’s COVID infection, but why this patient got it and others don’t is unknown,” Dr. Gershon said in an interview. “The full spectrum of neurological complications of COVID were not yet known [at the time]. We didn’t know, and still don’t know, what the causative links are between COVID and suddenly having seizures and brain swelling.”
He said he’d treat a similar patient differently now and give dexamethasone earlier in the clinical course, although “there is no data to tell us if any therapy could have reversed it.” Specifically, he said, “I’d give dexamethasone at the first sign of brain involvement, using the dosing recommended for cerebral edema, and try to get the MRI earlier in the course.”
Dr. Gershon and colleagues noted another case of fatal cerebral edema in a child, a 7-year-old boy who was treated in New York state. That case “shows that fatal cerebral edema may complicate pediatric multisystem inflammatory syndrome,” they wrote.
Pediatric critical care specialist Preetha Krishnan, MD, of Randall Children’s Hospital at Legacy Emanuel in Portland, Ore., helped develop the new definition of AFCE. In an interview, she said AFCE is difficult to diagnose because the signs/symptoms – such as fever, altered sensorium, and seizures – are found in other conditions such as febrile status epilepticus with a viral illness.
“The key to recognition of AFCE is that unlike other disease processes, these children have rapid neurologic progression,” she said. “In addition, many of our AFCE patients also had vomiting and/or headache, which in retrospect was likely an indication of elevated ICP [intracranial pressure] rather than viral infection.”
She added that “if a child with fever, seizures, and encephalopathy has cerebral edema on imaging and/or has neurologic progression, AFCE should be considered. Most of our cases of AFCE had fulminant progression within the first 3 days of their head imaging noting cerebral edema. There are other neurologic diseases, such as acute necrotizing encephalopathy of childhood, that also have progressive signs/symptoms, but head imaging and lab work should help differentiate many of these etiologies.”
In regard to treatment, she said, “our unit would likely err on the side of providing as much neuroprotective measures as is reasonable, such as maintaining normothermia, consideration of hyperosmolar therapy, maintaining normocarbia and normoxemia, managing seizures, etc. I would recommend getting the entire neurocritical care team involved in the management discussion. This varies by center, but will likely include neurology, ID [infectious disease], possibly neurosurgery, and PICU.”
As for the new case report, Krishnan said COVID-19 has been linked to neurologic complications, “so it does not surprise me that AFCE is part of the neurologic spectrum of disease.”
No funding was reported, and the authors report no relevant disclosures. Dr. Krishnan has no disclosures.
FROM CNS 2021
Maternal SSRI use linked to more encephalopathy in newborns, risk still small
, although the overall risk remains extremely low, a new study finds.
The findings were presented in a poster at the 50th annual meeting of the Child Neurology Society.
“Our work showed that neonates exposed to SSRI in utero had higher risks of neonatal encephalopathy even when adjusting for confounders such as maternal mental health disorders and age. SSRIs could cause side effects such as encephalopathy in neonates, and these risks need to be balanced carefully with the potential benefits of treatment to the mother,” study lead author Marie Cornet, MD, a neonatology fellow with Benioff Children’s Hospital at the University of California, San Francisco, said in an interview.
According to Dr. Cornet, “we know that SSRI exposure in utero is associated with increased risks of respiratory distress at birth, need for positive-pressure ventilation, and an abnormal neurologic exam.” The researchers launched the new study to determine if the estimated 4%-8% of pregnant women who take SSRIs may be putting their newborns at greater risk of NE.
The researchers retrospectively tracked 305,426 infants who were born in the Kaiser Permanente Northern California health system (≥35 weeks) from 2011 to 2019. The mothers had an average age of 31 years, and approximately 34.7% were White, 34.7% of unknown race, 23.3% Asian, and 6.2% Black.
The researchers defined NE as a “5-minute APGAR score <7 and abnormal level of consciousness, activity, tone, or reflexes.”
A total of 8,024 infants (2.6%) had mothers who used SSRIs in the third trimester, and 510 (0.17%) were determined to have had NE.
After adjustment for maternal depression or anxiety, maternal age, race, and hospital, exposed neonates had 2.7 times higher odds of NE (odds ratio, 2.7).
Each 25 mg per day increase in the dose of SSRIs, as equalized to doses of sertraline (Zoloft), was linked to a significant 31% increase in the odds of developing NE (OR, 1.31).
The study doesn’t examine the benefits of SSRI treatment in pregnancy. Those taking SSRIs were much more likely to have depression during pregnancy (76.5% vs. 13.5%) and anxiety (56.7% vs. 6.9%), compared with those who did not take the drug.
The possible connection between SSRIs and NE is unclear. “SSRIs may contribute to NE by a withdrawal mechanism or by a toxicity mechanism. It is also possible that SSRIs themselves are not responsible for encephalopathy, or that the severity of maternal mental health is itself responsible for increased neonatal encephalopathy,” Dr. Cornet said. “However, we believe we adjusted our results thoroughly for that. Furthermore, in this cohort, neonates born from mothers with untreated depression were not at higher risk of encephalopathy than neonates born to mothers without depression.”
She added: “When infants have acidosis or require prolonged resuscitation after birth, they get treated with therapeutic hypothermia. This invasive treatment was shown to decrease mortality and morbidity in neonates with hypoxic-ischemic encephalopathy. However, therapeutic hypothermia may not be helpful in infants with encephalopathy due to other causes than acute hypoxia-ischemia, such as infection, inflammation, genetic conditions, or exposure to toxins. In the case of SSRIs, our results show that, while neonates often have encephalopathy, this encephalopathy is often mild and self-resolved. We did not see a statistically significant increase in acidosis or treatment with therapeutic hypothermia.”
In the future neurologists should consider SSRI use as a potential cause in cases of NE, Dr. Cornet said. “If there are no signs of hypoxic-ischemic encephalopathy – no evidence of acidosis, acute perinatal event – treatment with therapeutic hypothermia may not be indicated.”
Dr. Cornet said more research is in the works. “Studying the long-term side effect of SSRIs on neonatal brain development and injury is essential,” she said. “We plan to compare brain injury in neonates exposed and unexposed to SSRIs and examine long-term outcomes to assess if the effect of SSRI exposure is transient or has a lasting impact.”
This study was funded by the Thrasher Early Career Research Grant and by the Newborn Brain Research Innovation Award at UCSF. The authors have no relevant disclosures.
, although the overall risk remains extremely low, a new study finds.
The findings were presented in a poster at the 50th annual meeting of the Child Neurology Society.
“Our work showed that neonates exposed to SSRI in utero had higher risks of neonatal encephalopathy even when adjusting for confounders such as maternal mental health disorders and age. SSRIs could cause side effects such as encephalopathy in neonates, and these risks need to be balanced carefully with the potential benefits of treatment to the mother,” study lead author Marie Cornet, MD, a neonatology fellow with Benioff Children’s Hospital at the University of California, San Francisco, said in an interview.
According to Dr. Cornet, “we know that SSRI exposure in utero is associated with increased risks of respiratory distress at birth, need for positive-pressure ventilation, and an abnormal neurologic exam.” The researchers launched the new study to determine if the estimated 4%-8% of pregnant women who take SSRIs may be putting their newborns at greater risk of NE.
The researchers retrospectively tracked 305,426 infants who were born in the Kaiser Permanente Northern California health system (≥35 weeks) from 2011 to 2019. The mothers had an average age of 31 years, and approximately 34.7% were White, 34.7% of unknown race, 23.3% Asian, and 6.2% Black.
The researchers defined NE as a “5-minute APGAR score <7 and abnormal level of consciousness, activity, tone, or reflexes.”
A total of 8,024 infants (2.6%) had mothers who used SSRIs in the third trimester, and 510 (0.17%) were determined to have had NE.
After adjustment for maternal depression or anxiety, maternal age, race, and hospital, exposed neonates had 2.7 times higher odds of NE (odds ratio, 2.7).
Each 25 mg per day increase in the dose of SSRIs, as equalized to doses of sertraline (Zoloft), was linked to a significant 31% increase in the odds of developing NE (OR, 1.31).
The study doesn’t examine the benefits of SSRI treatment in pregnancy. Those taking SSRIs were much more likely to have depression during pregnancy (76.5% vs. 13.5%) and anxiety (56.7% vs. 6.9%), compared with those who did not take the drug.
The possible connection between SSRIs and NE is unclear. “SSRIs may contribute to NE by a withdrawal mechanism or by a toxicity mechanism. It is also possible that SSRIs themselves are not responsible for encephalopathy, or that the severity of maternal mental health is itself responsible for increased neonatal encephalopathy,” Dr. Cornet said. “However, we believe we adjusted our results thoroughly for that. Furthermore, in this cohort, neonates born from mothers with untreated depression were not at higher risk of encephalopathy than neonates born to mothers without depression.”
She added: “When infants have acidosis or require prolonged resuscitation after birth, they get treated with therapeutic hypothermia. This invasive treatment was shown to decrease mortality and morbidity in neonates with hypoxic-ischemic encephalopathy. However, therapeutic hypothermia may not be helpful in infants with encephalopathy due to other causes than acute hypoxia-ischemia, such as infection, inflammation, genetic conditions, or exposure to toxins. In the case of SSRIs, our results show that, while neonates often have encephalopathy, this encephalopathy is often mild and self-resolved. We did not see a statistically significant increase in acidosis or treatment with therapeutic hypothermia.”
In the future neurologists should consider SSRI use as a potential cause in cases of NE, Dr. Cornet said. “If there are no signs of hypoxic-ischemic encephalopathy – no evidence of acidosis, acute perinatal event – treatment with therapeutic hypothermia may not be indicated.”
Dr. Cornet said more research is in the works. “Studying the long-term side effect of SSRIs on neonatal brain development and injury is essential,” she said. “We plan to compare brain injury in neonates exposed and unexposed to SSRIs and examine long-term outcomes to assess if the effect of SSRI exposure is transient or has a lasting impact.”
This study was funded by the Thrasher Early Career Research Grant and by the Newborn Brain Research Innovation Award at UCSF. The authors have no relevant disclosures.
, although the overall risk remains extremely low, a new study finds.
The findings were presented in a poster at the 50th annual meeting of the Child Neurology Society.
“Our work showed that neonates exposed to SSRI in utero had higher risks of neonatal encephalopathy even when adjusting for confounders such as maternal mental health disorders and age. SSRIs could cause side effects such as encephalopathy in neonates, and these risks need to be balanced carefully with the potential benefits of treatment to the mother,” study lead author Marie Cornet, MD, a neonatology fellow with Benioff Children’s Hospital at the University of California, San Francisco, said in an interview.
According to Dr. Cornet, “we know that SSRI exposure in utero is associated with increased risks of respiratory distress at birth, need for positive-pressure ventilation, and an abnormal neurologic exam.” The researchers launched the new study to determine if the estimated 4%-8% of pregnant women who take SSRIs may be putting their newborns at greater risk of NE.
The researchers retrospectively tracked 305,426 infants who were born in the Kaiser Permanente Northern California health system (≥35 weeks) from 2011 to 2019. The mothers had an average age of 31 years, and approximately 34.7% were White, 34.7% of unknown race, 23.3% Asian, and 6.2% Black.
The researchers defined NE as a “5-minute APGAR score <7 and abnormal level of consciousness, activity, tone, or reflexes.”
A total of 8,024 infants (2.6%) had mothers who used SSRIs in the third trimester, and 510 (0.17%) were determined to have had NE.
After adjustment for maternal depression or anxiety, maternal age, race, and hospital, exposed neonates had 2.7 times higher odds of NE (odds ratio, 2.7).
Each 25 mg per day increase in the dose of SSRIs, as equalized to doses of sertraline (Zoloft), was linked to a significant 31% increase in the odds of developing NE (OR, 1.31).
The study doesn’t examine the benefits of SSRI treatment in pregnancy. Those taking SSRIs were much more likely to have depression during pregnancy (76.5% vs. 13.5%) and anxiety (56.7% vs. 6.9%), compared with those who did not take the drug.
The possible connection between SSRIs and NE is unclear. “SSRIs may contribute to NE by a withdrawal mechanism or by a toxicity mechanism. It is also possible that SSRIs themselves are not responsible for encephalopathy, or that the severity of maternal mental health is itself responsible for increased neonatal encephalopathy,” Dr. Cornet said. “However, we believe we adjusted our results thoroughly for that. Furthermore, in this cohort, neonates born from mothers with untreated depression were not at higher risk of encephalopathy than neonates born to mothers without depression.”
She added: “When infants have acidosis or require prolonged resuscitation after birth, they get treated with therapeutic hypothermia. This invasive treatment was shown to decrease mortality and morbidity in neonates with hypoxic-ischemic encephalopathy. However, therapeutic hypothermia may not be helpful in infants with encephalopathy due to other causes than acute hypoxia-ischemia, such as infection, inflammation, genetic conditions, or exposure to toxins. In the case of SSRIs, our results show that, while neonates often have encephalopathy, this encephalopathy is often mild and self-resolved. We did not see a statistically significant increase in acidosis or treatment with therapeutic hypothermia.”
In the future neurologists should consider SSRI use as a potential cause in cases of NE, Dr. Cornet said. “If there are no signs of hypoxic-ischemic encephalopathy – no evidence of acidosis, acute perinatal event – treatment with therapeutic hypothermia may not be indicated.”
Dr. Cornet said more research is in the works. “Studying the long-term side effect of SSRIs on neonatal brain development and injury is essential,” she said. “We plan to compare brain injury in neonates exposed and unexposed to SSRIs and examine long-term outcomes to assess if the effect of SSRI exposure is transient or has a lasting impact.”
This study was funded by the Thrasher Early Career Research Grant and by the Newborn Brain Research Innovation Award at UCSF. The authors have no relevant disclosures.
FROM CNS 2021
A safer way to use Botox to treat challenging dystonia type?
, new research suggests.
Oromandibular dystonia causes an involuntary opening of the mouth, which can be disabling and disfiguring. Although injection of the lateral pterygoid muscle with botulinum toxin is the preferred treatment for oromandibular dystonia, a potential complication concerns the maxillary artery, which can run either lateral or medial to the lateral pterygoid muscle.
In a study of 200 Turkish patients, researchers documented significant variations between men and women in the anatomical location of the maxillary artery – and even found lateral versus medial differences on the left and right side in the same individual.
“The results showed that the maxillary artery runs lateral to the muscle in 67% of the Turkish patients,” Rezzak Yilmaz, MD, department of neurology, University of Ankara Medical School, Turkey, reported at the International Congress of Parkinson’s Disease and Movement Disorders.
Given this high rate, there is a high risk for injury “that may result in pain and hematoma” when using preauricular extraoral injections, Dr. Yilmaz and colleagues noted. Instead, they recommend an intraoral injection approach to the lateral pterygoid muscle. “However, this critical anatomical variation is still unrecognized by most clinicians performing [botulinum toxin] injections,” they wrote.
Significant gender differences
The maxillary artery is the largest branch of the external carotid artery.
In the current study, the researchers used magnetic resonance angiography to assess the relevant anatomy in a cohort of 200 individuals (mean age, 56.4 years; 64% women) without a history of facial trauma or movement disorders.
Results showed that the maxillary artery ran lateral to the lateral pterygoid muscle in 67% of the study population.
“This result was also more frequent in females compared with males. Also, there was a considerable variability between the left and the right side in 20% of the participants,” Dr. Yilmaz reported.
Statistically significant gender differences were found for the artery running lateral to the lateral pterygoid muscle on both sides (71.1% in women vs. 58.5% in men; P = .007) and for the artery running lateral to the lateral pterygoid muscle on just the left side (69.8% in women vs. 53.5% in men; P = .02).
In an email exchange, Dr. Yilmaz said if medical personnel are not trained to perform an intraoral approach, “imaging to visualize the path of the maxillary artery before an extraoral/transcutaneous injection can be recommended.”
“If the imaging reveals that the maxillary artery passes lateral to the muscle, then the patient needs to be referred to another center for an intraoral injection,” unless the clinician is trained for an intraoral approach, he added.
Useful education
Commenting on the study, Michele Tagliati, MD, director of the Movement Disorders Program at Cedars-Sinai Medical Center, Los Angeles, said the results were educational. “I didn’t know about all this variability. I was working under the assumption that the artery was medial,” said Dr. Tagliati, who was not involved with the research.
Among his large practice of about 2,000 patients, Dr. Tagliati estimated having five patients for whom he provides this type of injection – and has never encountered a problem with them.
“Maybe all my patients are medial, but now that I’m aware I’ll probably pay more attention,” Dr. Tagliati said. He does not currently perform magnetic resonance angiography before injecting them, “although maybe I should,” he said.
When asked if it is worth the time and expense to perform magnetic resonance angiography on every patient who comes in for lateral pterygoid muscle injections, Dr. Tagliati said that although he has done the injections without problems in his current patients, he may “start obtaining imaging studies to make sure that we’re not taking unnecessary risk” if the maxillary artery is lateral to the lateral pterygoid muscle in new patients.
If there is a risk, he’ll then consider talking with colleagues in oral or facial surgery. Dr. Tagliati added that the number of patients he sees with oromandibular dystonia is rather small, so this extra step would not add a lot of additional imaging.
Overall, Dr. Tagliati noted that the study outcome was significant enough to want to use it for professional education. “I can definitely tell you that I’m going to bring it to the attention of my Fellows. [Every year] I teach one or two Fellows to inject Botox,” he said.
There was no funding for the study. Dr. Yilmaz and Dr. Tagliati have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests.
Oromandibular dystonia causes an involuntary opening of the mouth, which can be disabling and disfiguring. Although injection of the lateral pterygoid muscle with botulinum toxin is the preferred treatment for oromandibular dystonia, a potential complication concerns the maxillary artery, which can run either lateral or medial to the lateral pterygoid muscle.
In a study of 200 Turkish patients, researchers documented significant variations between men and women in the anatomical location of the maxillary artery – and even found lateral versus medial differences on the left and right side in the same individual.
“The results showed that the maxillary artery runs lateral to the muscle in 67% of the Turkish patients,” Rezzak Yilmaz, MD, department of neurology, University of Ankara Medical School, Turkey, reported at the International Congress of Parkinson’s Disease and Movement Disorders.
Given this high rate, there is a high risk for injury “that may result in pain and hematoma” when using preauricular extraoral injections, Dr. Yilmaz and colleagues noted. Instead, they recommend an intraoral injection approach to the lateral pterygoid muscle. “However, this critical anatomical variation is still unrecognized by most clinicians performing [botulinum toxin] injections,” they wrote.
Significant gender differences
The maxillary artery is the largest branch of the external carotid artery.
In the current study, the researchers used magnetic resonance angiography to assess the relevant anatomy in a cohort of 200 individuals (mean age, 56.4 years; 64% women) without a history of facial trauma or movement disorders.
Results showed that the maxillary artery ran lateral to the lateral pterygoid muscle in 67% of the study population.
“This result was also more frequent in females compared with males. Also, there was a considerable variability between the left and the right side in 20% of the participants,” Dr. Yilmaz reported.
Statistically significant gender differences were found for the artery running lateral to the lateral pterygoid muscle on both sides (71.1% in women vs. 58.5% in men; P = .007) and for the artery running lateral to the lateral pterygoid muscle on just the left side (69.8% in women vs. 53.5% in men; P = .02).
In an email exchange, Dr. Yilmaz said if medical personnel are not trained to perform an intraoral approach, “imaging to visualize the path of the maxillary artery before an extraoral/transcutaneous injection can be recommended.”
“If the imaging reveals that the maxillary artery passes lateral to the muscle, then the patient needs to be referred to another center for an intraoral injection,” unless the clinician is trained for an intraoral approach, he added.
Useful education
Commenting on the study, Michele Tagliati, MD, director of the Movement Disorders Program at Cedars-Sinai Medical Center, Los Angeles, said the results were educational. “I didn’t know about all this variability. I was working under the assumption that the artery was medial,” said Dr. Tagliati, who was not involved with the research.
Among his large practice of about 2,000 patients, Dr. Tagliati estimated having five patients for whom he provides this type of injection – and has never encountered a problem with them.
“Maybe all my patients are medial, but now that I’m aware I’ll probably pay more attention,” Dr. Tagliati said. He does not currently perform magnetic resonance angiography before injecting them, “although maybe I should,” he said.
When asked if it is worth the time and expense to perform magnetic resonance angiography on every patient who comes in for lateral pterygoid muscle injections, Dr. Tagliati said that although he has done the injections without problems in his current patients, he may “start obtaining imaging studies to make sure that we’re not taking unnecessary risk” if the maxillary artery is lateral to the lateral pterygoid muscle in new patients.
If there is a risk, he’ll then consider talking with colleagues in oral or facial surgery. Dr. Tagliati added that the number of patients he sees with oromandibular dystonia is rather small, so this extra step would not add a lot of additional imaging.
Overall, Dr. Tagliati noted that the study outcome was significant enough to want to use it for professional education. “I can definitely tell you that I’m going to bring it to the attention of my Fellows. [Every year] I teach one or two Fellows to inject Botox,” he said.
There was no funding for the study. Dr. Yilmaz and Dr. Tagliati have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, new research suggests.
Oromandibular dystonia causes an involuntary opening of the mouth, which can be disabling and disfiguring. Although injection of the lateral pterygoid muscle with botulinum toxin is the preferred treatment for oromandibular dystonia, a potential complication concerns the maxillary artery, which can run either lateral or medial to the lateral pterygoid muscle.
In a study of 200 Turkish patients, researchers documented significant variations between men and women in the anatomical location of the maxillary artery – and even found lateral versus medial differences on the left and right side in the same individual.
“The results showed that the maxillary artery runs lateral to the muscle in 67% of the Turkish patients,” Rezzak Yilmaz, MD, department of neurology, University of Ankara Medical School, Turkey, reported at the International Congress of Parkinson’s Disease and Movement Disorders.
Given this high rate, there is a high risk for injury “that may result in pain and hematoma” when using preauricular extraoral injections, Dr. Yilmaz and colleagues noted. Instead, they recommend an intraoral injection approach to the lateral pterygoid muscle. “However, this critical anatomical variation is still unrecognized by most clinicians performing [botulinum toxin] injections,” they wrote.
Significant gender differences
The maxillary artery is the largest branch of the external carotid artery.
In the current study, the researchers used magnetic resonance angiography to assess the relevant anatomy in a cohort of 200 individuals (mean age, 56.4 years; 64% women) without a history of facial trauma or movement disorders.
Results showed that the maxillary artery ran lateral to the lateral pterygoid muscle in 67% of the study population.
“This result was also more frequent in females compared with males. Also, there was a considerable variability between the left and the right side in 20% of the participants,” Dr. Yilmaz reported.
Statistically significant gender differences were found for the artery running lateral to the lateral pterygoid muscle on both sides (71.1% in women vs. 58.5% in men; P = .007) and for the artery running lateral to the lateral pterygoid muscle on just the left side (69.8% in women vs. 53.5% in men; P = .02).
In an email exchange, Dr. Yilmaz said if medical personnel are not trained to perform an intraoral approach, “imaging to visualize the path of the maxillary artery before an extraoral/transcutaneous injection can be recommended.”
“If the imaging reveals that the maxillary artery passes lateral to the muscle, then the patient needs to be referred to another center for an intraoral injection,” unless the clinician is trained for an intraoral approach, he added.
Useful education
Commenting on the study, Michele Tagliati, MD, director of the Movement Disorders Program at Cedars-Sinai Medical Center, Los Angeles, said the results were educational. “I didn’t know about all this variability. I was working under the assumption that the artery was medial,” said Dr. Tagliati, who was not involved with the research.
Among his large practice of about 2,000 patients, Dr. Tagliati estimated having five patients for whom he provides this type of injection – and has never encountered a problem with them.
“Maybe all my patients are medial, but now that I’m aware I’ll probably pay more attention,” Dr. Tagliati said. He does not currently perform magnetic resonance angiography before injecting them, “although maybe I should,” he said.
When asked if it is worth the time and expense to perform magnetic resonance angiography on every patient who comes in for lateral pterygoid muscle injections, Dr. Tagliati said that although he has done the injections without problems in his current patients, he may “start obtaining imaging studies to make sure that we’re not taking unnecessary risk” if the maxillary artery is lateral to the lateral pterygoid muscle in new patients.
If there is a risk, he’ll then consider talking with colleagues in oral or facial surgery. Dr. Tagliati added that the number of patients he sees with oromandibular dystonia is rather small, so this extra step would not add a lot of additional imaging.
Overall, Dr. Tagliati noted that the study outcome was significant enough to want to use it for professional education. “I can definitely tell you that I’m going to bring it to the attention of my Fellows. [Every year] I teach one or two Fellows to inject Botox,” he said.
There was no funding for the study. Dr. Yilmaz and Dr. Tagliati have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM MDS VIRTUAL CONGRESS 2021
‘Push the bar higher’: New statement on type 1 diabetes in adults
A newly published consensus statement on the management of type 1 diabetes in adults addresses the unique clinical needs of the population compared with those of children with type 1 diabetes or adults with type 2 diabetes.
“The focus on adults is kind of new and it is important. ... I do think it’s a bit of a forgotten population. Whenever we talk about diabetes in adults it’s assumed to be about type 2,” document coauthor M. Sue Kirkman, MD, said in an interview.
The document covers diagnosis of type 1 diabetes, goals and targets, schedule of care, self-management education and lifestyle, glucose monitoring, insulin therapy, hypoglycemia, psychosocial care, diabetic ketoacidosis (DKA), pancreas transplant/islet cell transplantation, adjunctive therapies, special populations (pregnant, older, hospitalized), and emergent and future perspectives.
Initially presented in draft form in June at the American Diabetes Association (ADA) 81st scientific sessions, the final version of the joint ADA/EASD statement was presented Oct. 1 at the annual meeting of the European Association for the Study of Diabetes and simultaneously published in Diabetologia and Diabetes Care.
“We are aware of the many and rapid advances in the diagnosis and treatment of type 1 diabetes ... However, despite these advances, there is also a growing recognition of the psychosocial burden of living with type 1 diabetes,” writing group cochair Richard I.G. Holt, MB BChir, PhD, professor of diabetes and endocrinology at the University of Southampton, England, said when introducing the 90-minute EASD session.
“Although there is guidance for the management of type 1 diabetes, the aim of this report is to highlight the major areas that health care professionals should consider when managing adults with type 1 diabetes,” he added.
Noting that the joint EASD/ADA consensus report on type 2 diabetes has been “highly influential,” Dr. Holt said, “EASD and ADA recognized the need to develop a comparable consensus report specifically addressing type 1 diabetes.”
The overriding goals, Dr. Holt said, are to “support people with type 1 diabetes to live a long and healthy life” with four specific strategies: delivery of insulin to keep glucose levels as close to target as possible to prevent complications while minimizing hypoglycemia and preventing DKA; managing cardiovascular risk factors; minimizing psychosocial burden; and promoting psychological well-being.
Diagnostic algorithm
Another coauthor, J. Hans de Vries, MD, PhD, professor of internal medicine at the University of Amsterdam, explained the recommended approach to distinguishing type 1 diabetes from type 2 diabetes or monogenic diabetes in adults, which is often a clinical challenge.
This also was the topic prompting the most questions during the EASD session.
“Especially in adults, misdiagnosis of type of diabetes is common, occurring in up to 40% of patients diagnosed after the age of 30 years,” Dr. de Vries said.
Among the many reasons for the confusion are that C-peptide levels, a reflection of endogenous insulin secretion, can still be relatively high at the time of clinical onset of type 1 diabetes, but islet antibodies don’t have 100% positive predictive value.
Obesity and type 2 diabetes are increasingly seen at younger ages, and DKA can occur in type 2 diabetes (“ketosis-prone”). In addition, monogenic forms of diabetes can be disguised as type 1 diabetes.
“So, we thought there was a need for a diagnostic algorithm,” Dr. de Vries said, adding that the algorithm – displayed as a graphic in the statement – is only for adults in whom type 1 diabetes is suspected, not other types. Also, it’s based on data from White European populations.
The first step is to test islet autoantibodies. If positive, the diagnosis of type 1 diabetes can be made. If negative and the person is younger than 35 years and without signs of type 2 diabetes, testing C-peptide is advised. If that’s below 200 pmol/L, type 1 diabetes is the diagnosis. If above 200 pmol/L, genetic testing for monogenic diabetes is advised. If there are signs of type 2 diabetes and/or the person is over age 35, type 2 diabetes is the most likely diagnosis.
And if uncertainty remains, the recommendation is to try noninsulin therapy and retest C-peptide again in 3 years, as by that time it will be below 200 pmol/L in a person with type 1 diabetes.
Dr. Kirkman commented regarding the algorithm: “It’s very much from a European population perspective. In some ways that’s a limitation, especially in the U.S. where the population is diverse, but I do think it’s still useful to help guide people through how to think about somebody who presents as an adult where it’s not obviously type 2 or type 1 ... There is a lot of in-between stuff.”
Psychosocial support: Essential but often overlooked
Frank J. Snoek, PhD, professor of psychology at Amsterdam University Medical Centers, Vrije Universiteit, presented the section on behavioral and psychosocial care. He pointed out that diabetes-related emotional distress is reported by 20%-40% of adults with type 1 diabetes, and that the risk of such distress is especially high at the time of diagnosis and when complications develop.
About 15% of people with type 1 diabetes have depression, which is linked to elevated A1c levels, increased complication risk, and mortality. Anxiety also is very common and linked with diabetes-specific fears including hypoglycemia. Eating disorders are more prevalent among people with type 1 diabetes than in the general population and can further complicate diabetes management.
Recommendations include periodic evaluation of psychological health and social barriers to self-management and having clear referral pathways and access to psychological or psychiatric care for individuals in need. “All members of the diabetes care team have a responsibility when it comes to offering psychosocial support as part of ongoing diabetes care and education.”
Dr. Kirkman had identified this section as noteworthy: “I think the focus on psychosocial care and making that an ongoing part of diabetes care and assessment is important.”
More data needed on diets, many other areas
During the discussion, several attendees asked about low-carbohydrate diets, embraced by many individuals with type 1 diabetes.
The document states: “While low-carbohydrate and very low-carbohydrate eating patterns have become increasingly popular and reduce A1c levels in the short term, it is important to incorporate these in conjunction with healthy eating guidelines. Additional components of the meal, including high fat and/or high protein, may contribute to delayed hyperglycemia and the need for insulin dose adjustments. Since this is highly variable between individuals, postprandial glucose measurements for up to 3 hours or more may be needed to determine initial dose adjustments.”
Beyond that, Tomasz Klupa, MD, PhD, of the department of metabolic diseases, Jagiellonian University, Krakow, Poland, responded: “We don’t have much data on low-carb diets in type 1 diabetes. ... Compliance to those diets is pretty poor. We don’t have long-term follow-up and the studies are simply not conclusive. Initial results do show reductions in body weight and A1c, but with time the compliance goes down dramatically.”
“Certainly, when we think of low-carb diets, we have to meet our patients where they are,” said Amy Hess-Fischl, a nutritionist and certified diabetes care and education specialist at the University of Chicago. “We don’t have enough data to really say there’s positive long-term evidence. But we can find a happy medium to find some benefits in glycemic and weight control. ... It’s really that collaboration with that person to identify what’s going to work for them in a healthy way.”
The EASD session concluded with writing group cochair Anne L. Peters, MD, director of clinical diabetes programs at the University of Southern California, Los Angeles, summing up the many other knowledge gaps, including personalizing use of diabetes technology, the problems of health disparities and lack of access to care, and the feasibility of prevention and/or cure.
She observed: “There is no one-size-fits-all approach to diabetes care, and the more we can individualize our approaches, the more successful we are likely to be. ... Hopefully this consensus statement has pushed the bar a bit higher, telling the powers that be that people with type 1 diabetes need and deserve the best.
“We have a very long way to go before all of our patients reach their goals and health equity is achieved. ... We need to provide each and every person the access to the care we describe in this consensus statement, so that all can prosper and thrive and look forward to a long and healthy life lived with type 1 diabetes.”
Dr. Holt has financial relationships with Novo Nordisk, Abbott, Eli Lilly, Otsuka, and Roche. Dr. de Vries has financial relationships with Afon, Eli Lilly, Novo Nordisk, Adocia, and Zealand Pharma. Ms. Hess-Fischl has financial relationships with Abbott Diabetes Care and Xeris. Dr. Klupa has financial relationships with numerous drug and device companies. Dr. Snoek has financial relationships with Abbott, Eli Lilly, Sanofi, and Novo Nordisk. Dr. Peters has financial relationships with Abbott Diabetes Care, Dexcom, Eli Lilly, Insulet, Novo Nordisk, Medscape, and Zealand Pharmaceuticals. She holds stock options in Omada Health and Livongo and is a special government employee of the Food and Drug Administration.
A version of this article first appeared on Medscape.com.
A newly published consensus statement on the management of type 1 diabetes in adults addresses the unique clinical needs of the population compared with those of children with type 1 diabetes or adults with type 2 diabetes.
“The focus on adults is kind of new and it is important. ... I do think it’s a bit of a forgotten population. Whenever we talk about diabetes in adults it’s assumed to be about type 2,” document coauthor M. Sue Kirkman, MD, said in an interview.
The document covers diagnosis of type 1 diabetes, goals and targets, schedule of care, self-management education and lifestyle, glucose monitoring, insulin therapy, hypoglycemia, psychosocial care, diabetic ketoacidosis (DKA), pancreas transplant/islet cell transplantation, adjunctive therapies, special populations (pregnant, older, hospitalized), and emergent and future perspectives.
Initially presented in draft form in June at the American Diabetes Association (ADA) 81st scientific sessions, the final version of the joint ADA/EASD statement was presented Oct. 1 at the annual meeting of the European Association for the Study of Diabetes and simultaneously published in Diabetologia and Diabetes Care.
“We are aware of the many and rapid advances in the diagnosis and treatment of type 1 diabetes ... However, despite these advances, there is also a growing recognition of the psychosocial burden of living with type 1 diabetes,” writing group cochair Richard I.G. Holt, MB BChir, PhD, professor of diabetes and endocrinology at the University of Southampton, England, said when introducing the 90-minute EASD session.
“Although there is guidance for the management of type 1 diabetes, the aim of this report is to highlight the major areas that health care professionals should consider when managing adults with type 1 diabetes,” he added.
Noting that the joint EASD/ADA consensus report on type 2 diabetes has been “highly influential,” Dr. Holt said, “EASD and ADA recognized the need to develop a comparable consensus report specifically addressing type 1 diabetes.”
The overriding goals, Dr. Holt said, are to “support people with type 1 diabetes to live a long and healthy life” with four specific strategies: delivery of insulin to keep glucose levels as close to target as possible to prevent complications while minimizing hypoglycemia and preventing DKA; managing cardiovascular risk factors; minimizing psychosocial burden; and promoting psychological well-being.
Diagnostic algorithm
Another coauthor, J. Hans de Vries, MD, PhD, professor of internal medicine at the University of Amsterdam, explained the recommended approach to distinguishing type 1 diabetes from type 2 diabetes or monogenic diabetes in adults, which is often a clinical challenge.
This also was the topic prompting the most questions during the EASD session.
“Especially in adults, misdiagnosis of type of diabetes is common, occurring in up to 40% of patients diagnosed after the age of 30 years,” Dr. de Vries said.
Among the many reasons for the confusion are that C-peptide levels, a reflection of endogenous insulin secretion, can still be relatively high at the time of clinical onset of type 1 diabetes, but islet antibodies don’t have 100% positive predictive value.
Obesity and type 2 diabetes are increasingly seen at younger ages, and DKA can occur in type 2 diabetes (“ketosis-prone”). In addition, monogenic forms of diabetes can be disguised as type 1 diabetes.
“So, we thought there was a need for a diagnostic algorithm,” Dr. de Vries said, adding that the algorithm – displayed as a graphic in the statement – is only for adults in whom type 1 diabetes is suspected, not other types. Also, it’s based on data from White European populations.
The first step is to test islet autoantibodies. If positive, the diagnosis of type 1 diabetes can be made. If negative and the person is younger than 35 years and without signs of type 2 diabetes, testing C-peptide is advised. If that’s below 200 pmol/L, type 1 diabetes is the diagnosis. If above 200 pmol/L, genetic testing for monogenic diabetes is advised. If there are signs of type 2 diabetes and/or the person is over age 35, type 2 diabetes is the most likely diagnosis.
And if uncertainty remains, the recommendation is to try noninsulin therapy and retest C-peptide again in 3 years, as by that time it will be below 200 pmol/L in a person with type 1 diabetes.
Dr. Kirkman commented regarding the algorithm: “It’s very much from a European population perspective. In some ways that’s a limitation, especially in the U.S. where the population is diverse, but I do think it’s still useful to help guide people through how to think about somebody who presents as an adult where it’s not obviously type 2 or type 1 ... There is a lot of in-between stuff.”
Psychosocial support: Essential but often overlooked
Frank J. Snoek, PhD, professor of psychology at Amsterdam University Medical Centers, Vrije Universiteit, presented the section on behavioral and psychosocial care. He pointed out that diabetes-related emotional distress is reported by 20%-40% of adults with type 1 diabetes, and that the risk of such distress is especially high at the time of diagnosis and when complications develop.
About 15% of people with type 1 diabetes have depression, which is linked to elevated A1c levels, increased complication risk, and mortality. Anxiety also is very common and linked with diabetes-specific fears including hypoglycemia. Eating disorders are more prevalent among people with type 1 diabetes than in the general population and can further complicate diabetes management.
Recommendations include periodic evaluation of psychological health and social barriers to self-management and having clear referral pathways and access to psychological or psychiatric care for individuals in need. “All members of the diabetes care team have a responsibility when it comes to offering psychosocial support as part of ongoing diabetes care and education.”
Dr. Kirkman had identified this section as noteworthy: “I think the focus on psychosocial care and making that an ongoing part of diabetes care and assessment is important.”
More data needed on diets, many other areas
During the discussion, several attendees asked about low-carbohydrate diets, embraced by many individuals with type 1 diabetes.
The document states: “While low-carbohydrate and very low-carbohydrate eating patterns have become increasingly popular and reduce A1c levels in the short term, it is important to incorporate these in conjunction with healthy eating guidelines. Additional components of the meal, including high fat and/or high protein, may contribute to delayed hyperglycemia and the need for insulin dose adjustments. Since this is highly variable between individuals, postprandial glucose measurements for up to 3 hours or more may be needed to determine initial dose adjustments.”
Beyond that, Tomasz Klupa, MD, PhD, of the department of metabolic diseases, Jagiellonian University, Krakow, Poland, responded: “We don’t have much data on low-carb diets in type 1 diabetes. ... Compliance to those diets is pretty poor. We don’t have long-term follow-up and the studies are simply not conclusive. Initial results do show reductions in body weight and A1c, but with time the compliance goes down dramatically.”
“Certainly, when we think of low-carb diets, we have to meet our patients where they are,” said Amy Hess-Fischl, a nutritionist and certified diabetes care and education specialist at the University of Chicago. “We don’t have enough data to really say there’s positive long-term evidence. But we can find a happy medium to find some benefits in glycemic and weight control. ... It’s really that collaboration with that person to identify what’s going to work for them in a healthy way.”
The EASD session concluded with writing group cochair Anne L. Peters, MD, director of clinical diabetes programs at the University of Southern California, Los Angeles, summing up the many other knowledge gaps, including personalizing use of diabetes technology, the problems of health disparities and lack of access to care, and the feasibility of prevention and/or cure.
She observed: “There is no one-size-fits-all approach to diabetes care, and the more we can individualize our approaches, the more successful we are likely to be. ... Hopefully this consensus statement has pushed the bar a bit higher, telling the powers that be that people with type 1 diabetes need and deserve the best.
“We have a very long way to go before all of our patients reach their goals and health equity is achieved. ... We need to provide each and every person the access to the care we describe in this consensus statement, so that all can prosper and thrive and look forward to a long and healthy life lived with type 1 diabetes.”
Dr. Holt has financial relationships with Novo Nordisk, Abbott, Eli Lilly, Otsuka, and Roche. Dr. de Vries has financial relationships with Afon, Eli Lilly, Novo Nordisk, Adocia, and Zealand Pharma. Ms. Hess-Fischl has financial relationships with Abbott Diabetes Care and Xeris. Dr. Klupa has financial relationships with numerous drug and device companies. Dr. Snoek has financial relationships with Abbott, Eli Lilly, Sanofi, and Novo Nordisk. Dr. Peters has financial relationships with Abbott Diabetes Care, Dexcom, Eli Lilly, Insulet, Novo Nordisk, Medscape, and Zealand Pharmaceuticals. She holds stock options in Omada Health and Livongo and is a special government employee of the Food and Drug Administration.
A version of this article first appeared on Medscape.com.
A newly published consensus statement on the management of type 1 diabetes in adults addresses the unique clinical needs of the population compared with those of children with type 1 diabetes or adults with type 2 diabetes.
“The focus on adults is kind of new and it is important. ... I do think it’s a bit of a forgotten population. Whenever we talk about diabetes in adults it’s assumed to be about type 2,” document coauthor M. Sue Kirkman, MD, said in an interview.
The document covers diagnosis of type 1 diabetes, goals and targets, schedule of care, self-management education and lifestyle, glucose monitoring, insulin therapy, hypoglycemia, psychosocial care, diabetic ketoacidosis (DKA), pancreas transplant/islet cell transplantation, adjunctive therapies, special populations (pregnant, older, hospitalized), and emergent and future perspectives.
Initially presented in draft form in June at the American Diabetes Association (ADA) 81st scientific sessions, the final version of the joint ADA/EASD statement was presented Oct. 1 at the annual meeting of the European Association for the Study of Diabetes and simultaneously published in Diabetologia and Diabetes Care.
“We are aware of the many and rapid advances in the diagnosis and treatment of type 1 diabetes ... However, despite these advances, there is also a growing recognition of the psychosocial burden of living with type 1 diabetes,” writing group cochair Richard I.G. Holt, MB BChir, PhD, professor of diabetes and endocrinology at the University of Southampton, England, said when introducing the 90-minute EASD session.
“Although there is guidance for the management of type 1 diabetes, the aim of this report is to highlight the major areas that health care professionals should consider when managing adults with type 1 diabetes,” he added.
Noting that the joint EASD/ADA consensus report on type 2 diabetes has been “highly influential,” Dr. Holt said, “EASD and ADA recognized the need to develop a comparable consensus report specifically addressing type 1 diabetes.”
The overriding goals, Dr. Holt said, are to “support people with type 1 diabetes to live a long and healthy life” with four specific strategies: delivery of insulin to keep glucose levels as close to target as possible to prevent complications while minimizing hypoglycemia and preventing DKA; managing cardiovascular risk factors; minimizing psychosocial burden; and promoting psychological well-being.
Diagnostic algorithm
Another coauthor, J. Hans de Vries, MD, PhD, professor of internal medicine at the University of Amsterdam, explained the recommended approach to distinguishing type 1 diabetes from type 2 diabetes or monogenic diabetes in adults, which is often a clinical challenge.
This also was the topic prompting the most questions during the EASD session.
“Especially in adults, misdiagnosis of type of diabetes is common, occurring in up to 40% of patients diagnosed after the age of 30 years,” Dr. de Vries said.
Among the many reasons for the confusion are that C-peptide levels, a reflection of endogenous insulin secretion, can still be relatively high at the time of clinical onset of type 1 diabetes, but islet antibodies don’t have 100% positive predictive value.
Obesity and type 2 diabetes are increasingly seen at younger ages, and DKA can occur in type 2 diabetes (“ketosis-prone”). In addition, monogenic forms of diabetes can be disguised as type 1 diabetes.
“So, we thought there was a need for a diagnostic algorithm,” Dr. de Vries said, adding that the algorithm – displayed as a graphic in the statement – is only for adults in whom type 1 diabetes is suspected, not other types. Also, it’s based on data from White European populations.
The first step is to test islet autoantibodies. If positive, the diagnosis of type 1 diabetes can be made. If negative and the person is younger than 35 years and without signs of type 2 diabetes, testing C-peptide is advised. If that’s below 200 pmol/L, type 1 diabetes is the diagnosis. If above 200 pmol/L, genetic testing for monogenic diabetes is advised. If there are signs of type 2 diabetes and/or the person is over age 35, type 2 diabetes is the most likely diagnosis.
And if uncertainty remains, the recommendation is to try noninsulin therapy and retest C-peptide again in 3 years, as by that time it will be below 200 pmol/L in a person with type 1 diabetes.
Dr. Kirkman commented regarding the algorithm: “It’s very much from a European population perspective. In some ways that’s a limitation, especially in the U.S. where the population is diverse, but I do think it’s still useful to help guide people through how to think about somebody who presents as an adult where it’s not obviously type 2 or type 1 ... There is a lot of in-between stuff.”
Psychosocial support: Essential but often overlooked
Frank J. Snoek, PhD, professor of psychology at Amsterdam University Medical Centers, Vrije Universiteit, presented the section on behavioral and psychosocial care. He pointed out that diabetes-related emotional distress is reported by 20%-40% of adults with type 1 diabetes, and that the risk of such distress is especially high at the time of diagnosis and when complications develop.
About 15% of people with type 1 diabetes have depression, which is linked to elevated A1c levels, increased complication risk, and mortality. Anxiety also is very common and linked with diabetes-specific fears including hypoglycemia. Eating disorders are more prevalent among people with type 1 diabetes than in the general population and can further complicate diabetes management.
Recommendations include periodic evaluation of psychological health and social barriers to self-management and having clear referral pathways and access to psychological or psychiatric care for individuals in need. “All members of the diabetes care team have a responsibility when it comes to offering psychosocial support as part of ongoing diabetes care and education.”
Dr. Kirkman had identified this section as noteworthy: “I think the focus on psychosocial care and making that an ongoing part of diabetes care and assessment is important.”
More data needed on diets, many other areas
During the discussion, several attendees asked about low-carbohydrate diets, embraced by many individuals with type 1 diabetes.
The document states: “While low-carbohydrate and very low-carbohydrate eating patterns have become increasingly popular and reduce A1c levels in the short term, it is important to incorporate these in conjunction with healthy eating guidelines. Additional components of the meal, including high fat and/or high protein, may contribute to delayed hyperglycemia and the need for insulin dose adjustments. Since this is highly variable between individuals, postprandial glucose measurements for up to 3 hours or more may be needed to determine initial dose adjustments.”
Beyond that, Tomasz Klupa, MD, PhD, of the department of metabolic diseases, Jagiellonian University, Krakow, Poland, responded: “We don’t have much data on low-carb diets in type 1 diabetes. ... Compliance to those diets is pretty poor. We don’t have long-term follow-up and the studies are simply not conclusive. Initial results do show reductions in body weight and A1c, but with time the compliance goes down dramatically.”
“Certainly, when we think of low-carb diets, we have to meet our patients where they are,” said Amy Hess-Fischl, a nutritionist and certified diabetes care and education specialist at the University of Chicago. “We don’t have enough data to really say there’s positive long-term evidence. But we can find a happy medium to find some benefits in glycemic and weight control. ... It’s really that collaboration with that person to identify what’s going to work for them in a healthy way.”
The EASD session concluded with writing group cochair Anne L. Peters, MD, director of clinical diabetes programs at the University of Southern California, Los Angeles, summing up the many other knowledge gaps, including personalizing use of diabetes technology, the problems of health disparities and lack of access to care, and the feasibility of prevention and/or cure.
She observed: “There is no one-size-fits-all approach to diabetes care, and the more we can individualize our approaches, the more successful we are likely to be. ... Hopefully this consensus statement has pushed the bar a bit higher, telling the powers that be that people with type 1 diabetes need and deserve the best.
“We have a very long way to go before all of our patients reach their goals and health equity is achieved. ... We need to provide each and every person the access to the care we describe in this consensus statement, so that all can prosper and thrive and look forward to a long and healthy life lived with type 1 diabetes.”
Dr. Holt has financial relationships with Novo Nordisk, Abbott, Eli Lilly, Otsuka, and Roche. Dr. de Vries has financial relationships with Afon, Eli Lilly, Novo Nordisk, Adocia, and Zealand Pharma. Ms. Hess-Fischl has financial relationships with Abbott Diabetes Care and Xeris. Dr. Klupa has financial relationships with numerous drug and device companies. Dr. Snoek has financial relationships with Abbott, Eli Lilly, Sanofi, and Novo Nordisk. Dr. Peters has financial relationships with Abbott Diabetes Care, Dexcom, Eli Lilly, Insulet, Novo Nordisk, Medscape, and Zealand Pharmaceuticals. She holds stock options in Omada Health and Livongo and is a special government employee of the Food and Drug Administration.
A version of this article first appeared on Medscape.com.
FROM EASD 2021
Cold viruses thrived in kids as other viruses faded in 2020
The common-cold viruses rhinovirus (RV) and enterovirus (EV) continued to circulate among children during the COVID-19 pandemic while there were sharp declines in influenza, respiratory syncytial virus (RSV), and other respiratory viruses, new data indicate.
Researchers used data from the Centers for Disease Control and Prevention’s New Vaccine Surveillance Network. The cases involved 37,676 children in seven geographically diverse U.S. medical centers between December 2016 and January 2021. Patients presented to emergency departments or were hospitalized with RV, EV, and other acute respiratory viruses.
The investigators found that the percentage of children in whom RV/EV was detected from March 2020 to January 2021 was similar to the percentage during the same months in 2017-2018 and 2019-2020. However, the proportion of children infected with influenza, RSV, and other respiratory viruses combined dropped significantly in comparison to the three prior seasons.
Danielle Rankin, MPH, lead author of the study and a doctoral candidate in pediatric infectious disease at Vanderbilt University, in Nashville, Tenn., presented the study on Sept. 30 during a press conference at IDWeek 2021, an annual scientific meeting on infectious diseases.
“Reasoning for rhinovirus and enterovirus circulation is unknown but may be attributed to a number of factors, such as different transmission routes or the prolonged survival of the virus on surfaces,” Ms. Rankin said. “Improved understanding of these persistent factors of RV/EV and the role of nonpharmaceutical interventions on transmission dynamics can further guide future prevention recommendations and guidelines.”
Coauthor Claire Midgley, PhD, an epidemiologist in the Division of Viral Diseases at the CDC, told reporters that further studies will assess why RV and EV remained during the pandemic and which virus types within the RV/EV group persisted.
“We do know that the virus can spread through secretions on people’s hands,” she said. “Washing kids’ hands regularly and trying not to touch your face where possible is a really effective way to prevent transmission,” Dr. Midgley said.
“The more we understand about all of these factors, the better we can inform prevention measures.”
Andrew T. Pavia, MD, chief, division of pediatric infectious diseases, University of Utah, Salt Lake City, who was not involved in the study, told this news organization that rhinoviruses can persist in the nose for a very long time, especially in younger children, which increases the opportunities for transmission.
“Very young children who are unable to wear masks or are unlikely to wear them well may be acting as the reservoir, allowing transmission in households,” he said. “There is also an enormous pool of diverse rhinoviruses, so past colds provide limited immunity, as everyone has found out from experience.”
Martha Perry, MD, associate professor at the University of North Carolina at Chapel Hill and chief of adolescent medicine, told this news organization that some of the differences in the prevalence of viruses may be because of their seasonality.
“Times when there were more mask mandates were times when RSV and influenza are more prevalent,” said Dr. Perry, who was not involved with the study. “We were masking more intently during those times, and there was loosening of restrictions when we see more enterovirus, particularly because that tends to be more of a summer/fall virus.”
She agreed that the differences may result from the way the viruses are transmitted.
“Perhaps masks were helping with RSV and influenza, but perhaps there was not as much hand washing or cleansing as needed to prevent the spread of rhinovirus and enterovirus, because those are viruses that require a bit more hand washing,” Dr. Perry said. “They are less aerosolized and better spread with hand-to-hand contact.”
Dr. Perry added that on the flip side, “it’s really exciting that there are ways we can prevent RSV and influenza, which tend to cause more severe infection.”
Ms. Rankin said limitations of the study include the fact that from March 2020 to January 2021, health care–seeking behaviors may have changed because of the pandemic and that the study does not include the frequency of respiratory viruses in the outpatient setting.
The sharp 2020-2021 decline in RSV reported in the study may have reversed after many of the COVID-19 restrictions were lifted this summer.
This news organization reported in June of this year that the CDC has issued a health advisory to notify clinicians and caregivers about an increase in cases of interseasonal RSV in parts of the southern United States.
The CDC has urged broader testing for RSV among patients presenting with acute respiratory illness who test negative for SARS-CoV-2.
The study’s authors, Ms. Pavia, and Dr. Perry have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The common-cold viruses rhinovirus (RV) and enterovirus (EV) continued to circulate among children during the COVID-19 pandemic while there were sharp declines in influenza, respiratory syncytial virus (RSV), and other respiratory viruses, new data indicate.
Researchers used data from the Centers for Disease Control and Prevention’s New Vaccine Surveillance Network. The cases involved 37,676 children in seven geographically diverse U.S. medical centers between December 2016 and January 2021. Patients presented to emergency departments or were hospitalized with RV, EV, and other acute respiratory viruses.
The investigators found that the percentage of children in whom RV/EV was detected from March 2020 to January 2021 was similar to the percentage during the same months in 2017-2018 and 2019-2020. However, the proportion of children infected with influenza, RSV, and other respiratory viruses combined dropped significantly in comparison to the three prior seasons.
Danielle Rankin, MPH, lead author of the study and a doctoral candidate in pediatric infectious disease at Vanderbilt University, in Nashville, Tenn., presented the study on Sept. 30 during a press conference at IDWeek 2021, an annual scientific meeting on infectious diseases.
“Reasoning for rhinovirus and enterovirus circulation is unknown but may be attributed to a number of factors, such as different transmission routes or the prolonged survival of the virus on surfaces,” Ms. Rankin said. “Improved understanding of these persistent factors of RV/EV and the role of nonpharmaceutical interventions on transmission dynamics can further guide future prevention recommendations and guidelines.”
Coauthor Claire Midgley, PhD, an epidemiologist in the Division of Viral Diseases at the CDC, told reporters that further studies will assess why RV and EV remained during the pandemic and which virus types within the RV/EV group persisted.
“We do know that the virus can spread through secretions on people’s hands,” she said. “Washing kids’ hands regularly and trying not to touch your face where possible is a really effective way to prevent transmission,” Dr. Midgley said.
“The more we understand about all of these factors, the better we can inform prevention measures.”
Andrew T. Pavia, MD, chief, division of pediatric infectious diseases, University of Utah, Salt Lake City, who was not involved in the study, told this news organization that rhinoviruses can persist in the nose for a very long time, especially in younger children, which increases the opportunities for transmission.
“Very young children who are unable to wear masks or are unlikely to wear them well may be acting as the reservoir, allowing transmission in households,” he said. “There is also an enormous pool of diverse rhinoviruses, so past colds provide limited immunity, as everyone has found out from experience.”
Martha Perry, MD, associate professor at the University of North Carolina at Chapel Hill and chief of adolescent medicine, told this news organization that some of the differences in the prevalence of viruses may be because of their seasonality.
“Times when there were more mask mandates were times when RSV and influenza are more prevalent,” said Dr. Perry, who was not involved with the study. “We were masking more intently during those times, and there was loosening of restrictions when we see more enterovirus, particularly because that tends to be more of a summer/fall virus.”
She agreed that the differences may result from the way the viruses are transmitted.
“Perhaps masks were helping with RSV and influenza, but perhaps there was not as much hand washing or cleansing as needed to prevent the spread of rhinovirus and enterovirus, because those are viruses that require a bit more hand washing,” Dr. Perry said. “They are less aerosolized and better spread with hand-to-hand contact.”
Dr. Perry added that on the flip side, “it’s really exciting that there are ways we can prevent RSV and influenza, which tend to cause more severe infection.”
Ms. Rankin said limitations of the study include the fact that from March 2020 to January 2021, health care–seeking behaviors may have changed because of the pandemic and that the study does not include the frequency of respiratory viruses in the outpatient setting.
The sharp 2020-2021 decline in RSV reported in the study may have reversed after many of the COVID-19 restrictions were lifted this summer.
This news organization reported in June of this year that the CDC has issued a health advisory to notify clinicians and caregivers about an increase in cases of interseasonal RSV in parts of the southern United States.
The CDC has urged broader testing for RSV among patients presenting with acute respiratory illness who test negative for SARS-CoV-2.
The study’s authors, Ms. Pavia, and Dr. Perry have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The common-cold viruses rhinovirus (RV) and enterovirus (EV) continued to circulate among children during the COVID-19 pandemic while there were sharp declines in influenza, respiratory syncytial virus (RSV), and other respiratory viruses, new data indicate.
Researchers used data from the Centers for Disease Control and Prevention’s New Vaccine Surveillance Network. The cases involved 37,676 children in seven geographically diverse U.S. medical centers between December 2016 and January 2021. Patients presented to emergency departments or were hospitalized with RV, EV, and other acute respiratory viruses.
The investigators found that the percentage of children in whom RV/EV was detected from March 2020 to January 2021 was similar to the percentage during the same months in 2017-2018 and 2019-2020. However, the proportion of children infected with influenza, RSV, and other respiratory viruses combined dropped significantly in comparison to the three prior seasons.
Danielle Rankin, MPH, lead author of the study and a doctoral candidate in pediatric infectious disease at Vanderbilt University, in Nashville, Tenn., presented the study on Sept. 30 during a press conference at IDWeek 2021, an annual scientific meeting on infectious diseases.
“Reasoning for rhinovirus and enterovirus circulation is unknown but may be attributed to a number of factors, such as different transmission routes or the prolonged survival of the virus on surfaces,” Ms. Rankin said. “Improved understanding of these persistent factors of RV/EV and the role of nonpharmaceutical interventions on transmission dynamics can further guide future prevention recommendations and guidelines.”
Coauthor Claire Midgley, PhD, an epidemiologist in the Division of Viral Diseases at the CDC, told reporters that further studies will assess why RV and EV remained during the pandemic and which virus types within the RV/EV group persisted.
“We do know that the virus can spread through secretions on people’s hands,” she said. “Washing kids’ hands regularly and trying not to touch your face where possible is a really effective way to prevent transmission,” Dr. Midgley said.
“The more we understand about all of these factors, the better we can inform prevention measures.”
Andrew T. Pavia, MD, chief, division of pediatric infectious diseases, University of Utah, Salt Lake City, who was not involved in the study, told this news organization that rhinoviruses can persist in the nose for a very long time, especially in younger children, which increases the opportunities for transmission.
“Very young children who are unable to wear masks or are unlikely to wear them well may be acting as the reservoir, allowing transmission in households,” he said. “There is also an enormous pool of diverse rhinoviruses, so past colds provide limited immunity, as everyone has found out from experience.”
Martha Perry, MD, associate professor at the University of North Carolina at Chapel Hill and chief of adolescent medicine, told this news organization that some of the differences in the prevalence of viruses may be because of their seasonality.
“Times when there were more mask mandates were times when RSV and influenza are more prevalent,” said Dr. Perry, who was not involved with the study. “We were masking more intently during those times, and there was loosening of restrictions when we see more enterovirus, particularly because that tends to be more of a summer/fall virus.”
She agreed that the differences may result from the way the viruses are transmitted.
“Perhaps masks were helping with RSV and influenza, but perhaps there was not as much hand washing or cleansing as needed to prevent the spread of rhinovirus and enterovirus, because those are viruses that require a bit more hand washing,” Dr. Perry said. “They are less aerosolized and better spread with hand-to-hand contact.”
Dr. Perry added that on the flip side, “it’s really exciting that there are ways we can prevent RSV and influenza, which tend to cause more severe infection.”
Ms. Rankin said limitations of the study include the fact that from March 2020 to January 2021, health care–seeking behaviors may have changed because of the pandemic and that the study does not include the frequency of respiratory viruses in the outpatient setting.
The sharp 2020-2021 decline in RSV reported in the study may have reversed after many of the COVID-19 restrictions were lifted this summer.
This news organization reported in June of this year that the CDC has issued a health advisory to notify clinicians and caregivers about an increase in cases of interseasonal RSV in parts of the southern United States.
The CDC has urged broader testing for RSV among patients presenting with acute respiratory illness who test negative for SARS-CoV-2.
The study’s authors, Ms. Pavia, and Dr. Perry have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.