User login
Will paying patients to take oral antipsychotics boost adherence?
COPENHAGEN – Paying patients with schizophrenia a modest sum to take their long-acting injectable antipsychotic agents is a proven, evidence-based strategy for achieving improved adherence. Now it’s time to find out whether the same approach will work in patients on oral antipsychotics, Daniel Guinart, MD, said at the annual congress of the European College of Neuropsychopharmacology.
He presented a systematic literature review that turned up four studies, including two randomized clinical trials, of economic incentives aimed at improving adherence to long-acting injectable antipsychotics. The studies, all positive, showed that small financial incentives improved adherence by 12%-15%. However, once the intervention ended, adherence drifted back downward, so the financial reinforcement needs to be ongoing.
This approach has not previously been tested in outpatients with severe mental illness who are on oral antipsychotics because of the intrinsic limitations of reliance upon patient self-reported adherence. But Dr. Guinart and his coinvestigator, John M. Kane, MD, professor and chair of the department of psychiatry at Hofstra University in Hempstead, N.Y., have launched a 25-patient proof-of-concept study using technology to measure outpatient adherence. Provided that the pilot study shows this approach is feasible, the plan is to conduct a larger, longer-term, randomized controlled trial, said Dr. Guinart, also at Hofstra University.
If the modest financial expenditures involved in payment for pill taking do indeed prove to improve outpatient adherence to oral antipsychotics, it could reap major dividends in terms of fewer relapses, emergency department visits, hospitalizations, suicide attempts, and legal problems for patients, he noted.
The financial incentive to take oral antipsychotics needs to be big enough to promote behavioral change, but not so large that it poses ethical issues or encourages patients to game the system by lowering their adherence in order to gain entrance into the program. Fortunately, prior studies of successful behavioral incentives to take antihypertensive medications and other oral nonpsychotrophic drugs provide guidance on this score.
“One to two dollars per day is considered a reasonable incentive because it generates behavioral change, yet $30 per month doesn’t really serve as a financial aid,” the psychiatrist explained in an interview.
In the pilot study, adherence to oral antipsychotics is being assessed by having patients snap a cell phone photo of their daily medications being held in hand. Proprietary software analyzes whether those are the correct pills as prescribed. If so, the patient gets rewarded.
“It’s possible that after taking the photo some patients may throw the pills away. In adherence studies, we’re not the police, so at some point we have to trust that the patient is taking the medication,” he said.
Dr. Guinart reported having no financial conflicts of interest regarding his presentation.
COPENHAGEN – Paying patients with schizophrenia a modest sum to take their long-acting injectable antipsychotic agents is a proven, evidence-based strategy for achieving improved adherence. Now it’s time to find out whether the same approach will work in patients on oral antipsychotics, Daniel Guinart, MD, said at the annual congress of the European College of Neuropsychopharmacology.
He presented a systematic literature review that turned up four studies, including two randomized clinical trials, of economic incentives aimed at improving adherence to long-acting injectable antipsychotics. The studies, all positive, showed that small financial incentives improved adherence by 12%-15%. However, once the intervention ended, adherence drifted back downward, so the financial reinforcement needs to be ongoing.
This approach has not previously been tested in outpatients with severe mental illness who are on oral antipsychotics because of the intrinsic limitations of reliance upon patient self-reported adherence. But Dr. Guinart and his coinvestigator, John M. Kane, MD, professor and chair of the department of psychiatry at Hofstra University in Hempstead, N.Y., have launched a 25-patient proof-of-concept study using technology to measure outpatient adherence. Provided that the pilot study shows this approach is feasible, the plan is to conduct a larger, longer-term, randomized controlled trial, said Dr. Guinart, also at Hofstra University.
If the modest financial expenditures involved in payment for pill taking do indeed prove to improve outpatient adherence to oral antipsychotics, it could reap major dividends in terms of fewer relapses, emergency department visits, hospitalizations, suicide attempts, and legal problems for patients, he noted.
The financial incentive to take oral antipsychotics needs to be big enough to promote behavioral change, but not so large that it poses ethical issues or encourages patients to game the system by lowering their adherence in order to gain entrance into the program. Fortunately, prior studies of successful behavioral incentives to take antihypertensive medications and other oral nonpsychotrophic drugs provide guidance on this score.
“One to two dollars per day is considered a reasonable incentive because it generates behavioral change, yet $30 per month doesn’t really serve as a financial aid,” the psychiatrist explained in an interview.
In the pilot study, adherence to oral antipsychotics is being assessed by having patients snap a cell phone photo of their daily medications being held in hand. Proprietary software analyzes whether those are the correct pills as prescribed. If so, the patient gets rewarded.
“It’s possible that after taking the photo some patients may throw the pills away. In adherence studies, we’re not the police, so at some point we have to trust that the patient is taking the medication,” he said.
Dr. Guinart reported having no financial conflicts of interest regarding his presentation.
COPENHAGEN – Paying patients with schizophrenia a modest sum to take their long-acting injectable antipsychotic agents is a proven, evidence-based strategy for achieving improved adherence. Now it’s time to find out whether the same approach will work in patients on oral antipsychotics, Daniel Guinart, MD, said at the annual congress of the European College of Neuropsychopharmacology.
He presented a systematic literature review that turned up four studies, including two randomized clinical trials, of economic incentives aimed at improving adherence to long-acting injectable antipsychotics. The studies, all positive, showed that small financial incentives improved adherence by 12%-15%. However, once the intervention ended, adherence drifted back downward, so the financial reinforcement needs to be ongoing.
This approach has not previously been tested in outpatients with severe mental illness who are on oral antipsychotics because of the intrinsic limitations of reliance upon patient self-reported adherence. But Dr. Guinart and his coinvestigator, John M. Kane, MD, professor and chair of the department of psychiatry at Hofstra University in Hempstead, N.Y., have launched a 25-patient proof-of-concept study using technology to measure outpatient adherence. Provided that the pilot study shows this approach is feasible, the plan is to conduct a larger, longer-term, randomized controlled trial, said Dr. Guinart, also at Hofstra University.
If the modest financial expenditures involved in payment for pill taking do indeed prove to improve outpatient adherence to oral antipsychotics, it could reap major dividends in terms of fewer relapses, emergency department visits, hospitalizations, suicide attempts, and legal problems for patients, he noted.
The financial incentive to take oral antipsychotics needs to be big enough to promote behavioral change, but not so large that it poses ethical issues or encourages patients to game the system by lowering their adherence in order to gain entrance into the program. Fortunately, prior studies of successful behavioral incentives to take antihypertensive medications and other oral nonpsychotrophic drugs provide guidance on this score.
“One to two dollars per day is considered a reasonable incentive because it generates behavioral change, yet $30 per month doesn’t really serve as a financial aid,” the psychiatrist explained in an interview.
In the pilot study, adherence to oral antipsychotics is being assessed by having patients snap a cell phone photo of their daily medications being held in hand. Proprietary software analyzes whether those are the correct pills as prescribed. If so, the patient gets rewarded.
“It’s possible that after taking the photo some patients may throw the pills away. In adherence studies, we’re not the police, so at some point we have to trust that the patient is taking the medication,” he said.
Dr. Guinart reported having no financial conflicts of interest regarding his presentation.
REPORTING FROM ECNP 2019
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
Sleep problems in pregnancy presage postnatal depression
COPENHAGEN – Tiina Paunio, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
“I think it is very important to understand that we need to screen pregnant women for sleep problems, even those without a history of depression, so we can have early treatment of insomnia – and also depression – because postnatal maternal depression is very much a risk for the child during a vulnerable period for development,” said Dr. Paunio, professor of psychiatry at the University of Helsinki.
She was a coinvestigator in a prospective study of the Finnish CHILD-SLEEP longitudinal birth cohort in which 1,398 women completed the Basic Nordic Sleep Questionnaire and the 10-item version of the Center for Epidemiological Studies Depression Scale (CES-D) at about gestational week 32 and again around 3 months following delivery. Postnatal depressiveness as defined by a CES-D score of at least 10 points was present in 10.3% of the mothers. After adjusting for prenatal depressiveness and other potential confounders, the investigators found that tiredness during the day, poor general sleep quality, getting less than 6 hours of sleep, taking longer than 20 minutes to fall asleep, and sleep loss of 2 hours or more per night during pregnancy were each associated with clinically significant postnatal depressive symptoms, with odds ratios of 1.87-2.19.
The full details of the study have been published (Arch Womens Ment Health. 2019 Jun;22[3]:327-37).
The impetus for this study of sleep problems in pregnancy as a predictor of postnatal depressive symptoms was a body of evidence linking insomnia to depression in both men and women. But it turns out that insomnia is a significant predictor of later onset of a wide variety of psychiatric disorders, not only depression, as highlighted in a recent systematic review and meta-analysis conducted by an international team of investigators, Dr. Paunio observed.
Baseline insomnia symptoms were associated with a 183% increased risk of later onset of depression, a 223% increased risk of anxiety, a 35%greater risk of alcohol abuse, and a 28% increased risk of psychosis. However, the insomnia/psychosis link must be viewed as tentative, as it was examined in only a single published study. The investigators rated the overall risk of bias in the studies included in their meta-analysis as moderate (Sleep Med Rev. 2019 Feb;43:96-105).
For Dr. Paunio, these findings suggest that interventional studies of early and effective treatment of insomnia as a potential means of preventing psychiatric disorders are in order.
She reported receiving research funding from the Academy of Finland, the Gyllenberg Foundation, and Finska Lakaresallskapet.
COPENHAGEN – Tiina Paunio, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
“I think it is very important to understand that we need to screen pregnant women for sleep problems, even those without a history of depression, so we can have early treatment of insomnia – and also depression – because postnatal maternal depression is very much a risk for the child during a vulnerable period for development,” said Dr. Paunio, professor of psychiatry at the University of Helsinki.
She was a coinvestigator in a prospective study of the Finnish CHILD-SLEEP longitudinal birth cohort in which 1,398 women completed the Basic Nordic Sleep Questionnaire and the 10-item version of the Center for Epidemiological Studies Depression Scale (CES-D) at about gestational week 32 and again around 3 months following delivery. Postnatal depressiveness as defined by a CES-D score of at least 10 points was present in 10.3% of the mothers. After adjusting for prenatal depressiveness and other potential confounders, the investigators found that tiredness during the day, poor general sleep quality, getting less than 6 hours of sleep, taking longer than 20 minutes to fall asleep, and sleep loss of 2 hours or more per night during pregnancy were each associated with clinically significant postnatal depressive symptoms, with odds ratios of 1.87-2.19.
The full details of the study have been published (Arch Womens Ment Health. 2019 Jun;22[3]:327-37).
The impetus for this study of sleep problems in pregnancy as a predictor of postnatal depressive symptoms was a body of evidence linking insomnia to depression in both men and women. But it turns out that insomnia is a significant predictor of later onset of a wide variety of psychiatric disorders, not only depression, as highlighted in a recent systematic review and meta-analysis conducted by an international team of investigators, Dr. Paunio observed.
Baseline insomnia symptoms were associated with a 183% increased risk of later onset of depression, a 223% increased risk of anxiety, a 35%greater risk of alcohol abuse, and a 28% increased risk of psychosis. However, the insomnia/psychosis link must be viewed as tentative, as it was examined in only a single published study. The investigators rated the overall risk of bias in the studies included in their meta-analysis as moderate (Sleep Med Rev. 2019 Feb;43:96-105).
For Dr. Paunio, these findings suggest that interventional studies of early and effective treatment of insomnia as a potential means of preventing psychiatric disorders are in order.
She reported receiving research funding from the Academy of Finland, the Gyllenberg Foundation, and Finska Lakaresallskapet.
COPENHAGEN – Tiina Paunio, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
“I think it is very important to understand that we need to screen pregnant women for sleep problems, even those without a history of depression, so we can have early treatment of insomnia – and also depression – because postnatal maternal depression is very much a risk for the child during a vulnerable period for development,” said Dr. Paunio, professor of psychiatry at the University of Helsinki.
She was a coinvestigator in a prospective study of the Finnish CHILD-SLEEP longitudinal birth cohort in which 1,398 women completed the Basic Nordic Sleep Questionnaire and the 10-item version of the Center for Epidemiological Studies Depression Scale (CES-D) at about gestational week 32 and again around 3 months following delivery. Postnatal depressiveness as defined by a CES-D score of at least 10 points was present in 10.3% of the mothers. After adjusting for prenatal depressiveness and other potential confounders, the investigators found that tiredness during the day, poor general sleep quality, getting less than 6 hours of sleep, taking longer than 20 minutes to fall asleep, and sleep loss of 2 hours or more per night during pregnancy were each associated with clinically significant postnatal depressive symptoms, with odds ratios of 1.87-2.19.
The full details of the study have been published (Arch Womens Ment Health. 2019 Jun;22[3]:327-37).
The impetus for this study of sleep problems in pregnancy as a predictor of postnatal depressive symptoms was a body of evidence linking insomnia to depression in both men and women. But it turns out that insomnia is a significant predictor of later onset of a wide variety of psychiatric disorders, not only depression, as highlighted in a recent systematic review and meta-analysis conducted by an international team of investigators, Dr. Paunio observed.
Baseline insomnia symptoms were associated with a 183% increased risk of later onset of depression, a 223% increased risk of anxiety, a 35%greater risk of alcohol abuse, and a 28% increased risk of psychosis. However, the insomnia/psychosis link must be viewed as tentative, as it was examined in only a single published study. The investigators rated the overall risk of bias in the studies included in their meta-analysis as moderate (Sleep Med Rev. 2019 Feb;43:96-105).
For Dr. Paunio, these findings suggest that interventional studies of early and effective treatment of insomnia as a potential means of preventing psychiatric disorders are in order.
She reported receiving research funding from the Academy of Finland, the Gyllenberg Foundation, and Finska Lakaresallskapet.
REPORTING FROM ECNP 2019
Food addiction is pervasive among psychiatric patients
COPENHAGEN – Food addiction is threefold more prevalent among individuals with clinically diagnosed mental disorders than in the general population, according to a report from the Food Addiction Denmark (FADK) project.
This finding provides support for the hypothesis that food addiction is a key link in the chain connecting psychiatric disorders to increased risk of obesity, which in turn contributes to the substantially shorter life expectancy of psychiatric patients, Christina Horsager, MD, a cofounder of the project, said at the annual congress of the European College of Neuropsychopharmacology.
The FADK project is designed to fill in major gaps in the understanding of food addiction. The project included a 2018 Danish nationwide questionnaire survey of 1,394 individuals with various mental disorders and 1,699 others from the general population. The questionnaire included the Yale Food Addiction Scale Version 2.0 (Psychol Addict Behav. 2016 Feb;30[1]:113-21), which was used to identify affected individuals, as well as psychopathology rating scales, explained Dr. Horsager, of the child and adolescent psychiatry department at Aalborg (Denmark) University Hospital.
The prevalence of food addiction was 9% in the general population and 26.5% in individuals with mental disorders. The highest prevalence was, not surprisingly, in individuals with a DSM-5 diagnosis of an eating disorder. The rate was 30% in individuals with a DSM-5 personality disorder, 28% in those with a mood disorder, 17% with autism and other pervasive developmental disorders, just under 12% with a psychoactive substance use disorder, and 16% among patients with ADHD and other behavioral disorders.
But then again, the medications for ADHD tend to suppress appetite.
Obesity was significantly more prevalent among survey respondents who met criteria for food addiction, by a margin of 44.7% to 33.4%.
Food addiction is not an official DSM disorder. In fact, it’s a highly controversial construct: Some behavioral scientists think it has the classic hallmarks of a bona fide eating or substance use disorder; others don’t. Dr. Horsager highlighted the first systematic review of the evidence regarding food addiction, in which the University of Florida, Gainesville, authors concluded: “Overall, findings support food addiction as a unique construct consistent with criteria for other substance use disorder diagnoses. ... Though both behavioral and substance-related factors are implicated in the addictive process, symptoms appear to better fit criteria for substance use disorder than behavioral addiction” (Nutrients. 2018 Apr 12;10[4]:477. doi: 10.3390/nu10040477).
Food addiction is characterized by a compulsion to overeat calorie-dense, highly processed, super-palatable, sugar- and fat-laden foods. In this era of an ongoing global obesity epidemic, the public has become enthralled with the concept; a recent Google search of the term “food addiction” coughed up 288 million results.
The Food Addiction Denmark project findings warrant prospective studies examining whether treatment of food addiction might improve the prognosis of patients with mental disorders, according to Dr. Horsager.
She reported having no financial conflicts regarding her presentation.
COPENHAGEN – Food addiction is threefold more prevalent among individuals with clinically diagnosed mental disorders than in the general population, according to a report from the Food Addiction Denmark (FADK) project.
This finding provides support for the hypothesis that food addiction is a key link in the chain connecting psychiatric disorders to increased risk of obesity, which in turn contributes to the substantially shorter life expectancy of psychiatric patients, Christina Horsager, MD, a cofounder of the project, said at the annual congress of the European College of Neuropsychopharmacology.
The FADK project is designed to fill in major gaps in the understanding of food addiction. The project included a 2018 Danish nationwide questionnaire survey of 1,394 individuals with various mental disorders and 1,699 others from the general population. The questionnaire included the Yale Food Addiction Scale Version 2.0 (Psychol Addict Behav. 2016 Feb;30[1]:113-21), which was used to identify affected individuals, as well as psychopathology rating scales, explained Dr. Horsager, of the child and adolescent psychiatry department at Aalborg (Denmark) University Hospital.
The prevalence of food addiction was 9% in the general population and 26.5% in individuals with mental disorders. The highest prevalence was, not surprisingly, in individuals with a DSM-5 diagnosis of an eating disorder. The rate was 30% in individuals with a DSM-5 personality disorder, 28% in those with a mood disorder, 17% with autism and other pervasive developmental disorders, just under 12% with a psychoactive substance use disorder, and 16% among patients with ADHD and other behavioral disorders.
But then again, the medications for ADHD tend to suppress appetite.
Obesity was significantly more prevalent among survey respondents who met criteria for food addiction, by a margin of 44.7% to 33.4%.
Food addiction is not an official DSM disorder. In fact, it’s a highly controversial construct: Some behavioral scientists think it has the classic hallmarks of a bona fide eating or substance use disorder; others don’t. Dr. Horsager highlighted the first systematic review of the evidence regarding food addiction, in which the University of Florida, Gainesville, authors concluded: “Overall, findings support food addiction as a unique construct consistent with criteria for other substance use disorder diagnoses. ... Though both behavioral and substance-related factors are implicated in the addictive process, symptoms appear to better fit criteria for substance use disorder than behavioral addiction” (Nutrients. 2018 Apr 12;10[4]:477. doi: 10.3390/nu10040477).
Food addiction is characterized by a compulsion to overeat calorie-dense, highly processed, super-palatable, sugar- and fat-laden foods. In this era of an ongoing global obesity epidemic, the public has become enthralled with the concept; a recent Google search of the term “food addiction” coughed up 288 million results.
The Food Addiction Denmark project findings warrant prospective studies examining whether treatment of food addiction might improve the prognosis of patients with mental disorders, according to Dr. Horsager.
She reported having no financial conflicts regarding her presentation.
COPENHAGEN – Food addiction is threefold more prevalent among individuals with clinically diagnosed mental disorders than in the general population, according to a report from the Food Addiction Denmark (FADK) project.
This finding provides support for the hypothesis that food addiction is a key link in the chain connecting psychiatric disorders to increased risk of obesity, which in turn contributes to the substantially shorter life expectancy of psychiatric patients, Christina Horsager, MD, a cofounder of the project, said at the annual congress of the European College of Neuropsychopharmacology.
The FADK project is designed to fill in major gaps in the understanding of food addiction. The project included a 2018 Danish nationwide questionnaire survey of 1,394 individuals with various mental disorders and 1,699 others from the general population. The questionnaire included the Yale Food Addiction Scale Version 2.0 (Psychol Addict Behav. 2016 Feb;30[1]:113-21), which was used to identify affected individuals, as well as psychopathology rating scales, explained Dr. Horsager, of the child and adolescent psychiatry department at Aalborg (Denmark) University Hospital.
The prevalence of food addiction was 9% in the general population and 26.5% in individuals with mental disorders. The highest prevalence was, not surprisingly, in individuals with a DSM-5 diagnosis of an eating disorder. The rate was 30% in individuals with a DSM-5 personality disorder, 28% in those with a mood disorder, 17% with autism and other pervasive developmental disorders, just under 12% with a psychoactive substance use disorder, and 16% among patients with ADHD and other behavioral disorders.
But then again, the medications for ADHD tend to suppress appetite.
Obesity was significantly more prevalent among survey respondents who met criteria for food addiction, by a margin of 44.7% to 33.4%.
Food addiction is not an official DSM disorder. In fact, it’s a highly controversial construct: Some behavioral scientists think it has the classic hallmarks of a bona fide eating or substance use disorder; others don’t. Dr. Horsager highlighted the first systematic review of the evidence regarding food addiction, in which the University of Florida, Gainesville, authors concluded: “Overall, findings support food addiction as a unique construct consistent with criteria for other substance use disorder diagnoses. ... Though both behavioral and substance-related factors are implicated in the addictive process, symptoms appear to better fit criteria for substance use disorder than behavioral addiction” (Nutrients. 2018 Apr 12;10[4]:477. doi: 10.3390/nu10040477).
Food addiction is characterized by a compulsion to overeat calorie-dense, highly processed, super-palatable, sugar- and fat-laden foods. In this era of an ongoing global obesity epidemic, the public has become enthralled with the concept; a recent Google search of the term “food addiction” coughed up 288 million results.
The Food Addiction Denmark project findings warrant prospective studies examining whether treatment of food addiction might improve the prognosis of patients with mental disorders, according to Dr. Horsager.
She reported having no financial conflicts regarding her presentation.
REPORTING FROM ECNP 2019
Spotlight is on promising investigational antipsychotics
COPENHAGEN –
Two of the highlighted agents – pimavanserin and SEP-363856 – were designed to eschew the traditional antipsychotic target, the dopamine D2 receptor, in favor of other mechanisms of action aimed at the negative symptoms of schizophrenia, for which there is a long-recognized major unmet need for better therapies.
A third agent, known for now as ALKS 3831, is composed of a combination of olanzapine and samidorphan, an opioid receptor antagonist. This once-daily oral combination of olanzapine/samidorphan (OLA/SAM) is designed to retain the clinical efficacy of olanzapine while mitigating the drug’s limiting side effect of substantial weight gain.
OLA/SAM New Drug Application expected soon
Christine Graham, PhD, presented highlights of the pivotal phase 3 ENLIGHTEN-2 study, a double-blind clinical trial in which 661 U.S. outpatients with schizophrenia were randomized to OLA/SAM or olanzapine alone at 10 or 20 mg/day for 24 weeks, at which point everyone was switched to open-label OLA/SAM at 10 or 20 mg/10 mg for an additional 52-week extension safety study.
At 24 weeks, the OLA/SAM group had a mean 4.21% weight gain from baseline, significantly less than the 6.59% gain with olanzapine alone. A clinically meaningful and unwelcome weight gain of 7% or greater occurred in 27.5% of OLA/SAM patients, compared with 42.7% of controls, for an adjusted 50% reduction in risk in the group on the investigational medication. Similarly, a 10% or greater weight gain occurred in 17.8% of OLA/SAM patients and 29.8% of controls; once again, that represented a 50% relative risk reduction. The two therapies were equally effective, achieving roughly 10-point reductions in the Positive and Negative Syndrome Scale (PANSS) for schizophrenia total score.
Both treatments showed similar weight gain trajectories for the first 4 weeks. However, by week 6 the trajectories diverged, with body weight plateauing in the OLA/SAM group and remaining stable throughout the remainder of the 76-week, two-part study. Meanwhile, body weight continued to climb in the olanzapine-only group throughout the 24 weeks, reported Dr. Graham, senior clinical research scientist at Alkermes, in Waltham, Mass.
“The waist circumference results were surprising: We saw that waist circumference separated between the two groups as early as week 1, considerably earlier than the week 6 separation in weight. This suggests to us that even when weight gain is similar between the two treatments, OLA/SAM is showing an early effect at limiting central fat accumulation – and this has important health implications, as central fat has been shown to be potentially pathogenic for developing diabetes, cardiovascular disease, and even some forms of cancer,” she said.
The safety profile of OLA/SAM was essentially the same as for olanzapine-only, with the exception of the weight gain.
Alkermes is planning to submit its New Drug Application for OLA/SAM to the Food and Drug Administration before the year’s end. FDA officials have urged the company to broaden the application to include not only the treatment of schizophrenia, but bipolar I disorder as well, since olanzapine is an approved, well-established treatment for that disorder. Dr. Graham and coinvestigators have demonstrated that OLA/SAM has no clinically significant effect on the pharmacokinetics of lithium or valproate (Clin Drug Investig. 2019 Oct 4. doi: 10.1007/s40261-019-00860-y).
Phase 3 trial on pimavanserin underway
Pimavanserin is an oral selective serotonin inverse agonist, or SSIA, with a high affinity for 5-HT2A receptors, very low affinity for 5-HT2C receptors, and “absolutely no affinity” for dopaminergic, histaminergic, adrenergic, or muscarinic receptors, explained Dragana Bugarski-Kirola, MD, a psychiatrist and vice president of clinical development at Acadia Pharmaceuticals in San Diego.
“Those sites are thought to contribute to sedation, cognitive impairment, and orthostatic hypotension,” she noted.
Pimavanserin is at present FDA approved for a narrow indication: Treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. But the drug’s unique mechanism of action suggests broad efficacy across a range of psychiatric disorders.
Indeed, after a successful phase 2 clinical trial of pimavanserin for treatment of Alzheimer’s-related psychosis, a phase 3 randomized, double-blind, placebo-controlled clinical trial of the drug for relapse prevention in dementia-related psychosis is now enrolling a planned 360 outpatients at 95 centers in 13 countries. This 26-week study, known as HARMONY, is preceded by open-label psychotherapy to ensure that study participants truly need pharmacotherapy. Patients are eligible regardless of their type of dementia, because psychosis in patients with various forms of dementia is clinically pretty much the same, whether the underlying disorder is Alzheimer’s disease, vascular dementia, Parkinson’s disease, or Lewy body dementia, according to Dr. Bugarski-Kirola.
In addition, pimavanserin also is the subject of an ongoing phase 3 randomized trial in patients with major depressive disorder inadequately responsive to an selective serotonin reuptake inhibitor or a selective norepinephrine reuptake inhibitor. A 380-patient phase 2 study of the drug as adjunctive treatment for negative symptoms of schizophrenia also is underway based upon earlier promising results.
Across the board for these potential indications, the drug has been well tolerated, with a side effect profile similar to that of placebo. Importantly, pimavanserin has not been associated with cognitive impairment when used for dementia-related psychosis, unlike the antipsychotics now being used off label in clinical practice, the psychiatrist said.
SEP-363856 part of ‘novel class’
SEP-363856 is a nondopaminergic D2, trace amine-associated receptor agonist (TAAR1) under development for treatment of schizophrenia. Phase 3 trials in adults and adolescents with schizophrenia will begin before the end of the year on the strength of positive phase 2 results, according to Kenneth S. Koblan, PhD, head of global translational medicine and early development, as well as head of discovery sciences, at Sunovion Pharmaceuticals, Marlborough, Mass.
“We believe that SEP-363856 actually represents the first candidate in a novel class of antipsychotics. It’s a monoamine receptor activator, unlike the atypical antipsychotics, which work through blockade of the monoamine receptor via dopamine and serotonin. We believe that it’s the monoamine receptor activation that leads to the safety and efficacy of the class,” he explained.
In the four-country, double-blind, 4-week phase 2 trial conducted in 245 hospitalized acutely psychotic patients, oral SEP-363856 flexibly dosed at 50 or 75 mg/day had a side effect profile like that of placebo. Negative symptoms as assessed via the Brief Negative Symptom Scale improved by an average of 7.1 points at 4 weeks with SEP-363856, significantly more than the 2.7-point improvement with placebo. The PANSS total score improved by 17.2 points in the SEP-363856 group and 9.7 points in controls at 4 weeks, with a further 10-point drop in PANSS during a 6-month open-label extension phase of the study. Moreover, the SEP-363856 cohort showed significant functional improvement at 4 weeks in the UCSD Performance-Based Skills Assessment, with continued improvement during the open-label extension study.
Dr. Koblan said the pharmaceutical industry has overemphasized the development of dopaminergic D2-based drugs for schizophrenia. In the past 2 decades, roughly 30,000 patients have been enrolled in industry-sponsored, placebo-controlled, phase 2 or 3 randomized trials of drugs with that mechanism. Many of the those drugs have reached the marketplace. In contrast, there have been far fewer RCTs – and no product launches – of antipsychotics with non-D2 mechanisms of action.
“When you consider that the cost is about $50,000 per research subject and 50,000 subjects have been studied since 2000, the pharmaceutical industry has invested on the order of billions of dollars to try to come up with the next breakthrough medication,” he said.
COPENHAGEN –
Two of the highlighted agents – pimavanserin and SEP-363856 – were designed to eschew the traditional antipsychotic target, the dopamine D2 receptor, in favor of other mechanisms of action aimed at the negative symptoms of schizophrenia, for which there is a long-recognized major unmet need for better therapies.
A third agent, known for now as ALKS 3831, is composed of a combination of olanzapine and samidorphan, an opioid receptor antagonist. This once-daily oral combination of olanzapine/samidorphan (OLA/SAM) is designed to retain the clinical efficacy of olanzapine while mitigating the drug’s limiting side effect of substantial weight gain.
OLA/SAM New Drug Application expected soon
Christine Graham, PhD, presented highlights of the pivotal phase 3 ENLIGHTEN-2 study, a double-blind clinical trial in which 661 U.S. outpatients with schizophrenia were randomized to OLA/SAM or olanzapine alone at 10 or 20 mg/day for 24 weeks, at which point everyone was switched to open-label OLA/SAM at 10 or 20 mg/10 mg for an additional 52-week extension safety study.
At 24 weeks, the OLA/SAM group had a mean 4.21% weight gain from baseline, significantly less than the 6.59% gain with olanzapine alone. A clinically meaningful and unwelcome weight gain of 7% or greater occurred in 27.5% of OLA/SAM patients, compared with 42.7% of controls, for an adjusted 50% reduction in risk in the group on the investigational medication. Similarly, a 10% or greater weight gain occurred in 17.8% of OLA/SAM patients and 29.8% of controls; once again, that represented a 50% relative risk reduction. The two therapies were equally effective, achieving roughly 10-point reductions in the Positive and Negative Syndrome Scale (PANSS) for schizophrenia total score.
Both treatments showed similar weight gain trajectories for the first 4 weeks. However, by week 6 the trajectories diverged, with body weight plateauing in the OLA/SAM group and remaining stable throughout the remainder of the 76-week, two-part study. Meanwhile, body weight continued to climb in the olanzapine-only group throughout the 24 weeks, reported Dr. Graham, senior clinical research scientist at Alkermes, in Waltham, Mass.
“The waist circumference results were surprising: We saw that waist circumference separated between the two groups as early as week 1, considerably earlier than the week 6 separation in weight. This suggests to us that even when weight gain is similar between the two treatments, OLA/SAM is showing an early effect at limiting central fat accumulation – and this has important health implications, as central fat has been shown to be potentially pathogenic for developing diabetes, cardiovascular disease, and even some forms of cancer,” she said.
The safety profile of OLA/SAM was essentially the same as for olanzapine-only, with the exception of the weight gain.
Alkermes is planning to submit its New Drug Application for OLA/SAM to the Food and Drug Administration before the year’s end. FDA officials have urged the company to broaden the application to include not only the treatment of schizophrenia, but bipolar I disorder as well, since olanzapine is an approved, well-established treatment for that disorder. Dr. Graham and coinvestigators have demonstrated that OLA/SAM has no clinically significant effect on the pharmacokinetics of lithium or valproate (Clin Drug Investig. 2019 Oct 4. doi: 10.1007/s40261-019-00860-y).
Phase 3 trial on pimavanserin underway
Pimavanserin is an oral selective serotonin inverse agonist, or SSIA, with a high affinity for 5-HT2A receptors, very low affinity for 5-HT2C receptors, and “absolutely no affinity” for dopaminergic, histaminergic, adrenergic, or muscarinic receptors, explained Dragana Bugarski-Kirola, MD, a psychiatrist and vice president of clinical development at Acadia Pharmaceuticals in San Diego.
“Those sites are thought to contribute to sedation, cognitive impairment, and orthostatic hypotension,” she noted.
Pimavanserin is at present FDA approved for a narrow indication: Treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. But the drug’s unique mechanism of action suggests broad efficacy across a range of psychiatric disorders.
Indeed, after a successful phase 2 clinical trial of pimavanserin for treatment of Alzheimer’s-related psychosis, a phase 3 randomized, double-blind, placebo-controlled clinical trial of the drug for relapse prevention in dementia-related psychosis is now enrolling a planned 360 outpatients at 95 centers in 13 countries. This 26-week study, known as HARMONY, is preceded by open-label psychotherapy to ensure that study participants truly need pharmacotherapy. Patients are eligible regardless of their type of dementia, because psychosis in patients with various forms of dementia is clinically pretty much the same, whether the underlying disorder is Alzheimer’s disease, vascular dementia, Parkinson’s disease, or Lewy body dementia, according to Dr. Bugarski-Kirola.
In addition, pimavanserin also is the subject of an ongoing phase 3 randomized trial in patients with major depressive disorder inadequately responsive to an selective serotonin reuptake inhibitor or a selective norepinephrine reuptake inhibitor. A 380-patient phase 2 study of the drug as adjunctive treatment for negative symptoms of schizophrenia also is underway based upon earlier promising results.
Across the board for these potential indications, the drug has been well tolerated, with a side effect profile similar to that of placebo. Importantly, pimavanserin has not been associated with cognitive impairment when used for dementia-related psychosis, unlike the antipsychotics now being used off label in clinical practice, the psychiatrist said.
SEP-363856 part of ‘novel class’
SEP-363856 is a nondopaminergic D2, trace amine-associated receptor agonist (TAAR1) under development for treatment of schizophrenia. Phase 3 trials in adults and adolescents with schizophrenia will begin before the end of the year on the strength of positive phase 2 results, according to Kenneth S. Koblan, PhD, head of global translational medicine and early development, as well as head of discovery sciences, at Sunovion Pharmaceuticals, Marlborough, Mass.
“We believe that SEP-363856 actually represents the first candidate in a novel class of antipsychotics. It’s a monoamine receptor activator, unlike the atypical antipsychotics, which work through blockade of the monoamine receptor via dopamine and serotonin. We believe that it’s the monoamine receptor activation that leads to the safety and efficacy of the class,” he explained.
In the four-country, double-blind, 4-week phase 2 trial conducted in 245 hospitalized acutely psychotic patients, oral SEP-363856 flexibly dosed at 50 or 75 mg/day had a side effect profile like that of placebo. Negative symptoms as assessed via the Brief Negative Symptom Scale improved by an average of 7.1 points at 4 weeks with SEP-363856, significantly more than the 2.7-point improvement with placebo. The PANSS total score improved by 17.2 points in the SEP-363856 group and 9.7 points in controls at 4 weeks, with a further 10-point drop in PANSS during a 6-month open-label extension phase of the study. Moreover, the SEP-363856 cohort showed significant functional improvement at 4 weeks in the UCSD Performance-Based Skills Assessment, with continued improvement during the open-label extension study.
Dr. Koblan said the pharmaceutical industry has overemphasized the development of dopaminergic D2-based drugs for schizophrenia. In the past 2 decades, roughly 30,000 patients have been enrolled in industry-sponsored, placebo-controlled, phase 2 or 3 randomized trials of drugs with that mechanism. Many of the those drugs have reached the marketplace. In contrast, there have been far fewer RCTs – and no product launches – of antipsychotics with non-D2 mechanisms of action.
“When you consider that the cost is about $50,000 per research subject and 50,000 subjects have been studied since 2000, the pharmaceutical industry has invested on the order of billions of dollars to try to come up with the next breakthrough medication,” he said.
COPENHAGEN –
Two of the highlighted agents – pimavanserin and SEP-363856 – were designed to eschew the traditional antipsychotic target, the dopamine D2 receptor, in favor of other mechanisms of action aimed at the negative symptoms of schizophrenia, for which there is a long-recognized major unmet need for better therapies.
A third agent, known for now as ALKS 3831, is composed of a combination of olanzapine and samidorphan, an opioid receptor antagonist. This once-daily oral combination of olanzapine/samidorphan (OLA/SAM) is designed to retain the clinical efficacy of olanzapine while mitigating the drug’s limiting side effect of substantial weight gain.
OLA/SAM New Drug Application expected soon
Christine Graham, PhD, presented highlights of the pivotal phase 3 ENLIGHTEN-2 study, a double-blind clinical trial in which 661 U.S. outpatients with schizophrenia were randomized to OLA/SAM or olanzapine alone at 10 or 20 mg/day for 24 weeks, at which point everyone was switched to open-label OLA/SAM at 10 or 20 mg/10 mg for an additional 52-week extension safety study.
At 24 weeks, the OLA/SAM group had a mean 4.21% weight gain from baseline, significantly less than the 6.59% gain with olanzapine alone. A clinically meaningful and unwelcome weight gain of 7% or greater occurred in 27.5% of OLA/SAM patients, compared with 42.7% of controls, for an adjusted 50% reduction in risk in the group on the investigational medication. Similarly, a 10% or greater weight gain occurred in 17.8% of OLA/SAM patients and 29.8% of controls; once again, that represented a 50% relative risk reduction. The two therapies were equally effective, achieving roughly 10-point reductions in the Positive and Negative Syndrome Scale (PANSS) for schizophrenia total score.
Both treatments showed similar weight gain trajectories for the first 4 weeks. However, by week 6 the trajectories diverged, with body weight plateauing in the OLA/SAM group and remaining stable throughout the remainder of the 76-week, two-part study. Meanwhile, body weight continued to climb in the olanzapine-only group throughout the 24 weeks, reported Dr. Graham, senior clinical research scientist at Alkermes, in Waltham, Mass.
“The waist circumference results were surprising: We saw that waist circumference separated between the two groups as early as week 1, considerably earlier than the week 6 separation in weight. This suggests to us that even when weight gain is similar between the two treatments, OLA/SAM is showing an early effect at limiting central fat accumulation – and this has important health implications, as central fat has been shown to be potentially pathogenic for developing diabetes, cardiovascular disease, and even some forms of cancer,” she said.
The safety profile of OLA/SAM was essentially the same as for olanzapine-only, with the exception of the weight gain.
Alkermes is planning to submit its New Drug Application for OLA/SAM to the Food and Drug Administration before the year’s end. FDA officials have urged the company to broaden the application to include not only the treatment of schizophrenia, but bipolar I disorder as well, since olanzapine is an approved, well-established treatment for that disorder. Dr. Graham and coinvestigators have demonstrated that OLA/SAM has no clinically significant effect on the pharmacokinetics of lithium or valproate (Clin Drug Investig. 2019 Oct 4. doi: 10.1007/s40261-019-00860-y).
Phase 3 trial on pimavanserin underway
Pimavanserin is an oral selective serotonin inverse agonist, or SSIA, with a high affinity for 5-HT2A receptors, very low affinity for 5-HT2C receptors, and “absolutely no affinity” for dopaminergic, histaminergic, adrenergic, or muscarinic receptors, explained Dragana Bugarski-Kirola, MD, a psychiatrist and vice president of clinical development at Acadia Pharmaceuticals in San Diego.
“Those sites are thought to contribute to sedation, cognitive impairment, and orthostatic hypotension,” she noted.
Pimavanserin is at present FDA approved for a narrow indication: Treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. But the drug’s unique mechanism of action suggests broad efficacy across a range of psychiatric disorders.
Indeed, after a successful phase 2 clinical trial of pimavanserin for treatment of Alzheimer’s-related psychosis, a phase 3 randomized, double-blind, placebo-controlled clinical trial of the drug for relapse prevention in dementia-related psychosis is now enrolling a planned 360 outpatients at 95 centers in 13 countries. This 26-week study, known as HARMONY, is preceded by open-label psychotherapy to ensure that study participants truly need pharmacotherapy. Patients are eligible regardless of their type of dementia, because psychosis in patients with various forms of dementia is clinically pretty much the same, whether the underlying disorder is Alzheimer’s disease, vascular dementia, Parkinson’s disease, or Lewy body dementia, according to Dr. Bugarski-Kirola.
In addition, pimavanserin also is the subject of an ongoing phase 3 randomized trial in patients with major depressive disorder inadequately responsive to an selective serotonin reuptake inhibitor or a selective norepinephrine reuptake inhibitor. A 380-patient phase 2 study of the drug as adjunctive treatment for negative symptoms of schizophrenia also is underway based upon earlier promising results.
Across the board for these potential indications, the drug has been well tolerated, with a side effect profile similar to that of placebo. Importantly, pimavanserin has not been associated with cognitive impairment when used for dementia-related psychosis, unlike the antipsychotics now being used off label in clinical practice, the psychiatrist said.
SEP-363856 part of ‘novel class’
SEP-363856 is a nondopaminergic D2, trace amine-associated receptor agonist (TAAR1) under development for treatment of schizophrenia. Phase 3 trials in adults and adolescents with schizophrenia will begin before the end of the year on the strength of positive phase 2 results, according to Kenneth S. Koblan, PhD, head of global translational medicine and early development, as well as head of discovery sciences, at Sunovion Pharmaceuticals, Marlborough, Mass.
“We believe that SEP-363856 actually represents the first candidate in a novel class of antipsychotics. It’s a monoamine receptor activator, unlike the atypical antipsychotics, which work through blockade of the monoamine receptor via dopamine and serotonin. We believe that it’s the monoamine receptor activation that leads to the safety and efficacy of the class,” he explained.
In the four-country, double-blind, 4-week phase 2 trial conducted in 245 hospitalized acutely psychotic patients, oral SEP-363856 flexibly dosed at 50 or 75 mg/day had a side effect profile like that of placebo. Negative symptoms as assessed via the Brief Negative Symptom Scale improved by an average of 7.1 points at 4 weeks with SEP-363856, significantly more than the 2.7-point improvement with placebo. The PANSS total score improved by 17.2 points in the SEP-363856 group and 9.7 points in controls at 4 weeks, with a further 10-point drop in PANSS during a 6-month open-label extension phase of the study. Moreover, the SEP-363856 cohort showed significant functional improvement at 4 weeks in the UCSD Performance-Based Skills Assessment, with continued improvement during the open-label extension study.
Dr. Koblan said the pharmaceutical industry has overemphasized the development of dopaminergic D2-based drugs for schizophrenia. In the past 2 decades, roughly 30,000 patients have been enrolled in industry-sponsored, placebo-controlled, phase 2 or 3 randomized trials of drugs with that mechanism. Many of the those drugs have reached the marketplace. In contrast, there have been far fewer RCTs – and no product launches – of antipsychotics with non-D2 mechanisms of action.
“When you consider that the cost is about $50,000 per research subject and 50,000 subjects have been studied since 2000, the pharmaceutical industry has invested on the order of billions of dollars to try to come up with the next breakthrough medication,” he said.
REPORTING FROM ECNP 2019
Certain diabetes drugs may thwart dementia
COPENHAGEN – Selected antidiabetes medications appear to blunt the increased risk of dementia associated with type 2 diabetes, according to a Danish national case control registry study.
This benefit applies to the newer antidiabetic agents – specifically, the dipeptidyl peptidase 4 (DPP4) inhibitors, the glucagon-like peptide 1 (GLP1) analogs, and the sodium-glucose transport protein 2 (SGLT2) inhibitors – and metformin as well, Merete Osler, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
In contrast, neither insulin nor the sulfonylureas showed any signal of a protective effect against development of dementia. In fact, the use of sulfonylureas was associated with a small but statistically significant 7% increased risk, added Dr. Osler, of the University of Copenhagen.
Elsewhere at the meeting, investigators tapped a Swedish national registry to demonstrate that individuals with type 1 diabetes have a sharply reduced risk of developing schizophrenia.
Type 2 diabetes medications and dementia
Dr. Osler and colleagues are among several groups of investigators who have previously shown that patients with type 2 diabetes have an increased risk of dementia.
“This has raised the question of the role of dysregulated glucose metabolism in the development of this neurodegenerative disorder, and the possible effect of antidiabetic medications,” she noted.
To further explore this issue, which links two great ongoing global epidemics, Dr. Osler and coinvestigators conducted a nested case-control study including all 176,250 patients with type 2 diabetes in the comprehensive Danish National Diabetes Register for 1995-2012. The 11,619 patients with type 2 diabetes who received a dementia diagnosis were matched with 46,476 type 2 diabetes patients without dementia. The objective was to determine associations between dementia and ever-use and cumulative dose of antidiabetes drugs, alone and in combination, in logistic regression analyses adjusted for demographics, comorbid conditions, marital status, diabetic complications, and year of dementia diagnosis.
Patients who had ever used metformin had an adjusted 6% reduction in the likelihood of dementia compared with metformin nonusers, a modest but statistically significant difference. Those on a DPP4 inhibitor had a 20% reduction in risk. The GLP1 analogs were associated with a 42% decrease in risk. So were the SGLT2 inhibitors. A dose-response relationship was evident: The higher the cumulative exposure to these agents, the lower the odds of dementia.
Combination therapy is common in type 2 diabetes, so the investigators scrutinized the impact of a variety of multidrug combinations. Combinations including a DPP4 inhibitor or GLP1 analog were also associated with significantly reduced dementia risk.
Records of glycemic control in the form of hemoglobin A1c values were available on only 1,446 type 2 diabetic dementia patients and 4,003 matched controls. An analysis that incorporated this variable showed that the observed anti-dementia effect of selected diabetes drugs was independent of glycemic control, according to Dr. Osler.
The protective effect appeared to extend to both Alzheimer’s disease and vascular dementias, although firm conclusions can’t be drawn on this score because the study was insufficiently powered to address that issue.
Dr. Osler noted that the Danish study confirms a recent Taiwanese study showing an apparent protective effect against dementia for metformin in patients with type 2 diabetes (Aging Dis. 2019 Feb 1;10(1):37-48).
“Ours is the first study on the newer diabetic drugs, so our results need to be confirmed,” she pointed out.
If confirmed, however, it would warrant exploration of these drugs more generally as potential interventions to prevent dementia. That could open a whole new chapter in the remarkable story of the SGLT2 inhibitors, a class of drugs originally developed for treatment of type 2 diabetes but which in major randomized clinical trials later proved to be so effective in the treatment of heart failure that they are now considered cardiology drugs first.
Asked if she thinks these antidiabetes agents have a general neuroprotective effect or, instead, that the observed reduced risk of dementia is a function of patients being treated better early on with modern drugs, the psychiatrist replied, “I think it might be a combination of both, especially because we find different risk estimates between the drugs.”
Dr. Osler reported having no financial conflicts of interest regarding the study, which was funded by the Danish Diabetes Foundation, the Danish Medical Association, and several other foundations.
The full study details were published online shortly before her presentation at ECNP 2019 (Eur J Endocrinol. 2019 Aug 1. pii: EJE-19-0259.R1. doi: 10.1530/EJE-19-0259).
Type 1 diabetes and schizophrenia risk
Kristina Melkersson, MD, PhD, presented a cohort study that utilized Swedish national registries to examine the relationship between type 1 diabetes and schizophrenia. The study comprised 1,745,977 individuals, of whom 10,117 had type 1 diabetes, who were followed for a median of 9.7 and maximum of 18 years from their 13th birthday. During follow-up, 1,280 individuals were diagnosed with schizophrenia and 649 others with schizoaffective disorder. The adjusted risk of schizophrenia was 70% lower in patients with type 1 diabetes. However, there was no difference in the risk of schizoaffective disorder in the type 1 diabetic versus nondiabetic subjects.
The Swedish data confirm the findings of an earlier Finnish national study showing that the risk of schizophrenia is reduced in patients with type 1 diabetes (Arch Gen Psychiatry. 2007 Aug;64(8):894-9). These findings raise the intriguing possibility that autoimmunity somehow figures into the etiology of the psychiatric disorder. Other investigators have previously reported a reduced prevalence of rheumatoid arthritis in patients with schizophrenia, noted Dr. Melkersson of the Karolinska Institute in Stockholm.
She reported having no financial conflicts regarding her study.
SOURCE: Osler M. ECNP Abstract P180. Melkersson K. Abstract 81.
COPENHAGEN – Selected antidiabetes medications appear to blunt the increased risk of dementia associated with type 2 diabetes, according to a Danish national case control registry study.
This benefit applies to the newer antidiabetic agents – specifically, the dipeptidyl peptidase 4 (DPP4) inhibitors, the glucagon-like peptide 1 (GLP1) analogs, and the sodium-glucose transport protein 2 (SGLT2) inhibitors – and metformin as well, Merete Osler, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
In contrast, neither insulin nor the sulfonylureas showed any signal of a protective effect against development of dementia. In fact, the use of sulfonylureas was associated with a small but statistically significant 7% increased risk, added Dr. Osler, of the University of Copenhagen.
Elsewhere at the meeting, investigators tapped a Swedish national registry to demonstrate that individuals with type 1 diabetes have a sharply reduced risk of developing schizophrenia.
Type 2 diabetes medications and dementia
Dr. Osler and colleagues are among several groups of investigators who have previously shown that patients with type 2 diabetes have an increased risk of dementia.
“This has raised the question of the role of dysregulated glucose metabolism in the development of this neurodegenerative disorder, and the possible effect of antidiabetic medications,” she noted.
To further explore this issue, which links two great ongoing global epidemics, Dr. Osler and coinvestigators conducted a nested case-control study including all 176,250 patients with type 2 diabetes in the comprehensive Danish National Diabetes Register for 1995-2012. The 11,619 patients with type 2 diabetes who received a dementia diagnosis were matched with 46,476 type 2 diabetes patients without dementia. The objective was to determine associations between dementia and ever-use and cumulative dose of antidiabetes drugs, alone and in combination, in logistic regression analyses adjusted for demographics, comorbid conditions, marital status, diabetic complications, and year of dementia diagnosis.
Patients who had ever used metformin had an adjusted 6% reduction in the likelihood of dementia compared with metformin nonusers, a modest but statistically significant difference. Those on a DPP4 inhibitor had a 20% reduction in risk. The GLP1 analogs were associated with a 42% decrease in risk. So were the SGLT2 inhibitors. A dose-response relationship was evident: The higher the cumulative exposure to these agents, the lower the odds of dementia.
Combination therapy is common in type 2 diabetes, so the investigators scrutinized the impact of a variety of multidrug combinations. Combinations including a DPP4 inhibitor or GLP1 analog were also associated with significantly reduced dementia risk.
Records of glycemic control in the form of hemoglobin A1c values were available on only 1,446 type 2 diabetic dementia patients and 4,003 matched controls. An analysis that incorporated this variable showed that the observed anti-dementia effect of selected diabetes drugs was independent of glycemic control, according to Dr. Osler.
The protective effect appeared to extend to both Alzheimer’s disease and vascular dementias, although firm conclusions can’t be drawn on this score because the study was insufficiently powered to address that issue.
Dr. Osler noted that the Danish study confirms a recent Taiwanese study showing an apparent protective effect against dementia for metformin in patients with type 2 diabetes (Aging Dis. 2019 Feb 1;10(1):37-48).
“Ours is the first study on the newer diabetic drugs, so our results need to be confirmed,” she pointed out.
If confirmed, however, it would warrant exploration of these drugs more generally as potential interventions to prevent dementia. That could open a whole new chapter in the remarkable story of the SGLT2 inhibitors, a class of drugs originally developed for treatment of type 2 diabetes but which in major randomized clinical trials later proved to be so effective in the treatment of heart failure that they are now considered cardiology drugs first.
Asked if she thinks these antidiabetes agents have a general neuroprotective effect or, instead, that the observed reduced risk of dementia is a function of patients being treated better early on with modern drugs, the psychiatrist replied, “I think it might be a combination of both, especially because we find different risk estimates between the drugs.”
Dr. Osler reported having no financial conflicts of interest regarding the study, which was funded by the Danish Diabetes Foundation, the Danish Medical Association, and several other foundations.
The full study details were published online shortly before her presentation at ECNP 2019 (Eur J Endocrinol. 2019 Aug 1. pii: EJE-19-0259.R1. doi: 10.1530/EJE-19-0259).
Type 1 diabetes and schizophrenia risk
Kristina Melkersson, MD, PhD, presented a cohort study that utilized Swedish national registries to examine the relationship between type 1 diabetes and schizophrenia. The study comprised 1,745,977 individuals, of whom 10,117 had type 1 diabetes, who were followed for a median of 9.7 and maximum of 18 years from their 13th birthday. During follow-up, 1,280 individuals were diagnosed with schizophrenia and 649 others with schizoaffective disorder. The adjusted risk of schizophrenia was 70% lower in patients with type 1 diabetes. However, there was no difference in the risk of schizoaffective disorder in the type 1 diabetic versus nondiabetic subjects.
The Swedish data confirm the findings of an earlier Finnish national study showing that the risk of schizophrenia is reduced in patients with type 1 diabetes (Arch Gen Psychiatry. 2007 Aug;64(8):894-9). These findings raise the intriguing possibility that autoimmunity somehow figures into the etiology of the psychiatric disorder. Other investigators have previously reported a reduced prevalence of rheumatoid arthritis in patients with schizophrenia, noted Dr. Melkersson of the Karolinska Institute in Stockholm.
She reported having no financial conflicts regarding her study.
SOURCE: Osler M. ECNP Abstract P180. Melkersson K. Abstract 81.
COPENHAGEN – Selected antidiabetes medications appear to blunt the increased risk of dementia associated with type 2 diabetes, according to a Danish national case control registry study.
This benefit applies to the newer antidiabetic agents – specifically, the dipeptidyl peptidase 4 (DPP4) inhibitors, the glucagon-like peptide 1 (GLP1) analogs, and the sodium-glucose transport protein 2 (SGLT2) inhibitors – and metformin as well, Merete Osler, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
In contrast, neither insulin nor the sulfonylureas showed any signal of a protective effect against development of dementia. In fact, the use of sulfonylureas was associated with a small but statistically significant 7% increased risk, added Dr. Osler, of the University of Copenhagen.
Elsewhere at the meeting, investigators tapped a Swedish national registry to demonstrate that individuals with type 1 diabetes have a sharply reduced risk of developing schizophrenia.
Type 2 diabetes medications and dementia
Dr. Osler and colleagues are among several groups of investigators who have previously shown that patients with type 2 diabetes have an increased risk of dementia.
“This has raised the question of the role of dysregulated glucose metabolism in the development of this neurodegenerative disorder, and the possible effect of antidiabetic medications,” she noted.
To further explore this issue, which links two great ongoing global epidemics, Dr. Osler and coinvestigators conducted a nested case-control study including all 176,250 patients with type 2 diabetes in the comprehensive Danish National Diabetes Register for 1995-2012. The 11,619 patients with type 2 diabetes who received a dementia diagnosis were matched with 46,476 type 2 diabetes patients without dementia. The objective was to determine associations between dementia and ever-use and cumulative dose of antidiabetes drugs, alone and in combination, in logistic regression analyses adjusted for demographics, comorbid conditions, marital status, diabetic complications, and year of dementia diagnosis.
Patients who had ever used metformin had an adjusted 6% reduction in the likelihood of dementia compared with metformin nonusers, a modest but statistically significant difference. Those on a DPP4 inhibitor had a 20% reduction in risk. The GLP1 analogs were associated with a 42% decrease in risk. So were the SGLT2 inhibitors. A dose-response relationship was evident: The higher the cumulative exposure to these agents, the lower the odds of dementia.
Combination therapy is common in type 2 diabetes, so the investigators scrutinized the impact of a variety of multidrug combinations. Combinations including a DPP4 inhibitor or GLP1 analog were also associated with significantly reduced dementia risk.
Records of glycemic control in the form of hemoglobin A1c values were available on only 1,446 type 2 diabetic dementia patients and 4,003 matched controls. An analysis that incorporated this variable showed that the observed anti-dementia effect of selected diabetes drugs was independent of glycemic control, according to Dr. Osler.
The protective effect appeared to extend to both Alzheimer’s disease and vascular dementias, although firm conclusions can’t be drawn on this score because the study was insufficiently powered to address that issue.
Dr. Osler noted that the Danish study confirms a recent Taiwanese study showing an apparent protective effect against dementia for metformin in patients with type 2 diabetes (Aging Dis. 2019 Feb 1;10(1):37-48).
“Ours is the first study on the newer diabetic drugs, so our results need to be confirmed,” she pointed out.
If confirmed, however, it would warrant exploration of these drugs more generally as potential interventions to prevent dementia. That could open a whole new chapter in the remarkable story of the SGLT2 inhibitors, a class of drugs originally developed for treatment of type 2 diabetes but which in major randomized clinical trials later proved to be so effective in the treatment of heart failure that they are now considered cardiology drugs first.
Asked if she thinks these antidiabetes agents have a general neuroprotective effect or, instead, that the observed reduced risk of dementia is a function of patients being treated better early on with modern drugs, the psychiatrist replied, “I think it might be a combination of both, especially because we find different risk estimates between the drugs.”
Dr. Osler reported having no financial conflicts of interest regarding the study, which was funded by the Danish Diabetes Foundation, the Danish Medical Association, and several other foundations.
The full study details were published online shortly before her presentation at ECNP 2019 (Eur J Endocrinol. 2019 Aug 1. pii: EJE-19-0259.R1. doi: 10.1530/EJE-19-0259).
Type 1 diabetes and schizophrenia risk
Kristina Melkersson, MD, PhD, presented a cohort study that utilized Swedish national registries to examine the relationship between type 1 diabetes and schizophrenia. The study comprised 1,745,977 individuals, of whom 10,117 had type 1 diabetes, who were followed for a median of 9.7 and maximum of 18 years from their 13th birthday. During follow-up, 1,280 individuals were diagnosed with schizophrenia and 649 others with schizoaffective disorder. The adjusted risk of schizophrenia was 70% lower in patients with type 1 diabetes. However, there was no difference in the risk of schizoaffective disorder in the type 1 diabetic versus nondiabetic subjects.
The Swedish data confirm the findings of an earlier Finnish national study showing that the risk of schizophrenia is reduced in patients with type 1 diabetes (Arch Gen Psychiatry. 2007 Aug;64(8):894-9). These findings raise the intriguing possibility that autoimmunity somehow figures into the etiology of the psychiatric disorder. Other investigators have previously reported a reduced prevalence of rheumatoid arthritis in patients with schizophrenia, noted Dr. Melkersson of the Karolinska Institute in Stockholm.
She reported having no financial conflicts regarding her study.
SOURCE: Osler M. ECNP Abstract P180. Melkersson K. Abstract 81.
REPORTING FROM ECNP 2019