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Disentangling sleep problems and bipolar disorder
COPENHAGEN – Sleep spindle density is diminished in euthymic patients with bipolar disorder, suggesting that this sleep architecture abnormality might offer potential for early differentiation of bipolar from unipolar depression, Philipp S. Ritter, MD, said at the annual congress of the European College of Neuropsychopharmacology.
“Hopefully in the future our finding, if replicated, might have clinical utility. It might be a kind of soft biomarker that could be used in early detection, or, in people having their first depressive episode, you could perhaps use this to risk-stratify. And if you see there’s a great reduction in spindle density then a patient might have a higher likelihood of a bipolar disorder, so you might not want to treat with antidepressants that have a high switch rate,” explained Dr. Ritter, a psychiatrist at Technical University of Dresden (Germany).
Sleep spindles are a specific sleep architecture formation evident on the sleep EEG. They are sudden high-amplitude bursts occurring in stage N2 sleep. They are thought to be associated with sensory gating and memory processes. Other investigators have repeatedly demonstrated that patients with schizophrenia, as well as their asymptomatic first-degree relatives, have a reduced density of fast spindles greater than 13 Hz, compared with the general population. In contrast, patients with unipolar depression do not display this polysomnographic abnormality.
These findings prompted Dr. Ritter and his coinvestigators to conduct an all-night polysomnographic study in 24 euthymic patients with bipolar disorder and 25 healthy controls. The bipolar patients demonstrated a reduced density and mean frequency of fast sleep spindles, but not slow spindles (Acta Psychiatr Scand. 2018 Aug;138[2]:163-72).
These sleep spindle findings implicate thalamic dysfunction as a potential neurobiologic mechanism in bipolar disorder, since spindles are generated in the thalamus and spun off in thalamocortical feedback loops, Dr. Ritter observed.
Which came first: the chicken (bipolar disorder) or the egg (sleep disturbance)?
Sleep problems are a prominent issue in patients with bipolar disorder, even when they are euthymic.
“Anybody who deals with bipolar patients knows that sleep is a constant issue. You are always talking to your patients about their sleep. They’re sleeping too much, or not enough, or they’re sleeping just about right but it’s unsatisfactory. They do not sleep well. And if there’s something that disrupts their sleep, it can precipitate episodes,” Dr. Ritter said.
He wondered whether sleep problems are an intrinsic part of the bipolar illness, or a byproduct of the stress of having a severe mental disorder, perhaps a medication side effect, or whether the disordered sleep actually precedes the clinical expression of the mood disorder. So he and his coinvestigators turned to a Munich-based cohort sample of 3,021 adolescents and young adults assessed via the standardized Composite International Diagnostic Interview four times during 10 years of prospective follow-up.
Among 1,943 participants in the epidemiologic study who were free of major mental disorders at entry, the presence of sleep disturbance at baseline as quantified using the Symptom Checklist-90-Revised doubled the risk of developing bipolar disorder within the next 10 years. After the researchers controlled for potential confounders, including parental mood disorder, gender, age, and a history of alcohol or cannabis dependence, poor sleep quality at baseline remained independently associated with a 1.75-fold increased chance of subsequently developing bipolar disorder (J Psychiatr Res. 2015 Sep;68:76-82).
“This is a little bit higher, actually, than the odds ratio usually found for depressive disorders,” said Dr. Ritter.
he added.
Dr. Ritter reported having no financial conflicts regarding these studies.
COPENHAGEN – Sleep spindle density is diminished in euthymic patients with bipolar disorder, suggesting that this sleep architecture abnormality might offer potential for early differentiation of bipolar from unipolar depression, Philipp S. Ritter, MD, said at the annual congress of the European College of Neuropsychopharmacology.
“Hopefully in the future our finding, if replicated, might have clinical utility. It might be a kind of soft biomarker that could be used in early detection, or, in people having their first depressive episode, you could perhaps use this to risk-stratify. And if you see there’s a great reduction in spindle density then a patient might have a higher likelihood of a bipolar disorder, so you might not want to treat with antidepressants that have a high switch rate,” explained Dr. Ritter, a psychiatrist at Technical University of Dresden (Germany).
Sleep spindles are a specific sleep architecture formation evident on the sleep EEG. They are sudden high-amplitude bursts occurring in stage N2 sleep. They are thought to be associated with sensory gating and memory processes. Other investigators have repeatedly demonstrated that patients with schizophrenia, as well as their asymptomatic first-degree relatives, have a reduced density of fast spindles greater than 13 Hz, compared with the general population. In contrast, patients with unipolar depression do not display this polysomnographic abnormality.
These findings prompted Dr. Ritter and his coinvestigators to conduct an all-night polysomnographic study in 24 euthymic patients with bipolar disorder and 25 healthy controls. The bipolar patients demonstrated a reduced density and mean frequency of fast sleep spindles, but not slow spindles (Acta Psychiatr Scand. 2018 Aug;138[2]:163-72).
These sleep spindle findings implicate thalamic dysfunction as a potential neurobiologic mechanism in bipolar disorder, since spindles are generated in the thalamus and spun off in thalamocortical feedback loops, Dr. Ritter observed.
Which came first: the chicken (bipolar disorder) or the egg (sleep disturbance)?
Sleep problems are a prominent issue in patients with bipolar disorder, even when they are euthymic.
“Anybody who deals with bipolar patients knows that sleep is a constant issue. You are always talking to your patients about their sleep. They’re sleeping too much, or not enough, or they’re sleeping just about right but it’s unsatisfactory. They do not sleep well. And if there’s something that disrupts their sleep, it can precipitate episodes,” Dr. Ritter said.
He wondered whether sleep problems are an intrinsic part of the bipolar illness, or a byproduct of the stress of having a severe mental disorder, perhaps a medication side effect, or whether the disordered sleep actually precedes the clinical expression of the mood disorder. So he and his coinvestigators turned to a Munich-based cohort sample of 3,021 adolescents and young adults assessed via the standardized Composite International Diagnostic Interview four times during 10 years of prospective follow-up.
Among 1,943 participants in the epidemiologic study who were free of major mental disorders at entry, the presence of sleep disturbance at baseline as quantified using the Symptom Checklist-90-Revised doubled the risk of developing bipolar disorder within the next 10 years. After the researchers controlled for potential confounders, including parental mood disorder, gender, age, and a history of alcohol or cannabis dependence, poor sleep quality at baseline remained independently associated with a 1.75-fold increased chance of subsequently developing bipolar disorder (J Psychiatr Res. 2015 Sep;68:76-82).
“This is a little bit higher, actually, than the odds ratio usually found for depressive disorders,” said Dr. Ritter.
he added.
Dr. Ritter reported having no financial conflicts regarding these studies.
COPENHAGEN – Sleep spindle density is diminished in euthymic patients with bipolar disorder, suggesting that this sleep architecture abnormality might offer potential for early differentiation of bipolar from unipolar depression, Philipp S. Ritter, MD, said at the annual congress of the European College of Neuropsychopharmacology.
“Hopefully in the future our finding, if replicated, might have clinical utility. It might be a kind of soft biomarker that could be used in early detection, or, in people having their first depressive episode, you could perhaps use this to risk-stratify. And if you see there’s a great reduction in spindle density then a patient might have a higher likelihood of a bipolar disorder, so you might not want to treat with antidepressants that have a high switch rate,” explained Dr. Ritter, a psychiatrist at Technical University of Dresden (Germany).
Sleep spindles are a specific sleep architecture formation evident on the sleep EEG. They are sudden high-amplitude bursts occurring in stage N2 sleep. They are thought to be associated with sensory gating and memory processes. Other investigators have repeatedly demonstrated that patients with schizophrenia, as well as their asymptomatic first-degree relatives, have a reduced density of fast spindles greater than 13 Hz, compared with the general population. In contrast, patients with unipolar depression do not display this polysomnographic abnormality.
These findings prompted Dr. Ritter and his coinvestigators to conduct an all-night polysomnographic study in 24 euthymic patients with bipolar disorder and 25 healthy controls. The bipolar patients demonstrated a reduced density and mean frequency of fast sleep spindles, but not slow spindles (Acta Psychiatr Scand. 2018 Aug;138[2]:163-72).
These sleep spindle findings implicate thalamic dysfunction as a potential neurobiologic mechanism in bipolar disorder, since spindles are generated in the thalamus and spun off in thalamocortical feedback loops, Dr. Ritter observed.
Which came first: the chicken (bipolar disorder) or the egg (sleep disturbance)?
Sleep problems are a prominent issue in patients with bipolar disorder, even when they are euthymic.
“Anybody who deals with bipolar patients knows that sleep is a constant issue. You are always talking to your patients about their sleep. They’re sleeping too much, or not enough, or they’re sleeping just about right but it’s unsatisfactory. They do not sleep well. And if there’s something that disrupts their sleep, it can precipitate episodes,” Dr. Ritter said.
He wondered whether sleep problems are an intrinsic part of the bipolar illness, or a byproduct of the stress of having a severe mental disorder, perhaps a medication side effect, or whether the disordered sleep actually precedes the clinical expression of the mood disorder. So he and his coinvestigators turned to a Munich-based cohort sample of 3,021 adolescents and young adults assessed via the standardized Composite International Diagnostic Interview four times during 10 years of prospective follow-up.
Among 1,943 participants in the epidemiologic study who were free of major mental disorders at entry, the presence of sleep disturbance at baseline as quantified using the Symptom Checklist-90-Revised doubled the risk of developing bipolar disorder within the next 10 years. After the researchers controlled for potential confounders, including parental mood disorder, gender, age, and a history of alcohol or cannabis dependence, poor sleep quality at baseline remained independently associated with a 1.75-fold increased chance of subsequently developing bipolar disorder (J Psychiatr Res. 2015 Sep;68:76-82).
“This is a little bit higher, actually, than the odds ratio usually found for depressive disorders,” said Dr. Ritter.
he added.
Dr. Ritter reported having no financial conflicts regarding these studies.
REPORTING FROM ECNP 2019
Reappraising standard treatment of comorbid insomnia/depression
COPENHAGEN – The traditional treatment paradigm for patients with comorbid depression and insomnia has been to focus on the depression in expectation that the sleep problems will fade away with the depressive symptoms.
Big mistake, Kerstin Blom, PhD, said during the annual congress of the European College of Neuropsychopharmacology.
That treatment strategy is insufficient, because untreated insomnia seldom improves. It hinders recovery from depression, increases the risk of new depressive episodes, and causes continued suffering because of poor sleep, asserted Dr. Blom, a clinical psychologist and researcher at the Internet Psychiatry Clinic at the Karolinska Institute in Stockholm.
She presented highlights of a series of three randomized, controlled trials for which she was first author. The take-home message: Insomnia with comorbid depression is not merely a symptom of depression; it requires specific treatment.
“Insomnia needs to be treated according to guidelines – that is, with cognitive-behavioral therapy – when it’s comorbid with depression,” she declared. “Insomnia therapy also treats comorbid depression, but it’s not so much the other way around. There are some effects on insomnia when you treat depression, but they’re not very large.”
The first study in her series included 43 adults with psychiatrist-diagnosed comorbid insomnia and major depression who were randomized to an 8-week course of psychologist-guided, Internet-delivered cognitive-behavioral therapy (ICBT) for one disorder or the other. At 6- and 12-month follow-up, patients who received ICBT for insomnia had significantly greater improvement in their insomnia as measured by the self-rated Insomnia Severity Index than did those who got ICBT for depression, while both forms of treatment were similarly effective in reducing depression severity as reflected in Montgomery-Åsberg Depression Rating Scale (MADRS) scores (Sleep. 2015 Feb 1;38[2]:267-77).
At 3-year follow-up, the beneficial impact of ICBT for insomnia remained strong, with recipients reporting less need for additional sleep treatment and less use of sleep medication than did the patients who got ICBT for depression. Both groups were left with mild depression, pointing to the need to develop a combined form of CBT that would simultaneously address both disorders in patients with comorbid depression and insomnia (Sleep. 2017 Aug 1;40[8]. doi. 10.1093/sleep/zsx108).
The Swedish investigators went on to create a 9-week course of psychologist-guided combination ICBT for both insomnia and depression. Then they randomized 126 dual-diagnosis patients to that treatment program or to therapist-guided ICBT for depression plus a placebo sleep intervention, which included education about sleep hygiene, stress management, and use of a sleep diary. At 6 months of follow-up, the dual-target ICBT group had a significantly greater reduction in Insomnia Severity Index scores than those who got ICBT for depression plus placebo. No between-group difference were found in the reduction in MADRS scores.
Dr. Blom observed. Follow-up out to 36 months is ongoing.
The third study included 148 nondepressed adults with insomnia who were randomized to the 8-week ICBT insomnia intervention or an active control treatment, which again included patient education, stress management, and a sleep diary. At 6 months, the active CBT-insomnia group had significantly lower Insomnia Severity Index scores than controls. However, at 12 and 36 months, the control group caught up, and there was no longer a between-group difference, with 74% of participants no longer meeting diagnostic criteria for insomnia at 36 months. The explanation for the catch-up? The control group used significantly more hypnotic sleep medications and more frequently sought additional insomnia treatments, including yoga and mindfulness, outside of the study setting during follow-up (Sleep. 2016 Jun 1;39[6]:1267-74).
It was Dr. Blom’s intent to also use this randomized, controlled trials to test the hypothesis that improving insomnia in nondepressed patients prevents future episodes of depression. She was thwarted in this attempt.
“After they got our low-intensity control version of a sleep intervention, they went out and got more treatment and that seems to have helped them, which is great,” Dr. Blom said. “But it sort of ruined our prediction study.”
However, in a post hoc analysis, study participants who were poor sleepers at 12 months had significantly more depressive symptoms at 36 months than did those with improved sleep at 12 months. The effect size was quite large, with a between-group 5.5-point difference in MADRS scores at 36 months in a study population that was nondepressed at baseline.
“So improved sleep may prevent depression long term,” Dr. Blom said. “The jury is still out on that one.”
She reported having no financial conflicts regarding her studies, which were supported by government research funding.
COPENHAGEN – The traditional treatment paradigm for patients with comorbid depression and insomnia has been to focus on the depression in expectation that the sleep problems will fade away with the depressive symptoms.
Big mistake, Kerstin Blom, PhD, said during the annual congress of the European College of Neuropsychopharmacology.
That treatment strategy is insufficient, because untreated insomnia seldom improves. It hinders recovery from depression, increases the risk of new depressive episodes, and causes continued suffering because of poor sleep, asserted Dr. Blom, a clinical psychologist and researcher at the Internet Psychiatry Clinic at the Karolinska Institute in Stockholm.
She presented highlights of a series of three randomized, controlled trials for which she was first author. The take-home message: Insomnia with comorbid depression is not merely a symptom of depression; it requires specific treatment.
“Insomnia needs to be treated according to guidelines – that is, with cognitive-behavioral therapy – when it’s comorbid with depression,” she declared. “Insomnia therapy also treats comorbid depression, but it’s not so much the other way around. There are some effects on insomnia when you treat depression, but they’re not very large.”
The first study in her series included 43 adults with psychiatrist-diagnosed comorbid insomnia and major depression who were randomized to an 8-week course of psychologist-guided, Internet-delivered cognitive-behavioral therapy (ICBT) for one disorder or the other. At 6- and 12-month follow-up, patients who received ICBT for insomnia had significantly greater improvement in their insomnia as measured by the self-rated Insomnia Severity Index than did those who got ICBT for depression, while both forms of treatment were similarly effective in reducing depression severity as reflected in Montgomery-Åsberg Depression Rating Scale (MADRS) scores (Sleep. 2015 Feb 1;38[2]:267-77).
At 3-year follow-up, the beneficial impact of ICBT for insomnia remained strong, with recipients reporting less need for additional sleep treatment and less use of sleep medication than did the patients who got ICBT for depression. Both groups were left with mild depression, pointing to the need to develop a combined form of CBT that would simultaneously address both disorders in patients with comorbid depression and insomnia (Sleep. 2017 Aug 1;40[8]. doi. 10.1093/sleep/zsx108).
The Swedish investigators went on to create a 9-week course of psychologist-guided combination ICBT for both insomnia and depression. Then they randomized 126 dual-diagnosis patients to that treatment program or to therapist-guided ICBT for depression plus a placebo sleep intervention, which included education about sleep hygiene, stress management, and use of a sleep diary. At 6 months of follow-up, the dual-target ICBT group had a significantly greater reduction in Insomnia Severity Index scores than those who got ICBT for depression plus placebo. No between-group difference were found in the reduction in MADRS scores.
Dr. Blom observed. Follow-up out to 36 months is ongoing.
The third study included 148 nondepressed adults with insomnia who were randomized to the 8-week ICBT insomnia intervention or an active control treatment, which again included patient education, stress management, and a sleep diary. At 6 months, the active CBT-insomnia group had significantly lower Insomnia Severity Index scores than controls. However, at 12 and 36 months, the control group caught up, and there was no longer a between-group difference, with 74% of participants no longer meeting diagnostic criteria for insomnia at 36 months. The explanation for the catch-up? The control group used significantly more hypnotic sleep medications and more frequently sought additional insomnia treatments, including yoga and mindfulness, outside of the study setting during follow-up (Sleep. 2016 Jun 1;39[6]:1267-74).
It was Dr. Blom’s intent to also use this randomized, controlled trials to test the hypothesis that improving insomnia in nondepressed patients prevents future episodes of depression. She was thwarted in this attempt.
“After they got our low-intensity control version of a sleep intervention, they went out and got more treatment and that seems to have helped them, which is great,” Dr. Blom said. “But it sort of ruined our prediction study.”
However, in a post hoc analysis, study participants who were poor sleepers at 12 months had significantly more depressive symptoms at 36 months than did those with improved sleep at 12 months. The effect size was quite large, with a between-group 5.5-point difference in MADRS scores at 36 months in a study population that was nondepressed at baseline.
“So improved sleep may prevent depression long term,” Dr. Blom said. “The jury is still out on that one.”
She reported having no financial conflicts regarding her studies, which were supported by government research funding.
COPENHAGEN – The traditional treatment paradigm for patients with comorbid depression and insomnia has been to focus on the depression in expectation that the sleep problems will fade away with the depressive symptoms.
Big mistake, Kerstin Blom, PhD, said during the annual congress of the European College of Neuropsychopharmacology.
That treatment strategy is insufficient, because untreated insomnia seldom improves. It hinders recovery from depression, increases the risk of new depressive episodes, and causes continued suffering because of poor sleep, asserted Dr. Blom, a clinical psychologist and researcher at the Internet Psychiatry Clinic at the Karolinska Institute in Stockholm.
She presented highlights of a series of three randomized, controlled trials for which she was first author. The take-home message: Insomnia with comorbid depression is not merely a symptom of depression; it requires specific treatment.
“Insomnia needs to be treated according to guidelines – that is, with cognitive-behavioral therapy – when it’s comorbid with depression,” she declared. “Insomnia therapy also treats comorbid depression, but it’s not so much the other way around. There are some effects on insomnia when you treat depression, but they’re not very large.”
The first study in her series included 43 adults with psychiatrist-diagnosed comorbid insomnia and major depression who were randomized to an 8-week course of psychologist-guided, Internet-delivered cognitive-behavioral therapy (ICBT) for one disorder or the other. At 6- and 12-month follow-up, patients who received ICBT for insomnia had significantly greater improvement in their insomnia as measured by the self-rated Insomnia Severity Index than did those who got ICBT for depression, while both forms of treatment were similarly effective in reducing depression severity as reflected in Montgomery-Åsberg Depression Rating Scale (MADRS) scores (Sleep. 2015 Feb 1;38[2]:267-77).
At 3-year follow-up, the beneficial impact of ICBT for insomnia remained strong, with recipients reporting less need for additional sleep treatment and less use of sleep medication than did the patients who got ICBT for depression. Both groups were left with mild depression, pointing to the need to develop a combined form of CBT that would simultaneously address both disorders in patients with comorbid depression and insomnia (Sleep. 2017 Aug 1;40[8]. doi. 10.1093/sleep/zsx108).
The Swedish investigators went on to create a 9-week course of psychologist-guided combination ICBT for both insomnia and depression. Then they randomized 126 dual-diagnosis patients to that treatment program or to therapist-guided ICBT for depression plus a placebo sleep intervention, which included education about sleep hygiene, stress management, and use of a sleep diary. At 6 months of follow-up, the dual-target ICBT group had a significantly greater reduction in Insomnia Severity Index scores than those who got ICBT for depression plus placebo. No between-group difference were found in the reduction in MADRS scores.
Dr. Blom observed. Follow-up out to 36 months is ongoing.
The third study included 148 nondepressed adults with insomnia who were randomized to the 8-week ICBT insomnia intervention or an active control treatment, which again included patient education, stress management, and a sleep diary. At 6 months, the active CBT-insomnia group had significantly lower Insomnia Severity Index scores than controls. However, at 12 and 36 months, the control group caught up, and there was no longer a between-group difference, with 74% of participants no longer meeting diagnostic criteria for insomnia at 36 months. The explanation for the catch-up? The control group used significantly more hypnotic sleep medications and more frequently sought additional insomnia treatments, including yoga and mindfulness, outside of the study setting during follow-up (Sleep. 2016 Jun 1;39[6]:1267-74).
It was Dr. Blom’s intent to also use this randomized, controlled trials to test the hypothesis that improving insomnia in nondepressed patients prevents future episodes of depression. She was thwarted in this attempt.
“After they got our low-intensity control version of a sleep intervention, they went out and got more treatment and that seems to have helped them, which is great,” Dr. Blom said. “But it sort of ruined our prediction study.”
However, in a post hoc analysis, study participants who were poor sleepers at 12 months had significantly more depressive symptoms at 36 months than did those with improved sleep at 12 months. The effect size was quite large, with a between-group 5.5-point difference in MADRS scores at 36 months in a study population that was nondepressed at baseline.
“So improved sleep may prevent depression long term,” Dr. Blom said. “The jury is still out on that one.”
She reported having no financial conflicts regarding her studies, which were supported by government research funding.
REPORTING FROM ECNP 2019
Dextromethorphan/bupropion combo is remarkably fast-acting antidepressant
COPENHAGEN – A novel investigational oral combination of dextromethorphan and bupropion achieved a strikingly rapid and clinically meaningful reduction in depressive symptoms in patients with major depressive disorder in a phase 2, active comparator–controlled study, Cedric O’Gorman, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
– and the between-group difference continued to grow over the course of the 6-week, double-blind randomized trial. Thus, AXS-05 shows the potential to help meet the widely recognized need for faster-acting, higher-response antidepressant therapies than are currently available, observed Dr. O’Gorman, senior vice president for clinical development and medical affairs at Axsome Therapeutics in New York.
AXS-05 has multimodal mechanisms of action. As a result, it is not only in late-stage clinical development for major depressive disorder, but also for nicotine dependence and agitation in patients with Alzheimer’s disease.
Dextromethorphan is an NMDA (N-methyl-D-aspartate)–receptor antagonist, a serotonin and norepinephrine reuptake inhibitor, a sigma-1–receptor agonist, and a nicotinic-receptor antagonist. Bupropion, too, is a nicotinic-receptor antagonist. In addition, it’s a dopamine and norepinephrine reuptake inhibitor, and it boosts plasma levels of dextromethorphan by inhibiting its metabolism, the psychiatrist explained.
The phase 2, double-blind clinical trial included 80 patients with confirmed major depressive disorder who were experiencing an acute moderate to severe depressive episode. Slightly more than half of them had a history of three or more prior depressive episodes. Their mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score was 32, with a mean Clinical Global Impressions-Severity (CGI-S) score of 4.5 on a 1-7 scale. Participants were randomized to 45 mg dextromethorphan/105 mg bupropion or to 105 mg of bupropion-only, twice daily for 6 weeks.
The primary study endpoint was the average weekly change in MADRS score from baseline to week 6. The difference was highly significant: 13.7 points in the AXS-05 group, 8.8 with bupropion. At week 6, the AXS-05 group averaged a 17.2-point reduction from baseline in MADRS total score, compared with a 12.1-point decrease in controls. The between-group difference numerically favored AXS-05 at week 1, achieving statistically significant superiority from week 2 on. At week 6, 47% of the AXS-05 group had achieved clinical remission as defined by a MADRS score of 10 or less, as did 16% of the bupropion group.
At week 1 – again, the earliest assessment – 18% of AXS-05-treated patients were rated much or very much improved on the CGI, as were 3% of bupropion-treated controls. At week 6, 59% of the AXS-05 group and 27% of controls were rated very much improved.
Twelve percent of patients in both study arms discontinued treatment because of adverse events, none serious. The most common adverse events in the dextromethorphan/bupropion group were nausea, dizziness, dry mouth, reduced appetite, and anxiety. There were no instances of weight gain, sexual dysfunction, or psychomimetic effects.
Two phase 3, double-blind, 6-week RCTs of AXS-05 in depression are ongoing. STRIDE 1 includes 250 patients with treatment-resistant depression randomized to AXS-05 or bupropion. GEMINI is a study of 300 patients with major depressive disorder assigned to AXS-05 or placebo.
COPENHAGEN – A novel investigational oral combination of dextromethorphan and bupropion achieved a strikingly rapid and clinically meaningful reduction in depressive symptoms in patients with major depressive disorder in a phase 2, active comparator–controlled study, Cedric O’Gorman, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
– and the between-group difference continued to grow over the course of the 6-week, double-blind randomized trial. Thus, AXS-05 shows the potential to help meet the widely recognized need for faster-acting, higher-response antidepressant therapies than are currently available, observed Dr. O’Gorman, senior vice president for clinical development and medical affairs at Axsome Therapeutics in New York.
AXS-05 has multimodal mechanisms of action. As a result, it is not only in late-stage clinical development for major depressive disorder, but also for nicotine dependence and agitation in patients with Alzheimer’s disease.
Dextromethorphan is an NMDA (N-methyl-D-aspartate)–receptor antagonist, a serotonin and norepinephrine reuptake inhibitor, a sigma-1–receptor agonist, and a nicotinic-receptor antagonist. Bupropion, too, is a nicotinic-receptor antagonist. In addition, it’s a dopamine and norepinephrine reuptake inhibitor, and it boosts plasma levels of dextromethorphan by inhibiting its metabolism, the psychiatrist explained.
The phase 2, double-blind clinical trial included 80 patients with confirmed major depressive disorder who were experiencing an acute moderate to severe depressive episode. Slightly more than half of them had a history of three or more prior depressive episodes. Their mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score was 32, with a mean Clinical Global Impressions-Severity (CGI-S) score of 4.5 on a 1-7 scale. Participants were randomized to 45 mg dextromethorphan/105 mg bupropion or to 105 mg of bupropion-only, twice daily for 6 weeks.
The primary study endpoint was the average weekly change in MADRS score from baseline to week 6. The difference was highly significant: 13.7 points in the AXS-05 group, 8.8 with bupropion. At week 6, the AXS-05 group averaged a 17.2-point reduction from baseline in MADRS total score, compared with a 12.1-point decrease in controls. The between-group difference numerically favored AXS-05 at week 1, achieving statistically significant superiority from week 2 on. At week 6, 47% of the AXS-05 group had achieved clinical remission as defined by a MADRS score of 10 or less, as did 16% of the bupropion group.
At week 1 – again, the earliest assessment – 18% of AXS-05-treated patients were rated much or very much improved on the CGI, as were 3% of bupropion-treated controls. At week 6, 59% of the AXS-05 group and 27% of controls were rated very much improved.
Twelve percent of patients in both study arms discontinued treatment because of adverse events, none serious. The most common adverse events in the dextromethorphan/bupropion group were nausea, dizziness, dry mouth, reduced appetite, and anxiety. There were no instances of weight gain, sexual dysfunction, or psychomimetic effects.
Two phase 3, double-blind, 6-week RCTs of AXS-05 in depression are ongoing. STRIDE 1 includes 250 patients with treatment-resistant depression randomized to AXS-05 or bupropion. GEMINI is a study of 300 patients with major depressive disorder assigned to AXS-05 or placebo.
COPENHAGEN – A novel investigational oral combination of dextromethorphan and bupropion achieved a strikingly rapid and clinically meaningful reduction in depressive symptoms in patients with major depressive disorder in a phase 2, active comparator–controlled study, Cedric O’Gorman, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
– and the between-group difference continued to grow over the course of the 6-week, double-blind randomized trial. Thus, AXS-05 shows the potential to help meet the widely recognized need for faster-acting, higher-response antidepressant therapies than are currently available, observed Dr. O’Gorman, senior vice president for clinical development and medical affairs at Axsome Therapeutics in New York.
AXS-05 has multimodal mechanisms of action. As a result, it is not only in late-stage clinical development for major depressive disorder, but also for nicotine dependence and agitation in patients with Alzheimer’s disease.
Dextromethorphan is an NMDA (N-methyl-D-aspartate)–receptor antagonist, a serotonin and norepinephrine reuptake inhibitor, a sigma-1–receptor agonist, and a nicotinic-receptor antagonist. Bupropion, too, is a nicotinic-receptor antagonist. In addition, it’s a dopamine and norepinephrine reuptake inhibitor, and it boosts plasma levels of dextromethorphan by inhibiting its metabolism, the psychiatrist explained.
The phase 2, double-blind clinical trial included 80 patients with confirmed major depressive disorder who were experiencing an acute moderate to severe depressive episode. Slightly more than half of them had a history of three or more prior depressive episodes. Their mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score was 32, with a mean Clinical Global Impressions-Severity (CGI-S) score of 4.5 on a 1-7 scale. Participants were randomized to 45 mg dextromethorphan/105 mg bupropion or to 105 mg of bupropion-only, twice daily for 6 weeks.
The primary study endpoint was the average weekly change in MADRS score from baseline to week 6. The difference was highly significant: 13.7 points in the AXS-05 group, 8.8 with bupropion. At week 6, the AXS-05 group averaged a 17.2-point reduction from baseline in MADRS total score, compared with a 12.1-point decrease in controls. The between-group difference numerically favored AXS-05 at week 1, achieving statistically significant superiority from week 2 on. At week 6, 47% of the AXS-05 group had achieved clinical remission as defined by a MADRS score of 10 or less, as did 16% of the bupropion group.
At week 1 – again, the earliest assessment – 18% of AXS-05-treated patients were rated much or very much improved on the CGI, as were 3% of bupropion-treated controls. At week 6, 59% of the AXS-05 group and 27% of controls were rated very much improved.
Twelve percent of patients in both study arms discontinued treatment because of adverse events, none serious. The most common adverse events in the dextromethorphan/bupropion group were nausea, dizziness, dry mouth, reduced appetite, and anxiety. There were no instances of weight gain, sexual dysfunction, or psychomimetic effects.
Two phase 3, double-blind, 6-week RCTs of AXS-05 in depression are ongoing. STRIDE 1 includes 250 patients with treatment-resistant depression randomized to AXS-05 or bupropion. GEMINI is a study of 300 patients with major depressive disorder assigned to AXS-05 or placebo.
REPORTING FROM ECNP 2019
Conduct disorder in girls gets overdue research attention
COPENHAGEN – The physiological and emotion-processing abnormalities that underpin conduct disorder in teen girls are essentially the same as in teen boys, although the clinical presentation of conduct disorder in the two groups is often different, according to preliminary results from the large pan-European FemNAT-CD study, the first large study of conduct disorder in girls.
“The main finding of the study, I think, is that we found no major differences in physiology between male and female conduct disorder. There are some differences, mainly related to having less LPE [low prosocial emotions] and more internalizing comorbidity in the girls, but when you look at conduct disorder overall, then you see that the physiological systems are about the same,” Lucres Nauta-Jansen, PhD, commented in presenting some of the early FemNAT-CD findings at the annual congress of the European College of Neuropsychopharmacology.
LPE is a term included in the DSM-5 as a descriptor of individuals with conduct disorder (CD) who exhibit callous-unemotional traits. The LPE specifier was present in 37% of the 296 adolescent girls with CD in FemNAT-CD, significantly less than the 50% prevalence in the 187 adolescent boys with CD in the study. This analysis from the ongoing study, which is being conducted at 13 universities across Europe, also included 363 age-matched girls and 164 age-matched boys without CD as controls. Average participant age was 14 years.
FemNAT-CD is a multidisciplinary study aimed at exploring sex differences between boys and girls with and without CD in terms of brain structure and function, genetics, hormone levels, emotion recognition and regulation, and autonomic nervous system (ANS) activity. At Amsterdam University Medical Center, where Dr. Nauta-Jansen serves as deputy head of the department of child and adolescent psychiatry, she and her coinvestigators have focused on the autonomic activity and emotion-processing portions of FemNAT-CD.
CD is less common in girls than boys, although the prevalence in girls is growing. The importance of FemNAT-CD lies in the fact that virtually all prior studies of CD were conducted in boys. As a result, there is no specific treatment intervention available for girls with CD.
“We actually don’t know anything about girls. There are a few previous studies, but they have small samples and contradictory results. We need to know more about the mechanisms that are involved in this kind of behavior to develop more specific treatments in the future,” Dr. Nauta-Jansen said.
In FemNAT-CD, the girls with CD not only had a lower rate of LPE symptoms than the boys with CD, they also had a significantly higher prevalence of anxiety and other internalizing comorbidities, by a margin of 32% to 22%. These differences are manifested in different expressions of antisocial behavior as described in the model of the neurobiology of CD developed by R. James Blair, PhD, director of the Center for Neurobehavioral Research at the Boys Town National Research Hospital in Omaha, Neb (Nat Rev Neurosci. 2013 Nov;14[11]:786-99).
According to the model’s low psychophysiological arousal theory, boys with the callous-unemotional form of CD have low basal ANS activity and low amygdala responsiveness to stressful events, making them more prone to sensation-seeking behavior.
“This might make them want to do ice climbing or sky diving. Or, in a more negative environment or in a bad neighborhood, it can also lead to aggressive and delinquent behavior,” Dr. Nauta-Jansen said.
The other core impairment that is common in a subset of CD patients as described in the Blair model – again, based upon studies in boys – involves a tendency to engage in threat-based reactive aggression with an increased ANS response to stress and a related difficulty in processing emotions.
Dr. Nauta-Jansen and coinvestigators conducted a series of tests of FemNAT-CD participants which demonstrated, for the first time, that both the callous-unemotional and threat-based reactive aggression forms of CD are present in girls as well as boys, albeit in different proportions.
The investigators found no differences in baseline ANS activity between girls and boys with CD and the controls as measured by heart rate, heart rate variability, and cardiac preejection period. Nor were there any differences in baseline ANS activity between boys and girls with CD and LPE. However, girls with CD and anxiety or other internalizing comorbidity displayed significantly lower heart rate variability than those without internalizing comorbidity or female controls.
Next, the investigators subjected study participants to an emotion provocation task in which they viewed two sadness-inducing film clips, including a heart-rending scene from the 1979 movie, “The Champ,” in which an ex-boxer played by Jon Voight returns to the ring to raise money to support his young son, played by Ricky Shroder. The champ wins by a knockout after taking such a beating that he subsequently dies in his dressing room as his son watches.
Both the girls and boys with CD had an increased heart rate response to “The Champ,” compared with the controls. And those with CD who did not have the LPE specifier showed the biggest ANS response of all. They were highly sensitive to negative emotions.
On a countdown task involving exposure to a loud, startling noise, the girls with CD did not learn to anticipate the pending startle at the autonomic level, whereas the boys with CD reacted no differently from controls.
On the Trier Social Stress Test, which entails public speaking and performing mental math calculations in front of a camera and a live audience of two, both the boys and girls with CD demonstrated a similarly lower heart rate response to the tasks than controls. Those with the LPE specifier had the lowest heart rate response of all.
“The conduct disorder subjects were impaired in their anticipatory response to fear and stress, but their responses to sadness were increased,” Dr. Nauta-Jansen observed.
“I think the main thing with these kids is they are mostly disturbed in their anticipation of bad situations. What you see in the countdown task is they don’t anticipate that there will be a bad event. And you see this also in clinical practice, that they sometimes get overwhelmed by things because they don’t learn from their previous experiences, including bad events. I think they don’t anticipate and therefore are more overwhelmed by bad events – especially the girls,” she said.
The take-home message from this phase of the FemNAT-CD study, she added, is straightforward: “ although you have to be very aware that they show different symptomatology in terms of internalizing comorbidity.”
The FemNAT-CD investigators have developed a multifaceted therapeutic intervention for girls with CD that shows early promise in clinical settings. It includes aggression regulation training, medication in some cases, and emotion-processing training to teach patients how to deal with negative emotions without exploding into aggression.
FemNAT-CD is funded by the European Commission. Dr. Nauta-Jansen reported having no financial conflicts regarding the study.
COPENHAGEN – The physiological and emotion-processing abnormalities that underpin conduct disorder in teen girls are essentially the same as in teen boys, although the clinical presentation of conduct disorder in the two groups is often different, according to preliminary results from the large pan-European FemNAT-CD study, the first large study of conduct disorder in girls.
“The main finding of the study, I think, is that we found no major differences in physiology between male and female conduct disorder. There are some differences, mainly related to having less LPE [low prosocial emotions] and more internalizing comorbidity in the girls, but when you look at conduct disorder overall, then you see that the physiological systems are about the same,” Lucres Nauta-Jansen, PhD, commented in presenting some of the early FemNAT-CD findings at the annual congress of the European College of Neuropsychopharmacology.
LPE is a term included in the DSM-5 as a descriptor of individuals with conduct disorder (CD) who exhibit callous-unemotional traits. The LPE specifier was present in 37% of the 296 adolescent girls with CD in FemNAT-CD, significantly less than the 50% prevalence in the 187 adolescent boys with CD in the study. This analysis from the ongoing study, which is being conducted at 13 universities across Europe, also included 363 age-matched girls and 164 age-matched boys without CD as controls. Average participant age was 14 years.
FemNAT-CD is a multidisciplinary study aimed at exploring sex differences between boys and girls with and without CD in terms of brain structure and function, genetics, hormone levels, emotion recognition and regulation, and autonomic nervous system (ANS) activity. At Amsterdam University Medical Center, where Dr. Nauta-Jansen serves as deputy head of the department of child and adolescent psychiatry, she and her coinvestigators have focused on the autonomic activity and emotion-processing portions of FemNAT-CD.
CD is less common in girls than boys, although the prevalence in girls is growing. The importance of FemNAT-CD lies in the fact that virtually all prior studies of CD were conducted in boys. As a result, there is no specific treatment intervention available for girls with CD.
“We actually don’t know anything about girls. There are a few previous studies, but they have small samples and contradictory results. We need to know more about the mechanisms that are involved in this kind of behavior to develop more specific treatments in the future,” Dr. Nauta-Jansen said.
In FemNAT-CD, the girls with CD not only had a lower rate of LPE symptoms than the boys with CD, they also had a significantly higher prevalence of anxiety and other internalizing comorbidities, by a margin of 32% to 22%. These differences are manifested in different expressions of antisocial behavior as described in the model of the neurobiology of CD developed by R. James Blair, PhD, director of the Center for Neurobehavioral Research at the Boys Town National Research Hospital in Omaha, Neb (Nat Rev Neurosci. 2013 Nov;14[11]:786-99).
According to the model’s low psychophysiological arousal theory, boys with the callous-unemotional form of CD have low basal ANS activity and low amygdala responsiveness to stressful events, making them more prone to sensation-seeking behavior.
“This might make them want to do ice climbing or sky diving. Or, in a more negative environment or in a bad neighborhood, it can also lead to aggressive and delinquent behavior,” Dr. Nauta-Jansen said.
The other core impairment that is common in a subset of CD patients as described in the Blair model – again, based upon studies in boys – involves a tendency to engage in threat-based reactive aggression with an increased ANS response to stress and a related difficulty in processing emotions.
Dr. Nauta-Jansen and coinvestigators conducted a series of tests of FemNAT-CD participants which demonstrated, for the first time, that both the callous-unemotional and threat-based reactive aggression forms of CD are present in girls as well as boys, albeit in different proportions.
The investigators found no differences in baseline ANS activity between girls and boys with CD and the controls as measured by heart rate, heart rate variability, and cardiac preejection period. Nor were there any differences in baseline ANS activity between boys and girls with CD and LPE. However, girls with CD and anxiety or other internalizing comorbidity displayed significantly lower heart rate variability than those without internalizing comorbidity or female controls.
Next, the investigators subjected study participants to an emotion provocation task in which they viewed two sadness-inducing film clips, including a heart-rending scene from the 1979 movie, “The Champ,” in which an ex-boxer played by Jon Voight returns to the ring to raise money to support his young son, played by Ricky Shroder. The champ wins by a knockout after taking such a beating that he subsequently dies in his dressing room as his son watches.
Both the girls and boys with CD had an increased heart rate response to “The Champ,” compared with the controls. And those with CD who did not have the LPE specifier showed the biggest ANS response of all. They were highly sensitive to negative emotions.
On a countdown task involving exposure to a loud, startling noise, the girls with CD did not learn to anticipate the pending startle at the autonomic level, whereas the boys with CD reacted no differently from controls.
On the Trier Social Stress Test, which entails public speaking and performing mental math calculations in front of a camera and a live audience of two, both the boys and girls with CD demonstrated a similarly lower heart rate response to the tasks than controls. Those with the LPE specifier had the lowest heart rate response of all.
“The conduct disorder subjects were impaired in their anticipatory response to fear and stress, but their responses to sadness were increased,” Dr. Nauta-Jansen observed.
“I think the main thing with these kids is they are mostly disturbed in their anticipation of bad situations. What you see in the countdown task is they don’t anticipate that there will be a bad event. And you see this also in clinical practice, that they sometimes get overwhelmed by things because they don’t learn from their previous experiences, including bad events. I think they don’t anticipate and therefore are more overwhelmed by bad events – especially the girls,” she said.
The take-home message from this phase of the FemNAT-CD study, she added, is straightforward: “ although you have to be very aware that they show different symptomatology in terms of internalizing comorbidity.”
The FemNAT-CD investigators have developed a multifaceted therapeutic intervention for girls with CD that shows early promise in clinical settings. It includes aggression regulation training, medication in some cases, and emotion-processing training to teach patients how to deal with negative emotions without exploding into aggression.
FemNAT-CD is funded by the European Commission. Dr. Nauta-Jansen reported having no financial conflicts regarding the study.
COPENHAGEN – The physiological and emotion-processing abnormalities that underpin conduct disorder in teen girls are essentially the same as in teen boys, although the clinical presentation of conduct disorder in the two groups is often different, according to preliminary results from the large pan-European FemNAT-CD study, the first large study of conduct disorder in girls.
“The main finding of the study, I think, is that we found no major differences in physiology between male and female conduct disorder. There are some differences, mainly related to having less LPE [low prosocial emotions] and more internalizing comorbidity in the girls, but when you look at conduct disorder overall, then you see that the physiological systems are about the same,” Lucres Nauta-Jansen, PhD, commented in presenting some of the early FemNAT-CD findings at the annual congress of the European College of Neuropsychopharmacology.
LPE is a term included in the DSM-5 as a descriptor of individuals with conduct disorder (CD) who exhibit callous-unemotional traits. The LPE specifier was present in 37% of the 296 adolescent girls with CD in FemNAT-CD, significantly less than the 50% prevalence in the 187 adolescent boys with CD in the study. This analysis from the ongoing study, which is being conducted at 13 universities across Europe, also included 363 age-matched girls and 164 age-matched boys without CD as controls. Average participant age was 14 years.
FemNAT-CD is a multidisciplinary study aimed at exploring sex differences between boys and girls with and without CD in terms of brain structure and function, genetics, hormone levels, emotion recognition and regulation, and autonomic nervous system (ANS) activity. At Amsterdam University Medical Center, where Dr. Nauta-Jansen serves as deputy head of the department of child and adolescent psychiatry, she and her coinvestigators have focused on the autonomic activity and emotion-processing portions of FemNAT-CD.
CD is less common in girls than boys, although the prevalence in girls is growing. The importance of FemNAT-CD lies in the fact that virtually all prior studies of CD were conducted in boys. As a result, there is no specific treatment intervention available for girls with CD.
“We actually don’t know anything about girls. There are a few previous studies, but they have small samples and contradictory results. We need to know more about the mechanisms that are involved in this kind of behavior to develop more specific treatments in the future,” Dr. Nauta-Jansen said.
In FemNAT-CD, the girls with CD not only had a lower rate of LPE symptoms than the boys with CD, they also had a significantly higher prevalence of anxiety and other internalizing comorbidities, by a margin of 32% to 22%. These differences are manifested in different expressions of antisocial behavior as described in the model of the neurobiology of CD developed by R. James Blair, PhD, director of the Center for Neurobehavioral Research at the Boys Town National Research Hospital in Omaha, Neb (Nat Rev Neurosci. 2013 Nov;14[11]:786-99).
According to the model’s low psychophysiological arousal theory, boys with the callous-unemotional form of CD have low basal ANS activity and low amygdala responsiveness to stressful events, making them more prone to sensation-seeking behavior.
“This might make them want to do ice climbing or sky diving. Or, in a more negative environment or in a bad neighborhood, it can also lead to aggressive and delinquent behavior,” Dr. Nauta-Jansen said.
The other core impairment that is common in a subset of CD patients as described in the Blair model – again, based upon studies in boys – involves a tendency to engage in threat-based reactive aggression with an increased ANS response to stress and a related difficulty in processing emotions.
Dr. Nauta-Jansen and coinvestigators conducted a series of tests of FemNAT-CD participants which demonstrated, for the first time, that both the callous-unemotional and threat-based reactive aggression forms of CD are present in girls as well as boys, albeit in different proportions.
The investigators found no differences in baseline ANS activity between girls and boys with CD and the controls as measured by heart rate, heart rate variability, and cardiac preejection period. Nor were there any differences in baseline ANS activity between boys and girls with CD and LPE. However, girls with CD and anxiety or other internalizing comorbidity displayed significantly lower heart rate variability than those without internalizing comorbidity or female controls.
Next, the investigators subjected study participants to an emotion provocation task in which they viewed two sadness-inducing film clips, including a heart-rending scene from the 1979 movie, “The Champ,” in which an ex-boxer played by Jon Voight returns to the ring to raise money to support his young son, played by Ricky Shroder. The champ wins by a knockout after taking such a beating that he subsequently dies in his dressing room as his son watches.
Both the girls and boys with CD had an increased heart rate response to “The Champ,” compared with the controls. And those with CD who did not have the LPE specifier showed the biggest ANS response of all. They were highly sensitive to negative emotions.
On a countdown task involving exposure to a loud, startling noise, the girls with CD did not learn to anticipate the pending startle at the autonomic level, whereas the boys with CD reacted no differently from controls.
On the Trier Social Stress Test, which entails public speaking and performing mental math calculations in front of a camera and a live audience of two, both the boys and girls with CD demonstrated a similarly lower heart rate response to the tasks than controls. Those with the LPE specifier had the lowest heart rate response of all.
“The conduct disorder subjects were impaired in their anticipatory response to fear and stress, but their responses to sadness were increased,” Dr. Nauta-Jansen observed.
“I think the main thing with these kids is they are mostly disturbed in their anticipation of bad situations. What you see in the countdown task is they don’t anticipate that there will be a bad event. And you see this also in clinical practice, that they sometimes get overwhelmed by things because they don’t learn from their previous experiences, including bad events. I think they don’t anticipate and therefore are more overwhelmed by bad events – especially the girls,” she said.
The take-home message from this phase of the FemNAT-CD study, she added, is straightforward: “ although you have to be very aware that they show different symptomatology in terms of internalizing comorbidity.”
The FemNAT-CD investigators have developed a multifaceted therapeutic intervention for girls with CD that shows early promise in clinical settings. It includes aggression regulation training, medication in some cases, and emotion-processing training to teach patients how to deal with negative emotions without exploding into aggression.
FemNAT-CD is funded by the European Commission. Dr. Nauta-Jansen reported having no financial conflicts regarding the study.
REPORTING FROM ECNP 2019
Psilocybin research is mind expanding
Microdosing tied to enhanced divergent thinking in the short term
COPENHAGEN – A single dose of psilocybin taken in a supportive social setting was associated with demonstrably enhanced empathy, creative thinking, and subjective well-being lasting for up to 7 days in an observational study, Kim P.C. Kuypers, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
The participants in this uncontrolled study were healthy individuals curious to experience psilocybin in a controlled environment, but the observed benefits are of special interest because of psilocybin’s potential role in the treatment of psychiatric disorders, including depression and PTSD, in which preliminary study results have been quite encouraging, observed Dr. Kuypers, a neuropsychologist at Maastricht (the Netherlands) University.
For example, hallmarks of depression include psychological inflexibility, negative thoughts, and disturbed empathy. As this study showed, psilocybin addresses all those issues, she said.
according to Dr. Kuypers.
She and her coinvestigators studied 55 participants at a psilocybin retreat. These are events sprouting up across Europe to accommodate people who are curious about psilocybin and interested in trying it in a supportive setting. The investigators administered structured tests of convergent and divergent thinking, emotional empathy, and satisfaction with life before participants ingested the so-called magic mushroom, the morning after, and again 7 days later. In the Netherlands, the above-ground portion of the plant is an illegal substance, but the underground stem is not. The average dose was 27 mg, slightly higher than is often used in controlled laboratory studies; however, there were no adverse events.
The results showed that divergent thinking was enhanced the morning after taking psilocybin, an effect that was not sustained at the 7-day mark. In contrast, convergent thinking, emotional empathy, and a satisfaction-with-life scores above baseline were maintained 7 days after ingestion.
Psilocybin is a 5-HT2A agonist. It is considered a classic psychedelic, as are LSD, mescaline, and ayahuasca. These agents are often used recreationally to broaden consciousness, for relaxation, and to amplify emotions. Cave paintings indicate that psilocybin has been used medicinally for 11,000 years. But even early hunter-gatherers could not possibly have envisioned the current phenomenon of psilocybin microdosing to enhance work performance as adopted by hard-driving Silicon Valley professionals and similarly motivated strivers elsewhere around the world.
Microdosing for enhanced performance
Microdosing of psychedelics, especially psilocybin and LSD, is the practice of taking a low dose – typically 1/10th of a full recreational dose, which is too small an amount to cause full-blown perceptual alterations – once every several days in order to stimulate productivity. Psychedelic microdosing has garnered considerable mass media attention as an increasingly popular practice among younger professionals in the fields of computer science, engineering, mathematics, and technology. But it hasn’t been subjected to much scientific scrutiny.
Dr. Kuypers and colleagues wanted to find out whether it is actually effective and whether there are negative effects. They conducted an online questionnaire survey during a 5-month period of 2018 that drew 1,116 respondents, 80% of whom were currently microdosing, while the other 20% were former microdosers who had stopped completely.
The most common motivation for microdosing was indeed to stimulate productivity through increased focus, energy, and creativity. Almost half of microdosers indicated that they designed their own dosing schedule – typically once every 2-4 days – and two-thirds of microdosers were oblivious as to the consumed dose.
The most common reasons that respondents stopped microdosing were negative experiences or loss of interest because of lack of efficacy. The negative experiences typically involved acute anxiety or other psychological symptoms limited to when they were under the influence (Int J Neuropsychopharmacol. 2019 Jul 1;22[7]:426-34).
A subset of survey respondents microdosed to alleviate symptoms of a physician-diagnosed mental or physical health disorder. They were the focus of a separate analysis.
Microdosing for mental, physical health problems
Four hundred and ten survey respondents reported microdosing to self-treat a total of 901 physician-diagnosed mental and 161 physiologic conditions. They were asked three efficacy questions: Did it work? Did symptoms disappear? Did your quality of life improve?
The responses were disorder-specific. Individuals with anxiety disorders, ADHD, migraine, and other pain syndromes were the only ones to consistently rate microdosing as more effective than conventional treatment. Microdosing was rated less effective for symptom relief than were full-dose psychedelics only in respondents with depression or anxiety; individuals with other mental disorders or with physiological disorders rated the two dosing strategies similarly (Front Psychiatry. 2019 Sep 13. doi: 10.3389/fpsyt.2019.00672).
Future randomized controlled trials are warranted to more accurately assess efficacy claims for various psychedelics, optimal dosing, disorder specificity, and how they stack up compared with standard therapies, she said.
Dr. Kuypers reported having no financial conflicts of interest regarding her studies, which were conducted free of commercial support.
Microdosing tied to enhanced divergent thinking in the short term
Microdosing tied to enhanced divergent thinking in the short term
COPENHAGEN – A single dose of psilocybin taken in a supportive social setting was associated with demonstrably enhanced empathy, creative thinking, and subjective well-being lasting for up to 7 days in an observational study, Kim P.C. Kuypers, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
The participants in this uncontrolled study were healthy individuals curious to experience psilocybin in a controlled environment, but the observed benefits are of special interest because of psilocybin’s potential role in the treatment of psychiatric disorders, including depression and PTSD, in which preliminary study results have been quite encouraging, observed Dr. Kuypers, a neuropsychologist at Maastricht (the Netherlands) University.
For example, hallmarks of depression include psychological inflexibility, negative thoughts, and disturbed empathy. As this study showed, psilocybin addresses all those issues, she said.
according to Dr. Kuypers.
She and her coinvestigators studied 55 participants at a psilocybin retreat. These are events sprouting up across Europe to accommodate people who are curious about psilocybin and interested in trying it in a supportive setting. The investigators administered structured tests of convergent and divergent thinking, emotional empathy, and satisfaction with life before participants ingested the so-called magic mushroom, the morning after, and again 7 days later. In the Netherlands, the above-ground portion of the plant is an illegal substance, but the underground stem is not. The average dose was 27 mg, slightly higher than is often used in controlled laboratory studies; however, there were no adverse events.
The results showed that divergent thinking was enhanced the morning after taking psilocybin, an effect that was not sustained at the 7-day mark. In contrast, convergent thinking, emotional empathy, and a satisfaction-with-life scores above baseline were maintained 7 days after ingestion.
Psilocybin is a 5-HT2A agonist. It is considered a classic psychedelic, as are LSD, mescaline, and ayahuasca. These agents are often used recreationally to broaden consciousness, for relaxation, and to amplify emotions. Cave paintings indicate that psilocybin has been used medicinally for 11,000 years. But even early hunter-gatherers could not possibly have envisioned the current phenomenon of psilocybin microdosing to enhance work performance as adopted by hard-driving Silicon Valley professionals and similarly motivated strivers elsewhere around the world.
Microdosing for enhanced performance
Microdosing of psychedelics, especially psilocybin and LSD, is the practice of taking a low dose – typically 1/10th of a full recreational dose, which is too small an amount to cause full-blown perceptual alterations – once every several days in order to stimulate productivity. Psychedelic microdosing has garnered considerable mass media attention as an increasingly popular practice among younger professionals in the fields of computer science, engineering, mathematics, and technology. But it hasn’t been subjected to much scientific scrutiny.
Dr. Kuypers and colleagues wanted to find out whether it is actually effective and whether there are negative effects. They conducted an online questionnaire survey during a 5-month period of 2018 that drew 1,116 respondents, 80% of whom were currently microdosing, while the other 20% were former microdosers who had stopped completely.
The most common motivation for microdosing was indeed to stimulate productivity through increased focus, energy, and creativity. Almost half of microdosers indicated that they designed their own dosing schedule – typically once every 2-4 days – and two-thirds of microdosers were oblivious as to the consumed dose.
The most common reasons that respondents stopped microdosing were negative experiences or loss of interest because of lack of efficacy. The negative experiences typically involved acute anxiety or other psychological symptoms limited to when they were under the influence (Int J Neuropsychopharmacol. 2019 Jul 1;22[7]:426-34).
A subset of survey respondents microdosed to alleviate symptoms of a physician-diagnosed mental or physical health disorder. They were the focus of a separate analysis.
Microdosing for mental, physical health problems
Four hundred and ten survey respondents reported microdosing to self-treat a total of 901 physician-diagnosed mental and 161 physiologic conditions. They were asked three efficacy questions: Did it work? Did symptoms disappear? Did your quality of life improve?
The responses were disorder-specific. Individuals with anxiety disorders, ADHD, migraine, and other pain syndromes were the only ones to consistently rate microdosing as more effective than conventional treatment. Microdosing was rated less effective for symptom relief than were full-dose psychedelics only in respondents with depression or anxiety; individuals with other mental disorders or with physiological disorders rated the two dosing strategies similarly (Front Psychiatry. 2019 Sep 13. doi: 10.3389/fpsyt.2019.00672).
Future randomized controlled trials are warranted to more accurately assess efficacy claims for various psychedelics, optimal dosing, disorder specificity, and how they stack up compared with standard therapies, she said.
Dr. Kuypers reported having no financial conflicts of interest regarding her studies, which were conducted free of commercial support.
COPENHAGEN – A single dose of psilocybin taken in a supportive social setting was associated with demonstrably enhanced empathy, creative thinking, and subjective well-being lasting for up to 7 days in an observational study, Kim P.C. Kuypers, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
The participants in this uncontrolled study were healthy individuals curious to experience psilocybin in a controlled environment, but the observed benefits are of special interest because of psilocybin’s potential role in the treatment of psychiatric disorders, including depression and PTSD, in which preliminary study results have been quite encouraging, observed Dr. Kuypers, a neuropsychologist at Maastricht (the Netherlands) University.
For example, hallmarks of depression include psychological inflexibility, negative thoughts, and disturbed empathy. As this study showed, psilocybin addresses all those issues, she said.
according to Dr. Kuypers.
She and her coinvestigators studied 55 participants at a psilocybin retreat. These are events sprouting up across Europe to accommodate people who are curious about psilocybin and interested in trying it in a supportive setting. The investigators administered structured tests of convergent and divergent thinking, emotional empathy, and satisfaction with life before participants ingested the so-called magic mushroom, the morning after, and again 7 days later. In the Netherlands, the above-ground portion of the plant is an illegal substance, but the underground stem is not. The average dose was 27 mg, slightly higher than is often used in controlled laboratory studies; however, there were no adverse events.
The results showed that divergent thinking was enhanced the morning after taking psilocybin, an effect that was not sustained at the 7-day mark. In contrast, convergent thinking, emotional empathy, and a satisfaction-with-life scores above baseline were maintained 7 days after ingestion.
Psilocybin is a 5-HT2A agonist. It is considered a classic psychedelic, as are LSD, mescaline, and ayahuasca. These agents are often used recreationally to broaden consciousness, for relaxation, and to amplify emotions. Cave paintings indicate that psilocybin has been used medicinally for 11,000 years. But even early hunter-gatherers could not possibly have envisioned the current phenomenon of psilocybin microdosing to enhance work performance as adopted by hard-driving Silicon Valley professionals and similarly motivated strivers elsewhere around the world.
Microdosing for enhanced performance
Microdosing of psychedelics, especially psilocybin and LSD, is the practice of taking a low dose – typically 1/10th of a full recreational dose, which is too small an amount to cause full-blown perceptual alterations – once every several days in order to stimulate productivity. Psychedelic microdosing has garnered considerable mass media attention as an increasingly popular practice among younger professionals in the fields of computer science, engineering, mathematics, and technology. But it hasn’t been subjected to much scientific scrutiny.
Dr. Kuypers and colleagues wanted to find out whether it is actually effective and whether there are negative effects. They conducted an online questionnaire survey during a 5-month period of 2018 that drew 1,116 respondents, 80% of whom were currently microdosing, while the other 20% were former microdosers who had stopped completely.
The most common motivation for microdosing was indeed to stimulate productivity through increased focus, energy, and creativity. Almost half of microdosers indicated that they designed their own dosing schedule – typically once every 2-4 days – and two-thirds of microdosers were oblivious as to the consumed dose.
The most common reasons that respondents stopped microdosing were negative experiences or loss of interest because of lack of efficacy. The negative experiences typically involved acute anxiety or other psychological symptoms limited to when they were under the influence (Int J Neuropsychopharmacol. 2019 Jul 1;22[7]:426-34).
A subset of survey respondents microdosed to alleviate symptoms of a physician-diagnosed mental or physical health disorder. They were the focus of a separate analysis.
Microdosing for mental, physical health problems
Four hundred and ten survey respondents reported microdosing to self-treat a total of 901 physician-diagnosed mental and 161 physiologic conditions. They were asked three efficacy questions: Did it work? Did symptoms disappear? Did your quality of life improve?
The responses were disorder-specific. Individuals with anxiety disorders, ADHD, migraine, and other pain syndromes were the only ones to consistently rate microdosing as more effective than conventional treatment. Microdosing was rated less effective for symptom relief than were full-dose psychedelics only in respondents with depression or anxiety; individuals with other mental disorders or with physiological disorders rated the two dosing strategies similarly (Front Psychiatry. 2019 Sep 13. doi: 10.3389/fpsyt.2019.00672).
Future randomized controlled trials are warranted to more accurately assess efficacy claims for various psychedelics, optimal dosing, disorder specificity, and how they stack up compared with standard therapies, she said.
Dr. Kuypers reported having no financial conflicts of interest regarding her studies, which were conducted free of commercial support.
EXPERT ANALYSIS FROM ECNP 2019
Oral JAK1/2 inhibitor promising in alopecia areata
MADRID – In a phase 2, dose-ranging study, 78% of patients with long-standing moderate or severe alopecia areata rated their condition as “much improved” or “very much improved” after 24 weeks on the top dose of an investigational oral selective Janus kinase 1 and 2 (JAK1/2) inhibitor, compared with 21% of placebo-treated controls, James V. Cassella, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.
The primary study endpoint – at least a 50% reduction in the Severity of Alopecia Tool (SALT) score between baseline and 24 weeks – was achieved in 58% of patients on the JAK1/2 inhibitor (known for now as CTP-543) at 12 mg twice a day, 47% of those on CTP-543 at 8 mg twice a day, 21% on 4 mg twice a day, and in 9% of controls on placebo in the double-blind randomized trial. The 4-mg twice-daily dosing will not move on to phase 3 studies because of its demonstrated lack of efficacy, according to Dr. Cassella, chief development officer at Concert Pharmaceuticals, the study sponsor.
The study included 149 adults whose current episode of alopecia areata was of 3-6 years’ duration, with an average lifetime 15-year history of active disease. Their average baseline score on the 0-100 SALT scale was in the upper 80s, indicative of 80% or greater hair loss.
A SALT 75 response, meaning at least a 75% reduction in SALT score from baseline, was achieved in a dose-dependent fashion: In 42% of patients at the top dose of CTP-543, 29% of those on 8 mg twice a day, 14% with 4 mg twice a day, and in 7% of controls. An even more rigorous SALT 90 response was attained in 36%, 16%, 2%, and no controls, respectively.
The 12-mg twice-daily dosing produced faster onset and greater magnitude of response than did the 8-mg twice-daily dosing, but this dose-ranging study is not the final word on that score, according to Dr. Cassella.
“Week 24 is not a magic number,” he said. “The slope of the efficacy line for 8 mg [twice a day] looked like it was still going up at week 24, and the 12-mg BID curve hadn’t completely plateaued. Those are things we will consider for the future in terms of long-term trials.”
Changes in the eyebrows and lashes weren’t formally assessed in this study, although they will be in future trials. Anecdotally, however, patients with alopecia areata at those sites typically experienced complete or nearly complete regrowth in response to the higher doses of CTP-543, he said.
Safety-wise, there was no trend for increased adverse events with increasing doses of CTP-543. The observed treatment side effects were those typical of JAK inhibitors as a class effect, mainly headache, nasopharyngitis, upper respiratory infections, and new-onset acne. In terms of hematologic findings of special interest, there was one case of reversible neutropenia in the control group and another in the 8-mg twice-daily group, which resolved upon temporary suspension of treatment.
“Nothing surprising to us, and nothing very serious,” Dr. Cassella said.
Most patients in the 12-mg twice daily group have enrolled in an ongoing long-term extension study. In addition, two phase 2 studies are ongoing, with a focus on once-daily versus twice-daily dosing at 8 mg or 12 mg. Phase 3 studies are in the planning stage, he added.
The phase 2 dose-ranging study was sponsored by Concert Pharmaceuticals.
CTP-543 is one of an array of oral JAK inhibitors now in the developmental pipeline for alopecia areata, a severe, psychosocially devastating disease for which at present there is no Food and Drug Administration–approved therapy.
MADRID – In a phase 2, dose-ranging study, 78% of patients with long-standing moderate or severe alopecia areata rated their condition as “much improved” or “very much improved” after 24 weeks on the top dose of an investigational oral selective Janus kinase 1 and 2 (JAK1/2) inhibitor, compared with 21% of placebo-treated controls, James V. Cassella, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.
The primary study endpoint – at least a 50% reduction in the Severity of Alopecia Tool (SALT) score between baseline and 24 weeks – was achieved in 58% of patients on the JAK1/2 inhibitor (known for now as CTP-543) at 12 mg twice a day, 47% of those on CTP-543 at 8 mg twice a day, 21% on 4 mg twice a day, and in 9% of controls on placebo in the double-blind randomized trial. The 4-mg twice-daily dosing will not move on to phase 3 studies because of its demonstrated lack of efficacy, according to Dr. Cassella, chief development officer at Concert Pharmaceuticals, the study sponsor.
The study included 149 adults whose current episode of alopecia areata was of 3-6 years’ duration, with an average lifetime 15-year history of active disease. Their average baseline score on the 0-100 SALT scale was in the upper 80s, indicative of 80% or greater hair loss.
A SALT 75 response, meaning at least a 75% reduction in SALT score from baseline, was achieved in a dose-dependent fashion: In 42% of patients at the top dose of CTP-543, 29% of those on 8 mg twice a day, 14% with 4 mg twice a day, and in 7% of controls. An even more rigorous SALT 90 response was attained in 36%, 16%, 2%, and no controls, respectively.
The 12-mg twice-daily dosing produced faster onset and greater magnitude of response than did the 8-mg twice-daily dosing, but this dose-ranging study is not the final word on that score, according to Dr. Cassella.
“Week 24 is not a magic number,” he said. “The slope of the efficacy line for 8 mg [twice a day] looked like it was still going up at week 24, and the 12-mg BID curve hadn’t completely plateaued. Those are things we will consider for the future in terms of long-term trials.”
Changes in the eyebrows and lashes weren’t formally assessed in this study, although they will be in future trials. Anecdotally, however, patients with alopecia areata at those sites typically experienced complete or nearly complete regrowth in response to the higher doses of CTP-543, he said.
Safety-wise, there was no trend for increased adverse events with increasing doses of CTP-543. The observed treatment side effects were those typical of JAK inhibitors as a class effect, mainly headache, nasopharyngitis, upper respiratory infections, and new-onset acne. In terms of hematologic findings of special interest, there was one case of reversible neutropenia in the control group and another in the 8-mg twice-daily group, which resolved upon temporary suspension of treatment.
“Nothing surprising to us, and nothing very serious,” Dr. Cassella said.
Most patients in the 12-mg twice daily group have enrolled in an ongoing long-term extension study. In addition, two phase 2 studies are ongoing, with a focus on once-daily versus twice-daily dosing at 8 mg or 12 mg. Phase 3 studies are in the planning stage, he added.
The phase 2 dose-ranging study was sponsored by Concert Pharmaceuticals.
CTP-543 is one of an array of oral JAK inhibitors now in the developmental pipeline for alopecia areata, a severe, psychosocially devastating disease for which at present there is no Food and Drug Administration–approved therapy.
MADRID – In a phase 2, dose-ranging study, 78% of patients with long-standing moderate or severe alopecia areata rated their condition as “much improved” or “very much improved” after 24 weeks on the top dose of an investigational oral selective Janus kinase 1 and 2 (JAK1/2) inhibitor, compared with 21% of placebo-treated controls, James V. Cassella, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.
The primary study endpoint – at least a 50% reduction in the Severity of Alopecia Tool (SALT) score between baseline and 24 weeks – was achieved in 58% of patients on the JAK1/2 inhibitor (known for now as CTP-543) at 12 mg twice a day, 47% of those on CTP-543 at 8 mg twice a day, 21% on 4 mg twice a day, and in 9% of controls on placebo in the double-blind randomized trial. The 4-mg twice-daily dosing will not move on to phase 3 studies because of its demonstrated lack of efficacy, according to Dr. Cassella, chief development officer at Concert Pharmaceuticals, the study sponsor.
The study included 149 adults whose current episode of alopecia areata was of 3-6 years’ duration, with an average lifetime 15-year history of active disease. Their average baseline score on the 0-100 SALT scale was in the upper 80s, indicative of 80% or greater hair loss.
A SALT 75 response, meaning at least a 75% reduction in SALT score from baseline, was achieved in a dose-dependent fashion: In 42% of patients at the top dose of CTP-543, 29% of those on 8 mg twice a day, 14% with 4 mg twice a day, and in 7% of controls. An even more rigorous SALT 90 response was attained in 36%, 16%, 2%, and no controls, respectively.
The 12-mg twice-daily dosing produced faster onset and greater magnitude of response than did the 8-mg twice-daily dosing, but this dose-ranging study is not the final word on that score, according to Dr. Cassella.
“Week 24 is not a magic number,” he said. “The slope of the efficacy line for 8 mg [twice a day] looked like it was still going up at week 24, and the 12-mg BID curve hadn’t completely plateaued. Those are things we will consider for the future in terms of long-term trials.”
Changes in the eyebrows and lashes weren’t formally assessed in this study, although they will be in future trials. Anecdotally, however, patients with alopecia areata at those sites typically experienced complete or nearly complete regrowth in response to the higher doses of CTP-543, he said.
Safety-wise, there was no trend for increased adverse events with increasing doses of CTP-543. The observed treatment side effects were those typical of JAK inhibitors as a class effect, mainly headache, nasopharyngitis, upper respiratory infections, and new-onset acne. In terms of hematologic findings of special interest, there was one case of reversible neutropenia in the control group and another in the 8-mg twice-daily group, which resolved upon temporary suspension of treatment.
“Nothing surprising to us, and nothing very serious,” Dr. Cassella said.
Most patients in the 12-mg twice daily group have enrolled in an ongoing long-term extension study. In addition, two phase 2 studies are ongoing, with a focus on once-daily versus twice-daily dosing at 8 mg or 12 mg. Phase 3 studies are in the planning stage, he added.
The phase 2 dose-ranging study was sponsored by Concert Pharmaceuticals.
CTP-543 is one of an array of oral JAK inhibitors now in the developmental pipeline for alopecia areata, a severe, psychosocially devastating disease for which at present there is no Food and Drug Administration–approved therapy.
REPORTING FROM THE EADV CONGRESS
Rapid improvement seen with nemolizumab for prurigo nodularis in phase 2b study
MADRID – Nemolizumab, an investigational humanized monoclonal antibody targeting the interleukin-31 receptor alpha subunit, achieved rapid and clinically meaningful improvement in both itch and skin lesions of severe prurigo nodularis in a phase 2b, randomized trial, Sonja Stander, MD, said at the annual congress of the European Academy of Dermatology and Venereology.
“We saw onset of pruritus improvement in week 1 and onset of lesion healing at week 4,” reported Dr. Stander, professor of dermatology and neurodermatology and head of the Center for Chronic Pruritus at the University of Münster (Germany).
The study results confirm IL-31 signaling as an important therapeutic target in prurigo nodularis and herald the arrival of nemolizumab as a promising potential therapy for severely affected patients, she added.
Prurigo nodularis is a chronic, highly pruritic disease that is difficult to treat and carries a high disease burden. While the disease’s pathogenesis is not completely understood, IL-31 is up-regulated in affected patients. And IL-31, a proinflammatory and immunomodulatory cytokine, is known to have a broad range of actions, including serving as a link between the immune and neural systems, as well as induction of itch and skin lesions.
Dr. Stander presented the results of a 20-center, double-blind, at weeks 0, 4, and 8, then followed off therapy out to week 18. These were severely affected patients: their mean weekly peak pruritus score on a 0-10 numeric rating scale was 8.4, with 7 being the accepted threshold for severe itch. The group had a mean Dermatologic Life Quality Index score of 16.4; 40% of patients had more than 100 nodules on their body, and the rest had 20-100.
The primary endpoint was the percentage decrease in the peak pruritus score from baseline to week 4, at which point they had only received one dose. The nemolizumab group averaged a 53.4% reduction, compared with 15.3% in placebo-treated controls. At week 12, a full month after the final injection, the split was 63.2% versus 20.2%. And at week 18, the nemolizumab group maintained a mean 58.2% reduction from baseline versus 20.9% in controls.
“The effect starts at week 1, with a 26% reduction in itch intensity in the nemolizumab group, compared to 6.7% with placebo,” the dermatologist observed.
The absolute decrease in weekly peak pruritus score at week 12 was 5.2 points with nemolizumab and 1.7 points with placebo.
Among the secondary endpoints was achievement of an Investigator Global Assessment score of 0-1, meaning clear or almost clear of skin lesions. The rate in the nemolizumab group climbed steadily from week 4 on, reaching 38.2% and still rising without a plateau at week 18, versus 5.6% in controls.
Another secondary endpoint was 75% or greater healing on the 7-item Prurigo Activity Scale. By week 4 there was already a statistically significant between-group difference: 23.5% versus 11.2%. Once again, in the nemolizumab group, this rate climbed without a plateau through the study’s end at week 18, by which point it was 44.1%, compared with 8.4% among those on placebo.
Scores on the Dermatologic Life Quality Index improved by an average of 10.2 points at week 4 in patients on nemolizumab, compared with 6 points among controls.
Self-reported sleep disturbance scores improved by 56% at week 4 in the nemolizumab group and 22.9% with placebo.
The safety profile of nemolizumab was similar to that of placebo, with roughly 5.7% of patients in each study arm withdrawing because of treatment-emergent adverse events. Unlike in the positive studies of the IL-31 inhibitor in patients with atopic dermatitis – another potential indication under active investigation – there was no signal of an increased risk of staphylococcal skin infections, conjunctivitis, or head and neck dermatitis in patients on nemolizumab for prurigo nodularis. Patients with comorbid atopic dermatitis were excluded from the prurigo nodularis trial in order to get a clearer picture of the biologic’s efficacy and safety specifically for that condition.
Dr. Stander reported serving as a consultant to Galderma, the study sponsor, as well as numerous other pharmaceutical companies.
MADRID – Nemolizumab, an investigational humanized monoclonal antibody targeting the interleukin-31 receptor alpha subunit, achieved rapid and clinically meaningful improvement in both itch and skin lesions of severe prurigo nodularis in a phase 2b, randomized trial, Sonja Stander, MD, said at the annual congress of the European Academy of Dermatology and Venereology.
“We saw onset of pruritus improvement in week 1 and onset of lesion healing at week 4,” reported Dr. Stander, professor of dermatology and neurodermatology and head of the Center for Chronic Pruritus at the University of Münster (Germany).
The study results confirm IL-31 signaling as an important therapeutic target in prurigo nodularis and herald the arrival of nemolizumab as a promising potential therapy for severely affected patients, she added.
Prurigo nodularis is a chronic, highly pruritic disease that is difficult to treat and carries a high disease burden. While the disease’s pathogenesis is not completely understood, IL-31 is up-regulated in affected patients. And IL-31, a proinflammatory and immunomodulatory cytokine, is known to have a broad range of actions, including serving as a link between the immune and neural systems, as well as induction of itch and skin lesions.
Dr. Stander presented the results of a 20-center, double-blind, at weeks 0, 4, and 8, then followed off therapy out to week 18. These were severely affected patients: their mean weekly peak pruritus score on a 0-10 numeric rating scale was 8.4, with 7 being the accepted threshold for severe itch. The group had a mean Dermatologic Life Quality Index score of 16.4; 40% of patients had more than 100 nodules on their body, and the rest had 20-100.
The primary endpoint was the percentage decrease in the peak pruritus score from baseline to week 4, at which point they had only received one dose. The nemolizumab group averaged a 53.4% reduction, compared with 15.3% in placebo-treated controls. At week 12, a full month after the final injection, the split was 63.2% versus 20.2%. And at week 18, the nemolizumab group maintained a mean 58.2% reduction from baseline versus 20.9% in controls.
“The effect starts at week 1, with a 26% reduction in itch intensity in the nemolizumab group, compared to 6.7% with placebo,” the dermatologist observed.
The absolute decrease in weekly peak pruritus score at week 12 was 5.2 points with nemolizumab and 1.7 points with placebo.
Among the secondary endpoints was achievement of an Investigator Global Assessment score of 0-1, meaning clear or almost clear of skin lesions. The rate in the nemolizumab group climbed steadily from week 4 on, reaching 38.2% and still rising without a plateau at week 18, versus 5.6% in controls.
Another secondary endpoint was 75% or greater healing on the 7-item Prurigo Activity Scale. By week 4 there was already a statistically significant between-group difference: 23.5% versus 11.2%. Once again, in the nemolizumab group, this rate climbed without a plateau through the study’s end at week 18, by which point it was 44.1%, compared with 8.4% among those on placebo.
Scores on the Dermatologic Life Quality Index improved by an average of 10.2 points at week 4 in patients on nemolizumab, compared with 6 points among controls.
Self-reported sleep disturbance scores improved by 56% at week 4 in the nemolizumab group and 22.9% with placebo.
The safety profile of nemolizumab was similar to that of placebo, with roughly 5.7% of patients in each study arm withdrawing because of treatment-emergent adverse events. Unlike in the positive studies of the IL-31 inhibitor in patients with atopic dermatitis – another potential indication under active investigation – there was no signal of an increased risk of staphylococcal skin infections, conjunctivitis, or head and neck dermatitis in patients on nemolizumab for prurigo nodularis. Patients with comorbid atopic dermatitis were excluded from the prurigo nodularis trial in order to get a clearer picture of the biologic’s efficacy and safety specifically for that condition.
Dr. Stander reported serving as a consultant to Galderma, the study sponsor, as well as numerous other pharmaceutical companies.
MADRID – Nemolizumab, an investigational humanized monoclonal antibody targeting the interleukin-31 receptor alpha subunit, achieved rapid and clinically meaningful improvement in both itch and skin lesions of severe prurigo nodularis in a phase 2b, randomized trial, Sonja Stander, MD, said at the annual congress of the European Academy of Dermatology and Venereology.
“We saw onset of pruritus improvement in week 1 and onset of lesion healing at week 4,” reported Dr. Stander, professor of dermatology and neurodermatology and head of the Center for Chronic Pruritus at the University of Münster (Germany).
The study results confirm IL-31 signaling as an important therapeutic target in prurigo nodularis and herald the arrival of nemolizumab as a promising potential therapy for severely affected patients, she added.
Prurigo nodularis is a chronic, highly pruritic disease that is difficult to treat and carries a high disease burden. While the disease’s pathogenesis is not completely understood, IL-31 is up-regulated in affected patients. And IL-31, a proinflammatory and immunomodulatory cytokine, is known to have a broad range of actions, including serving as a link between the immune and neural systems, as well as induction of itch and skin lesions.
Dr. Stander presented the results of a 20-center, double-blind, at weeks 0, 4, and 8, then followed off therapy out to week 18. These were severely affected patients: their mean weekly peak pruritus score on a 0-10 numeric rating scale was 8.4, with 7 being the accepted threshold for severe itch. The group had a mean Dermatologic Life Quality Index score of 16.4; 40% of patients had more than 100 nodules on their body, and the rest had 20-100.
The primary endpoint was the percentage decrease in the peak pruritus score from baseline to week 4, at which point they had only received one dose. The nemolizumab group averaged a 53.4% reduction, compared with 15.3% in placebo-treated controls. At week 12, a full month after the final injection, the split was 63.2% versus 20.2%. And at week 18, the nemolizumab group maintained a mean 58.2% reduction from baseline versus 20.9% in controls.
“The effect starts at week 1, with a 26% reduction in itch intensity in the nemolizumab group, compared to 6.7% with placebo,” the dermatologist observed.
The absolute decrease in weekly peak pruritus score at week 12 was 5.2 points with nemolizumab and 1.7 points with placebo.
Among the secondary endpoints was achievement of an Investigator Global Assessment score of 0-1, meaning clear or almost clear of skin lesions. The rate in the nemolizumab group climbed steadily from week 4 on, reaching 38.2% and still rising without a plateau at week 18, versus 5.6% in controls.
Another secondary endpoint was 75% or greater healing on the 7-item Prurigo Activity Scale. By week 4 there was already a statistically significant between-group difference: 23.5% versus 11.2%. Once again, in the nemolizumab group, this rate climbed without a plateau through the study’s end at week 18, by which point it was 44.1%, compared with 8.4% among those on placebo.
Scores on the Dermatologic Life Quality Index improved by an average of 10.2 points at week 4 in patients on nemolizumab, compared with 6 points among controls.
Self-reported sleep disturbance scores improved by 56% at week 4 in the nemolizumab group and 22.9% with placebo.
The safety profile of nemolizumab was similar to that of placebo, with roughly 5.7% of patients in each study arm withdrawing because of treatment-emergent adverse events. Unlike in the positive studies of the IL-31 inhibitor in patients with atopic dermatitis – another potential indication under active investigation – there was no signal of an increased risk of staphylococcal skin infections, conjunctivitis, or head and neck dermatitis in patients on nemolizumab for prurigo nodularis. Patients with comorbid atopic dermatitis were excluded from the prurigo nodularis trial in order to get a clearer picture of the biologic’s efficacy and safety specifically for that condition.
Dr. Stander reported serving as a consultant to Galderma, the study sponsor, as well as numerous other pharmaceutical companies.
REPORTING FROM THE EADV CONGRESS
More evidence that statins reduce HCC risk
SAN ANTONIO – The evidence that statin therapy reduces the risk of developing hepatocellular carcinoma, while not rising to the highest-level 1A strata, is nonetheless sufficiently persuasive at this point that consideration should be given to prescribing a statin in all patients with risk factors for the malignancy, regardless of their cardiovascular risk profile, Muhammad Talal Sarmini, MD, asserted at the annual meeting of the American College of Gastroenterology.
This includes individuals with hepatitis B or C virus infection as well as those with cirrhosis. The jury is still out as to whether nonalcoholic steatohepatitis is a risk factor for hepatocellular carcinoma (HCC), observed Dr. Sarmini of the Cleveland Clinic.
He presented a new meta-analysis, which concluded that patients on statin therapy had a 43% lower risk of new-onset HCC than persons not taking a statin. This meta-analysis – the largest ever addressing the issue – included 20 studies totaling more than 2.6 million patients and 24,341 cases of new-onset HCC. There were 11 retrospective case-control studies, 6 cohort studies, and 3 randomized trials. Five studies were from the United States, nine from Asia, and six were European.
In subgroup analyses aimed at assessing the consistency of the study results across various domains, there was a 45% reduction in the risk of HCC in association with statin therapy in the three studies of patients with hepatitis B virus, and significant reductions as well in Asia, Europe, and the United States when those participants were evaluated separately. The reduction was significant in both the case-control and cohort studies, but not when the three randomized, controlled trials (RCTs) were analyzed collectively. However, Dr. Sarmini shrugged off the neutral RCT results.
“It’s worth noting that the RCTs reported data from patients who were on statins with 4-5 years of follow-up. They were not at high risk for HCC. Given the nature of the disease and the relatively short period of follow-up, these studies only reported 81 cases of HCC. So they were very limited,” he said.
Audience members were eager to learn if Dr. Sarmini had found a differential preventive effect for lipophilic statins, such as atorvastatin or simvastatin, versus hydrophilic statins. He replied that, unfortunately, the published study results don’t allow for such an analysis. However, a large, propensity-matched cohort study published too recently for inclusion in his meta-analysis shed light on this matter. This Swedish national registry study included 16,668 propensity score–matched adults with chronic hepatitis B or C infection, of whom 6,554 initiated lipophilic statin therapy, 1,780 began treatment with a hydrophilic statin, and the rest were statin nonusers. The lipophilic statin users had an adjusted 44% reduction in 10-year HCC risk, compared with nonusers, while hydrophilic statins weren’t associated with a significant preventive effect (Ann Intern Med. 2019 Sep 3;171[5]:318-27).
Dr. Sarmini said that the meta-analysis results, together with the Swedish registry findings, highlight the need for additional well-designed cohort studies and RCTs of statins in populations at high risk for HCC in order to verify the existence of an HCC preventive effect and pinpoint which statins are effective at what dosages.
HCC is the fourth-leading cause of cancer-related mortality globally, accounting for 800,000 deaths annually. And the incidence is rising on a year-by-year basis.
Dr. Sarmini reported having no financial conflicts regarding his study, which was conducted free of commercial support.
SAN ANTONIO – The evidence that statin therapy reduces the risk of developing hepatocellular carcinoma, while not rising to the highest-level 1A strata, is nonetheless sufficiently persuasive at this point that consideration should be given to prescribing a statin in all patients with risk factors for the malignancy, regardless of their cardiovascular risk profile, Muhammad Talal Sarmini, MD, asserted at the annual meeting of the American College of Gastroenterology.
This includes individuals with hepatitis B or C virus infection as well as those with cirrhosis. The jury is still out as to whether nonalcoholic steatohepatitis is a risk factor for hepatocellular carcinoma (HCC), observed Dr. Sarmini of the Cleveland Clinic.
He presented a new meta-analysis, which concluded that patients on statin therapy had a 43% lower risk of new-onset HCC than persons not taking a statin. This meta-analysis – the largest ever addressing the issue – included 20 studies totaling more than 2.6 million patients and 24,341 cases of new-onset HCC. There were 11 retrospective case-control studies, 6 cohort studies, and 3 randomized trials. Five studies were from the United States, nine from Asia, and six were European.
In subgroup analyses aimed at assessing the consistency of the study results across various domains, there was a 45% reduction in the risk of HCC in association with statin therapy in the three studies of patients with hepatitis B virus, and significant reductions as well in Asia, Europe, and the United States when those participants were evaluated separately. The reduction was significant in both the case-control and cohort studies, but not when the three randomized, controlled trials (RCTs) were analyzed collectively. However, Dr. Sarmini shrugged off the neutral RCT results.
“It’s worth noting that the RCTs reported data from patients who were on statins with 4-5 years of follow-up. They were not at high risk for HCC. Given the nature of the disease and the relatively short period of follow-up, these studies only reported 81 cases of HCC. So they were very limited,” he said.
Audience members were eager to learn if Dr. Sarmini had found a differential preventive effect for lipophilic statins, such as atorvastatin or simvastatin, versus hydrophilic statins. He replied that, unfortunately, the published study results don’t allow for such an analysis. However, a large, propensity-matched cohort study published too recently for inclusion in his meta-analysis shed light on this matter. This Swedish national registry study included 16,668 propensity score–matched adults with chronic hepatitis B or C infection, of whom 6,554 initiated lipophilic statin therapy, 1,780 began treatment with a hydrophilic statin, and the rest were statin nonusers. The lipophilic statin users had an adjusted 44% reduction in 10-year HCC risk, compared with nonusers, while hydrophilic statins weren’t associated with a significant preventive effect (Ann Intern Med. 2019 Sep 3;171[5]:318-27).
Dr. Sarmini said that the meta-analysis results, together with the Swedish registry findings, highlight the need for additional well-designed cohort studies and RCTs of statins in populations at high risk for HCC in order to verify the existence of an HCC preventive effect and pinpoint which statins are effective at what dosages.
HCC is the fourth-leading cause of cancer-related mortality globally, accounting for 800,000 deaths annually. And the incidence is rising on a year-by-year basis.
Dr. Sarmini reported having no financial conflicts regarding his study, which was conducted free of commercial support.
SAN ANTONIO – The evidence that statin therapy reduces the risk of developing hepatocellular carcinoma, while not rising to the highest-level 1A strata, is nonetheless sufficiently persuasive at this point that consideration should be given to prescribing a statin in all patients with risk factors for the malignancy, regardless of their cardiovascular risk profile, Muhammad Talal Sarmini, MD, asserted at the annual meeting of the American College of Gastroenterology.
This includes individuals with hepatitis B or C virus infection as well as those with cirrhosis. The jury is still out as to whether nonalcoholic steatohepatitis is a risk factor for hepatocellular carcinoma (HCC), observed Dr. Sarmini of the Cleveland Clinic.
He presented a new meta-analysis, which concluded that patients on statin therapy had a 43% lower risk of new-onset HCC than persons not taking a statin. This meta-analysis – the largest ever addressing the issue – included 20 studies totaling more than 2.6 million patients and 24,341 cases of new-onset HCC. There were 11 retrospective case-control studies, 6 cohort studies, and 3 randomized trials. Five studies were from the United States, nine from Asia, and six were European.
In subgroup analyses aimed at assessing the consistency of the study results across various domains, there was a 45% reduction in the risk of HCC in association with statin therapy in the three studies of patients with hepatitis B virus, and significant reductions as well in Asia, Europe, and the United States when those participants were evaluated separately. The reduction was significant in both the case-control and cohort studies, but not when the three randomized, controlled trials (RCTs) were analyzed collectively. However, Dr. Sarmini shrugged off the neutral RCT results.
“It’s worth noting that the RCTs reported data from patients who were on statins with 4-5 years of follow-up. They were not at high risk for HCC. Given the nature of the disease and the relatively short period of follow-up, these studies only reported 81 cases of HCC. So they were very limited,” he said.
Audience members were eager to learn if Dr. Sarmini had found a differential preventive effect for lipophilic statins, such as atorvastatin or simvastatin, versus hydrophilic statins. He replied that, unfortunately, the published study results don’t allow for such an analysis. However, a large, propensity-matched cohort study published too recently for inclusion in his meta-analysis shed light on this matter. This Swedish national registry study included 16,668 propensity score–matched adults with chronic hepatitis B or C infection, of whom 6,554 initiated lipophilic statin therapy, 1,780 began treatment with a hydrophilic statin, and the rest were statin nonusers. The lipophilic statin users had an adjusted 44% reduction in 10-year HCC risk, compared with nonusers, while hydrophilic statins weren’t associated with a significant preventive effect (Ann Intern Med. 2019 Sep 3;171[5]:318-27).
Dr. Sarmini said that the meta-analysis results, together with the Swedish registry findings, highlight the need for additional well-designed cohort studies and RCTs of statins in populations at high risk for HCC in order to verify the existence of an HCC preventive effect and pinpoint which statins are effective at what dosages.
HCC is the fourth-leading cause of cancer-related mortality globally, accounting for 800,000 deaths annually. And the incidence is rising on a year-by-year basis.
Dr. Sarmini reported having no financial conflicts regarding his study, which was conducted free of commercial support.
REPORTING FROM ACG 2019
Over-the-scope hemoclip prevails for upper GI bleeding
SAN ANTONIO – Use of a large over-the-scope hemoclip for initial endoscopic treatment of severe nonvariceal upper gastrointestinal bleeding resulted in a markedly lower 30-day rebleeding rate compared with standard endoscopic hemostasis in the first-ever randomized prospective clinical trial addressing the issue, Dennis M. Jensen, MD, reported at the annual meeting of the American College of Gastroenterology.
The over-the-scope clip also resulted in significantly fewer complications and cut the red blood cell transfusion rate in half, added Dr. Jensen, professor of medicine at the University of California, Los Angeles.
“The results appear to relate to the clip’s superior ability to obliterate critical arterial blood flow underneath the stigmata of hemorrhage and thereby reduce lesion rebleeding,” according to Dr. Jensen.
However, he emphasized a couple of caveats regarding this highly effective intervention.
First, it’s best reserved for patients with major stigmata of hemorrhage: that is, active arterial bleeding, a nonbleeding visible vessel, and/or adherent clot. That’s where all the benefit lies. Study participants with minor stigmata of hemorrhage – mere oozing bleeding or flat spots with arterial flow by Doppler – did just fine with standard endoscopic hemostasis, and in that setting the over-the-scope clip offered no additional benefit.
Second, there’s a significant learning curve involved in successful use of the clip.
“If someone’s going to be using this they have to get additional training. There’s a lot of tricks to using this,” the gastroenterologist cautioned.
The two-center prospective trial included 49 patients with severe nonvariceal upper GI bleeding who were randomized double-blind to the over-the-scope clip or standard hemostasis with hemoclips and/or application of a multipolar probe with epinephrine pre-injection as initial therapy. The severe bleeding was due to peptic ulcers in 40 patients and Dieulafoy’s lesions in the rest. All participants received high-dose proton pump inhibitor therapy after randomization.
The primary endpoint was clinically significant rebleeding within 30 days following initial therapy. This occurred in 7 of 25 patients (28%) on standard treatment and in 1 of 24 (4%) treated with the over-the-scope clip. This translated to an 85% relative risk reduction, with an impressive low number-needed-to-treat of 4.2.
Among the 35 patients with major stigmata of hemorrhage, the rebleeding rate was 35% in the over-the-scope clip group, compared with 6.3% with standard therapy, with a number-needed-to-treat of 3.5.
All four severe complications – a stroke, aspiration pneumonia, a case of severe heart failure, and a bleeding ischemic ulcer secondary to angiographic embolization – occurred in the standard therapy group. Patients in that group also averaged a 1.3-day-longer hospital length of stay and 2.8 more days in the ICU; however, those trends didn’t achieve statistical significance because of the small study size.
One audience member leapt to his feet to declare: “This is the study we’ve all been waiting for.” He pressed Dr. Jensen for technical details about the procedure.
Dr. Jensen explained that the large clip goes over an 11-mm-diameter endoscope with a 3-mm hood and no teeth. But he cautioned that some gastroenterologists in a busy community practice may find the procedure too time- and labor-intensive for their liking.
“It really takes two people to treat a duodenal ulcer. Somebody has to push quite firmly and suction very hard as you try to deploy this. By suctioning hard, the clip will burrow in so long as it’s centered on the stigmata of hemorrhage; that’s really key,” according to Dr. Jensen.
The procedure takes longer than standard endoscopic hemostasis because the over-the-scope clip limits visualization. So the patient must be scoped twice: the first time with a clipless diagnostic endoscope, so the operator can get his or her bearings; then that scope needs to be taken out, the patient is reintubated, and the over-the-scope clip is brought to bear.
“You shouldn’t just grab this off the shelf and try to use it in an emergency. You’ll really have problems. People have to be taught with porcine models and they need to review the stigmata,” Dr. Jensen said.
He reported having no financial conflicts regarding this study, conducted free of commercial support.
SOURCE: Jensen DM. ACG 2019, Abstract 8.
SAN ANTONIO – Use of a large over-the-scope hemoclip for initial endoscopic treatment of severe nonvariceal upper gastrointestinal bleeding resulted in a markedly lower 30-day rebleeding rate compared with standard endoscopic hemostasis in the first-ever randomized prospective clinical trial addressing the issue, Dennis M. Jensen, MD, reported at the annual meeting of the American College of Gastroenterology.
The over-the-scope clip also resulted in significantly fewer complications and cut the red blood cell transfusion rate in half, added Dr. Jensen, professor of medicine at the University of California, Los Angeles.
“The results appear to relate to the clip’s superior ability to obliterate critical arterial blood flow underneath the stigmata of hemorrhage and thereby reduce lesion rebleeding,” according to Dr. Jensen.
However, he emphasized a couple of caveats regarding this highly effective intervention.
First, it’s best reserved for patients with major stigmata of hemorrhage: that is, active arterial bleeding, a nonbleeding visible vessel, and/or adherent clot. That’s where all the benefit lies. Study participants with minor stigmata of hemorrhage – mere oozing bleeding or flat spots with arterial flow by Doppler – did just fine with standard endoscopic hemostasis, and in that setting the over-the-scope clip offered no additional benefit.
Second, there’s a significant learning curve involved in successful use of the clip.
“If someone’s going to be using this they have to get additional training. There’s a lot of tricks to using this,” the gastroenterologist cautioned.
The two-center prospective trial included 49 patients with severe nonvariceal upper GI bleeding who were randomized double-blind to the over-the-scope clip or standard hemostasis with hemoclips and/or application of a multipolar probe with epinephrine pre-injection as initial therapy. The severe bleeding was due to peptic ulcers in 40 patients and Dieulafoy’s lesions in the rest. All participants received high-dose proton pump inhibitor therapy after randomization.
The primary endpoint was clinically significant rebleeding within 30 days following initial therapy. This occurred in 7 of 25 patients (28%) on standard treatment and in 1 of 24 (4%) treated with the over-the-scope clip. This translated to an 85% relative risk reduction, with an impressive low number-needed-to-treat of 4.2.
Among the 35 patients with major stigmata of hemorrhage, the rebleeding rate was 35% in the over-the-scope clip group, compared with 6.3% with standard therapy, with a number-needed-to-treat of 3.5.
All four severe complications – a stroke, aspiration pneumonia, a case of severe heart failure, and a bleeding ischemic ulcer secondary to angiographic embolization – occurred in the standard therapy group. Patients in that group also averaged a 1.3-day-longer hospital length of stay and 2.8 more days in the ICU; however, those trends didn’t achieve statistical significance because of the small study size.
One audience member leapt to his feet to declare: “This is the study we’ve all been waiting for.” He pressed Dr. Jensen for technical details about the procedure.
Dr. Jensen explained that the large clip goes over an 11-mm-diameter endoscope with a 3-mm hood and no teeth. But he cautioned that some gastroenterologists in a busy community practice may find the procedure too time- and labor-intensive for their liking.
“It really takes two people to treat a duodenal ulcer. Somebody has to push quite firmly and suction very hard as you try to deploy this. By suctioning hard, the clip will burrow in so long as it’s centered on the stigmata of hemorrhage; that’s really key,” according to Dr. Jensen.
The procedure takes longer than standard endoscopic hemostasis because the over-the-scope clip limits visualization. So the patient must be scoped twice: the first time with a clipless diagnostic endoscope, so the operator can get his or her bearings; then that scope needs to be taken out, the patient is reintubated, and the over-the-scope clip is brought to bear.
“You shouldn’t just grab this off the shelf and try to use it in an emergency. You’ll really have problems. People have to be taught with porcine models and they need to review the stigmata,” Dr. Jensen said.
He reported having no financial conflicts regarding this study, conducted free of commercial support.
SOURCE: Jensen DM. ACG 2019, Abstract 8.
SAN ANTONIO – Use of a large over-the-scope hemoclip for initial endoscopic treatment of severe nonvariceal upper gastrointestinal bleeding resulted in a markedly lower 30-day rebleeding rate compared with standard endoscopic hemostasis in the first-ever randomized prospective clinical trial addressing the issue, Dennis M. Jensen, MD, reported at the annual meeting of the American College of Gastroenterology.
The over-the-scope clip also resulted in significantly fewer complications and cut the red blood cell transfusion rate in half, added Dr. Jensen, professor of medicine at the University of California, Los Angeles.
“The results appear to relate to the clip’s superior ability to obliterate critical arterial blood flow underneath the stigmata of hemorrhage and thereby reduce lesion rebleeding,” according to Dr. Jensen.
However, he emphasized a couple of caveats regarding this highly effective intervention.
First, it’s best reserved for patients with major stigmata of hemorrhage: that is, active arterial bleeding, a nonbleeding visible vessel, and/or adherent clot. That’s where all the benefit lies. Study participants with minor stigmata of hemorrhage – mere oozing bleeding or flat spots with arterial flow by Doppler – did just fine with standard endoscopic hemostasis, and in that setting the over-the-scope clip offered no additional benefit.
Second, there’s a significant learning curve involved in successful use of the clip.
“If someone’s going to be using this they have to get additional training. There’s a lot of tricks to using this,” the gastroenterologist cautioned.
The two-center prospective trial included 49 patients with severe nonvariceal upper GI bleeding who were randomized double-blind to the over-the-scope clip or standard hemostasis with hemoclips and/or application of a multipolar probe with epinephrine pre-injection as initial therapy. The severe bleeding was due to peptic ulcers in 40 patients and Dieulafoy’s lesions in the rest. All participants received high-dose proton pump inhibitor therapy after randomization.
The primary endpoint was clinically significant rebleeding within 30 days following initial therapy. This occurred in 7 of 25 patients (28%) on standard treatment and in 1 of 24 (4%) treated with the over-the-scope clip. This translated to an 85% relative risk reduction, with an impressive low number-needed-to-treat of 4.2.
Among the 35 patients with major stigmata of hemorrhage, the rebleeding rate was 35% in the over-the-scope clip group, compared with 6.3% with standard therapy, with a number-needed-to-treat of 3.5.
All four severe complications – a stroke, aspiration pneumonia, a case of severe heart failure, and a bleeding ischemic ulcer secondary to angiographic embolization – occurred in the standard therapy group. Patients in that group also averaged a 1.3-day-longer hospital length of stay and 2.8 more days in the ICU; however, those trends didn’t achieve statistical significance because of the small study size.
One audience member leapt to his feet to declare: “This is the study we’ve all been waiting for.” He pressed Dr. Jensen for technical details about the procedure.
Dr. Jensen explained that the large clip goes over an 11-mm-diameter endoscope with a 3-mm hood and no teeth. But he cautioned that some gastroenterologists in a busy community practice may find the procedure too time- and labor-intensive for their liking.
“It really takes two people to treat a duodenal ulcer. Somebody has to push quite firmly and suction very hard as you try to deploy this. By suctioning hard, the clip will burrow in so long as it’s centered on the stigmata of hemorrhage; that’s really key,” according to Dr. Jensen.
The procedure takes longer than standard endoscopic hemostasis because the over-the-scope clip limits visualization. So the patient must be scoped twice: the first time with a clipless diagnostic endoscope, so the operator can get his or her bearings; then that scope needs to be taken out, the patient is reintubated, and the over-the-scope clip is brought to bear.
“You shouldn’t just grab this off the shelf and try to use it in an emergency. You’ll really have problems. People have to be taught with porcine models and they need to review the stigmata,” Dr. Jensen said.
He reported having no financial conflicts regarding this study, conducted free of commercial support.
SOURCE: Jensen DM. ACG 2019, Abstract 8.
REPORTING FROM ACG 2019
Closing the missing link between childhood risk factors and adult cardiovascular outcomes
PARIS – Arguably one of the most important and far-reaching studies presented at the annual congress of the European Society of Cardiology didn’t take place in the massive main ballroom with dazzling lights and sound and thousands of cardiologists in attendance, but in a tiny, makeshift, open-sided venue slapped together of cardboard and fiberboard and plunked down in the noisy poster hall.
It was there that Terence Dwyer, MBBS, MD, began by observing, “We know quite a bit about the relationship of cardiovascular risk factors in adults to cardiovascular disease; we know virtually nothing about the relationship of those risk factors in childhood because – until now – there has been no direct evidence relating to this. What I’m going to present to you is some direct evidence.”
The data come from the International Childhood Cardiovascular Cohort (i3C) Consortium, which includes investigators from seven pioneering prospective child cohort studies, which collectively measured major cardiovascular risk factors in more than 42,000 children beginning back in the 1970s.
Some of these studies will be familiar names to many American physicians and epidemiologists. They include the Bogolusa Heart Study, the Muscatine Study, the Princeton Lipid Research Clinic Study, and the Minneapolis Childhood Cohort Studies. Similar studies were launched decades ago in Australia and Finland. The oldest of these cohorts are now in their 50s, and they are developing cardiovascular disease. The new i3C findings based on pooled data from these studies provides the first direct evidence that high serum cholesterol, blood pressure, body mass index, and smoking in childhood are linked to increased risk of hospitalization for acute MI, stroke, and peripheral artery disease in early middle age, said Dr. Dwyer, emeritus professor of epidemiology at the University of Oxford (England).
The analysis showed that each 10% increase above average in serum cholesterol in childhood was associated with a 16% increased risk of hospitalization for a cardiovascular event at a mean age of 49 years. A 2-point rise in BMI was associated with a 20% higher risk. A 10% increase above average in systolic blood pressure in childhood was linked to a 40% increase in risk of a cardiovascular event in later life. And smoking in childhood or adolescence was associated with a 77% higher risk of a cardiovascular event.
The i3C analysis also demonstrated that For example, individuals who both as adults and children had two or more of the four major cardiovascular risk factors studied had a sixfold greater risk of a major cardiovascular event in early middle age than if they had two or more risk factors as adults but none as children. If they had two or more risk factors as adults and one risk factor in childhood, their risk of a cardiovascular event was roughly twice as great as if they had no risk factors as a child. And if they had two or more risk factors present in childhood but none in adulthood, their risk of an event was threefold higher than if none of the four major cardiovascular risk factors were present during both periods of life, he continued.
The investigators consider their findings preliminary because most participants in the cohort studies are just reaching age 50 years.
“As we follow them for another 5 years, because of their age, the number of cardiovascular events will increase dramatically,” Dr. Dwyer explained. “One of the reasons we’re presenting this data now in preliminary form is these cohort studies will be the only data of this kind for about another 20 years. We want it out there when it can be most useful. It’s not like the situation with RCTs [randomized, controlled trials] where you’re able to wait 2 years for the next RCT.”
Clinical and policy implications
Asked about the clinical implications of the i3C findings, he replied, “At the very least, at this stage, consideration should be given to lowering risk factors in childhood as a greater priority in the cardiovascular disease prevention field.”
From my experience on national committees that look at what we do about cardiovascular prevention in childhood, they generally say we’re unprepared to take a strong stance on this because we have no direct evidence that these risk factors and what underpins them are a genuine problem,” according to Dr. Dwyer.
That’s no longer the case. By the end of the year, the i3C investigators expect to publish their results. As word reaches the public, he expects to finally see a growing momentum for cardiovascular prevention in pediatrics.
“Just imagine saying to a parent, ‘It looks highly likely that if you don’t do anything about the weight your children have put on, or other risk factors, they will be left at the end of childhood with a residual risk for cardiovascular disease that it doesn’t appear can be completely eradicated. It can be reduced by interventions in adulthood, but something’s happened there in childhood that was important.’ I think parents will demand action at that time,” he said.
In an interview, Donald Lloyd-Jones, MD, called the i3C data “incredibly important.”
“The risk factor values that they’re looking at in kids are not abnormal, they’re at the higher range of what we consider very normal, and yet those slightly elevated exposures within the normal range are causing damage. These kids are accruing risk for atherosclerosis down the road, even within what’s considered to be normal ranges,” commented Dr. Lloyd-Jones, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.
“I think it’s very telling that, early in life, we can delineate trajectories already emerging about how these kids are going to play out the rest of their lives in terms of their atherosclerosis and cardiovascular risk. That’s a very important thing to recognize, and we haven’t always thought that way. We always thought you arrive at your 21st birthday and then things start to matter, and by the time you got to 50, now it really matters. But the truth is the horse is already well out of the barn at age 50 and it’s coming out of the barn at age 21. That’s what the i3C data are starting to tell us: that it’s incredibly important that we move further upstream,” the cardiologist added.
What’s the best way forward?
“We have to create an environment where we tilt the playing field towards healthy choices. Sometimes that means taxation policy: It worked for alcohol and tobacco. Sometimes that means frank prohibition: indoor smoking laws have had a huge beneficial effect on public health. Sometimes it’s more controversial, like taxes on sugar-sweetened beverages, but I think that’s an experiment we have to play out to see if it works,” according to Dr. Lloyd-Jones. “I think our best solutions are going to come through policy, environmental change, and lifestyle in the early years because it’s just not practical to think about introducing foreign substances to mass amounts of kids.”
He noted that the National Heart, Lung and Blood Institute has held two workshops within the past year focused on these very issues.
Dr. Lloyd-Jones, past-honored as the American Heart Association Physician of the Year in recognition of his decades of work with that organization in advancing cardiovascular prevention, said “there’s a very good chance” the AHA will take on a major role in what he anticipates will be a much greater emphasis on cardiovascular prevention starting in early life in order to favorably alter life trajectories.
“Stay tuned in the next few months. We’re coming to a decade change, so as we enter 2020, the AHA will be promulgating its strategic goals for the next decade. The AHA is a much bigger, better-funded organization than it was even 10 years ago, and they’re looking to partner with groups like the Robert Woods Johnson Foundation, the Centers for Disease Control, [and] the NIH, to actually make major policy initiatives on cardiovascular prevention,” he said.
The i3C study was funded by the National Heart, Lung, and Blood Institute. Dr. Dwyer reported having no financial conflicts of interest.
PARIS – Arguably one of the most important and far-reaching studies presented at the annual congress of the European Society of Cardiology didn’t take place in the massive main ballroom with dazzling lights and sound and thousands of cardiologists in attendance, but in a tiny, makeshift, open-sided venue slapped together of cardboard and fiberboard and plunked down in the noisy poster hall.
It was there that Terence Dwyer, MBBS, MD, began by observing, “We know quite a bit about the relationship of cardiovascular risk factors in adults to cardiovascular disease; we know virtually nothing about the relationship of those risk factors in childhood because – until now – there has been no direct evidence relating to this. What I’m going to present to you is some direct evidence.”
The data come from the International Childhood Cardiovascular Cohort (i3C) Consortium, which includes investigators from seven pioneering prospective child cohort studies, which collectively measured major cardiovascular risk factors in more than 42,000 children beginning back in the 1970s.
Some of these studies will be familiar names to many American physicians and epidemiologists. They include the Bogolusa Heart Study, the Muscatine Study, the Princeton Lipid Research Clinic Study, and the Minneapolis Childhood Cohort Studies. Similar studies were launched decades ago in Australia and Finland. The oldest of these cohorts are now in their 50s, and they are developing cardiovascular disease. The new i3C findings based on pooled data from these studies provides the first direct evidence that high serum cholesterol, blood pressure, body mass index, and smoking in childhood are linked to increased risk of hospitalization for acute MI, stroke, and peripheral artery disease in early middle age, said Dr. Dwyer, emeritus professor of epidemiology at the University of Oxford (England).
The analysis showed that each 10% increase above average in serum cholesterol in childhood was associated with a 16% increased risk of hospitalization for a cardiovascular event at a mean age of 49 years. A 2-point rise in BMI was associated with a 20% higher risk. A 10% increase above average in systolic blood pressure in childhood was linked to a 40% increase in risk of a cardiovascular event in later life. And smoking in childhood or adolescence was associated with a 77% higher risk of a cardiovascular event.
The i3C analysis also demonstrated that For example, individuals who both as adults and children had two or more of the four major cardiovascular risk factors studied had a sixfold greater risk of a major cardiovascular event in early middle age than if they had two or more risk factors as adults but none as children. If they had two or more risk factors as adults and one risk factor in childhood, their risk of a cardiovascular event was roughly twice as great as if they had no risk factors as a child. And if they had two or more risk factors present in childhood but none in adulthood, their risk of an event was threefold higher than if none of the four major cardiovascular risk factors were present during both periods of life, he continued.
The investigators consider their findings preliminary because most participants in the cohort studies are just reaching age 50 years.
“As we follow them for another 5 years, because of their age, the number of cardiovascular events will increase dramatically,” Dr. Dwyer explained. “One of the reasons we’re presenting this data now in preliminary form is these cohort studies will be the only data of this kind for about another 20 years. We want it out there when it can be most useful. It’s not like the situation with RCTs [randomized, controlled trials] where you’re able to wait 2 years for the next RCT.”
Clinical and policy implications
Asked about the clinical implications of the i3C findings, he replied, “At the very least, at this stage, consideration should be given to lowering risk factors in childhood as a greater priority in the cardiovascular disease prevention field.”
From my experience on national committees that look at what we do about cardiovascular prevention in childhood, they generally say we’re unprepared to take a strong stance on this because we have no direct evidence that these risk factors and what underpins them are a genuine problem,” according to Dr. Dwyer.
That’s no longer the case. By the end of the year, the i3C investigators expect to publish their results. As word reaches the public, he expects to finally see a growing momentum for cardiovascular prevention in pediatrics.
“Just imagine saying to a parent, ‘It looks highly likely that if you don’t do anything about the weight your children have put on, or other risk factors, they will be left at the end of childhood with a residual risk for cardiovascular disease that it doesn’t appear can be completely eradicated. It can be reduced by interventions in adulthood, but something’s happened there in childhood that was important.’ I think parents will demand action at that time,” he said.
In an interview, Donald Lloyd-Jones, MD, called the i3C data “incredibly important.”
“The risk factor values that they’re looking at in kids are not abnormal, they’re at the higher range of what we consider very normal, and yet those slightly elevated exposures within the normal range are causing damage. These kids are accruing risk for atherosclerosis down the road, even within what’s considered to be normal ranges,” commented Dr. Lloyd-Jones, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.
“I think it’s very telling that, early in life, we can delineate trajectories already emerging about how these kids are going to play out the rest of their lives in terms of their atherosclerosis and cardiovascular risk. That’s a very important thing to recognize, and we haven’t always thought that way. We always thought you arrive at your 21st birthday and then things start to matter, and by the time you got to 50, now it really matters. But the truth is the horse is already well out of the barn at age 50 and it’s coming out of the barn at age 21. That’s what the i3C data are starting to tell us: that it’s incredibly important that we move further upstream,” the cardiologist added.
What’s the best way forward?
“We have to create an environment where we tilt the playing field towards healthy choices. Sometimes that means taxation policy: It worked for alcohol and tobacco. Sometimes that means frank prohibition: indoor smoking laws have had a huge beneficial effect on public health. Sometimes it’s more controversial, like taxes on sugar-sweetened beverages, but I think that’s an experiment we have to play out to see if it works,” according to Dr. Lloyd-Jones. “I think our best solutions are going to come through policy, environmental change, and lifestyle in the early years because it’s just not practical to think about introducing foreign substances to mass amounts of kids.”
He noted that the National Heart, Lung and Blood Institute has held two workshops within the past year focused on these very issues.
Dr. Lloyd-Jones, past-honored as the American Heart Association Physician of the Year in recognition of his decades of work with that organization in advancing cardiovascular prevention, said “there’s a very good chance” the AHA will take on a major role in what he anticipates will be a much greater emphasis on cardiovascular prevention starting in early life in order to favorably alter life trajectories.
“Stay tuned in the next few months. We’re coming to a decade change, so as we enter 2020, the AHA will be promulgating its strategic goals for the next decade. The AHA is a much bigger, better-funded organization than it was even 10 years ago, and they’re looking to partner with groups like the Robert Woods Johnson Foundation, the Centers for Disease Control, [and] the NIH, to actually make major policy initiatives on cardiovascular prevention,” he said.
The i3C study was funded by the National Heart, Lung, and Blood Institute. Dr. Dwyer reported having no financial conflicts of interest.
PARIS – Arguably one of the most important and far-reaching studies presented at the annual congress of the European Society of Cardiology didn’t take place in the massive main ballroom with dazzling lights and sound and thousands of cardiologists in attendance, but in a tiny, makeshift, open-sided venue slapped together of cardboard and fiberboard and plunked down in the noisy poster hall.
It was there that Terence Dwyer, MBBS, MD, began by observing, “We know quite a bit about the relationship of cardiovascular risk factors in adults to cardiovascular disease; we know virtually nothing about the relationship of those risk factors in childhood because – until now – there has been no direct evidence relating to this. What I’m going to present to you is some direct evidence.”
The data come from the International Childhood Cardiovascular Cohort (i3C) Consortium, which includes investigators from seven pioneering prospective child cohort studies, which collectively measured major cardiovascular risk factors in more than 42,000 children beginning back in the 1970s.
Some of these studies will be familiar names to many American physicians and epidemiologists. They include the Bogolusa Heart Study, the Muscatine Study, the Princeton Lipid Research Clinic Study, and the Minneapolis Childhood Cohort Studies. Similar studies were launched decades ago in Australia and Finland. The oldest of these cohorts are now in their 50s, and they are developing cardiovascular disease. The new i3C findings based on pooled data from these studies provides the first direct evidence that high serum cholesterol, blood pressure, body mass index, and smoking in childhood are linked to increased risk of hospitalization for acute MI, stroke, and peripheral artery disease in early middle age, said Dr. Dwyer, emeritus professor of epidemiology at the University of Oxford (England).
The analysis showed that each 10% increase above average in serum cholesterol in childhood was associated with a 16% increased risk of hospitalization for a cardiovascular event at a mean age of 49 years. A 2-point rise in BMI was associated with a 20% higher risk. A 10% increase above average in systolic blood pressure in childhood was linked to a 40% increase in risk of a cardiovascular event in later life. And smoking in childhood or adolescence was associated with a 77% higher risk of a cardiovascular event.
The i3C analysis also demonstrated that For example, individuals who both as adults and children had two or more of the four major cardiovascular risk factors studied had a sixfold greater risk of a major cardiovascular event in early middle age than if they had two or more risk factors as adults but none as children. If they had two or more risk factors as adults and one risk factor in childhood, their risk of a cardiovascular event was roughly twice as great as if they had no risk factors as a child. And if they had two or more risk factors present in childhood but none in adulthood, their risk of an event was threefold higher than if none of the four major cardiovascular risk factors were present during both periods of life, he continued.
The investigators consider their findings preliminary because most participants in the cohort studies are just reaching age 50 years.
“As we follow them for another 5 years, because of their age, the number of cardiovascular events will increase dramatically,” Dr. Dwyer explained. “One of the reasons we’re presenting this data now in preliminary form is these cohort studies will be the only data of this kind for about another 20 years. We want it out there when it can be most useful. It’s not like the situation with RCTs [randomized, controlled trials] where you’re able to wait 2 years for the next RCT.”
Clinical and policy implications
Asked about the clinical implications of the i3C findings, he replied, “At the very least, at this stage, consideration should be given to lowering risk factors in childhood as a greater priority in the cardiovascular disease prevention field.”
From my experience on national committees that look at what we do about cardiovascular prevention in childhood, they generally say we’re unprepared to take a strong stance on this because we have no direct evidence that these risk factors and what underpins them are a genuine problem,” according to Dr. Dwyer.
That’s no longer the case. By the end of the year, the i3C investigators expect to publish their results. As word reaches the public, he expects to finally see a growing momentum for cardiovascular prevention in pediatrics.
“Just imagine saying to a parent, ‘It looks highly likely that if you don’t do anything about the weight your children have put on, or other risk factors, they will be left at the end of childhood with a residual risk for cardiovascular disease that it doesn’t appear can be completely eradicated. It can be reduced by interventions in adulthood, but something’s happened there in childhood that was important.’ I think parents will demand action at that time,” he said.
In an interview, Donald Lloyd-Jones, MD, called the i3C data “incredibly important.”
“The risk factor values that they’re looking at in kids are not abnormal, they’re at the higher range of what we consider very normal, and yet those slightly elevated exposures within the normal range are causing damage. These kids are accruing risk for atherosclerosis down the road, even within what’s considered to be normal ranges,” commented Dr. Lloyd-Jones, senior associate dean for clinical and translational research and chair of the department of preventive medicine at Northwestern University, Chicago.
“I think it’s very telling that, early in life, we can delineate trajectories already emerging about how these kids are going to play out the rest of their lives in terms of their atherosclerosis and cardiovascular risk. That’s a very important thing to recognize, and we haven’t always thought that way. We always thought you arrive at your 21st birthday and then things start to matter, and by the time you got to 50, now it really matters. But the truth is the horse is already well out of the barn at age 50 and it’s coming out of the barn at age 21. That’s what the i3C data are starting to tell us: that it’s incredibly important that we move further upstream,” the cardiologist added.
What’s the best way forward?
“We have to create an environment where we tilt the playing field towards healthy choices. Sometimes that means taxation policy: It worked for alcohol and tobacco. Sometimes that means frank prohibition: indoor smoking laws have had a huge beneficial effect on public health. Sometimes it’s more controversial, like taxes on sugar-sweetened beverages, but I think that’s an experiment we have to play out to see if it works,” according to Dr. Lloyd-Jones. “I think our best solutions are going to come through policy, environmental change, and lifestyle in the early years because it’s just not practical to think about introducing foreign substances to mass amounts of kids.”
He noted that the National Heart, Lung and Blood Institute has held two workshops within the past year focused on these very issues.
Dr. Lloyd-Jones, past-honored as the American Heart Association Physician of the Year in recognition of his decades of work with that organization in advancing cardiovascular prevention, said “there’s a very good chance” the AHA will take on a major role in what he anticipates will be a much greater emphasis on cardiovascular prevention starting in early life in order to favorably alter life trajectories.
“Stay tuned in the next few months. We’re coming to a decade change, so as we enter 2020, the AHA will be promulgating its strategic goals for the next decade. The AHA is a much bigger, better-funded organization than it was even 10 years ago, and they’re looking to partner with groups like the Robert Woods Johnson Foundation, the Centers for Disease Control, [and] the NIH, to actually make major policy initiatives on cardiovascular prevention,” he said.
The i3C study was funded by the National Heart, Lung, and Blood Institute. Dr. Dwyer reported having no financial conflicts of interest.
REPORTING FROM THE ESC CONGRESS 2019