TBD Meeting (3567-22)

VIENNA – Inpatient treatment for major depressive disorder (MDD) can lead to brain connectivity increases that are associated with degree of symptom improvement, new research suggests.

In a “repeat” MRI study, adult participants with MDD had significantly lower brain connectivity compared with their healthy peers at baseline – but showed significant improvement at the 6-week follow-up. These improvements were associated with decreases in symptom severity, independent of whether they received electroconvulsive therapy (ECT) or other treatment modalities.

“This means that the brain structure of patients with serious clinical depression is not as fixed as we thought, and we can improve brain structure within a short time frame [of] around 6 weeks,” lead author Jonathan Repple, MD, now professor of predictive psychiatry at the University of Frankfurt, Germany, said in a release.

“This gives hope to patients who believe nothing can change and they have to live with a disease forever because it is ‘set in stone’ in their brain,” he added.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

‘Easily understandable picture’

Dr. Repple said in an interview that the investigators “were surprised to see how plastic” the brain could be.

“I’ve done a lot of imaging studies in the past where we looked at differences in depression vs. healthy controls, and then maybe had tiny effects. But we’ve never seen such a clear and easily understandable picture, where we see a deficit at the beginning and then a significant increase in whatever biomarker we were looking at, that even correlated with how successful the treatment was,” he said.

Dr. Repple noted that “this is the thing everyone is looking for when we’re talking about a biomarker: That we see this exact pattern” – and it is why they are so excited about the results.

However, he cautioned that the study included a “small sample” and the results need to be independently replicated.

“If this can be replicated, this might be a very good target for future intervention studies,” Dr. Repple said.

The investigators noted that altered brain structural connectivity has been implicated before in the pathophysiology of MDD.

However, it is not clear whether these changes are stable over time and indicate a biological predisposition, or are markers of current disease severity and can be altered by effective treatment.

To investigate further, the researchers used gray matter T1-weighted MRI to define nodes in the brain and diffusion-weighted imaging (DWI)-based tractography to determine connections between the nodes, to create a structural connectome or white matter network.

They performed assessments at baseline and at 6 weeks’ follow-up in 123 participants diagnosed with current MDD and receiving inpatient treatment, and 55 participants who acted as the healthy controls group.

Among the patients with MDD, 56 were treated with ECT and 67 received other antidepressant care, including psychological therapy or medications. Some patients had received all three treatment modalities.
 

Significant interactions

Results showed a significant interaction by group and time between the baseline and 6-week follow-up assessments (P < .05).

This was partly driven by the MDD group having a significantly lower connectivity strength at baseline than the healthy controls group (P < .05).

It was also partly driven by patients showing a significant improvement in connectivity strength between the baseline and follow-up assessments (P < .05), a pattern that was not seen in the nonpatients.

This increase in connectivity strength was associated with a significant decrease in depression symptom severity (P < .05). This was independent of the treatment modality, indicating that it was not linked to the use of ECT.

Dr. Repple acknowledged the relatively short follow-up period of the study, and added that he is not aware of longitudinal studies of the structural connectome with a longer follow-up.

He pointed out that the structural connectivity of the brain decreases with age, but there have been no studies that have assessed patients with depression and “measured the same person again after 2, 4, 6, or 8 years.”

Dr. Repple reported that the investigators will be following up with their participants, “so hopefully in a few years we’ll have more information on that.

“One thing I also need to stress is that, when we’re looking at the MRI brain scans, we see an increase in connectivity strength, but we really can’t say what the molecular mechanisms behind it are,” he said. “This is a black box for us.”
 

Several unanswered questions

Commenting in the release, Eric Ruhe, MD, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, said this was a “very interesting and difficult study to perform.”

However, Dr. Ruhe, who was not involved in the research, told this news organization that it is “very difficult to connect the lack of brain connectivity to the patient symptomatology because there is a huge gap between them.”

The problem is that, despite “lots of evidence” that they are effective, “we currently don’t know how antidepressant therapies work” in terms of their underlying mechanisms of action, he said.

“We think that these types of therapies all modulate the plasticity of the brain,” said Dr. Ruhe. “What this study showed is there are changes that you can detect even in 6 weeks,” although they may have been observed even sooner with a shorter follow-up.

He noted that big questions are whether the change is specific to the treatment given, and “can you modulate different brain network dysfunctions with different treatments?”

Moreover, he wondered if a brain scan could indicate which type of treatment should be used. “This is, of course, very new and very challenging, and we don’t know yet, but we should be pursuing this,” Dr. Ruhe said.

Another question is whether or not the brain connectivity changes shown in the study represent a persistent change – “and whether this is a persistent change that is associated with a consistent and persistent relief of depression.

“Again, this is something that needs to be followed up,” said Dr. Ruhe.

No funding was declared. The study authors and Dr. Ruhe report no relevant financial relationships.

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

VIENNA – Inpatient treatment for major depressive disorder (MDD) can lead to brain connectivity increases that are associated with degree of symptom improvement, new research suggests.

In a “repeat” MRI study, adult participants with MDD had significantly lower brain connectivity compared with their healthy peers at baseline – but showed significant improvement at the 6-week follow-up. These improvements were associated with decreases in symptom severity, independent of whether they received electroconvulsive therapy (ECT) or other treatment modalities.

“This means that the brain structure of patients with serious clinical depression is not as fixed as we thought, and we can improve brain structure within a short time frame [of] around 6 weeks,” lead author Jonathan Repple, MD, now professor of predictive psychiatry at the University of Frankfurt, Germany, said in a release.

“This gives hope to patients who believe nothing can change and they have to live with a disease forever because it is ‘set in stone’ in their brain,” he added.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

‘Easily understandable picture’

Dr. Repple said in an interview that the investigators “were surprised to see how plastic” the brain could be.

“I’ve done a lot of imaging studies in the past where we looked at differences in depression vs. healthy controls, and then maybe had tiny effects. But we’ve never seen such a clear and easily understandable picture, where we see a deficit at the beginning and then a significant increase in whatever biomarker we were looking at, that even correlated with how successful the treatment was,” he said.

Dr. Repple noted that “this is the thing everyone is looking for when we’re talking about a biomarker: That we see this exact pattern” – and it is why they are so excited about the results.

However, he cautioned that the study included a “small sample” and the results need to be independently replicated.

“If this can be replicated, this might be a very good target for future intervention studies,” Dr. Repple said.

The investigators noted that altered brain structural connectivity has been implicated before in the pathophysiology of MDD.

However, it is not clear whether these changes are stable over time and indicate a biological predisposition, or are markers of current disease severity and can be altered by effective treatment.

To investigate further, the researchers used gray matter T1-weighted MRI to define nodes in the brain and diffusion-weighted imaging (DWI)-based tractography to determine connections between the nodes, to create a structural connectome or white matter network.

They performed assessments at baseline and at 6 weeks’ follow-up in 123 participants diagnosed with current MDD and receiving inpatient treatment, and 55 participants who acted as the healthy controls group.

Among the patients with MDD, 56 were treated with ECT and 67 received other antidepressant care, including psychological therapy or medications. Some patients had received all three treatment modalities.
 

Significant interactions

Results showed a significant interaction by group and time between the baseline and 6-week follow-up assessments (P < .05).

This was partly driven by the MDD group having a significantly lower connectivity strength at baseline than the healthy controls group (P < .05).

It was also partly driven by patients showing a significant improvement in connectivity strength between the baseline and follow-up assessments (P < .05), a pattern that was not seen in the nonpatients.

This increase in connectivity strength was associated with a significant decrease in depression symptom severity (P < .05). This was independent of the treatment modality, indicating that it was not linked to the use of ECT.

Dr. Repple acknowledged the relatively short follow-up period of the study, and added that he is not aware of longitudinal studies of the structural connectome with a longer follow-up.

He pointed out that the structural connectivity of the brain decreases with age, but there have been no studies that have assessed patients with depression and “measured the same person again after 2, 4, 6, or 8 years.”

Dr. Repple reported that the investigators will be following up with their participants, “so hopefully in a few years we’ll have more information on that.

“One thing I also need to stress is that, when we’re looking at the MRI brain scans, we see an increase in connectivity strength, but we really can’t say what the molecular mechanisms behind it are,” he said. “This is a black box for us.”
 

Several unanswered questions

Commenting in the release, Eric Ruhe, MD, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, said this was a “very interesting and difficult study to perform.”

However, Dr. Ruhe, who was not involved in the research, told this news organization that it is “very difficult to connect the lack of brain connectivity to the patient symptomatology because there is a huge gap between them.”

The problem is that, despite “lots of evidence” that they are effective, “we currently don’t know how antidepressant therapies work” in terms of their underlying mechanisms of action, he said.

“We think that these types of therapies all modulate the plasticity of the brain,” said Dr. Ruhe. “What this study showed is there are changes that you can detect even in 6 weeks,” although they may have been observed even sooner with a shorter follow-up.

He noted that big questions are whether the change is specific to the treatment given, and “can you modulate different brain network dysfunctions with different treatments?”

Moreover, he wondered if a brain scan could indicate which type of treatment should be used. “This is, of course, very new and very challenging, and we don’t know yet, but we should be pursuing this,” Dr. Ruhe said.

Another question is whether or not the brain connectivity changes shown in the study represent a persistent change – “and whether this is a persistent change that is associated with a consistent and persistent relief of depression.

“Again, this is something that needs to be followed up,” said Dr. Ruhe.

No funding was declared. The study authors and Dr. Ruhe report no relevant financial relationships.

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

VIENNA – Inpatient treatment for major depressive disorder (MDD) can lead to brain connectivity increases that are associated with degree of symptom improvement, new research suggests.

In a “repeat” MRI study, adult participants with MDD had significantly lower brain connectivity compared with their healthy peers at baseline – but showed significant improvement at the 6-week follow-up. These improvements were associated with decreases in symptom severity, independent of whether they received electroconvulsive therapy (ECT) or other treatment modalities.

“This means that the brain structure of patients with serious clinical depression is not as fixed as we thought, and we can improve brain structure within a short time frame [of] around 6 weeks,” lead author Jonathan Repple, MD, now professor of predictive psychiatry at the University of Frankfurt, Germany, said in a release.

“This gives hope to patients who believe nothing can change and they have to live with a disease forever because it is ‘set in stone’ in their brain,” he added.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

‘Easily understandable picture’

Dr. Repple said in an interview that the investigators “were surprised to see how plastic” the brain could be.

“I’ve done a lot of imaging studies in the past where we looked at differences in depression vs. healthy controls, and then maybe had tiny effects. But we’ve never seen such a clear and easily understandable picture, where we see a deficit at the beginning and then a significant increase in whatever biomarker we were looking at, that even correlated with how successful the treatment was,” he said.

Dr. Repple noted that “this is the thing everyone is looking for when we’re talking about a biomarker: That we see this exact pattern” – and it is why they are so excited about the results.

However, he cautioned that the study included a “small sample” and the results need to be independently replicated.

“If this can be replicated, this might be a very good target for future intervention studies,” Dr. Repple said.

The investigators noted that altered brain structural connectivity has been implicated before in the pathophysiology of MDD.

However, it is not clear whether these changes are stable over time and indicate a biological predisposition, or are markers of current disease severity and can be altered by effective treatment.

To investigate further, the researchers used gray matter T1-weighted MRI to define nodes in the brain and diffusion-weighted imaging (DWI)-based tractography to determine connections between the nodes, to create a structural connectome or white matter network.

They performed assessments at baseline and at 6 weeks’ follow-up in 123 participants diagnosed with current MDD and receiving inpatient treatment, and 55 participants who acted as the healthy controls group.

Among the patients with MDD, 56 were treated with ECT and 67 received other antidepressant care, including psychological therapy or medications. Some patients had received all three treatment modalities.
 

Significant interactions

Results showed a significant interaction by group and time between the baseline and 6-week follow-up assessments (P < .05).

This was partly driven by the MDD group having a significantly lower connectivity strength at baseline than the healthy controls group (P < .05).

It was also partly driven by patients showing a significant improvement in connectivity strength between the baseline and follow-up assessments (P < .05), a pattern that was not seen in the nonpatients.

This increase in connectivity strength was associated with a significant decrease in depression symptom severity (P < .05). This was independent of the treatment modality, indicating that it was not linked to the use of ECT.

Dr. Repple acknowledged the relatively short follow-up period of the study, and added that he is not aware of longitudinal studies of the structural connectome with a longer follow-up.

He pointed out that the structural connectivity of the brain decreases with age, but there have been no studies that have assessed patients with depression and “measured the same person again after 2, 4, 6, or 8 years.”

Dr. Repple reported that the investigators will be following up with their participants, “so hopefully in a few years we’ll have more information on that.

“One thing I also need to stress is that, when we’re looking at the MRI brain scans, we see an increase in connectivity strength, but we really can’t say what the molecular mechanisms behind it are,” he said. “This is a black box for us.”
 

Several unanswered questions

Commenting in the release, Eric Ruhe, MD, PhD, Radboud University Medical Center, Nijmegen, the Netherlands, said this was a “very interesting and difficult study to perform.”

However, Dr. Ruhe, who was not involved in the research, told this news organization that it is “very difficult to connect the lack of brain connectivity to the patient symptomatology because there is a huge gap between them.”

The problem is that, despite “lots of evidence” that they are effective, “we currently don’t know how antidepressant therapies work” in terms of their underlying mechanisms of action, he said.

“We think that these types of therapies all modulate the plasticity of the brain,” said Dr. Ruhe. “What this study showed is there are changes that you can detect even in 6 weeks,” although they may have been observed even sooner with a shorter follow-up.

He noted that big questions are whether the change is specific to the treatment given, and “can you modulate different brain network dysfunctions with different treatments?”

Moreover, he wondered if a brain scan could indicate which type of treatment should be used. “This is, of course, very new and very challenging, and we don’t know yet, but we should be pursuing this,” Dr. Ruhe said.

Another question is whether or not the brain connectivity changes shown in the study represent a persistent change – “and whether this is a persistent change that is associated with a consistent and persistent relief of depression.

“Again, this is something that needs to be followed up,” said Dr. Ruhe.

No funding was declared. The study authors and Dr. Ruhe report no relevant financial relationships.

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

VIENNA – The production of estrogen in the thalamus appears to be curtailed by just one dose of nicotine, equivalent to that in a cigarette, reveals a whole brain analysis of healthy women in the first study of its kind.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.

The researchers performed both MRI and positron emission tomography (PET) scans in 10 healthy women using a tracer that binds to aromatase, also known as estrogen synthase.

They found that, following an intranasal spray delivering 1 mg of nicotine, there was a significant reduction in estrogen synthase in both the right and left thalamus.

“For the first time, we can see that nicotine works to shut down the estrogen production mechanism in the brains of women,” said lead researcher Erika Comasco, PhD, department of neuroscience, Uppsala University, Sweden, in a release.

“We were surprised to see that this effect could be seen even with a single dose of nicotine, equivalent to just one cigarette, showing how powerful the effects of smoking are on a woman’s brain.”

Emphasizing the preliminary nature of the study and the need for a larger sample, she added: “We’re still not sure what the behavioral or cognitive outcomes are, only that nicotine acts on this area of the brain.

“However, we note that the affected brain system is a target for addictive drugs, such as nicotine.”

Previous research has revealed that women are less successful at quitting smoking than men, and appear to be more resistant to nicotine replacement therapy, and experience more relapses.

There is evidence to suggest that there is a complex interaction between sex and steroid hormones and the reward effect of nicotine, modulated by the dopaminergic system.

Moreover, women who smoke enter menopause earlier than nonsmokers, and have lower plasma estrogen levels, Dr. Camasco told this news organization.

Dr. Comasco explained that “besides its role in reproductive function and sexual behavior, estrogen has an impact on the brain wherever there are receptors, which is basically regions that are related to emotional regulation, cognitive function, and so on.”

Estrogen, she continued, has two main mechanisms of action, via dopaminergic and serotonergic signaling. However, levels of the hormone cannot be measured directly in the brain.

The researchers therefore turned to estrogen synthase, which regulates the synthesis of estrogen, and is highly expressed in the limbic system, a brain region associated with addiction.

Moreover, estrogen synthase levels can be measured in vivo, and previous animal studies have indicated that nicotine inhibits estrogen synthase.

To investigate its impact in humans, the researchers performed structural MRI and two ¹¹C-cetrozole PET scans in 10 healthy women.

The assessments were performed before and after the nasal administration of 1 mg of nicotine, the dose contained in one cigarette, via two sprays of a nasal spray each containing 0.5 mg of nicotine.

A whole brain analysis was then used to determine changes in nondisplaceable binding potential of ¹¹C-cetrozole to estrogen synthase between the two scans to indicate the availability of the enzyme at the two time points.

The results showed that, at baseline, high availability of estrogen synthase was observed in the thalamus, hypothalamus, and amygdala, with the highest levels in the right and left thalamus.

However, nicotine exposure was associated with a significant reduction in estrogen binding bilaterally in the thalamus when averaged across the participants (P < .01).

Region-of-interest analysis using within-individual voxel-wise comparison confirmed reduced estrogen synthase levels in both the right and left thalamus (P < .05), as well as in the subthalamic area.

Next, Dr. Comasco would like to test the impact of nicotine on estrogen synthase in men.

While men have lower levels of estrogen then women, “the reaction will take place anyway,” she said, although the “impact would be different.”

She would also like to look at the behavioral effects of reductions in estrogen synthase, and look at the effect of nicotine from a functional point of view.

Wim van den Brink, MD, PhD, professor of psychiatry and addiction at the Academic Medical Center, University of Amsterdam, commented that this is an “important first finding.”

“Smoking has many adverse effects in men and in women, but this particular effect of nicotine on the reduction of estrogen production in women was not known before,” he added in the release.

However, he underlined that tobacco addition is a “complex disorder” and it is “unlikely that this specific effect of nicotine on the thalamus explains all the observed differences in the development, treatment, and outcomes between male and female smokers.”

“It is still a long way from a nicotine-induced reduction in estrogen production to a reduced risk of nicotine addiction and negative effects of treatment and relapse in female cigarette smokers, but this work merits further investigation,” Dr. van den Brink said.

The study was funded by the Science for Life Laboratory/Uppsala University.

No relevant financial relationships were declared.

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

VIENNA – The production of estrogen in the thalamus appears to be curtailed by just one dose of nicotine, equivalent to that in a cigarette, reveals a whole brain analysis of healthy women in the first study of its kind.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.

The researchers performed both MRI and positron emission tomography (PET) scans in 10 healthy women using a tracer that binds to aromatase, also known as estrogen synthase.

They found that, following an intranasal spray delivering 1 mg of nicotine, there was a significant reduction in estrogen synthase in both the right and left thalamus.

“For the first time, we can see that nicotine works to shut down the estrogen production mechanism in the brains of women,” said lead researcher Erika Comasco, PhD, department of neuroscience, Uppsala University, Sweden, in a release.

“We were surprised to see that this effect could be seen even with a single dose of nicotine, equivalent to just one cigarette, showing how powerful the effects of smoking are on a woman’s brain.”

Emphasizing the preliminary nature of the study and the need for a larger sample, she added: “We’re still not sure what the behavioral or cognitive outcomes are, only that nicotine acts on this area of the brain.

“However, we note that the affected brain system is a target for addictive drugs, such as nicotine.”

Previous research has revealed that women are less successful at quitting smoking than men, and appear to be more resistant to nicotine replacement therapy, and experience more relapses.

There is evidence to suggest that there is a complex interaction between sex and steroid hormones and the reward effect of nicotine, modulated by the dopaminergic system.

Moreover, women who smoke enter menopause earlier than nonsmokers, and have lower plasma estrogen levels, Dr. Camasco told this news organization.

Dr. Comasco explained that “besides its role in reproductive function and sexual behavior, estrogen has an impact on the brain wherever there are receptors, which is basically regions that are related to emotional regulation, cognitive function, and so on.”

Estrogen, she continued, has two main mechanisms of action, via dopaminergic and serotonergic signaling. However, levels of the hormone cannot be measured directly in the brain.

The researchers therefore turned to estrogen synthase, which regulates the synthesis of estrogen, and is highly expressed in the limbic system, a brain region associated with addiction.

Moreover, estrogen synthase levels can be measured in vivo, and previous animal studies have indicated that nicotine inhibits estrogen synthase.

To investigate its impact in humans, the researchers performed structural MRI and two ¹¹C-cetrozole PET scans in 10 healthy women.

The assessments were performed before and after the nasal administration of 1 mg of nicotine, the dose contained in one cigarette, via two sprays of a nasal spray each containing 0.5 mg of nicotine.

A whole brain analysis was then used to determine changes in nondisplaceable binding potential of ¹¹C-cetrozole to estrogen synthase between the two scans to indicate the availability of the enzyme at the two time points.

The results showed that, at baseline, high availability of estrogen synthase was observed in the thalamus, hypothalamus, and amygdala, with the highest levels in the right and left thalamus.

However, nicotine exposure was associated with a significant reduction in estrogen binding bilaterally in the thalamus when averaged across the participants (P < .01).

Region-of-interest analysis using within-individual voxel-wise comparison confirmed reduced estrogen synthase levels in both the right and left thalamus (P < .05), as well as in the subthalamic area.

Next, Dr. Comasco would like to test the impact of nicotine on estrogen synthase in men.

While men have lower levels of estrogen then women, “the reaction will take place anyway,” she said, although the “impact would be different.”

She would also like to look at the behavioral effects of reductions in estrogen synthase, and look at the effect of nicotine from a functional point of view.

Wim van den Brink, MD, PhD, professor of psychiatry and addiction at the Academic Medical Center, University of Amsterdam, commented that this is an “important first finding.”

“Smoking has many adverse effects in men and in women, but this particular effect of nicotine on the reduction of estrogen production in women was not known before,” he added in the release.

However, he underlined that tobacco addition is a “complex disorder” and it is “unlikely that this specific effect of nicotine on the thalamus explains all the observed differences in the development, treatment, and outcomes between male and female smokers.”

“It is still a long way from a nicotine-induced reduction in estrogen production to a reduced risk of nicotine addiction and negative effects of treatment and relapse in female cigarette smokers, but this work merits further investigation,” Dr. van den Brink said.

The study was funded by the Science for Life Laboratory/Uppsala University.

No relevant financial relationships were declared.

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

VIENNA – The production of estrogen in the thalamus appears to be curtailed by just one dose of nicotine, equivalent to that in a cigarette, reveals a whole brain analysis of healthy women in the first study of its kind.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.

The researchers performed both MRI and positron emission tomography (PET) scans in 10 healthy women using a tracer that binds to aromatase, also known as estrogen synthase.

They found that, following an intranasal spray delivering 1 mg of nicotine, there was a significant reduction in estrogen synthase in both the right and left thalamus.

“For the first time, we can see that nicotine works to shut down the estrogen production mechanism in the brains of women,” said lead researcher Erika Comasco, PhD, department of neuroscience, Uppsala University, Sweden, in a release.

“We were surprised to see that this effect could be seen even with a single dose of nicotine, equivalent to just one cigarette, showing how powerful the effects of smoking are on a woman’s brain.”

Emphasizing the preliminary nature of the study and the need for a larger sample, she added: “We’re still not sure what the behavioral or cognitive outcomes are, only that nicotine acts on this area of the brain.

“However, we note that the affected brain system is a target for addictive drugs, such as nicotine.”

Previous research has revealed that women are less successful at quitting smoking than men, and appear to be more resistant to nicotine replacement therapy, and experience more relapses.

There is evidence to suggest that there is a complex interaction between sex and steroid hormones and the reward effect of nicotine, modulated by the dopaminergic system.

Moreover, women who smoke enter menopause earlier than nonsmokers, and have lower plasma estrogen levels, Dr. Camasco told this news organization.

Dr. Comasco explained that “besides its role in reproductive function and sexual behavior, estrogen has an impact on the brain wherever there are receptors, which is basically regions that are related to emotional regulation, cognitive function, and so on.”

Estrogen, she continued, has two main mechanisms of action, via dopaminergic and serotonergic signaling. However, levels of the hormone cannot be measured directly in the brain.

The researchers therefore turned to estrogen synthase, which regulates the synthesis of estrogen, and is highly expressed in the limbic system, a brain region associated with addiction.

Moreover, estrogen synthase levels can be measured in vivo, and previous animal studies have indicated that nicotine inhibits estrogen synthase.

To investigate its impact in humans, the researchers performed structural MRI and two ¹¹C-cetrozole PET scans in 10 healthy women.

The assessments were performed before and after the nasal administration of 1 mg of nicotine, the dose contained in one cigarette, via two sprays of a nasal spray each containing 0.5 mg of nicotine.

A whole brain analysis was then used to determine changes in nondisplaceable binding potential of ¹¹C-cetrozole to estrogen synthase between the two scans to indicate the availability of the enzyme at the two time points.

The results showed that, at baseline, high availability of estrogen synthase was observed in the thalamus, hypothalamus, and amygdala, with the highest levels in the right and left thalamus.

However, nicotine exposure was associated with a significant reduction in estrogen binding bilaterally in the thalamus when averaged across the participants (P < .01).

Region-of-interest analysis using within-individual voxel-wise comparison confirmed reduced estrogen synthase levels in both the right and left thalamus (P < .05), as well as in the subthalamic area.

Next, Dr. Comasco would like to test the impact of nicotine on estrogen synthase in men.

While men have lower levels of estrogen then women, “the reaction will take place anyway,” she said, although the “impact would be different.”

She would also like to look at the behavioral effects of reductions in estrogen synthase, and look at the effect of nicotine from a functional point of view.

Wim van den Brink, MD, PhD, professor of psychiatry and addiction at the Academic Medical Center, University of Amsterdam, commented that this is an “important first finding.”

“Smoking has many adverse effects in men and in women, but this particular effect of nicotine on the reduction of estrogen production in women was not known before,” he added in the release.

However, he underlined that tobacco addition is a “complex disorder” and it is “unlikely that this specific effect of nicotine on the thalamus explains all the observed differences in the development, treatment, and outcomes between male and female smokers.”

“It is still a long way from a nicotine-induced reduction in estrogen production to a reduced risk of nicotine addiction and negative effects of treatment and relapse in female cigarette smokers, but this work merits further investigation,” Dr. van den Brink said.

The study was funded by the Science for Life Laboratory/Uppsala University.

No relevant financial relationships were declared.

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

VIENNA – Following a healthy, balanced diet and avoiding excessive consumption of stressful news helped prevent anxiety and depressive symptoms during the COVID-19 pandemic, new research suggests.

Results from a longitudinal Spanish survey study of more than 1,000 adults showed that being outside, relaxing, participating in physical activities, and drinking plenty of water were also beneficial. However, social contact with friends and relatives, following a routine, and pursuing hobbies had no significant impact.

“This was a little surprising,” lead author Joaquim Radua, MD, PhD, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, said in a release.

“Like many people, we had assumed that personal contact would play a bigger part in avoiding anxiety and depression during stressful times,” he added.

However, Dr. Radua said that because the study was conducted during the COVID-19 pandemic, “people who socialized may also have been anxious about getting infected.”

Consequently, “it may be that this specific behavior cannot be extrapolated to other times, when there is no pandemic,” he said.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

Correlational versus longitudinal studies

Dr. Radua emphasized that individuals “should socialize,” of course.

“We think it’s important that people continue to follow what works for them and that if you enjoy seeing friends or following a hobby, you continue to do so,” he said.

“Our work was centered on COVID, but we now need to see if these factors apply to other stressful circumstances. These simple behaviors may prevent anxiety and depression, and prevention is better than cure,” he added.

The researchers note that, in “times of uncertainty” such as the COVID-19 pandemic, many individuals experience increases in both anxiety and depressive symptoms.

Although a range of behaviors are recommended to help people cope, the investigators add that some of the recommendations are based on correlational studies.

Indeed, the researchers previously identified a correlation between following a healthy/balanced diet, among other measures, and lower anxiety and depressive symptoms during the pandemic.

However, it is unclear from cross-sectional studies whether the behavior alters the symptoms, in which case the behavior could be considered “helpful,” or conversely whether the symptoms alter an individual’s behavior, in which case the behaviors “may be useless,” the investigators note.

The investigative team therefore set out to provide more robust evidence for making recommendations and conducted a prospective longitudinal study.

They recruited 1,049 adults online via social networks, matching them to the regional, age and sex, and urbanicity distribution of the overall Spanish population.

Every 2 weeks for 12 months, the researchers administered the General Anxiety Disorder (GAD)-7, the Patient Health Questionnaire (PHQ)-9, and a two-item ecological momentary assessment to minimize recall bias, among other measures. They also asked about 10 self-report coping behaviors.
 

Significant coping behaviors

The study was completed by 942 individuals, indicating a retention of 90%.

Among both completers and non-completers there was an over-representation of individuals aged 18-34 years and women, compared with the general population, and fewer participants aged at least 65 years.

Pre-recruitment, the mean baseline GAD-7 score among completers was 7.4, falling to around 5.5 at the time of the first questionnaire. Scores on the PHQ-9 were 7.6 and 5.6, respectively.

Performing population-weighted autoregressive moving average models to analyze the relationship between the current frequency of the coping behaviors and future changes in anxiety and depressive symptoms, the investigators found that the greatest effect was from following a healthy, balanced diet, with an impact size of 0.95.

This was followed by avoiding too much stressful news (impact size, 0.91), staying outdoors or looking outside (0.40), doing relaxing activities (0.33), participating in physical exercise (0.32), and drinking water to hydrate (0.25).

Overall, these coping behaviors were associated with a significant reduction in anxiety and depressive symptoms (all, P < .001).

On the other hand, there was no impact on future symptoms from socializing with friends and relatives, whether or not they lived in the same household. There was also no effect from following a routine, pursuing hobbies, or performing home tasks.

The researchers note that similar results were obtained when excluding participants with hazardous alcohol consumption, defined as a score on the Alcohol Use Disorders Identification Test of 8 or higher.

However, they point out that despite its prospective design and large cohort, the study was not interventional. Therefore, they “cannot rule out the possibility that decreasing the frequency of a behavior is an early sign of some mechanism that later leads to increased anxiety and depression symptoms.”

Nevertheless, they believe that possibility “seems unlikely.”
 

Reflective of a unique time?

Commenting on the findings, Catherine Harmer, PhD, director of the Psychopharmacology and Emotional Research Lab, department of psychiatry, University of Oxford (England), said in the release this was an “interesting study” that “provides some important insights as to which behaviors may protect our mental health during times of significant stress.”

She said the finding that social contact was not beneficial was “surprising” but may reflect the fact that, during the pandemic, it was “stressful even to have those social contacts, even if we managed to meet a friend outside.”

The results of the study may therefore be “reflective of the unique experience” of the COVID-19 pandemic, said Dr. Harmer, who was not involved with the research.

“I wouldn’t think that reading too much news would generally be something that has a negative impact on depression and anxiety, but I think it was very much at the time,” she said.

With the pandemic overwhelming one country after another, “the more you read about it, the more frightening it was,” she added, noting that it is “easy to forget how frightened we were at the beginning.”

Dr. Harmer noted that “it would be interesting” if the study was repeated and the same factors came out – or if they were unique to that time.

This would be “useful to know, as these times may come again. And the more information we have to cope with a pandemic, the better,” she concluded.

The research was supported by the AXA Research Fund via an AXA Award granted to Dr. Radua from the call for projects “mitigating risk in the wake of the COVID-19 pandemic.” The investigators and Dr. Harmer report no relevant financial relationships.

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

VIENNA – Following a healthy, balanced diet and avoiding excessive consumption of stressful news helped prevent anxiety and depressive symptoms during the COVID-19 pandemic, new research suggests.

Results from a longitudinal Spanish survey study of more than 1,000 adults showed that being outside, relaxing, participating in physical activities, and drinking plenty of water were also beneficial. However, social contact with friends and relatives, following a routine, and pursuing hobbies had no significant impact.

“This was a little surprising,” lead author Joaquim Radua, MD, PhD, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, said in a release.

“Like many people, we had assumed that personal contact would play a bigger part in avoiding anxiety and depression during stressful times,” he added.

However, Dr. Radua said that because the study was conducted during the COVID-19 pandemic, “people who socialized may also have been anxious about getting infected.”

Consequently, “it may be that this specific behavior cannot be extrapolated to other times, when there is no pandemic,” he said.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

Correlational versus longitudinal studies

Dr. Radua emphasized that individuals “should socialize,” of course.

“We think it’s important that people continue to follow what works for them and that if you enjoy seeing friends or following a hobby, you continue to do so,” he said.

“Our work was centered on COVID, but we now need to see if these factors apply to other stressful circumstances. These simple behaviors may prevent anxiety and depression, and prevention is better than cure,” he added.

The researchers note that, in “times of uncertainty” such as the COVID-19 pandemic, many individuals experience increases in both anxiety and depressive symptoms.

Although a range of behaviors are recommended to help people cope, the investigators add that some of the recommendations are based on correlational studies.

Indeed, the researchers previously identified a correlation between following a healthy/balanced diet, among other measures, and lower anxiety and depressive symptoms during the pandemic.

However, it is unclear from cross-sectional studies whether the behavior alters the symptoms, in which case the behavior could be considered “helpful,” or conversely whether the symptoms alter an individual’s behavior, in which case the behaviors “may be useless,” the investigators note.

The investigative team therefore set out to provide more robust evidence for making recommendations and conducted a prospective longitudinal study.

They recruited 1,049 adults online via social networks, matching them to the regional, age and sex, and urbanicity distribution of the overall Spanish population.

Every 2 weeks for 12 months, the researchers administered the General Anxiety Disorder (GAD)-7, the Patient Health Questionnaire (PHQ)-9, and a two-item ecological momentary assessment to minimize recall bias, among other measures. They also asked about 10 self-report coping behaviors.
 

Significant coping behaviors

The study was completed by 942 individuals, indicating a retention of 90%.

Among both completers and non-completers there was an over-representation of individuals aged 18-34 years and women, compared with the general population, and fewer participants aged at least 65 years.

Pre-recruitment, the mean baseline GAD-7 score among completers was 7.4, falling to around 5.5 at the time of the first questionnaire. Scores on the PHQ-9 were 7.6 and 5.6, respectively.

Performing population-weighted autoregressive moving average models to analyze the relationship between the current frequency of the coping behaviors and future changes in anxiety and depressive symptoms, the investigators found that the greatest effect was from following a healthy, balanced diet, with an impact size of 0.95.

This was followed by avoiding too much stressful news (impact size, 0.91), staying outdoors or looking outside (0.40), doing relaxing activities (0.33), participating in physical exercise (0.32), and drinking water to hydrate (0.25).

Overall, these coping behaviors were associated with a significant reduction in anxiety and depressive symptoms (all, P < .001).

On the other hand, there was no impact on future symptoms from socializing with friends and relatives, whether or not they lived in the same household. There was also no effect from following a routine, pursuing hobbies, or performing home tasks.

The researchers note that similar results were obtained when excluding participants with hazardous alcohol consumption, defined as a score on the Alcohol Use Disorders Identification Test of 8 or higher.

However, they point out that despite its prospective design and large cohort, the study was not interventional. Therefore, they “cannot rule out the possibility that decreasing the frequency of a behavior is an early sign of some mechanism that later leads to increased anxiety and depression symptoms.”

Nevertheless, they believe that possibility “seems unlikely.”
 

Reflective of a unique time?

Commenting on the findings, Catherine Harmer, PhD, director of the Psychopharmacology and Emotional Research Lab, department of psychiatry, University of Oxford (England), said in the release this was an “interesting study” that “provides some important insights as to which behaviors may protect our mental health during times of significant stress.”

She said the finding that social contact was not beneficial was “surprising” but may reflect the fact that, during the pandemic, it was “stressful even to have those social contacts, even if we managed to meet a friend outside.”

The results of the study may therefore be “reflective of the unique experience” of the COVID-19 pandemic, said Dr. Harmer, who was not involved with the research.

“I wouldn’t think that reading too much news would generally be something that has a negative impact on depression and anxiety, but I think it was very much at the time,” she said.

With the pandemic overwhelming one country after another, “the more you read about it, the more frightening it was,” she added, noting that it is “easy to forget how frightened we were at the beginning.”

Dr. Harmer noted that “it would be interesting” if the study was repeated and the same factors came out – or if they were unique to that time.

This would be “useful to know, as these times may come again. And the more information we have to cope with a pandemic, the better,” she concluded.

The research was supported by the AXA Research Fund via an AXA Award granted to Dr. Radua from the call for projects “mitigating risk in the wake of the COVID-19 pandemic.” The investigators and Dr. Harmer report no relevant financial relationships.

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

VIENNA – Following a healthy, balanced diet and avoiding excessive consumption of stressful news helped prevent anxiety and depressive symptoms during the COVID-19 pandemic, new research suggests.

Results from a longitudinal Spanish survey study of more than 1,000 adults showed that being outside, relaxing, participating in physical activities, and drinking plenty of water were also beneficial. However, social contact with friends and relatives, following a routine, and pursuing hobbies had no significant impact.

“This was a little surprising,” lead author Joaquim Radua, MD, PhD, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, said in a release.

“Like many people, we had assumed that personal contact would play a bigger part in avoiding anxiety and depression during stressful times,” he added.

However, Dr. Radua said that because the study was conducted during the COVID-19 pandemic, “people who socialized may also have been anxious about getting infected.”

Consequently, “it may be that this specific behavior cannot be extrapolated to other times, when there is no pandemic,” he said.

The findings were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

Correlational versus longitudinal studies

Dr. Radua emphasized that individuals “should socialize,” of course.

“We think it’s important that people continue to follow what works for them and that if you enjoy seeing friends or following a hobby, you continue to do so,” he said.

“Our work was centered on COVID, but we now need to see if these factors apply to other stressful circumstances. These simple behaviors may prevent anxiety and depression, and prevention is better than cure,” he added.

The researchers note that, in “times of uncertainty” such as the COVID-19 pandemic, many individuals experience increases in both anxiety and depressive symptoms.

Although a range of behaviors are recommended to help people cope, the investigators add that some of the recommendations are based on correlational studies.

Indeed, the researchers previously identified a correlation between following a healthy/balanced diet, among other measures, and lower anxiety and depressive symptoms during the pandemic.

However, it is unclear from cross-sectional studies whether the behavior alters the symptoms, in which case the behavior could be considered “helpful,” or conversely whether the symptoms alter an individual’s behavior, in which case the behaviors “may be useless,” the investigators note.

The investigative team therefore set out to provide more robust evidence for making recommendations and conducted a prospective longitudinal study.

They recruited 1,049 adults online via social networks, matching them to the regional, age and sex, and urbanicity distribution of the overall Spanish population.

Every 2 weeks for 12 months, the researchers administered the General Anxiety Disorder (GAD)-7, the Patient Health Questionnaire (PHQ)-9, and a two-item ecological momentary assessment to minimize recall bias, among other measures. They also asked about 10 self-report coping behaviors.
 

Significant coping behaviors

The study was completed by 942 individuals, indicating a retention of 90%.

Among both completers and non-completers there was an over-representation of individuals aged 18-34 years and women, compared with the general population, and fewer participants aged at least 65 years.

Pre-recruitment, the mean baseline GAD-7 score among completers was 7.4, falling to around 5.5 at the time of the first questionnaire. Scores on the PHQ-9 were 7.6 and 5.6, respectively.

Performing population-weighted autoregressive moving average models to analyze the relationship between the current frequency of the coping behaviors and future changes in anxiety and depressive symptoms, the investigators found that the greatest effect was from following a healthy, balanced diet, with an impact size of 0.95.

This was followed by avoiding too much stressful news (impact size, 0.91), staying outdoors or looking outside (0.40), doing relaxing activities (0.33), participating in physical exercise (0.32), and drinking water to hydrate (0.25).

Overall, these coping behaviors were associated with a significant reduction in anxiety and depressive symptoms (all, P < .001).

On the other hand, there was no impact on future symptoms from socializing with friends and relatives, whether or not they lived in the same household. There was also no effect from following a routine, pursuing hobbies, or performing home tasks.

The researchers note that similar results were obtained when excluding participants with hazardous alcohol consumption, defined as a score on the Alcohol Use Disorders Identification Test of 8 or higher.

However, they point out that despite its prospective design and large cohort, the study was not interventional. Therefore, they “cannot rule out the possibility that decreasing the frequency of a behavior is an early sign of some mechanism that later leads to increased anxiety and depression symptoms.”

Nevertheless, they believe that possibility “seems unlikely.”
 

Reflective of a unique time?

Commenting on the findings, Catherine Harmer, PhD, director of the Psychopharmacology and Emotional Research Lab, department of psychiatry, University of Oxford (England), said in the release this was an “interesting study” that “provides some important insights as to which behaviors may protect our mental health during times of significant stress.”

She said the finding that social contact was not beneficial was “surprising” but may reflect the fact that, during the pandemic, it was “stressful even to have those social contacts, even if we managed to meet a friend outside.”

The results of the study may therefore be “reflective of the unique experience” of the COVID-19 pandemic, said Dr. Harmer, who was not involved with the research.

“I wouldn’t think that reading too much news would generally be something that has a negative impact on depression and anxiety, but I think it was very much at the time,” she said.

With the pandemic overwhelming one country after another, “the more you read about it, the more frightening it was,” she added, noting that it is “easy to forget how frightened we were at the beginning.”

Dr. Harmer noted that “it would be interesting” if the study was repeated and the same factors came out – or if they were unique to that time.

This would be “useful to know, as these times may come again. And the more information we have to cope with a pandemic, the better,” she concluded.

The research was supported by the AXA Research Fund via an AXA Award granted to Dr. Radua from the call for projects “mitigating risk in the wake of the COVID-19 pandemic.” The investigators and Dr. Harmer report no relevant financial relationships.

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

VIENNA – Prescription drugs designed to boost cognition in neurodevelopmental disorders do not increase overall cognitive performance in healthy individuals – and may even reduce productivity, new research suggests.

In a randomized controlled trial, 40 healthy adults were given the attention-deficit/hyperactivity disorder (ADHD) treatments methylphenidate or dexamphetamine or the wakefulness-promoting drug modafinil vs. placebo.

While receiving the so-called “smart drugs,” participants spent more time and made more moves more quickly while solving each problem on a complex cognitive task than when given the placebo. But with no significant improvement in overall performance, all drugs were associated with a significant reduction in efficiency.

The findings “reinforce the idea that, while the drugs administered were motivational, the resulting increase in effort came at a cost in the loss of productivity,” said study presenter David Coghill, MD, PhD, chair of developmental mental health, the University of Melbourne.

This was especially true for individuals who scored high when receiving placebo, “who ended up producing below average productivity when on the drugs,” he noted.

“Overall, these drugs don’t increase the performance. Instead, they cause a regression to the mean, and appear to have a more negative effect on those who performed best at baseline,” Dr. Coghill added.

He presented the findings at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

Past evidence ambiguous

Dr. Coghill noted that prescription-only stimulant drugs are increasingly used by employees and students as “smart drugs” to enhance workplace or academic productivity.

He conducted the study with colleagues from the department of economics at his institution, because of “their interest in people using cognitive enhancers within the financial industry, in the hope that that would increase their productivity in what is a very competitive industry on the floor of the trading rooms.”

However, while “there’s a subjective belief” that these drugs are effective as cognitive enhancers, the evidence to actually demonstrate that in healthy individuals “is, at best, ambiguous,” he told meeting attendees.

Improvements in cognitive capacities, such as working memory and improved planning, are most evident in clinical populations such as those with ADHD, which could be due to a “ceiling effect” of the cognitive tasks in healthy individuals, Dr. Coghill noted.

To investigate further, the researchers conducted a randomized, double-blinded trial of standard adult doses of methylphenidate (30 mg), dexamphetamine (15 mg), and modafinil (200 mg) vs. placebo. The healthy participants (n = 40), all of whom were aged 18-35 years, crossed to each of the other treatment groups over the course of four intervention sessions.

All were asked to solve eight instances of the knapsack task, the aim of which is to place theoretical objects in a knapsack to achieve the maximum value within a certain weight limit.

“This looks very simple but as the number of items increases, it becomes incredibly complex to compute, and actually is not computable using standard approaches. You have to deal with trial and error,” Dr. Coghill said.

The participants also completed several CANTAB cognitive tasks.

‘Surprising’ findings

Results showed that, overall, the drugs did not have a significant effect on task performance (slope = –0.16; P = .011).

Moreover, the drugs, both individually and collectively, had a significant negative effect on the value attained during any one attempt at the knapsack task (slope = –0.003; P = .02), an effect that extended “across the whole range” of task complexity, Dr. Coghill reported.

He went on to show that “participants actually looked as if they were working harder” when they took the three active drugs than when they were given a placebo. They also “spent more time solving each problem,” he added.

When taking the active drugs, participants made more moves during each task than when taking placebo, and made their moves more quickly.

“So these medications increased motivation,” Dr. Coghill said. “If you were sitting [and] watching this person, you would think that they were working harder.”

Yet their productivity, defined as the average gain in value per move on the knapsack task, was lower. Regression analysis identified a “significant and sizable drop in productivity” vs. placebo, Dr. Coghill noted.

This was the case for methylphenidate (P < .001), dexamphetamine (P < .001), and modafinil (P < .05), “whether you looked at the mean or median performance,” he said.

“Breaking it down a little bit more, when you looked at the individual participant level, you find substantial heterogeneity across participants,” noted Dr. Coghill.

“More than that, we found a significant negative correlation between productivity under methylphenidate compared to productivity under placebo, and this suggests a regression to the mean,” with participants who performed better under placebo performing worse with methylphenidate, he explained.

While the relationship was “exactly the same with modafinil,” it was not found with dexamphetamine, with a strong negative correlation between the productivity effects between dexamphetamine and methylphenidate (slope = –0.29; P < .0001).

“This is surprising because we assume that methylphenidate and dexamphetamine are working in very similar ways,” Dr. Coghill said.
 

Time to rethink, rewind?

Commenting for this article, session chair John F. Cryan, PhD, department of anatomy and neuroscience, University College Cork, Ireland, said that, based on the current data, “we might need to rethink [how] ‘smart’ psychopharmacological agents are.”

Dr. Cryan, chair of the ECNP Scientific Program Committee, added that there may be a need to revisit the difficulty of different types of cognitive tasks used in studies assessing the abilities of cognitive enhancing drugs and to “rewind conventional wisdom” around them.

Also commenting, Andrew Westbrook, PhD, of the department of cognitive linguistics and psychological sciences, Brown University, Providence, R.I., said the results seem “reasonable” and are “consistent with my own perspective.”

However, he told this news organization, “some caveats are warranted,” not least that the context of the task can have an impact on the results it obtains.

“We have hypothesized that pharmacologically-enhanced striatal dopamine signaling can boost a kind of cognitive impulsivity, leading to errors and diminished performance, especially for people who already have high striatal dopamine functioning.”

He added that this impulsivity can also lead to errors “in situations where there are highly likely actions, thoughts, or behaviors” in a task, “which they would have to override to be successful” in performing it.

Dr. Westbrook gave the example of the “Stroop task where you are presented with words presented in some color ink and your job is to name the color of the ink but not read the word.”

If the word “green,” for example, was presented in green ink, “you may have no trouble naming the ink color,” but if it was presented in red ink “then you may impulsively read the word, because that is what we normally do with words. 

“Overriding this kind of habitual action can be particularly slippery business when striatal dopamine signaling is pharmacologically enhanced,” Dr. Westbrook said.

No funding for the study was reported. Dr. Coghill reported relationships with Medice, Novartis, Servier, Takeda/Shire Cambridge University Press, and Oxford University Press.

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

VIENNA – Prescription drugs designed to boost cognition in neurodevelopmental disorders do not increase overall cognitive performance in healthy individuals – and may even reduce productivity, new research suggests.

In a randomized controlled trial, 40 healthy adults were given the attention-deficit/hyperactivity disorder (ADHD) treatments methylphenidate or dexamphetamine or the wakefulness-promoting drug modafinil vs. placebo.

While receiving the so-called “smart drugs,” participants spent more time and made more moves more quickly while solving each problem on a complex cognitive task than when given the placebo. But with no significant improvement in overall performance, all drugs were associated with a significant reduction in efficiency.

The findings “reinforce the idea that, while the drugs administered were motivational, the resulting increase in effort came at a cost in the loss of productivity,” said study presenter David Coghill, MD, PhD, chair of developmental mental health, the University of Melbourne.

This was especially true for individuals who scored high when receiving placebo, “who ended up producing below average productivity when on the drugs,” he noted.

“Overall, these drugs don’t increase the performance. Instead, they cause a regression to the mean, and appear to have a more negative effect on those who performed best at baseline,” Dr. Coghill added.

He presented the findings at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

Past evidence ambiguous

Dr. Coghill noted that prescription-only stimulant drugs are increasingly used by employees and students as “smart drugs” to enhance workplace or academic productivity.

He conducted the study with colleagues from the department of economics at his institution, because of “their interest in people using cognitive enhancers within the financial industry, in the hope that that would increase their productivity in what is a very competitive industry on the floor of the trading rooms.”

However, while “there’s a subjective belief” that these drugs are effective as cognitive enhancers, the evidence to actually demonstrate that in healthy individuals “is, at best, ambiguous,” he told meeting attendees.

Improvements in cognitive capacities, such as working memory and improved planning, are most evident in clinical populations such as those with ADHD, which could be due to a “ceiling effect” of the cognitive tasks in healthy individuals, Dr. Coghill noted.

To investigate further, the researchers conducted a randomized, double-blinded trial of standard adult doses of methylphenidate (30 mg), dexamphetamine (15 mg), and modafinil (200 mg) vs. placebo. The healthy participants (n = 40), all of whom were aged 18-35 years, crossed to each of the other treatment groups over the course of four intervention sessions.

All were asked to solve eight instances of the knapsack task, the aim of which is to place theoretical objects in a knapsack to achieve the maximum value within a certain weight limit.

“This looks very simple but as the number of items increases, it becomes incredibly complex to compute, and actually is not computable using standard approaches. You have to deal with trial and error,” Dr. Coghill said.

The participants also completed several CANTAB cognitive tasks.

‘Surprising’ findings

Results showed that, overall, the drugs did not have a significant effect on task performance (slope = –0.16; P = .011).

Moreover, the drugs, both individually and collectively, had a significant negative effect on the value attained during any one attempt at the knapsack task (slope = –0.003; P = .02), an effect that extended “across the whole range” of task complexity, Dr. Coghill reported.

He went on to show that “participants actually looked as if they were working harder” when they took the three active drugs than when they were given a placebo. They also “spent more time solving each problem,” he added.

When taking the active drugs, participants made more moves during each task than when taking placebo, and made their moves more quickly.

“So these medications increased motivation,” Dr. Coghill said. “If you were sitting [and] watching this person, you would think that they were working harder.”

Yet their productivity, defined as the average gain in value per move on the knapsack task, was lower. Regression analysis identified a “significant and sizable drop in productivity” vs. placebo, Dr. Coghill noted.

This was the case for methylphenidate (P < .001), dexamphetamine (P < .001), and modafinil (P < .05), “whether you looked at the mean or median performance,” he said.

“Breaking it down a little bit more, when you looked at the individual participant level, you find substantial heterogeneity across participants,” noted Dr. Coghill.

“More than that, we found a significant negative correlation between productivity under methylphenidate compared to productivity under placebo, and this suggests a regression to the mean,” with participants who performed better under placebo performing worse with methylphenidate, he explained.

While the relationship was “exactly the same with modafinil,” it was not found with dexamphetamine, with a strong negative correlation between the productivity effects between dexamphetamine and methylphenidate (slope = –0.29; P < .0001).

“This is surprising because we assume that methylphenidate and dexamphetamine are working in very similar ways,” Dr. Coghill said.
 

Time to rethink, rewind?

Commenting for this article, session chair John F. Cryan, PhD, department of anatomy and neuroscience, University College Cork, Ireland, said that, based on the current data, “we might need to rethink [how] ‘smart’ psychopharmacological agents are.”

Dr. Cryan, chair of the ECNP Scientific Program Committee, added that there may be a need to revisit the difficulty of different types of cognitive tasks used in studies assessing the abilities of cognitive enhancing drugs and to “rewind conventional wisdom” around them.

Also commenting, Andrew Westbrook, PhD, of the department of cognitive linguistics and psychological sciences, Brown University, Providence, R.I., said the results seem “reasonable” and are “consistent with my own perspective.”

However, he told this news organization, “some caveats are warranted,” not least that the context of the task can have an impact on the results it obtains.

“We have hypothesized that pharmacologically-enhanced striatal dopamine signaling can boost a kind of cognitive impulsivity, leading to errors and diminished performance, especially for people who already have high striatal dopamine functioning.”

He added that this impulsivity can also lead to errors “in situations where there are highly likely actions, thoughts, or behaviors” in a task, “which they would have to override to be successful” in performing it.

Dr. Westbrook gave the example of the “Stroop task where you are presented with words presented in some color ink and your job is to name the color of the ink but not read the word.”

If the word “green,” for example, was presented in green ink, “you may have no trouble naming the ink color,” but if it was presented in red ink “then you may impulsively read the word, because that is what we normally do with words. 

“Overriding this kind of habitual action can be particularly slippery business when striatal dopamine signaling is pharmacologically enhanced,” Dr. Westbrook said.

No funding for the study was reported. Dr. Coghill reported relationships with Medice, Novartis, Servier, Takeda/Shire Cambridge University Press, and Oxford University Press.

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

VIENNA – Prescription drugs designed to boost cognition in neurodevelopmental disorders do not increase overall cognitive performance in healthy individuals – and may even reduce productivity, new research suggests.

In a randomized controlled trial, 40 healthy adults were given the attention-deficit/hyperactivity disorder (ADHD) treatments methylphenidate or dexamphetamine or the wakefulness-promoting drug modafinil vs. placebo.

While receiving the so-called “smart drugs,” participants spent more time and made more moves more quickly while solving each problem on a complex cognitive task than when given the placebo. But with no significant improvement in overall performance, all drugs were associated with a significant reduction in efficiency.

The findings “reinforce the idea that, while the drugs administered were motivational, the resulting increase in effort came at a cost in the loss of productivity,” said study presenter David Coghill, MD, PhD, chair of developmental mental health, the University of Melbourne.

This was especially true for individuals who scored high when receiving placebo, “who ended up producing below average productivity when on the drugs,” he noted.

“Overall, these drugs don’t increase the performance. Instead, they cause a regression to the mean, and appear to have a more negative effect on those who performed best at baseline,” Dr. Coghill added.

He presented the findings at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

Past evidence ambiguous

Dr. Coghill noted that prescription-only stimulant drugs are increasingly used by employees and students as “smart drugs” to enhance workplace or academic productivity.

He conducted the study with colleagues from the department of economics at his institution, because of “their interest in people using cognitive enhancers within the financial industry, in the hope that that would increase their productivity in what is a very competitive industry on the floor of the trading rooms.”

However, while “there’s a subjective belief” that these drugs are effective as cognitive enhancers, the evidence to actually demonstrate that in healthy individuals “is, at best, ambiguous,” he told meeting attendees.

Improvements in cognitive capacities, such as working memory and improved planning, are most evident in clinical populations such as those with ADHD, which could be due to a “ceiling effect” of the cognitive tasks in healthy individuals, Dr. Coghill noted.

To investigate further, the researchers conducted a randomized, double-blinded trial of standard adult doses of methylphenidate (30 mg), dexamphetamine (15 mg), and modafinil (200 mg) vs. placebo. The healthy participants (n = 40), all of whom were aged 18-35 years, crossed to each of the other treatment groups over the course of four intervention sessions.

All were asked to solve eight instances of the knapsack task, the aim of which is to place theoretical objects in a knapsack to achieve the maximum value within a certain weight limit.

“This looks very simple but as the number of items increases, it becomes incredibly complex to compute, and actually is not computable using standard approaches. You have to deal with trial and error,” Dr. Coghill said.

The participants also completed several CANTAB cognitive tasks.

‘Surprising’ findings

Results showed that, overall, the drugs did not have a significant effect on task performance (slope = –0.16; P = .011).

Moreover, the drugs, both individually and collectively, had a significant negative effect on the value attained during any one attempt at the knapsack task (slope = –0.003; P = .02), an effect that extended “across the whole range” of task complexity, Dr. Coghill reported.

He went on to show that “participants actually looked as if they were working harder” when they took the three active drugs than when they were given a placebo. They also “spent more time solving each problem,” he added.

When taking the active drugs, participants made more moves during each task than when taking placebo, and made their moves more quickly.

“So these medications increased motivation,” Dr. Coghill said. “If you were sitting [and] watching this person, you would think that they were working harder.”

Yet their productivity, defined as the average gain in value per move on the knapsack task, was lower. Regression analysis identified a “significant and sizable drop in productivity” vs. placebo, Dr. Coghill noted.

This was the case for methylphenidate (P < .001), dexamphetamine (P < .001), and modafinil (P < .05), “whether you looked at the mean or median performance,” he said.

“Breaking it down a little bit more, when you looked at the individual participant level, you find substantial heterogeneity across participants,” noted Dr. Coghill.

“More than that, we found a significant negative correlation between productivity under methylphenidate compared to productivity under placebo, and this suggests a regression to the mean,” with participants who performed better under placebo performing worse with methylphenidate, he explained.

While the relationship was “exactly the same with modafinil,” it was not found with dexamphetamine, with a strong negative correlation between the productivity effects between dexamphetamine and methylphenidate (slope = –0.29; P < .0001).

“This is surprising because we assume that methylphenidate and dexamphetamine are working in very similar ways,” Dr. Coghill said.
 

Time to rethink, rewind?

Commenting for this article, session chair John F. Cryan, PhD, department of anatomy and neuroscience, University College Cork, Ireland, said that, based on the current data, “we might need to rethink [how] ‘smart’ psychopharmacological agents are.”

Dr. Cryan, chair of the ECNP Scientific Program Committee, added that there may be a need to revisit the difficulty of different types of cognitive tasks used in studies assessing the abilities of cognitive enhancing drugs and to “rewind conventional wisdom” around them.

Also commenting, Andrew Westbrook, PhD, of the department of cognitive linguistics and psychological sciences, Brown University, Providence, R.I., said the results seem “reasonable” and are “consistent with my own perspective.”

However, he told this news organization, “some caveats are warranted,” not least that the context of the task can have an impact on the results it obtains.

“We have hypothesized that pharmacologically-enhanced striatal dopamine signaling can boost a kind of cognitive impulsivity, leading to errors and diminished performance, especially for people who already have high striatal dopamine functioning.”

He added that this impulsivity can also lead to errors “in situations where there are highly likely actions, thoughts, or behaviors” in a task, “which they would have to override to be successful” in performing it.

Dr. Westbrook gave the example of the “Stroop task where you are presented with words presented in some color ink and your job is to name the color of the ink but not read the word.”

If the word “green,” for example, was presented in green ink, “you may have no trouble naming the ink color,” but if it was presented in red ink “then you may impulsively read the word, because that is what we normally do with words. 

“Overriding this kind of habitual action can be particularly slippery business when striatal dopamine signaling is pharmacologically enhanced,” Dr. Westbrook said.

No funding for the study was reported. Dr. Coghill reported relationships with Medice, Novartis, Servier, Takeda/Shire Cambridge University Press, and Oxford University Press.

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

VIENNA – The investigational agent xanomeline-trospium (KarXT, Karuna Therapeutics) achieves significant and clinically meaningful improvements in schizophrenia symptom scores without causing problematic adverse effects, new research suggests.

Results from the phase 3 EMERGENT-2 trial, which included more than 250 patients with schizophrenia, showed that those who received xanomeline-trospium for 5 weeks achieved a significant reduction in Positive and Negative Syndrome Scale (PANSS) total scores of more than nine points compared with their peers who received placebo. In addition, the improvements started at week 2.

Alongside significant reductions in both positive and negative symptoms, the results suggest the agent was well tolerated, with treatment-emergent adverse events (TEAEs) largely mild to moderate and transient in nature.

Lead investigator Christoph U. Correll, MD, professor of psychiatry at the Zucker School of Medicine at Hofstra/Northwell, Uniondale, New York, told this news organization that the upcoming EMERGENT-3 study will have a “European component” and that the “readout is expected most likely in the first quarter of next year.”

Dr. Correll suggested that if leads to “two positive studies and reasonable safety,” the novel agent may become part of the “next generation of antipsychotics that are not related to postsynaptic dopamine blockade.”

The findings for EMERGENT-2, presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress as a poster and as an oral presentation, were an update of topline results released earlier this year.
 

Novel compound

Xanomeline-trospium is a novel compound that combines the dual M1/M4-preferring muscarinic receptor agonist effect of xanomeline with the peripherally restricted muscarinic receptor antagonist effect of trospium.

A previous phase 2 trial that compared the drug with placebo in almost 200 patients suggested it significantly reduced psychosis symptoms, leading to the current phase 3 trial.

Dr. Correll noted that xanomeline-trospium reduces psychosis via a “bottom up and top down approach.”

He said that on one hand, M4 agonism decreases acetylcholine in the ventral tegmental area and the associated stratum, “which then decreases dopamine levels from the bottom up,” while the M1 agonism stimulates GABA and decreases dopamine from the “top down.”

M1 agonism, however, also stimulates the cholinergic system peripherally, “which can give you nausea, vomiting, and also some blood pressure and pulse” problems, Dr. Correll said.

That was the limitation when this approach was studied by Lilly as a treatment for patients with Alzheimer’s disease, but the addition of trospium means “you’re buffering somewhat the cholinergic peripheral effects,” he said.

While that can conversely lead to dyspepsia, dry mouth, and constipation, Dr. Correll noted that the adverse effects of the novel agent are “mitigated by titration,” with patients taking up to 8 days to reach the full dose.

The result is that the drug was “overall tolerated, and the effect sizes were quite astounding,” he reported.
 

Intermittent, time limited TEAEs

The current trial included 252 patients aged 18-65 years (mean age, 45 years) who were confirmed to have schizophrenia and who had recently experienced a worsening of psychotic symptoms that warranted hospitalization. Three-quarters of the participants were men, and a similar proportion were Black. Approximately one quarter were White.

All were randomly assigned in a 1:1 ratio to receive either xanomeline-trospium or placebo following a 2-week screening period.

Xanomeline and trospium were titrated from 50 mg/20 mg twice daily to 125 mg/30 mg twice daily, and patients were treated for a total of 5 weeks. Efficacy and safety analyses were conducted in those who had received at least one dose of the study drug.

At the end of the treatment period, xanomeline-trospium was associated with a significant 9.6-point reduction in PANSS total scores relative to placebo; scores fell by 21.2 points with the active treatment, vs. 11.6 points with placebo (P < .0001).

The significant improvement in PANSS total score began at week 2 (P < .05) and continued to accrue over the course of the study.

Xanomeline-trospium was also associated with significant reductions in PANSS positive subscale scores in comparison with placebo (P < .0001), as well as with reductions in PANSS negative subscale scores (P < .01) and PANSS Marder negative subscale scores (P < .01).

Although 75.4% of patients who received xanomeline-trospium experienced a TEAE, in comparison with 58.4% of the placebo group, very few experienced a serious TEAE (just 1.6% in both groups).

TEAEs leading to discontinuation occurred in 7.1% of the active-treatment group, vs. 5.6% of the placebo group. The overall discontinuation rates from the trial were 25% and 21%, respectively.

The most common TEAEs with xanomeline-trospium were constipation (21.4%), dyspepsia (19.0%), nausea (19.0%), vomiting (14.3%), and headache (13.5%).

The results showed that cholinergic TEAEs typically began within the first 2 weeks of treatment and were “intermittent and time limited in nature,” the investigators noted. Moreover, average blood pressure levels were “similar” between the xanomeline-trospium and placebo groups “at each time point throughout the trial,” they added.

Dr. Correll reported that whereas the EMERGENT studies are testing xanomeline-trospium as a monotherapy, the ARISE program will be examining it as an “augmentation” treatment. “And that’s relevant because, let’s face it, patients do not switch” treatments, he said.

He suggested that if xanomeline-trospium is able to have a synergistic effect with other drugs, “we might be able to treat people who are currently not benefiting enough from postsynaptic dopamine blockade to maybe get a little bit closer” to the benefits seen with clozapine, which “also has problematic side effects.”
 

‘Really revolutionary’

Following the oral presentation of the study by coauthor Stephen K. Brannan, MD, chief medical officer, Karuna Therapeutics, Boston, the results were warmly received.

Session cochair Mark Weiser, MD, chairman at the department of psychiatry, Sackler School of Medicine, Tel Aviv University, Israel, said the agent is “really revolutionary in the field.

“It’s a non-dopamine compound which helps for schizophrenia, so we’re all very optimistic about it,” Dr. Weiser added.

Nevertheless, he asked Dr. Brannan whether the occurrence of gastrointestinal adverse effects with xanomeline-trospium led to “functional unblinding of the study.”

Dr. Brannan answered that the investigators were “really worried about this prior to EMERGENT-1” but that formal testing suggested it was not a problem.

Dr. Brannan said that although this has not yet been formally tested for the current trial, he believes that it is “highly unlikely” that functional unblinding occurred, inasmuch as the “percentages are about in the same range as we saw in EMERGENT-1.”

Speaking to ECNP Congress Daily in a conference roundup video, session cochair Andreas Reif, MD, PhD, professor of psychiatry, psychosomatic medicine, and psychotherapy at the University Hospital of Frankfurt (Germany), also highlighted the study.

He said that along with a study of dexmedetomidine sublingual film for agitation associated with schizophrenia or bipolar disorder that was also presented in the session, the current trial is “pivotal.”

Dr. Reif noted that the effect size shown with xanomeline-trospium was “really amazing.”

“We are in a really exciting time in treating mental disorders,” he said. “Industry is finally investing again, and really has new compounds that will make it to the market.”

Karuna plans to submit a new drug application with the Food and Drug Administration for KarXT in mid-2023. The drug is also in development for the treatment of psychiatric and neurologic conditions other than schizophrenia, including Alzheimer’s disease.

The study was funded by Karuna Therapeutics. Dr. Correll has reported relationships with Karuna, as well as AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Axsome, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Damitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Otsuka, Pfizer, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, Servier, SK Life Science, Sumitomo Dainippon, Sunovion, Sun Pharma, Supernus, Takeda, Teva, Viatris, Otsuka, and UpToDate.

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

VIENNA – The investigational agent xanomeline-trospium (KarXT, Karuna Therapeutics) achieves significant and clinically meaningful improvements in schizophrenia symptom scores without causing problematic adverse effects, new research suggests.

Results from the phase 3 EMERGENT-2 trial, which included more than 250 patients with schizophrenia, showed that those who received xanomeline-trospium for 5 weeks achieved a significant reduction in Positive and Negative Syndrome Scale (PANSS) total scores of more than nine points compared with their peers who received placebo. In addition, the improvements started at week 2.

Alongside significant reductions in both positive and negative symptoms, the results suggest the agent was well tolerated, with treatment-emergent adverse events (TEAEs) largely mild to moderate and transient in nature.

Lead investigator Christoph U. Correll, MD, professor of psychiatry at the Zucker School of Medicine at Hofstra/Northwell, Uniondale, New York, told this news organization that the upcoming EMERGENT-3 study will have a “European component” and that the “readout is expected most likely in the first quarter of next year.”

Dr. Correll suggested that if leads to “two positive studies and reasonable safety,” the novel agent may become part of the “next generation of antipsychotics that are not related to postsynaptic dopamine blockade.”

The findings for EMERGENT-2, presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress as a poster and as an oral presentation, were an update of topline results released earlier this year.
 

Novel compound

Xanomeline-trospium is a novel compound that combines the dual M1/M4-preferring muscarinic receptor agonist effect of xanomeline with the peripherally restricted muscarinic receptor antagonist effect of trospium.

A previous phase 2 trial that compared the drug with placebo in almost 200 patients suggested it significantly reduced psychosis symptoms, leading to the current phase 3 trial.

Dr. Correll noted that xanomeline-trospium reduces psychosis via a “bottom up and top down approach.”

He said that on one hand, M4 agonism decreases acetylcholine in the ventral tegmental area and the associated stratum, “which then decreases dopamine levels from the bottom up,” while the M1 agonism stimulates GABA and decreases dopamine from the “top down.”

M1 agonism, however, also stimulates the cholinergic system peripherally, “which can give you nausea, vomiting, and also some blood pressure and pulse” problems, Dr. Correll said.

That was the limitation when this approach was studied by Lilly as a treatment for patients with Alzheimer’s disease, but the addition of trospium means “you’re buffering somewhat the cholinergic peripheral effects,” he said.

While that can conversely lead to dyspepsia, dry mouth, and constipation, Dr. Correll noted that the adverse effects of the novel agent are “mitigated by titration,” with patients taking up to 8 days to reach the full dose.

The result is that the drug was “overall tolerated, and the effect sizes were quite astounding,” he reported.
 

Intermittent, time limited TEAEs

The current trial included 252 patients aged 18-65 years (mean age, 45 years) who were confirmed to have schizophrenia and who had recently experienced a worsening of psychotic symptoms that warranted hospitalization. Three-quarters of the participants were men, and a similar proportion were Black. Approximately one quarter were White.

All were randomly assigned in a 1:1 ratio to receive either xanomeline-trospium or placebo following a 2-week screening period.

Xanomeline and trospium were titrated from 50 mg/20 mg twice daily to 125 mg/30 mg twice daily, and patients were treated for a total of 5 weeks. Efficacy and safety analyses were conducted in those who had received at least one dose of the study drug.

At the end of the treatment period, xanomeline-trospium was associated with a significant 9.6-point reduction in PANSS total scores relative to placebo; scores fell by 21.2 points with the active treatment, vs. 11.6 points with placebo (P < .0001).

The significant improvement in PANSS total score began at week 2 (P < .05) and continued to accrue over the course of the study.

Xanomeline-trospium was also associated with significant reductions in PANSS positive subscale scores in comparison with placebo (P < .0001), as well as with reductions in PANSS negative subscale scores (P < .01) and PANSS Marder negative subscale scores (P < .01).

Although 75.4% of patients who received xanomeline-trospium experienced a TEAE, in comparison with 58.4% of the placebo group, very few experienced a serious TEAE (just 1.6% in both groups).

TEAEs leading to discontinuation occurred in 7.1% of the active-treatment group, vs. 5.6% of the placebo group. The overall discontinuation rates from the trial were 25% and 21%, respectively.

The most common TEAEs with xanomeline-trospium were constipation (21.4%), dyspepsia (19.0%), nausea (19.0%), vomiting (14.3%), and headache (13.5%).

The results showed that cholinergic TEAEs typically began within the first 2 weeks of treatment and were “intermittent and time limited in nature,” the investigators noted. Moreover, average blood pressure levels were “similar” between the xanomeline-trospium and placebo groups “at each time point throughout the trial,” they added.

Dr. Correll reported that whereas the EMERGENT studies are testing xanomeline-trospium as a monotherapy, the ARISE program will be examining it as an “augmentation” treatment. “And that’s relevant because, let’s face it, patients do not switch” treatments, he said.

He suggested that if xanomeline-trospium is able to have a synergistic effect with other drugs, “we might be able to treat people who are currently not benefiting enough from postsynaptic dopamine blockade to maybe get a little bit closer” to the benefits seen with clozapine, which “also has problematic side effects.”
 

‘Really revolutionary’

Following the oral presentation of the study by coauthor Stephen K. Brannan, MD, chief medical officer, Karuna Therapeutics, Boston, the results were warmly received.

Session cochair Mark Weiser, MD, chairman at the department of psychiatry, Sackler School of Medicine, Tel Aviv University, Israel, said the agent is “really revolutionary in the field.

“It’s a non-dopamine compound which helps for schizophrenia, so we’re all very optimistic about it,” Dr. Weiser added.

Nevertheless, he asked Dr. Brannan whether the occurrence of gastrointestinal adverse effects with xanomeline-trospium led to “functional unblinding of the study.”

Dr. Brannan answered that the investigators were “really worried about this prior to EMERGENT-1” but that formal testing suggested it was not a problem.

Dr. Brannan said that although this has not yet been formally tested for the current trial, he believes that it is “highly unlikely” that functional unblinding occurred, inasmuch as the “percentages are about in the same range as we saw in EMERGENT-1.”

Speaking to ECNP Congress Daily in a conference roundup video, session cochair Andreas Reif, MD, PhD, professor of psychiatry, psychosomatic medicine, and psychotherapy at the University Hospital of Frankfurt (Germany), also highlighted the study.

He said that along with a study of dexmedetomidine sublingual film for agitation associated with schizophrenia or bipolar disorder that was also presented in the session, the current trial is “pivotal.”

Dr. Reif noted that the effect size shown with xanomeline-trospium was “really amazing.”

“We are in a really exciting time in treating mental disorders,” he said. “Industry is finally investing again, and really has new compounds that will make it to the market.”

Karuna plans to submit a new drug application with the Food and Drug Administration for KarXT in mid-2023. The drug is also in development for the treatment of psychiatric and neurologic conditions other than schizophrenia, including Alzheimer’s disease.

The study was funded by Karuna Therapeutics. Dr. Correll has reported relationships with Karuna, as well as AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Axsome, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Damitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Otsuka, Pfizer, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, Servier, SK Life Science, Sumitomo Dainippon, Sunovion, Sun Pharma, Supernus, Takeda, Teva, Viatris, Otsuka, and UpToDate.

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

VIENNA – The investigational agent xanomeline-trospium (KarXT, Karuna Therapeutics) achieves significant and clinically meaningful improvements in schizophrenia symptom scores without causing problematic adverse effects, new research suggests.

Results from the phase 3 EMERGENT-2 trial, which included more than 250 patients with schizophrenia, showed that those who received xanomeline-trospium for 5 weeks achieved a significant reduction in Positive and Negative Syndrome Scale (PANSS) total scores of more than nine points compared with their peers who received placebo. In addition, the improvements started at week 2.

Alongside significant reductions in both positive and negative symptoms, the results suggest the agent was well tolerated, with treatment-emergent adverse events (TEAEs) largely mild to moderate and transient in nature.

Lead investigator Christoph U. Correll, MD, professor of psychiatry at the Zucker School of Medicine at Hofstra/Northwell, Uniondale, New York, told this news organization that the upcoming EMERGENT-3 study will have a “European component” and that the “readout is expected most likely in the first quarter of next year.”

Dr. Correll suggested that if leads to “two positive studies and reasonable safety,” the novel agent may become part of the “next generation of antipsychotics that are not related to postsynaptic dopamine blockade.”

The findings for EMERGENT-2, presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress as a poster and as an oral presentation, were an update of topline results released earlier this year.
 

Novel compound

Xanomeline-trospium is a novel compound that combines the dual M1/M4-preferring muscarinic receptor agonist effect of xanomeline with the peripherally restricted muscarinic receptor antagonist effect of trospium.

A previous phase 2 trial that compared the drug with placebo in almost 200 patients suggested it significantly reduced psychosis symptoms, leading to the current phase 3 trial.

Dr. Correll noted that xanomeline-trospium reduces psychosis via a “bottom up and top down approach.”

He said that on one hand, M4 agonism decreases acetylcholine in the ventral tegmental area and the associated stratum, “which then decreases dopamine levels from the bottom up,” while the M1 agonism stimulates GABA and decreases dopamine from the “top down.”

M1 agonism, however, also stimulates the cholinergic system peripherally, “which can give you nausea, vomiting, and also some blood pressure and pulse” problems, Dr. Correll said.

That was the limitation when this approach was studied by Lilly as a treatment for patients with Alzheimer’s disease, but the addition of trospium means “you’re buffering somewhat the cholinergic peripheral effects,” he said.

While that can conversely lead to dyspepsia, dry mouth, and constipation, Dr. Correll noted that the adverse effects of the novel agent are “mitigated by titration,” with patients taking up to 8 days to reach the full dose.

The result is that the drug was “overall tolerated, and the effect sizes were quite astounding,” he reported.
 

Intermittent, time limited TEAEs

The current trial included 252 patients aged 18-65 years (mean age, 45 years) who were confirmed to have schizophrenia and who had recently experienced a worsening of psychotic symptoms that warranted hospitalization. Three-quarters of the participants were men, and a similar proportion were Black. Approximately one quarter were White.

All were randomly assigned in a 1:1 ratio to receive either xanomeline-trospium or placebo following a 2-week screening period.

Xanomeline and trospium were titrated from 50 mg/20 mg twice daily to 125 mg/30 mg twice daily, and patients were treated for a total of 5 weeks. Efficacy and safety analyses were conducted in those who had received at least one dose of the study drug.

At the end of the treatment period, xanomeline-trospium was associated with a significant 9.6-point reduction in PANSS total scores relative to placebo; scores fell by 21.2 points with the active treatment, vs. 11.6 points with placebo (P < .0001).

The significant improvement in PANSS total score began at week 2 (P < .05) and continued to accrue over the course of the study.

Xanomeline-trospium was also associated with significant reductions in PANSS positive subscale scores in comparison with placebo (P < .0001), as well as with reductions in PANSS negative subscale scores (P < .01) and PANSS Marder negative subscale scores (P < .01).

Although 75.4% of patients who received xanomeline-trospium experienced a TEAE, in comparison with 58.4% of the placebo group, very few experienced a serious TEAE (just 1.6% in both groups).

TEAEs leading to discontinuation occurred in 7.1% of the active-treatment group, vs. 5.6% of the placebo group. The overall discontinuation rates from the trial were 25% and 21%, respectively.

The most common TEAEs with xanomeline-trospium were constipation (21.4%), dyspepsia (19.0%), nausea (19.0%), vomiting (14.3%), and headache (13.5%).

The results showed that cholinergic TEAEs typically began within the first 2 weeks of treatment and were “intermittent and time limited in nature,” the investigators noted. Moreover, average blood pressure levels were “similar” between the xanomeline-trospium and placebo groups “at each time point throughout the trial,” they added.

Dr. Correll reported that whereas the EMERGENT studies are testing xanomeline-trospium as a monotherapy, the ARISE program will be examining it as an “augmentation” treatment. “And that’s relevant because, let’s face it, patients do not switch” treatments, he said.

He suggested that if xanomeline-trospium is able to have a synergistic effect with other drugs, “we might be able to treat people who are currently not benefiting enough from postsynaptic dopamine blockade to maybe get a little bit closer” to the benefits seen with clozapine, which “also has problematic side effects.”
 

‘Really revolutionary’

Following the oral presentation of the study by coauthor Stephen K. Brannan, MD, chief medical officer, Karuna Therapeutics, Boston, the results were warmly received.

Session cochair Mark Weiser, MD, chairman at the department of psychiatry, Sackler School of Medicine, Tel Aviv University, Israel, said the agent is “really revolutionary in the field.

“It’s a non-dopamine compound which helps for schizophrenia, so we’re all very optimistic about it,” Dr. Weiser added.

Nevertheless, he asked Dr. Brannan whether the occurrence of gastrointestinal adverse effects with xanomeline-trospium led to “functional unblinding of the study.”

Dr. Brannan answered that the investigators were “really worried about this prior to EMERGENT-1” but that formal testing suggested it was not a problem.

Dr. Brannan said that although this has not yet been formally tested for the current trial, he believes that it is “highly unlikely” that functional unblinding occurred, inasmuch as the “percentages are about in the same range as we saw in EMERGENT-1.”

Speaking to ECNP Congress Daily in a conference roundup video, session cochair Andreas Reif, MD, PhD, professor of psychiatry, psychosomatic medicine, and psychotherapy at the University Hospital of Frankfurt (Germany), also highlighted the study.

He said that along with a study of dexmedetomidine sublingual film for agitation associated with schizophrenia or bipolar disorder that was also presented in the session, the current trial is “pivotal.”

Dr. Reif noted that the effect size shown with xanomeline-trospium was “really amazing.”

“We are in a really exciting time in treating mental disorders,” he said. “Industry is finally investing again, and really has new compounds that will make it to the market.”

Karuna plans to submit a new drug application with the Food and Drug Administration for KarXT in mid-2023. The drug is also in development for the treatment of psychiatric and neurologic conditions other than schizophrenia, including Alzheimer’s disease.

The study was funded by Karuna Therapeutics. Dr. Correll has reported relationships with Karuna, as well as AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Axsome, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Damitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Otsuka, Pfizer, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, Servier, SK Life Science, Sumitomo Dainippon, Sunovion, Sun Pharma, Supernus, Takeda, Teva, Viatris, Otsuka, and UpToDate.

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

VIENNA – Individuals born to younger or older parents are at increased risk of developing bipolar disorder, new research suggests.

Results from a meta-analysis of more than 210,000 patients with bipolar disorder and over 13 million healthy individuals showed that children of mothers younger than 20 years had a 23% increased risk for bipolar disorder vs. those whose parents were aged 25-29 years. For participants whose mothers were aged 35-39 years, there was a 10% increased risk for bipolar disorder, which rose to 20% if the mother was aged 40 or older.

Having a father younger than 20 years conferred a 29% increased risk for bipolar disorder, which was the same increase in risk found in individuals whose fathers were aged 45 years or older.

These findings, which are an update of data published in the journal European Pharmacology, were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

Fourteen studies included

Previous studies have suggested that parental age at birth is a risk factor for several psychiatric disorders in offspring, including bipolar disorder, and that advanced parental age, specifically, is associated with earlier onset schizophrenia.

To investigate further, the current researchers conducted a systematic review and meta-analysis, searching the PubMed/MEDLINE, EMBASE, Scopus, and PsychINFO databases for relevant studies published to Dec. 1, 2021.

From 712 studies initially identified, 16 met all the inclusion criteria and 14 were included in the quantitative analysis.

Five studies reported only paternal age and risk for bipolar disorder in their offspring, one included just maternal age, and eight reported both maternal and paternal age in relation to the risk for offspring bipolar disorder.

Individuals with a history of any psychiatric disorders were excluded, leaving a total of 13.4 million individuals without bipolar disorder and 217,089 who had received a diagnosis for the disorder.

The investigators also corrected for both socioeconomic status and, when assessing the impact of maternal or paternal age at birth, corrected for the age of the other parent. However, they were unable to correct for the number of children in a family.

Results after stratifying maternal and paternal age showed that, compared with those born to parents aged 25-29 years, there was an increased risk for bipolar disorder in the offspring of both fathers and mothers younger than 20 years of age, with adjusted odds ratios of 1.29 (95% confidence interval, 1.13-1.48) and 1.23 (95% CI, 1.14-1.33), respectively.

Compared with those aged 25-29 years, there was also an increased risk for bipolar disorder in children born to mothers aged 35-39 years (adjusted OR, 1.1; 95% CI, 1.01-1.19) and aged 40 or older (OR, 1.2; 95% CI, 1.02-1.40).

Among fathers, there was increased risk for offspring bipolar disorder in those aged 45 or older vs. those aged 25-29 years (adjusted OR, 1.29; 95% CI, 1.15-1.46).
 

Several hypotheses

There are several hypotheses that could explain the results, lead study author Giovanna Fico, MD, bipolar and depressive disorders unit, Hospital Clínic Barcelona, told this news organization.

In older age, it may be “more related to genetic or epigenetic modification, especially in fathers,” Dr. Fico said. “Some studies have shown that there are de novo mutations in the germ lines, which increase the risk of several diseases, including schizophrenia.”

In younger individuals, there could be a “mixed effect between sociocultural factors, such as substance abuse, low educational status,” and other issues, Dr. Fico noted.

Moreover, as bipolar disorder onset can be as late as 30 years of age, the younger group could include “undiagnosed patients with bipolar disorder, which would increase the risk” of the disease in their offspring, she added.

Dr. Fico noted the investigators are now planning on studying the impact of environmental factors such as pollution, climate change, and urbanization on risk for bipolar disorder, with the aim of being better able to inform parents or to develop prevention strategies.

Psychoeducation is “very common for infertility, birth defects, and Down syndrome, but it’s not so common for psychiatric disorders because we need more data. But I think it’s important that parents know they have an increased risk,” she said.

Nevertheless, “We must stress that this risk is moderate, and it must be kept in perspective,” Dr. Fico said in a news release.
 

‘Exciting’ questions raised

The study “raises several exciting research questions, including the possibility of early prevention and intervention,” Maj Vinberg, MD, PhD, clinical professor, department of clinical medicine, University of Copenhagen, said in the release.

She said she agrees there are likely to be different factors at play at different ages, with the risk for bipolar disorder associated with younger-age parenthood more likely to be related to socioeconomic status.

For older parents, “there has been a lot of speculation around the father’s age especially, which everybody thought didn’t matter,” said Dr. Vinberg, who was not involved with the research.

“But you might have some epigenetic changes as you grow older that might transfer into the next generation,” given that there is 20 years of additional exposure to potential epigenetic changes between a man aged 25 years and one aged 45 years, she noted.

Dr. Vinberg also highlighted that there could be cases of undiagnosed bipolar disorder among the younger parents, and she noted that “men with bipolar disorder tend to have more children,” particularly during manic phases.

She explained that if someone were to get divorced at 35 years of age, then have a new manic episode at 45 “and have a new wife and children, I don’t know whether it’s possible to correct for that.”

The research is supported by a fellowship from “la Caixa” Foundation. The investigators have reported no relevant financial relationships. Dr. Vinberg reported having relationships with Lundbeck and Janssen.

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

VIENNA – Individuals born to younger or older parents are at increased risk of developing bipolar disorder, new research suggests.

Results from a meta-analysis of more than 210,000 patients with bipolar disorder and over 13 million healthy individuals showed that children of mothers younger than 20 years had a 23% increased risk for bipolar disorder vs. those whose parents were aged 25-29 years. For participants whose mothers were aged 35-39 years, there was a 10% increased risk for bipolar disorder, which rose to 20% if the mother was aged 40 or older.

Having a father younger than 20 years conferred a 29% increased risk for bipolar disorder, which was the same increase in risk found in individuals whose fathers were aged 45 years or older.

These findings, which are an update of data published in the journal European Pharmacology, were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

Fourteen studies included

Previous studies have suggested that parental age at birth is a risk factor for several psychiatric disorders in offspring, including bipolar disorder, and that advanced parental age, specifically, is associated with earlier onset schizophrenia.

To investigate further, the current researchers conducted a systematic review and meta-analysis, searching the PubMed/MEDLINE, EMBASE, Scopus, and PsychINFO databases for relevant studies published to Dec. 1, 2021.

From 712 studies initially identified, 16 met all the inclusion criteria and 14 were included in the quantitative analysis.

Five studies reported only paternal age and risk for bipolar disorder in their offspring, one included just maternal age, and eight reported both maternal and paternal age in relation to the risk for offspring bipolar disorder.

Individuals with a history of any psychiatric disorders were excluded, leaving a total of 13.4 million individuals without bipolar disorder and 217,089 who had received a diagnosis for the disorder.

The investigators also corrected for both socioeconomic status and, when assessing the impact of maternal or paternal age at birth, corrected for the age of the other parent. However, they were unable to correct for the number of children in a family.

Results after stratifying maternal and paternal age showed that, compared with those born to parents aged 25-29 years, there was an increased risk for bipolar disorder in the offspring of both fathers and mothers younger than 20 years of age, with adjusted odds ratios of 1.29 (95% confidence interval, 1.13-1.48) and 1.23 (95% CI, 1.14-1.33), respectively.

Compared with those aged 25-29 years, there was also an increased risk for bipolar disorder in children born to mothers aged 35-39 years (adjusted OR, 1.1; 95% CI, 1.01-1.19) and aged 40 or older (OR, 1.2; 95% CI, 1.02-1.40).

Among fathers, there was increased risk for offspring bipolar disorder in those aged 45 or older vs. those aged 25-29 years (adjusted OR, 1.29; 95% CI, 1.15-1.46).
 

Several hypotheses

There are several hypotheses that could explain the results, lead study author Giovanna Fico, MD, bipolar and depressive disorders unit, Hospital Clínic Barcelona, told this news organization.

In older age, it may be “more related to genetic or epigenetic modification, especially in fathers,” Dr. Fico said. “Some studies have shown that there are de novo mutations in the germ lines, which increase the risk of several diseases, including schizophrenia.”

In younger individuals, there could be a “mixed effect between sociocultural factors, such as substance abuse, low educational status,” and other issues, Dr. Fico noted.

Moreover, as bipolar disorder onset can be as late as 30 years of age, the younger group could include “undiagnosed patients with bipolar disorder, which would increase the risk” of the disease in their offspring, she added.

Dr. Fico noted the investigators are now planning on studying the impact of environmental factors such as pollution, climate change, and urbanization on risk for bipolar disorder, with the aim of being better able to inform parents or to develop prevention strategies.

Psychoeducation is “very common for infertility, birth defects, and Down syndrome, but it’s not so common for psychiatric disorders because we need more data. But I think it’s important that parents know they have an increased risk,” she said.

Nevertheless, “We must stress that this risk is moderate, and it must be kept in perspective,” Dr. Fico said in a news release.
 

‘Exciting’ questions raised

The study “raises several exciting research questions, including the possibility of early prevention and intervention,” Maj Vinberg, MD, PhD, clinical professor, department of clinical medicine, University of Copenhagen, said in the release.

She said she agrees there are likely to be different factors at play at different ages, with the risk for bipolar disorder associated with younger-age parenthood more likely to be related to socioeconomic status.

For older parents, “there has been a lot of speculation around the father’s age especially, which everybody thought didn’t matter,” said Dr. Vinberg, who was not involved with the research.

“But you might have some epigenetic changes as you grow older that might transfer into the next generation,” given that there is 20 years of additional exposure to potential epigenetic changes between a man aged 25 years and one aged 45 years, she noted.

Dr. Vinberg also highlighted that there could be cases of undiagnosed bipolar disorder among the younger parents, and she noted that “men with bipolar disorder tend to have more children,” particularly during manic phases.

She explained that if someone were to get divorced at 35 years of age, then have a new manic episode at 45 “and have a new wife and children, I don’t know whether it’s possible to correct for that.”

The research is supported by a fellowship from “la Caixa” Foundation. The investigators have reported no relevant financial relationships. Dr. Vinberg reported having relationships with Lundbeck and Janssen.

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

VIENNA – Individuals born to younger or older parents are at increased risk of developing bipolar disorder, new research suggests.

Results from a meta-analysis of more than 210,000 patients with bipolar disorder and over 13 million healthy individuals showed that children of mothers younger than 20 years had a 23% increased risk for bipolar disorder vs. those whose parents were aged 25-29 years. For participants whose mothers were aged 35-39 years, there was a 10% increased risk for bipolar disorder, which rose to 20% if the mother was aged 40 or older.

Having a father younger than 20 years conferred a 29% increased risk for bipolar disorder, which was the same increase in risk found in individuals whose fathers were aged 45 years or older.

These findings, which are an update of data published in the journal European Pharmacology, were presented at the 35th European College of Neuropsychopharmacology (ECNP) Congress.
 

Fourteen studies included

Previous studies have suggested that parental age at birth is a risk factor for several psychiatric disorders in offspring, including bipolar disorder, and that advanced parental age, specifically, is associated with earlier onset schizophrenia.

To investigate further, the current researchers conducted a systematic review and meta-analysis, searching the PubMed/MEDLINE, EMBASE, Scopus, and PsychINFO databases for relevant studies published to Dec. 1, 2021.

From 712 studies initially identified, 16 met all the inclusion criteria and 14 were included in the quantitative analysis.

Five studies reported only paternal age and risk for bipolar disorder in their offspring, one included just maternal age, and eight reported both maternal and paternal age in relation to the risk for offspring bipolar disorder.

Individuals with a history of any psychiatric disorders were excluded, leaving a total of 13.4 million individuals without bipolar disorder and 217,089 who had received a diagnosis for the disorder.

The investigators also corrected for both socioeconomic status and, when assessing the impact of maternal or paternal age at birth, corrected for the age of the other parent. However, they were unable to correct for the number of children in a family.

Results after stratifying maternal and paternal age showed that, compared with those born to parents aged 25-29 years, there was an increased risk for bipolar disorder in the offspring of both fathers and mothers younger than 20 years of age, with adjusted odds ratios of 1.29 (95% confidence interval, 1.13-1.48) and 1.23 (95% CI, 1.14-1.33), respectively.

Compared with those aged 25-29 years, there was also an increased risk for bipolar disorder in children born to mothers aged 35-39 years (adjusted OR, 1.1; 95% CI, 1.01-1.19) and aged 40 or older (OR, 1.2; 95% CI, 1.02-1.40).

Among fathers, there was increased risk for offspring bipolar disorder in those aged 45 or older vs. those aged 25-29 years (adjusted OR, 1.29; 95% CI, 1.15-1.46).
 

Several hypotheses

There are several hypotheses that could explain the results, lead study author Giovanna Fico, MD, bipolar and depressive disorders unit, Hospital Clínic Barcelona, told this news organization.

In older age, it may be “more related to genetic or epigenetic modification, especially in fathers,” Dr. Fico said. “Some studies have shown that there are de novo mutations in the germ lines, which increase the risk of several diseases, including schizophrenia.”

In younger individuals, there could be a “mixed effect between sociocultural factors, such as substance abuse, low educational status,” and other issues, Dr. Fico noted.

Moreover, as bipolar disorder onset can be as late as 30 years of age, the younger group could include “undiagnosed patients with bipolar disorder, which would increase the risk” of the disease in their offspring, she added.

Dr. Fico noted the investigators are now planning on studying the impact of environmental factors such as pollution, climate change, and urbanization on risk for bipolar disorder, with the aim of being better able to inform parents or to develop prevention strategies.

Psychoeducation is “very common for infertility, birth defects, and Down syndrome, but it’s not so common for psychiatric disorders because we need more data. But I think it’s important that parents know they have an increased risk,” she said.

Nevertheless, “We must stress that this risk is moderate, and it must be kept in perspective,” Dr. Fico said in a news release.
 

‘Exciting’ questions raised

The study “raises several exciting research questions, including the possibility of early prevention and intervention,” Maj Vinberg, MD, PhD, clinical professor, department of clinical medicine, University of Copenhagen, said in the release.

She said she agrees there are likely to be different factors at play at different ages, with the risk for bipolar disorder associated with younger-age parenthood more likely to be related to socioeconomic status.

For older parents, “there has been a lot of speculation around the father’s age especially, which everybody thought didn’t matter,” said Dr. Vinberg, who was not involved with the research.

“But you might have some epigenetic changes as you grow older that might transfer into the next generation,” given that there is 20 years of additional exposure to potential epigenetic changes between a man aged 25 years and one aged 45 years, she noted.

Dr. Vinberg also highlighted that there could be cases of undiagnosed bipolar disorder among the younger parents, and she noted that “men with bipolar disorder tend to have more children,” particularly during manic phases.

She explained that if someone were to get divorced at 35 years of age, then have a new manic episode at 45 “and have a new wife and children, I don’t know whether it’s possible to correct for that.”

The research is supported by a fellowship from “la Caixa” Foundation. The investigators have reported no relevant financial relationships. Dr. Vinberg reported having relationships with Lundbeck and Janssen.

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