ECNP Congress 2015

AMSTERDAM – For decades, researchers have studied whether oxytocin has the potential to have a therapeutic effect in schizophrenia. Recently, however, the lack of consistently positive findings has caused some to wonder whether the hormone’s value as a schizophrenia treatment is at a dead end.

“There are plenty of good reasons to study this,” said Dr. Mark Weiser, chair of the psychiatry department at Tel Aviv University, in an interview conducted at the annual congress of the European College of Neuropsychopharmacology. “It looks really promising from the nonclinical data.”

One recent study found that patients with schizophrenia tend to have lower plasma levels of the hormone but more positive symptoms of the disease than do controls. People on the autism spectrum who have resulting social deficits, similar to those in schizophrenia, also have been shown to have lower plasma levels of oxytocin (Biol Psychiatry. 2007 Feb 15;61:498-503); (Proc Natl Acad Sci U S A. 2010 Mar 2;107[9]:4389-94.); and (Biol Psychiatry. 2010 Apr 1;67[7]:692-4.).

A study published earlier this year showed that while oxytocin pathway genes were not implicated in a person’s susceptibility to psychotic disorders, variations in the genes “might play a role in the development of impaired social behavior” (Front Hum Neurosci. 2015 Jan 23;9:9). Still, the absence of replicable positive studies and the increasing number of investigations with negative results, such as the randomized, controlled trial conducted by Dr. Weiser and his colleagues, has led Dr. Weiser to conclude that despite intimations of promise over the years, it’s time to just move on.

“There is a reasonable amount of clinical data raising questions about whether it’s worth spending time and effort on doing further clinical trials [on oxytocin in schizophrenia],” Dr. Weiser said. “Even when you look at the so-called positive findings and go into the data, they don’t really come out to be positive.”

He cited a recent meta-analysis that concluded oxytocin’s effect on cognition was “too diverse for meta-analyses, and inspection of these data showed no consistent benefit” (Schizophr Res. 2015 Apr 23. pii: S0920-9964[15]00174-7.).

Dr. Weiser began his own inquiry under the premise that the “feel-good” hormone implicated in a person’s experience of love and intimacy would help those with schizophrenia better read and understand the emotional cues of others, fostering better social functioning as a result.

Previous studies have shown that oxytocin in people with schizophrenia mitigate their positive and negative symptoms, and the hormone has been associated with increased levels of trust (Depress Anxiety. 2012 Nov;29[11]: 924-30); (Physiol Behav. 2011 Feb 1;102[2]:221-4.).

But in Dr. Weiser’s study, only nonsignificant differences were found in social functioning between those given placebo, and either supportive therapy or social skills training and those given intranasal oxytocin and one of the two talk therapies.

“My data do not support developing this,” Dr. Weiser said in the interview. There is “perhaps” promise, he said for those who’d like to spend the time and effort conducting meta-analyses of individual patient data from a range of studies and doing comparative analyses. But the time necessary to do so, plus the theoretical issues to clarify, such as whether it would be better to separate patients with well-established schizophrenia from those with first-episode or to evaluate them together, or what the primary outcome measures should be, make it unlikely such an analysis will take place. “It’s what should be done,” but, he said, “Given the negative findings, no one is going to fund it.”

Yet some experts – such as Inga D. Neumann, Ph.D., chair of behavioral and molecular neurobiology at the University of Regensburg (Germany) – argue that the therapeutic promise of oxytocin in schizophrenia is there. But they say the studies to date have not been well designed.

According to Dr. Neumann, the duration of treatment and the levels of synthetic oxytocin used in human studies interfere with the endogenous oxytocin system. In an interview at the ECNP meeting, Dr. Neumann said the typical human study uses more oxytocin “than the body’s entire pituitary content and is supplied in a single shot twice daily over 5 or 6 weeks.” Animal studies have shown that such intense and chronic treatment leads to the decrease of oxytocin receptors in the brain and overall impairment of the oxytocin system. “The down-regulation of the receptors is important to consider” but often isn’t, she said.

The level of damage to the endogenous system incurred, and whether it is permanent in these bench studies remain unknown. But levels of oxytocin receptors in the limbic regions of the brain are still suppressed at least 3 weeks after oxytocin treatments are stopped. “These are only in animal studies,” Dr. Neumann said. “What we could do in humans is to test their oxytocin systems right before treatment, right after it, and then, say, half a year later to see if there are changes in the system.”

Dr. Neumann believes clinical studies also should first determine what a high level of oxytocin looks like in healthy people whose oxytocin systems have been stimulated vs. what constitutes a high level in those whose systems are impaired, such in those with schizophrenia. In her work with animals, Dr. Neumann said she has found that different kinds of stimulation, whether it be exercise, sex, or stress, lead to different levels of oxytocin released into the blood stream. These kinds of data from humans would help determine the right amount of the hormone necessary to establish a positive treatment effect. “This should be done more in laboratories, not just the taking of basal levels. Basal levels mean nothing.”

Deanna L. Kelly, Pharm.D., professor of psychiatry and the director of the treatment research program at the University of Maryland, Baltimore, also wonders about trial designs, albeit her more pressing concerns are how the study drug is administered and in what setting.

“I think it’s important for us as a field to make sure we’re delivering [oxytocin] appropriately,” Dr. Kelly said during a presentation at the meeting. She noted her theory that, of the single-dose challenge studies in schizophrenia that have shown an effect on social cognition, most were likely conducted under tight supervision to ensure the medication was “delivered properly.”

Dr. Kelly presented her own negative data from a study of 56 people, mostly men in their mid- to late 40s with schizophrenia or schizoaffective disorder, selected for their enduring negative symptoms. Participants were treated either in an in- or outpatient setting based on their normal treatment regimen and were randomly assigned to receive either placebo, oxytocin, or the acetylcholinesterase inhibitor galantamine.

Oxytocin, which was administered intranasally at 24 IU twice daily, was chosen for its effect on negative symptoms in schizophrenia. Galantamine – often used to treat impaired cognition in Alzheimer’s disease – was dosed orally at 12 mg twice daily and was intended to address cognitive deficits. After a 4-week lead-in phase and 6 weeks of double-blind treatment, neither of the study drugs was found superior to placebo when it came to improving either negative symptoms or cognitive processes.

Some differences were found between those in the in- and outpatient settings, although they were not significant. However, in a previous study, Dr. Kelly conducted with her colleagues, patients treated with intranasal oxytocin in the inpatient setting showed significant improvement vs. controls treated in the inpatient setting. However, they did not find an overall negative symptom effect, and no difference was found among those treated as outpatients (Schizophr Res. 2013 Apr;145[0]:110-5).

“It could be that these patients are more closely watched by the nursing staff, and they’re getting the six sprays twice daily into the nose, whereas the outpatients might not be spraying it correctly ... [so that] it gets into the brain,” Dr. Kelly said.

For his part, Dr. Weiser said his study might have been too short in duration with too few subjects who already were too far into their disease state. The 48 people in his 3-week study were typically male, 37 years old, and with an average age of disease onset of about 23 years. Positive and Negative Syndrome Scale (PANSS) scores were about 69 for the study group and 66 for the placebo group.

“Perhaps patients with more severe PANSS scores might show more improvement,” Dr. Weiser said in his presentation.

Regardless, unless a genetic breakthrough occurs that helps identify subgroups of people in whom oxytocin treatments would have a positive effect, Dr. Weiser thinks interest in oxytocin for schizophrenia should end.

“The field is thirsty for something that works for schizophrenia,” said Dr. Weiser in the interview. “But regardless of wonderful preclinical [findings] on oxytocin, if the bottom line is that when you give it to patients they don’t get better, then we need to figure out a different intervention to try.”

Not so fast, Dr. Neumann says. “We have to look more carefully. We can’t just take any patients, treat them with a huge, superficial dose and then think, ‘Oh, this will do something.’ We have to do better homework.”

Dr. Weiser’s and Dr. Kelly’s respective research is funded by the Stanley Medical Research Institute. Dr. Kelly is an adviser to Lundbeck and XOMA.

[email protected]

On Twitter @whitneymcknight

AMSTERDAM – For decades, researchers have studied whether oxytocin has the potential to have a therapeutic effect in schizophrenia. Recently, however, the lack of consistently positive findings has caused some to wonder whether the hormone’s value as a schizophrenia treatment is at a dead end.

“There are plenty of good reasons to study this,” said Dr. Mark Weiser, chair of the psychiatry department at Tel Aviv University, in an interview conducted at the annual congress of the European College of Neuropsychopharmacology. “It looks really promising from the nonclinical data.”

One recent study found that patients with schizophrenia tend to have lower plasma levels of the hormone but more positive symptoms of the disease than do controls. People on the autism spectrum who have resulting social deficits, similar to those in schizophrenia, also have been shown to have lower plasma levels of oxytocin (Biol Psychiatry. 2007 Feb 15;61:498-503); (Proc Natl Acad Sci U S A. 2010 Mar 2;107[9]:4389-94.); and (Biol Psychiatry. 2010 Apr 1;67[7]:692-4.).

A study published earlier this year showed that while oxytocin pathway genes were not implicated in a person’s susceptibility to psychotic disorders, variations in the genes “might play a role in the development of impaired social behavior” (Front Hum Neurosci. 2015 Jan 23;9:9). Still, the absence of replicable positive studies and the increasing number of investigations with negative results, such as the randomized, controlled trial conducted by Dr. Weiser and his colleagues, has led Dr. Weiser to conclude that despite intimations of promise over the years, it’s time to just move on.

“There is a reasonable amount of clinical data raising questions about whether it’s worth spending time and effort on doing further clinical trials [on oxytocin in schizophrenia],” Dr. Weiser said. “Even when you look at the so-called positive findings and go into the data, they don’t really come out to be positive.”

He cited a recent meta-analysis that concluded oxytocin’s effect on cognition was “too diverse for meta-analyses, and inspection of these data showed no consistent benefit” (Schizophr Res. 2015 Apr 23. pii: S0920-9964[15]00174-7.).

Dr. Weiser began his own inquiry under the premise that the “feel-good” hormone implicated in a person’s experience of love and intimacy would help those with schizophrenia better read and understand the emotional cues of others, fostering better social functioning as a result.

Previous studies have shown that oxytocin in people with schizophrenia mitigate their positive and negative symptoms, and the hormone has been associated with increased levels of trust (Depress Anxiety. 2012 Nov;29[11]: 924-30); (Physiol Behav. 2011 Feb 1;102[2]:221-4.).

But in Dr. Weiser’s study, only nonsignificant differences were found in social functioning between those given placebo, and either supportive therapy or social skills training and those given intranasal oxytocin and one of the two talk therapies.

“My data do not support developing this,” Dr. Weiser said in the interview. There is “perhaps” promise, he said for those who’d like to spend the time and effort conducting meta-analyses of individual patient data from a range of studies and doing comparative analyses. But the time necessary to do so, plus the theoretical issues to clarify, such as whether it would be better to separate patients with well-established schizophrenia from those with first-episode or to evaluate them together, or what the primary outcome measures should be, make it unlikely such an analysis will take place. “It’s what should be done,” but, he said, “Given the negative findings, no one is going to fund it.”

Yet some experts – such as Inga D. Neumann, Ph.D., chair of behavioral and molecular neurobiology at the University of Regensburg (Germany) – argue that the therapeutic promise of oxytocin in schizophrenia is there. But they say the studies to date have not been well designed.

According to Dr. Neumann, the duration of treatment and the levels of synthetic oxytocin used in human studies interfere with the endogenous oxytocin system. In an interview at the ECNP meeting, Dr. Neumann said the typical human study uses more oxytocin “than the body’s entire pituitary content and is supplied in a single shot twice daily over 5 or 6 weeks.” Animal studies have shown that such intense and chronic treatment leads to the decrease of oxytocin receptors in the brain and overall impairment of the oxytocin system. “The down-regulation of the receptors is important to consider” but often isn’t, she said.

The level of damage to the endogenous system incurred, and whether it is permanent in these bench studies remain unknown. But levels of oxytocin receptors in the limbic regions of the brain are still suppressed at least 3 weeks after oxytocin treatments are stopped. “These are only in animal studies,” Dr. Neumann said. “What we could do in humans is to test their oxytocin systems right before treatment, right after it, and then, say, half a year later to see if there are changes in the system.”

Dr. Neumann believes clinical studies also should first determine what a high level of oxytocin looks like in healthy people whose oxytocin systems have been stimulated vs. what constitutes a high level in those whose systems are impaired, such in those with schizophrenia. In her work with animals, Dr. Neumann said she has found that different kinds of stimulation, whether it be exercise, sex, or stress, lead to different levels of oxytocin released into the blood stream. These kinds of data from humans would help determine the right amount of the hormone necessary to establish a positive treatment effect. “This should be done more in laboratories, not just the taking of basal levels. Basal levels mean nothing.”

Deanna L. Kelly, Pharm.D., professor of psychiatry and the director of the treatment research program at the University of Maryland, Baltimore, also wonders about trial designs, albeit her more pressing concerns are how the study drug is administered and in what setting.

“I think it’s important for us as a field to make sure we’re delivering [oxytocin] appropriately,” Dr. Kelly said during a presentation at the meeting. She noted her theory that, of the single-dose challenge studies in schizophrenia that have shown an effect on social cognition, most were likely conducted under tight supervision to ensure the medication was “delivered properly.”

Dr. Kelly presented her own negative data from a study of 56 people, mostly men in their mid- to late 40s with schizophrenia or schizoaffective disorder, selected for their enduring negative symptoms. Participants were treated either in an in- or outpatient setting based on their normal treatment regimen and were randomly assigned to receive either placebo, oxytocin, or the acetylcholinesterase inhibitor galantamine.

Oxytocin, which was administered intranasally at 24 IU twice daily, was chosen for its effect on negative symptoms in schizophrenia. Galantamine – often used to treat impaired cognition in Alzheimer’s disease – was dosed orally at 12 mg twice daily and was intended to address cognitive deficits. After a 4-week lead-in phase and 6 weeks of double-blind treatment, neither of the study drugs was found superior to placebo when it came to improving either negative symptoms or cognitive processes.

Some differences were found between those in the in- and outpatient settings, although they were not significant. However, in a previous study, Dr. Kelly conducted with her colleagues, patients treated with intranasal oxytocin in the inpatient setting showed significant improvement vs. controls treated in the inpatient setting. However, they did not find an overall negative symptom effect, and no difference was found among those treated as outpatients (Schizophr Res. 2013 Apr;145[0]:110-5).

“It could be that these patients are more closely watched by the nursing staff, and they’re getting the six sprays twice daily into the nose, whereas the outpatients might not be spraying it correctly ... [so that] it gets into the brain,” Dr. Kelly said.

For his part, Dr. Weiser said his study might have been too short in duration with too few subjects who already were too far into their disease state. The 48 people in his 3-week study were typically male, 37 years old, and with an average age of disease onset of about 23 years. Positive and Negative Syndrome Scale (PANSS) scores were about 69 for the study group and 66 for the placebo group.

“Perhaps patients with more severe PANSS scores might show more improvement,” Dr. Weiser said in his presentation.

Regardless, unless a genetic breakthrough occurs that helps identify subgroups of people in whom oxytocin treatments would have a positive effect, Dr. Weiser thinks interest in oxytocin for schizophrenia should end.

“The field is thirsty for something that works for schizophrenia,” said Dr. Weiser in the interview. “But regardless of wonderful preclinical [findings] on oxytocin, if the bottom line is that when you give it to patients they don’t get better, then we need to figure out a different intervention to try.”

Not so fast, Dr. Neumann says. “We have to look more carefully. We can’t just take any patients, treat them with a huge, superficial dose and then think, ‘Oh, this will do something.’ We have to do better homework.”

Dr. Weiser’s and Dr. Kelly’s respective research is funded by the Stanley Medical Research Institute. Dr. Kelly is an adviser to Lundbeck and XOMA.

[email protected]

On Twitter @whitneymcknight

AMSTERDAM – For decades, researchers have studied whether oxytocin has the potential to have a therapeutic effect in schizophrenia. Recently, however, the lack of consistently positive findings has caused some to wonder whether the hormone’s value as a schizophrenia treatment is at a dead end.

“There are plenty of good reasons to study this,” said Dr. Mark Weiser, chair of the psychiatry department at Tel Aviv University, in an interview conducted at the annual congress of the European College of Neuropsychopharmacology. “It looks really promising from the nonclinical data.”

One recent study found that patients with schizophrenia tend to have lower plasma levels of the hormone but more positive symptoms of the disease than do controls. People on the autism spectrum who have resulting social deficits, similar to those in schizophrenia, also have been shown to have lower plasma levels of oxytocin (Biol Psychiatry. 2007 Feb 15;61:498-503); (Proc Natl Acad Sci U S A. 2010 Mar 2;107[9]:4389-94.); and (Biol Psychiatry. 2010 Apr 1;67[7]:692-4.).

A study published earlier this year showed that while oxytocin pathway genes were not implicated in a person’s susceptibility to psychotic disorders, variations in the genes “might play a role in the development of impaired social behavior” (Front Hum Neurosci. 2015 Jan 23;9:9). Still, the absence of replicable positive studies and the increasing number of investigations with negative results, such as the randomized, controlled trial conducted by Dr. Weiser and his colleagues, has led Dr. Weiser to conclude that despite intimations of promise over the years, it’s time to just move on.

“There is a reasonable amount of clinical data raising questions about whether it’s worth spending time and effort on doing further clinical trials [on oxytocin in schizophrenia],” Dr. Weiser said. “Even when you look at the so-called positive findings and go into the data, they don’t really come out to be positive.”

He cited a recent meta-analysis that concluded oxytocin’s effect on cognition was “too diverse for meta-analyses, and inspection of these data showed no consistent benefit” (Schizophr Res. 2015 Apr 23. pii: S0920-9964[15]00174-7.).

Dr. Weiser began his own inquiry under the premise that the “feel-good” hormone implicated in a person’s experience of love and intimacy would help those with schizophrenia better read and understand the emotional cues of others, fostering better social functioning as a result.

Previous studies have shown that oxytocin in people with schizophrenia mitigate their positive and negative symptoms, and the hormone has been associated with increased levels of trust (Depress Anxiety. 2012 Nov;29[11]: 924-30); (Physiol Behav. 2011 Feb 1;102[2]:221-4.).

But in Dr. Weiser’s study, only nonsignificant differences were found in social functioning between those given placebo, and either supportive therapy or social skills training and those given intranasal oxytocin and one of the two talk therapies.

“My data do not support developing this,” Dr. Weiser said in the interview. There is “perhaps” promise, he said for those who’d like to spend the time and effort conducting meta-analyses of individual patient data from a range of studies and doing comparative analyses. But the time necessary to do so, plus the theoretical issues to clarify, such as whether it would be better to separate patients with well-established schizophrenia from those with first-episode or to evaluate them together, or what the primary outcome measures should be, make it unlikely such an analysis will take place. “It’s what should be done,” but, he said, “Given the negative findings, no one is going to fund it.”

Yet some experts – such as Inga D. Neumann, Ph.D., chair of behavioral and molecular neurobiology at the University of Regensburg (Germany) – argue that the therapeutic promise of oxytocin in schizophrenia is there. But they say the studies to date have not been well designed.

According to Dr. Neumann, the duration of treatment and the levels of synthetic oxytocin used in human studies interfere with the endogenous oxytocin system. In an interview at the ECNP meeting, Dr. Neumann said the typical human study uses more oxytocin “than the body’s entire pituitary content and is supplied in a single shot twice daily over 5 or 6 weeks.” Animal studies have shown that such intense and chronic treatment leads to the decrease of oxytocin receptors in the brain and overall impairment of the oxytocin system. “The down-regulation of the receptors is important to consider” but often isn’t, she said.

The level of damage to the endogenous system incurred, and whether it is permanent in these bench studies remain unknown. But levels of oxytocin receptors in the limbic regions of the brain are still suppressed at least 3 weeks after oxytocin treatments are stopped. “These are only in animal studies,” Dr. Neumann said. “What we could do in humans is to test their oxytocin systems right before treatment, right after it, and then, say, half a year later to see if there are changes in the system.”

Dr. Neumann believes clinical studies also should first determine what a high level of oxytocin looks like in healthy people whose oxytocin systems have been stimulated vs. what constitutes a high level in those whose systems are impaired, such in those with schizophrenia. In her work with animals, Dr. Neumann said she has found that different kinds of stimulation, whether it be exercise, sex, or stress, lead to different levels of oxytocin released into the blood stream. These kinds of data from humans would help determine the right amount of the hormone necessary to establish a positive treatment effect. “This should be done more in laboratories, not just the taking of basal levels. Basal levels mean nothing.”

Deanna L. Kelly, Pharm.D., professor of psychiatry and the director of the treatment research program at the University of Maryland, Baltimore, also wonders about trial designs, albeit her more pressing concerns are how the study drug is administered and in what setting.

“I think it’s important for us as a field to make sure we’re delivering [oxytocin] appropriately,” Dr. Kelly said during a presentation at the meeting. She noted her theory that, of the single-dose challenge studies in schizophrenia that have shown an effect on social cognition, most were likely conducted under tight supervision to ensure the medication was “delivered properly.”

Dr. Kelly presented her own negative data from a study of 56 people, mostly men in their mid- to late 40s with schizophrenia or schizoaffective disorder, selected for their enduring negative symptoms. Participants were treated either in an in- or outpatient setting based on their normal treatment regimen and were randomly assigned to receive either placebo, oxytocin, or the acetylcholinesterase inhibitor galantamine.

Oxytocin, which was administered intranasally at 24 IU twice daily, was chosen for its effect on negative symptoms in schizophrenia. Galantamine – often used to treat impaired cognition in Alzheimer’s disease – was dosed orally at 12 mg twice daily and was intended to address cognitive deficits. After a 4-week lead-in phase and 6 weeks of double-blind treatment, neither of the study drugs was found superior to placebo when it came to improving either negative symptoms or cognitive processes.

Some differences were found between those in the in- and outpatient settings, although they were not significant. However, in a previous study, Dr. Kelly conducted with her colleagues, patients treated with intranasal oxytocin in the inpatient setting showed significant improvement vs. controls treated in the inpatient setting. However, they did not find an overall negative symptom effect, and no difference was found among those treated as outpatients (Schizophr Res. 2013 Apr;145[0]:110-5).

“It could be that these patients are more closely watched by the nursing staff, and they’re getting the six sprays twice daily into the nose, whereas the outpatients might not be spraying it correctly ... [so that] it gets into the brain,” Dr. Kelly said.

For his part, Dr. Weiser said his study might have been too short in duration with too few subjects who already were too far into their disease state. The 48 people in his 3-week study were typically male, 37 years old, and with an average age of disease onset of about 23 years. Positive and Negative Syndrome Scale (PANSS) scores were about 69 for the study group and 66 for the placebo group.

“Perhaps patients with more severe PANSS scores might show more improvement,” Dr. Weiser said in his presentation.

Regardless, unless a genetic breakthrough occurs that helps identify subgroups of people in whom oxytocin treatments would have a positive effect, Dr. Weiser thinks interest in oxytocin for schizophrenia should end.

“The field is thirsty for something that works for schizophrenia,” said Dr. Weiser in the interview. “But regardless of wonderful preclinical [findings] on oxytocin, if the bottom line is that when you give it to patients they don’t get better, then we need to figure out a different intervention to try.”

Not so fast, Dr. Neumann says. “We have to look more carefully. We can’t just take any patients, treat them with a huge, superficial dose and then think, ‘Oh, this will do something.’ We have to do better homework.”

Dr. Weiser’s and Dr. Kelly’s respective research is funded by the Stanley Medical Research Institute. Dr. Kelly is an adviser to Lundbeck and XOMA.

[email protected]

On Twitter @whitneymcknight

AMSTERDAM – Neurometabolite deficiencies in the dorsolateral prefrontal cortex may contribute to the lack of insight people with severe mental illness have into their condition, a study showed.

Previous studies have shown that insight lives in the prefrontal cortex, which also is involved in cognitive flexibility and executive function, two other functions often impaired in severe mental illness. Previous studies also have shown a relationship between psychosis and reduced N-acetylaspartate (NAA) in the prefrontal cortex, which is thought to indicate impaired brain function or damage.

©Thinkstock.com

Daouia Larabi, a researcher and PhD candidate at the University of Groningen (the Netherlands), and her colleagues administered the Birchwood Insight Scale (BIS) and the Positive and Negative Syndrome Scale (PANSS) to 80 adult patients with severe mental illness to determine their levels of insight into their illness. The results were then correlated with those from each individual participant’s NAA tests done with an imaging technique called proton magnetic resonance spectroscopy, which measures neurometabolite levels and their ratio to creatine in the white matter of the brain, specifically the dorsolateral prefrontal cortex. Illness duration, use of antipsychotics, gray matter content, and cerebrospinal fluid content were covariates.

Ms. Larabi and her colleagues found that patients with poorer insight as scored on the PANSS also had significantly lower levels of NAA in the prefrontal cortex (P = .045), although the investigators did not find a significant correlation between insight and other neurometabolites such as glutamate in the same region of the brain. There also was a significant positive correlation between NAA to creatine levels and the BIS scores (P = .004). Both results indicate that reductions in NAA were associated with poorer insight, Ms. Larabi said at the annual congress of the European Congress of Neuropsychopharmacology.

Although she said this is the first study to show an association between decreased NAA concentrations and impaired insight, the study still does not offer any conclusions about whether one causes the other. However, because poor insight has been linked to treatment nonadherence and more hospitalizations in the severely mentally ill, the findings are exciting, according to Dr. Andreas Meyer-Lindenberg, editor-in-chief of the journal European Neuropsychopharmacology.

“Insight is highly relevant for the prognosis of people with schizophrenia and psychosis, and linking it to dysfunction in a specific brain system, if replicated, may point to new therapeutic or diagnostic approaches in the future,” Dr. Meyer-Lindenberg said in a statement.

Ms. Larabi said she had no conflicts to disclose.

[email protected]

On Twitter @whitneymcknight

AMSTERDAM – Neurometabolite deficiencies in the dorsolateral prefrontal cortex may contribute to the lack of insight people with severe mental illness have into their condition, a study showed.

Previous studies have shown that insight lives in the prefrontal cortex, which also is involved in cognitive flexibility and executive function, two other functions often impaired in severe mental illness. Previous studies also have shown a relationship between psychosis and reduced N-acetylaspartate (NAA) in the prefrontal cortex, which is thought to indicate impaired brain function or damage.

©Thinkstock.com

Daouia Larabi, a researcher and PhD candidate at the University of Groningen (the Netherlands), and her colleagues administered the Birchwood Insight Scale (BIS) and the Positive and Negative Syndrome Scale (PANSS) to 80 adult patients with severe mental illness to determine their levels of insight into their illness. The results were then correlated with those from each individual participant’s NAA tests done with an imaging technique called proton magnetic resonance spectroscopy, which measures neurometabolite levels and their ratio to creatine in the white matter of the brain, specifically the dorsolateral prefrontal cortex. Illness duration, use of antipsychotics, gray matter content, and cerebrospinal fluid content were covariates.

Ms. Larabi and her colleagues found that patients with poorer insight as scored on the PANSS also had significantly lower levels of NAA in the prefrontal cortex (P = .045), although the investigators did not find a significant correlation between insight and other neurometabolites such as glutamate in the same region of the brain. There also was a significant positive correlation between NAA to creatine levels and the BIS scores (P = .004). Both results indicate that reductions in NAA were associated with poorer insight, Ms. Larabi said at the annual congress of the European Congress of Neuropsychopharmacology.

Although she said this is the first study to show an association between decreased NAA concentrations and impaired insight, the study still does not offer any conclusions about whether one causes the other. However, because poor insight has been linked to treatment nonadherence and more hospitalizations in the severely mentally ill, the findings are exciting, according to Dr. Andreas Meyer-Lindenberg, editor-in-chief of the journal European Neuropsychopharmacology.

“Insight is highly relevant for the prognosis of people with schizophrenia and psychosis, and linking it to dysfunction in a specific brain system, if replicated, may point to new therapeutic or diagnostic approaches in the future,” Dr. Meyer-Lindenberg said in a statement.

Ms. Larabi said she had no conflicts to disclose.

[email protected]

On Twitter @whitneymcknight

AMSTERDAM – Neurometabolite deficiencies in the dorsolateral prefrontal cortex may contribute to the lack of insight people with severe mental illness have into their condition, a study showed.

Previous studies have shown that insight lives in the prefrontal cortex, which also is involved in cognitive flexibility and executive function, two other functions often impaired in severe mental illness. Previous studies also have shown a relationship between psychosis and reduced N-acetylaspartate (NAA) in the prefrontal cortex, which is thought to indicate impaired brain function or damage.

©Thinkstock.com

Daouia Larabi, a researcher and PhD candidate at the University of Groningen (the Netherlands), and her colleagues administered the Birchwood Insight Scale (BIS) and the Positive and Negative Syndrome Scale (PANSS) to 80 adult patients with severe mental illness to determine their levels of insight into their illness. The results were then correlated with those from each individual participant’s NAA tests done with an imaging technique called proton magnetic resonance spectroscopy, which measures neurometabolite levels and their ratio to creatine in the white matter of the brain, specifically the dorsolateral prefrontal cortex. Illness duration, use of antipsychotics, gray matter content, and cerebrospinal fluid content were covariates.

Ms. Larabi and her colleagues found that patients with poorer insight as scored on the PANSS also had significantly lower levels of NAA in the prefrontal cortex (P = .045), although the investigators did not find a significant correlation between insight and other neurometabolites such as glutamate in the same region of the brain. There also was a significant positive correlation between NAA to creatine levels and the BIS scores (P = .004). Both results indicate that reductions in NAA were associated with poorer insight, Ms. Larabi said at the annual congress of the European Congress of Neuropsychopharmacology.

Although she said this is the first study to show an association between decreased NAA concentrations and impaired insight, the study still does not offer any conclusions about whether one causes the other. However, because poor insight has been linked to treatment nonadherence and more hospitalizations in the severely mentally ill, the findings are exciting, according to Dr. Andreas Meyer-Lindenberg, editor-in-chief of the journal European Neuropsychopharmacology.

“Insight is highly relevant for the prognosis of people with schizophrenia and psychosis, and linking it to dysfunction in a specific brain system, if replicated, may point to new therapeutic or diagnostic approaches in the future,” Dr. Meyer-Lindenberg said in a statement.

Ms. Larabi said she had no conflicts to disclose.

[email protected]

On Twitter @whitneymcknight

AMSTERDAM – Patients with schizophrenia given the investigational drug cariprazine showed statistical improvements in negative symptoms such as apathy and withdrawal, compared with those given risperidone, results from a phase III clinical trial have shown. The data were presented at the annual congress of the European College of Neuropsychopharmacology.

Both drugs are antipsychotics, but risperidone is a dopaminergic antagonist, and cariprazine is a D2 and D3 receptor partial agonist, tending toward the D3 receptor. Currently, no drugs are on the market with a specific indication for treating the negative symptoms of schizophrenia, although several second-generation antipsychotics reduce negative symptoms as well as positive and general symptoms of schizophrenia. Several pharmacotherapies are available to treat the positive symptoms of the illness.

In this multicenter, international, double-blind study, 230 adults with schizophrenia were randomly assigned to receive cariprazine and 231 were assigned risperidone for 26 weeks, reported Dr. György Németh, one of the study’s lead authors and chief medical officer of the study’s sponsor, Gedeon Richter.

People included in the study had been stable for at least 6 months prior to screening, and for a subsequent 4 weeks prior to randomization. Those with a score of at least 24 or greater on the Negative Factor Scale of the Positive and Negative Syndrome Scale (PANSS-NFS) and a score of at least 4 on two of the three core negative symptoms, along with positive factor scores on the PANSS of at least 19 or more were considered for inclusion in the study. At baseline, both groups had similar PANSS scores: Negative factor scores in the study drug arm were 27.7 and 27.5 in controls. Positive factor scores were also similar: 8.8 in the study arm and 8.6 in controls.

Study participants also were measured at baseline on the Personal and Social Performance Scale. Scores were 48.8 in the study drug arm and 48.1 in the risperidone arm.

After a 2-week period of cross-titration and washout of previous medications, patients were treated with the target dose of 4.5 mg daily of their assigned drug for 24 weeks.

In the 77.4% of enrollees in both cohorts who completed the trial, those treated with cariprazine had the most improvement in both negative symptoms and personal and social performance, compared with the control group. At 26 weeks, the overall change from baseline in the study group for negative factor symptoms was –2.39, compared with –0.53 in controls (95% confidence interval; P = .002). Personal and social performance scores changed at 26 weeks from baseline by 2.71 in the study group and 6.56 in controls (95% CI; P less than .001).

Discontinuation rates were low, and the most common side effects were insomnia and headache (about 10% for each), mostly in the risperidone arm.

Dr. David Pickar, who was not involved in the study, said in an interview that when treating patients with schizophrenia “improvement in negative symptoms occurs a fair amount with improvements in positive symptoms. The problem is the persistence of negative symptoms,” said Dr. Pickar of the department of psychiatry at Johns Hopkins University, Baltimore, and former branch chief of intramural experimental therapeutics at the National Institute of Mental Health.

This trial was sponsored by Gedeon Richter.

[email protected]

On Twitter @whitneymcknight

AMSTERDAM – Patients with schizophrenia given the investigational drug cariprazine showed statistical improvements in negative symptoms such as apathy and withdrawal, compared with those given risperidone, results from a phase III clinical trial have shown. The data were presented at the annual congress of the European College of Neuropsychopharmacology.

Both drugs are antipsychotics, but risperidone is a dopaminergic antagonist, and cariprazine is a D2 and D3 receptor partial agonist, tending toward the D3 receptor. Currently, no drugs are on the market with a specific indication for treating the negative symptoms of schizophrenia, although several second-generation antipsychotics reduce negative symptoms as well as positive and general symptoms of schizophrenia. Several pharmacotherapies are available to treat the positive symptoms of the illness.

In this multicenter, international, double-blind study, 230 adults with schizophrenia were randomly assigned to receive cariprazine and 231 were assigned risperidone for 26 weeks, reported Dr. György Németh, one of the study’s lead authors and chief medical officer of the study’s sponsor, Gedeon Richter.

People included in the study had been stable for at least 6 months prior to screening, and for a subsequent 4 weeks prior to randomization. Those with a score of at least 24 or greater on the Negative Factor Scale of the Positive and Negative Syndrome Scale (PANSS-NFS) and a score of at least 4 on two of the three core negative symptoms, along with positive factor scores on the PANSS of at least 19 or more were considered for inclusion in the study. At baseline, both groups had similar PANSS scores: Negative factor scores in the study drug arm were 27.7 and 27.5 in controls. Positive factor scores were also similar: 8.8 in the study arm and 8.6 in controls.

Study participants also were measured at baseline on the Personal and Social Performance Scale. Scores were 48.8 in the study drug arm and 48.1 in the risperidone arm.

After a 2-week period of cross-titration and washout of previous medications, patients were treated with the target dose of 4.5 mg daily of their assigned drug for 24 weeks.

In the 77.4% of enrollees in both cohorts who completed the trial, those treated with cariprazine had the most improvement in both negative symptoms and personal and social performance, compared with the control group. At 26 weeks, the overall change from baseline in the study group for negative factor symptoms was –2.39, compared with –0.53 in controls (95% confidence interval; P = .002). Personal and social performance scores changed at 26 weeks from baseline by 2.71 in the study group and 6.56 in controls (95% CI; P less than .001).

Discontinuation rates were low, and the most common side effects were insomnia and headache (about 10% for each), mostly in the risperidone arm.

Dr. David Pickar, who was not involved in the study, said in an interview that when treating patients with schizophrenia “improvement in negative symptoms occurs a fair amount with improvements in positive symptoms. The problem is the persistence of negative symptoms,” said Dr. Pickar of the department of psychiatry at Johns Hopkins University, Baltimore, and former branch chief of intramural experimental therapeutics at the National Institute of Mental Health.

This trial was sponsored by Gedeon Richter.

[email protected]

On Twitter @whitneymcknight

AMSTERDAM – Patients with schizophrenia given the investigational drug cariprazine showed statistical improvements in negative symptoms such as apathy and withdrawal, compared with those given risperidone, results from a phase III clinical trial have shown. The data were presented at the annual congress of the European College of Neuropsychopharmacology.

Both drugs are antipsychotics, but risperidone is a dopaminergic antagonist, and cariprazine is a D2 and D3 receptor partial agonist, tending toward the D3 receptor. Currently, no drugs are on the market with a specific indication for treating the negative symptoms of schizophrenia, although several second-generation antipsychotics reduce negative symptoms as well as positive and general symptoms of schizophrenia. Several pharmacotherapies are available to treat the positive symptoms of the illness.

In this multicenter, international, double-blind study, 230 adults with schizophrenia were randomly assigned to receive cariprazine and 231 were assigned risperidone for 26 weeks, reported Dr. György Németh, one of the study’s lead authors and chief medical officer of the study’s sponsor, Gedeon Richter.

People included in the study had been stable for at least 6 months prior to screening, and for a subsequent 4 weeks prior to randomization. Those with a score of at least 24 or greater on the Negative Factor Scale of the Positive and Negative Syndrome Scale (PANSS-NFS) and a score of at least 4 on two of the three core negative symptoms, along with positive factor scores on the PANSS of at least 19 or more were considered for inclusion in the study. At baseline, both groups had similar PANSS scores: Negative factor scores in the study drug arm were 27.7 and 27.5 in controls. Positive factor scores were also similar: 8.8 in the study arm and 8.6 in controls.

Study participants also were measured at baseline on the Personal and Social Performance Scale. Scores were 48.8 in the study drug arm and 48.1 in the risperidone arm.

After a 2-week period of cross-titration and washout of previous medications, patients were treated with the target dose of 4.5 mg daily of their assigned drug for 24 weeks.

In the 77.4% of enrollees in both cohorts who completed the trial, those treated with cariprazine had the most improvement in both negative symptoms and personal and social performance, compared with the control group. At 26 weeks, the overall change from baseline in the study group for negative factor symptoms was –2.39, compared with –0.53 in controls (95% confidence interval; P = .002). Personal and social performance scores changed at 26 weeks from baseline by 2.71 in the study group and 6.56 in controls (95% CI; P less than .001).

Discontinuation rates were low, and the most common side effects were insomnia and headache (about 10% for each), mostly in the risperidone arm.

Dr. David Pickar, who was not involved in the study, said in an interview that when treating patients with schizophrenia “improvement in negative symptoms occurs a fair amount with improvements in positive symptoms. The problem is the persistence of negative symptoms,” said Dr. Pickar of the department of psychiatry at Johns Hopkins University, Baltimore, and former branch chief of intramural experimental therapeutics at the National Institute of Mental Health.

This trial was sponsored by Gedeon Richter.

[email protected]

On Twitter @whitneymcknight

AMSTERDAM – Electroconvulsive therapy’s efficacy in rapid relief from depression is well-established, particularly in the elderly, but the best ways to improve the treatment’s overall effectiveness over time remain a puzzle.

“There are still some questions,” said Dr. Willem A. Nolen, an emeritus professor of psychiatry at the University of Groningen (the Netherlands) and chair of a panel of ECT experts at the annual congress of the European College of Neuropsychopharmacology.

Whitney McKnight/Frontline Medical News

“There is a high relapse rate [with ECT]. So, how should we continue treatment? Do we use medication, continuation ECT, or psychological therapies?”

A meta-analysis published in 2013 showed that 27% of people with depression who were given ECT relapsed after 3 months. Just over half did so after 1 year, mostly in the first 6 months (37.7%). After 2 years, 50.2% of those treated with ECT had relapsed. The study also found that in randomized, controlled trials, antidepressants given after ECT cut the risk of relapse in half in the first 6 months, compared with placebo. The most effective antidepressants, according to the study, were tricyclics, but the researchers could not find enough data on other maintenance therapies, including other pharmacotherapies, to offer a definitive conclusion on what therapy best extends ECT’s effectiveness (Neuropsychopharmacology. 2013 Nov;38[12]:2467-74. doi: 10.1038/npp.2013.149). According to Dr. Malek Bajbouj, a presenter at the meeting, and professor of psychiatry and affective neurosciences at Freie Universität Berlin, perhaps a new logic is required when it comes to determining the best combination of ECT and add-on therapies.

This ethos forms the underpinning of an approach Dr. Bajbouj says he and his colleagues in Berlin are using to integrate treatment modalities, seeking ways to successfully overlap psychotherapeutic interventions, brain stimulation techniques, and pharmacological interventions.

But the approach is not without obstacles.

“If you give two interventions, take for example, ECT and medication, you can do it simultaneously or sequentially, or in an interactive manner. The outcome could be that we all think one and one is two, but this is not always true or what we’d expect or wish,” Dr. Bajbouj told the audience.

“It might be that there is a positive synergy, but it might also be that there are negative or neutral effects where one and one is still one.”

Take the recent findings from a study that left him slightly bewildered.

In a prospective randomized, controlled study of 90 inpatients, mostly in their 60s and all with major depressive disorder who were given either medication, medication plus maintenance ECT, or medication and cognitive-behavioral therapy (CBT) after their initial acute intervention with right unilateral ultrabrief ECT, Dr. Bajbouj and his colleagues found that after 1 year, CBT plus medication significantly outperformed the other continuation therapies (Biol Psychiatry. 2014 Aug 1;76[3]:194-202. doi: 10.1016/j.biopsych.2013.11.030).“The findings were against my personal expectations,” Dr. Bajbouj said. Those expectations cost him: In a bet with a coinvestigator who predicted that the talk therapy arm would outperform the others, “I ended up having to buy her a bottle of champagne.”

A third of the initial study group did not respond to the initial acute ECT. But of the 60 who did and who were randomly assigned their add-on therapy, and followed at 6 months and 1 year, 77% of those given CBT plus medication remained in remission at 6 months, and an impressive 65% did so at 1 year. Meanwhile, the medication plus ECT group had a 40% remission rate at 6 months and a 28% remission rate at 1 year. The medication-only arm had a remission rate of 44% at 6 months and 33% at 1 year.

Dr. Bajbouj suggested some factors that might have turned the results against his own calculations.

For example, in the medication arm, patients were not given standardized treatments of nortriptyline and lithium, as established as effective by Harold A. Sackeim, Ph.D., and his colleagues (JAMA. 2001 Mar 14;285[10]:1299-307), but were treated according to current guidelines to both accelerate recruitment rates as well as to avoid any adverse cognitive effects from the interaction of nortriptyline and lithium with ECT.

“We might discuss whether this reduced the likelihood that the people maintained their response rates,” Dr. Bajbouj said. Nearly three-quarters of those in the medication arm were taking two or more antidepressants, more than half were taking an antipsychotic, and a third were taking a mood stabilizer.

An additional factor also could have been the underlying refractory nature of the depression across the cohorts, since after the acute ECT treatment phase, patients in the CBT arm had lower remission rates, compared with the other arms (47% vs. 55% in the ECT plus medication arm, and 64% in the medication-only arm) and had higher Hamilton Rating Scale for Depression scores (24-question version) than the other two groups (8.4 points vs. 5.6 in the ECT plus medication arm and 6.3 in the medication-only arm).

The choice of which type of ECT is best for continuation therapy also is in question. In this single-center study conducted in Berlin between 2004 and 2010, ultrabrief pulse ECT was administered weekly for 4 weeks, biweekly for 8 weeks, and monthly for 3 months, titrated based on the individual seizure threshold established during the first continuation treatment and kept constant thereafter.

In the study, Dr. Bajbouj and his coauthors noted that the results indicated that ultrabrief ECT as a continuation therapy might be less effective than more established forms of ECT with broader pulse widths. “The way we did the continuation ECT therapy is not the way we would do it today,” Dr. Bajbouj said.

So, what of this question of how to factor in possible synergies created when multiple treatments are administered? Dr. Bajbouj pointed to another of his studies, this one done to determine whether the molecular mechanisms of the pretreatments ketamine or lithium used in repetitive transcranial magnetic stimulation affected outcomes (Eur Arch Psychiatry Clin Neurosci. 2012 Feb;262[1]:87-91. doi: 10.1007/s00406-011-0217-3).

Dr. Bajbouj and his colleagues found that pretreatment with ketamine potentiated neuronal cells, while pretreatment with lithium attenuated the cellular response to repetitive magnetic stimulation.

“It’s very oversimplified,” Dr. Bajbouj said. However, a difference in cellular synergies was found, leading Dr. Bajbouj to say that the notion of treatment synergies is “not adequately regarded currently in the field of ECT.”

In the meantime, Dr. Bajbouj laid out a “wish list” for how he’d like to see ECT as well as other brain stimulation techniques become integrated into the mainstream of treatment techniques for depression. Included were the broader use of transcranial magnetic stimulation, more ECT in the depressed elderly and in those with refractory depression, and direct brain stimulation, which he said “might be something for the very severely ill and could prevent relapse.”

It might be a while, though. Despite plenty of data in support of ECT and Dr. Bajbouj’s own data in favor of combining CBT with pharmacotherapy after ECT, the results from an Internet survey showed that, “If you were to ask patients in Germany what they would do if they were depressed, ECT doesn’t even appear.” In the survey, psychotherapy ranked first. “Take antidepressants” ranked between “eat chocolate” and “go on vacation.”

Dr. Bajbouj did not have any relevant disclosures.

[email protected]

On Twitter @whitneymcknight

AMSTERDAM – Electroconvulsive therapy’s efficacy in rapid relief from depression is well-established, particularly in the elderly, but the best ways to improve the treatment’s overall effectiveness over time remain a puzzle.

“There are still some questions,” said Dr. Willem A. Nolen, an emeritus professor of psychiatry at the University of Groningen (the Netherlands) and chair of a panel of ECT experts at the annual congress of the European College of Neuropsychopharmacology.

Whitney McKnight/Frontline Medical News

“There is a high relapse rate [with ECT]. So, how should we continue treatment? Do we use medication, continuation ECT, or psychological therapies?”

A meta-analysis published in 2013 showed that 27% of people with depression who were given ECT relapsed after 3 months. Just over half did so after 1 year, mostly in the first 6 months (37.7%). After 2 years, 50.2% of those treated with ECT had relapsed. The study also found that in randomized, controlled trials, antidepressants given after ECT cut the risk of relapse in half in the first 6 months, compared with placebo. The most effective antidepressants, according to the study, were tricyclics, but the researchers could not find enough data on other maintenance therapies, including other pharmacotherapies, to offer a definitive conclusion on what therapy best extends ECT’s effectiveness (Neuropsychopharmacology. 2013 Nov;38[12]:2467-74. doi: 10.1038/npp.2013.149). According to Dr. Malek Bajbouj, a presenter at the meeting, and professor of psychiatry and affective neurosciences at Freie Universität Berlin, perhaps a new logic is required when it comes to determining the best combination of ECT and add-on therapies.

This ethos forms the underpinning of an approach Dr. Bajbouj says he and his colleagues in Berlin are using to integrate treatment modalities, seeking ways to successfully overlap psychotherapeutic interventions, brain stimulation techniques, and pharmacological interventions.

But the approach is not without obstacles.

“If you give two interventions, take for example, ECT and medication, you can do it simultaneously or sequentially, or in an interactive manner. The outcome could be that we all think one and one is two, but this is not always true or what we’d expect or wish,” Dr. Bajbouj told the audience.

“It might be that there is a positive synergy, but it might also be that there are negative or neutral effects where one and one is still one.”

Take the recent findings from a study that left him slightly bewildered.

In a prospective randomized, controlled study of 90 inpatients, mostly in their 60s and all with major depressive disorder who were given either medication, medication plus maintenance ECT, or medication and cognitive-behavioral therapy (CBT) after their initial acute intervention with right unilateral ultrabrief ECT, Dr. Bajbouj and his colleagues found that after 1 year, CBT plus medication significantly outperformed the other continuation therapies (Biol Psychiatry. 2014 Aug 1;76[3]:194-202. doi: 10.1016/j.biopsych.2013.11.030).“The findings were against my personal expectations,” Dr. Bajbouj said. Those expectations cost him: In a bet with a coinvestigator who predicted that the talk therapy arm would outperform the others, “I ended up having to buy her a bottle of champagne.”

A third of the initial study group did not respond to the initial acute ECT. But of the 60 who did and who were randomly assigned their add-on therapy, and followed at 6 months and 1 year, 77% of those given CBT plus medication remained in remission at 6 months, and an impressive 65% did so at 1 year. Meanwhile, the medication plus ECT group had a 40% remission rate at 6 months and a 28% remission rate at 1 year. The medication-only arm had a remission rate of 44% at 6 months and 33% at 1 year.

Dr. Bajbouj suggested some factors that might have turned the results against his own calculations.

For example, in the medication arm, patients were not given standardized treatments of nortriptyline and lithium, as established as effective by Harold A. Sackeim, Ph.D., and his colleagues (JAMA. 2001 Mar 14;285[10]:1299-307), but were treated according to current guidelines to both accelerate recruitment rates as well as to avoid any adverse cognitive effects from the interaction of nortriptyline and lithium with ECT.

“We might discuss whether this reduced the likelihood that the people maintained their response rates,” Dr. Bajbouj said. Nearly three-quarters of those in the medication arm were taking two or more antidepressants, more than half were taking an antipsychotic, and a third were taking a mood stabilizer.

An additional factor also could have been the underlying refractory nature of the depression across the cohorts, since after the acute ECT treatment phase, patients in the CBT arm had lower remission rates, compared with the other arms (47% vs. 55% in the ECT plus medication arm, and 64% in the medication-only arm) and had higher Hamilton Rating Scale for Depression scores (24-question version) than the other two groups (8.4 points vs. 5.6 in the ECT plus medication arm and 6.3 in the medication-only arm).

The choice of which type of ECT is best for continuation therapy also is in question. In this single-center study conducted in Berlin between 2004 and 2010, ultrabrief pulse ECT was administered weekly for 4 weeks, biweekly for 8 weeks, and monthly for 3 months, titrated based on the individual seizure threshold established during the first continuation treatment and kept constant thereafter.

In the study, Dr. Bajbouj and his coauthors noted that the results indicated that ultrabrief ECT as a continuation therapy might be less effective than more established forms of ECT with broader pulse widths. “The way we did the continuation ECT therapy is not the way we would do it today,” Dr. Bajbouj said.

So, what of this question of how to factor in possible synergies created when multiple treatments are administered? Dr. Bajbouj pointed to another of his studies, this one done to determine whether the molecular mechanisms of the pretreatments ketamine or lithium used in repetitive transcranial magnetic stimulation affected outcomes (Eur Arch Psychiatry Clin Neurosci. 2012 Feb;262[1]:87-91. doi: 10.1007/s00406-011-0217-3).

Dr. Bajbouj and his colleagues found that pretreatment with ketamine potentiated neuronal cells, while pretreatment with lithium attenuated the cellular response to repetitive magnetic stimulation.

“It’s very oversimplified,” Dr. Bajbouj said. However, a difference in cellular synergies was found, leading Dr. Bajbouj to say that the notion of treatment synergies is “not adequately regarded currently in the field of ECT.”

In the meantime, Dr. Bajbouj laid out a “wish list” for how he’d like to see ECT as well as other brain stimulation techniques become integrated into the mainstream of treatment techniques for depression. Included were the broader use of transcranial magnetic stimulation, more ECT in the depressed elderly and in those with refractory depression, and direct brain stimulation, which he said “might be something for the very severely ill and could prevent relapse.”

It might be a while, though. Despite plenty of data in support of ECT and Dr. Bajbouj’s own data in favor of combining CBT with pharmacotherapy after ECT, the results from an Internet survey showed that, “If you were to ask patients in Germany what they would do if they were depressed, ECT doesn’t even appear.” In the survey, psychotherapy ranked first. “Take antidepressants” ranked between “eat chocolate” and “go on vacation.”

Dr. Bajbouj did not have any relevant disclosures.

[email protected]

On Twitter @whitneymcknight

AMSTERDAM – Electroconvulsive therapy’s efficacy in rapid relief from depression is well-established, particularly in the elderly, but the best ways to improve the treatment’s overall effectiveness over time remain a puzzle.

“There are still some questions,” said Dr. Willem A. Nolen, an emeritus professor of psychiatry at the University of Groningen (the Netherlands) and chair of a panel of ECT experts at the annual congress of the European College of Neuropsychopharmacology.

Whitney McKnight/Frontline Medical News

“There is a high relapse rate [with ECT]. So, how should we continue treatment? Do we use medication, continuation ECT, or psychological therapies?”

A meta-analysis published in 2013 showed that 27% of people with depression who were given ECT relapsed after 3 months. Just over half did so after 1 year, mostly in the first 6 months (37.7%). After 2 years, 50.2% of those treated with ECT had relapsed. The study also found that in randomized, controlled trials, antidepressants given after ECT cut the risk of relapse in half in the first 6 months, compared with placebo. The most effective antidepressants, according to the study, were tricyclics, but the researchers could not find enough data on other maintenance therapies, including other pharmacotherapies, to offer a definitive conclusion on what therapy best extends ECT’s effectiveness (Neuropsychopharmacology. 2013 Nov;38[12]:2467-74. doi: 10.1038/npp.2013.149). According to Dr. Malek Bajbouj, a presenter at the meeting, and professor of psychiatry and affective neurosciences at Freie Universität Berlin, perhaps a new logic is required when it comes to determining the best combination of ECT and add-on therapies.

This ethos forms the underpinning of an approach Dr. Bajbouj says he and his colleagues in Berlin are using to integrate treatment modalities, seeking ways to successfully overlap psychotherapeutic interventions, brain stimulation techniques, and pharmacological interventions.

But the approach is not without obstacles.

“If you give two interventions, take for example, ECT and medication, you can do it simultaneously or sequentially, or in an interactive manner. The outcome could be that we all think one and one is two, but this is not always true or what we’d expect or wish,” Dr. Bajbouj told the audience.

“It might be that there is a positive synergy, but it might also be that there are negative or neutral effects where one and one is still one.”

Take the recent findings from a study that left him slightly bewildered.

In a prospective randomized, controlled study of 90 inpatients, mostly in their 60s and all with major depressive disorder who were given either medication, medication plus maintenance ECT, or medication and cognitive-behavioral therapy (CBT) after their initial acute intervention with right unilateral ultrabrief ECT, Dr. Bajbouj and his colleagues found that after 1 year, CBT plus medication significantly outperformed the other continuation therapies (Biol Psychiatry. 2014 Aug 1;76[3]:194-202. doi: 10.1016/j.biopsych.2013.11.030).“The findings were against my personal expectations,” Dr. Bajbouj said. Those expectations cost him: In a bet with a coinvestigator who predicted that the talk therapy arm would outperform the others, “I ended up having to buy her a bottle of champagne.”

A third of the initial study group did not respond to the initial acute ECT. But of the 60 who did and who were randomly assigned their add-on therapy, and followed at 6 months and 1 year, 77% of those given CBT plus medication remained in remission at 6 months, and an impressive 65% did so at 1 year. Meanwhile, the medication plus ECT group had a 40% remission rate at 6 months and a 28% remission rate at 1 year. The medication-only arm had a remission rate of 44% at 6 months and 33% at 1 year.

Dr. Bajbouj suggested some factors that might have turned the results against his own calculations.

For example, in the medication arm, patients were not given standardized treatments of nortriptyline and lithium, as established as effective by Harold A. Sackeim, Ph.D., and his colleagues (JAMA. 2001 Mar 14;285[10]:1299-307), but were treated according to current guidelines to both accelerate recruitment rates as well as to avoid any adverse cognitive effects from the interaction of nortriptyline and lithium with ECT.

“We might discuss whether this reduced the likelihood that the people maintained their response rates,” Dr. Bajbouj said. Nearly three-quarters of those in the medication arm were taking two or more antidepressants, more than half were taking an antipsychotic, and a third were taking a mood stabilizer.

An additional factor also could have been the underlying refractory nature of the depression across the cohorts, since after the acute ECT treatment phase, patients in the CBT arm had lower remission rates, compared with the other arms (47% vs. 55% in the ECT plus medication arm, and 64% in the medication-only arm) and had higher Hamilton Rating Scale for Depression scores (24-question version) than the other two groups (8.4 points vs. 5.6 in the ECT plus medication arm and 6.3 in the medication-only arm).

The choice of which type of ECT is best for continuation therapy also is in question. In this single-center study conducted in Berlin between 2004 and 2010, ultrabrief pulse ECT was administered weekly for 4 weeks, biweekly for 8 weeks, and monthly for 3 months, titrated based on the individual seizure threshold established during the first continuation treatment and kept constant thereafter.

In the study, Dr. Bajbouj and his coauthors noted that the results indicated that ultrabrief ECT as a continuation therapy might be less effective than more established forms of ECT with broader pulse widths. “The way we did the continuation ECT therapy is not the way we would do it today,” Dr. Bajbouj said.

So, what of this question of how to factor in possible synergies created when multiple treatments are administered? Dr. Bajbouj pointed to another of his studies, this one done to determine whether the molecular mechanisms of the pretreatments ketamine or lithium used in repetitive transcranial magnetic stimulation affected outcomes (Eur Arch Psychiatry Clin Neurosci. 2012 Feb;262[1]:87-91. doi: 10.1007/s00406-011-0217-3).

Dr. Bajbouj and his colleagues found that pretreatment with ketamine potentiated neuronal cells, while pretreatment with lithium attenuated the cellular response to repetitive magnetic stimulation.

“It’s very oversimplified,” Dr. Bajbouj said. However, a difference in cellular synergies was found, leading Dr. Bajbouj to say that the notion of treatment synergies is “not adequately regarded currently in the field of ECT.”

In the meantime, Dr. Bajbouj laid out a “wish list” for how he’d like to see ECT as well as other brain stimulation techniques become integrated into the mainstream of treatment techniques for depression. Included were the broader use of transcranial magnetic stimulation, more ECT in the depressed elderly and in those with refractory depression, and direct brain stimulation, which he said “might be something for the very severely ill and could prevent relapse.”

It might be a while, though. Despite plenty of data in support of ECT and Dr. Bajbouj’s own data in favor of combining CBT with pharmacotherapy after ECT, the results from an Internet survey showed that, “If you were to ask patients in Germany what they would do if they were depressed, ECT doesn’t even appear.” In the survey, psychotherapy ranked first. “Take antidepressants” ranked between “eat chocolate” and “go on vacation.”

Dr. Bajbouj did not have any relevant disclosures.

[email protected]

On Twitter @whitneymcknight

AMSTERDAM – Despite persistent stigma, electroconvulsive therapy endures as an effective treatment for depression, particularly when applied with a patient-specific approach, according to several study results presented at the annual congress of the European College of Neuropsychopharmacology.

Dr. Charles Kellner, professor of psychiatry at the Icahn School of Medicine at Mount Sinai, New York, said ECT is well established as effective in elderly populations with depression and is notable for its ability to rapidly curb suicidal ideation, as shown by unpublished data from his PRIDE study (Prolonging Remission in Depressed Elderly, NCT01028508). That study showed an 85% drop in suicidality in patients by the end of their ECT treatment course.

“ECT would be one of the very best treatments in all of medicine” if not for several factors, Dr. Kellner said. ECT cannot prevent relapse in depression unless it is used as maintenance therapy, and varying degrees of negative cognitive impact can come with the procedure, he said. In addition, ECT has been stigmatized by the popular media and others in the profession, and by the antipsychiatry movement, he said.

Despite all this, burgeoning data indicate clinicians have a variety of effective and efficacious ECT methods from which to choose. The overall calculus for which ECT method is best in a specific case “is severity of illness,” Dr. Kellner said in an interview. “It’s usually driven by suicidality and how dysfunctional the patient has become.”

In Dr. Kellner’s PRIDE phase I study, data indicated that 40% of 240 consenting patients with a mean age of 70 years and unipolar depression, given ultrabrief pulse right unilateral ECT three times weekly until remission, and augmented by a low dose of the selective serotonin reuptake inhibitor venlafaxine (up to 225 mg per day after any previous medication washout), were successfully treated for their depression after 1 week.

The response criteria was a 50% or greater reduction from baseline in at least 21 of 24 items on the Hamilton Rating Scale for Depression (HAM-D-24) after 1 week, while remission was defined as scoring 10 or less on the HAM-D-24 at two consecutive follow-up points each week. After two treatments, 8% of responders achieved remission, and nearly 18% remitted after a full week.

Meanwhile, patients who did not complete the study or meet the response and remission criteria still benefited, Dr. Kellner said. “Nonremitters [about 28% of the study] and dropouts [about 10%] get considerably better from whatever ECT they are able to have.”

ECT with a pulse width of less than 0.5 milliseconds is considered ultrabrief pulse ECT. Pulse widths of 0.5 msec or higher are considered standard ECT. Seizures induced by any pulse width are the theorized mechanism of action for reducing depression with ECT, but correlates between higher levels of energy and greater levels of negative cognitive effects are well established in the literature. Presenter Dr. Pascal Sienaert, a psychiatrist and director of the ECT program at the Catholic University of Leuven (Belgium), said that because the “ideal stimulus to depolarize a group of neurons would be 0.1 or 0.2 milliseconds,” ultrabrief pulse ECT should “theoretically” be the most effective with the least cognitive burden.

Whitney McKnight/Frontline Medical News

In the PRIDE study, nearly 85% of participants seized at the lowest stimulus dose during their first treatment when ultralow doses were used to determine each patient’s seizure threshold. Given the age of the cohort, this was a fortunate surprise, Dr. Kellner said, since it allowed subsequent dosing at six times the seizure threshold at low absolute stimulus charges. “This is a very efficient form of ECT for inducing a seizure,” Dr. Kellner said in his presentation.

About 10% of responders in the study experienced more than a 50% drop in their HAM-D scores after one treatment at the ultralow dose, which has created some debate over whether it was a placebo response. Dr. Kellner rejected this theory. “I think ECT is such a powerful biological treatment, it’s very hard to ascribe this to placebo.”

Rates of remission varied greatly in the PRIDE study, ranging from 20% remitting after 4 treatments, to 26% remitting after 10 treatments. “This speaks to the point that you can’t tell a patient how long their treatment will be. Some need fewer treatments; some need prolonged courses.”

But Dr. Sienaert’s own findings cast doubt on the ability of ultrabrief pulse ECT to ensure fewer cognitive burdens than standard ECT.

In a randomized comparison of ultrabrief bifrontal and unilateral ECT for patients with refractory depression, no significant differences were found in response and remission rates. However, the cohort treated with right unilateral ultrabrief pulse ECT required fewer treatments to reach response and remission (J Affect Disord. 2010 Apr;122[1-2]:60-7. doi: 10.1016/j.jad.2009.06.011).

Although all patients had baseline deficits across the cognitive domains, Dr. Sienaert’s study did not find any additional declines in cognition following ECT in either arm. Because the entire study group overall remained cognitively impaired, Dr. Sienaert theorized the sample was either previously cognitively scarred, putting them at risk for depression, or that the inverse was true: their depression left them vulnerable to cognitive deficits.

Taken with the results of a second study by Dr. Sienaert, there doesn’t seem to be any notable cognitive advantage to ultrabrief pulse ECT.

In the second study, a randomized, controlled comparison of right unilateral ultrabrief pulse ECT with right unilateral standard pulse ECT in 116 patients, standard pulse ECT performed significantly better than did ultrabrief pulse ECT, and had similar relapse rates at 3 and 6 months. Most of the patients in the study were women in their early 60s who were taking medication for their depression (J Affect Disord. 2015 Sep 15;184:137-44. doi: 10.1016/j.jad.2015.05.22).

Remission rates in both those who dropped out (58%) of the standard group and those who completed the standard ECT treatments (68.4%) were higher, compared with the ultrabrief intention-to-treat (41.4%) and completion (49%) groups. The standard ECT group also needed, on average, two fewer treatments to reach remission (7 vs. 9). Cognitive burdens in the two therapies were comparable.

However, a recently published meta-analysis of both standard and ultrabrief pulse ECT found that while ultrabrief pulse ECT has lower remission rates than standard ECT, it is associated with having less of a cognitive impact (J Clin Psychiatry. 2015 Jul 21).

Even though, according to Dr. Sienaert, many clinicians have changed their practice, adopting ultrabrief pulse ECT for all patients, he told the audience: “I don’t think it should be the standard of care. There is not one single technique that should be ... the data give us possibilities to tailor treatment to our patients.”

Having a range of treatments also helps to persuade patients who might be put off by near sadistic depictions of “shock therapy” in popular culture such as in the movie “One Flew Over the Cuckoo’s Nest” based on the novel by Ken Kesey and released in 1975. “It’s still responsible for the vast majority of stigma surrounding ECT,” Dr. Kellner said.

In an interview, Dr. Sienaert said having more options means, “You can choose treatments with less cognitive side effects for patients who are either afraid of [experiencing cognitive deficits] or who already have cognitive issues, such as might be in the elderly.”

Data presented by Dr. Declan McLoughlin, a research professor of psychiatry at Trinity College Dublin, considered the question of whether a specific ECT treatment’s efficacy might be outweighed by a lack of effectiveness.

Whitney McKnight/Frontline Medical News

Previous trials have tested whether standard bitemporal ECT has better efficacy than that of high-dose unilateral ECT, but whether a cognitive impact was too great proved unclear.

In a currently unpublished study, Dr. McLoughlin and his associates showed that both forms of treatment were efficacious and effective. The upshot was that high-dose ECT was not inferior and offered some cognitive advantages, “Particularly if cognitive side effects are an issue to begin with,” he said.

The study randomly assigned 138 patients with severe depression, two-thirds of whom were women primarily in their late 50s, to receive standard bitemporal ECT at 1.5 times the patient’s established seizure threshold twice weekly, or high-dose right unilateral ECT at 6.0 times the patient’s seizure threshold twice weekly. Patients received up to 12 sessions depending upon the treatment recommended by the individual clinician. All participants, except for the clinicians administering the treatments, were blinded. Patients were rated for their response and remission rates after every second ECT treatment and were followed for 12 months after their last treatment.

Nearly 51% of patients in the low-dose group met the primary clinical outcome with a 60% or greater change from baseline on their HAM-D-24, scoring 16 or less. Just under 61% of patients met the response criteria in the high-dose group.

Forty-two percent of patients in the low-dose group met remission criteria of at least a 60% decrease in their baseline HAM-D with a score of 10 or less on two consecutive rating sessions, while just over 46% did in the high-dose group.

“Over time, the unilateral group did slightly better, including at 6 months’ follow-up,” Dr. McLoughlin said.

The higher dose group outperformed the lower-dose group by just over 1 point on the HAM-D scores, within the noninferiority threshold.

At 6 months, nearly a third of remitters in each group had relapsed with a 10-point or higher increase from their HAM-D taken at the end of their treatment.

The high-dose patients also experienced less impairment to their autobiographical memory (details they told the clinician before receiving ECT) directly after treatment and at 6-month follow-up. The low-dose patients overall recalled about 60% of their autobiographical memory, compared with the high dose group’s 70%. However, Dr. McLoughlin noted that this is normal in the general population, “but it’s probably a bit worse in depressed patients.”

An as yet unpublished meta-analysis Dr. McLoughlin and his colleagues conducted of the six previous trials comparing the efficacy of these two forms of ECT also found no significant difference between the two regarding response or remission, and that higher doses of ECT offered better reorientation times, and better retrograde autobiographical memory, with no differences in global cognition, complex figure tests, or verbal learning.

While cognitive data from the PRIDE phase I and efficacy data from the study’s phase II are forthcoming, according to Dr. Kellner, he agreed with Dr. McLoughlin that overall, bilateral treatments were better, although the unilateral treatments approach the same efficacy levels. Ultimately, however, group data are irrelevant if they fail to jibe with what is happening in front of a clinician treating a patient.

“For an individual patient who doesn’t respond to right unilateral ECT, it’s imperative they be switched over to a different form of ECT,” said Dr. Kellner, since many right unilateral nonresponders will do well with bilateral ECT. “Particularly if patients are urgently ill, one should consider using bilateral ECT from the outset. I still believe that is a true clinical dictum.”

The lineup of international ECT experts drew roughly 200 audience members, the largest such ECT audiences Dr. Kellner and Dr. Sienaert said they’d ever seen.

“The biggest problem is ECT remains stigmatized,” Dr. Kellner said. “It needs to be said at any ECT gathering.”

Dr. Kellner is a consultant to Luitpold Pharmaceuticals. Dr. Sienaert noted he had received travel expenses in the past year from MECTA, and Dr. McLoughlin had no relevant disclosures.

[email protected]

On Twitter @whitneymcknight

AMSTERDAM – Despite persistent stigma, electroconvulsive therapy endures as an effective treatment for depression, particularly when applied with a patient-specific approach, according to several study results presented at the annual congress of the European College of Neuropsychopharmacology.

Dr. Charles Kellner, professor of psychiatry at the Icahn School of Medicine at Mount Sinai, New York, said ECT is well established as effective in elderly populations with depression and is notable for its ability to rapidly curb suicidal ideation, as shown by unpublished data from his PRIDE study (Prolonging Remission in Depressed Elderly, NCT01028508). That study showed an 85% drop in suicidality in patients by the end of their ECT treatment course.

“ECT would be one of the very best treatments in all of medicine” if not for several factors, Dr. Kellner said. ECT cannot prevent relapse in depression unless it is used as maintenance therapy, and varying degrees of negative cognitive impact can come with the procedure, he said. In addition, ECT has been stigmatized by the popular media and others in the profession, and by the antipsychiatry movement, he said.

Despite all this, burgeoning data indicate clinicians have a variety of effective and efficacious ECT methods from which to choose. The overall calculus for which ECT method is best in a specific case “is severity of illness,” Dr. Kellner said in an interview. “It’s usually driven by suicidality and how dysfunctional the patient has become.”

In Dr. Kellner’s PRIDE phase I study, data indicated that 40% of 240 consenting patients with a mean age of 70 years and unipolar depression, given ultrabrief pulse right unilateral ECT three times weekly until remission, and augmented by a low dose of the selective serotonin reuptake inhibitor venlafaxine (up to 225 mg per day after any previous medication washout), were successfully treated for their depression after 1 week.

The response criteria was a 50% or greater reduction from baseline in at least 21 of 24 items on the Hamilton Rating Scale for Depression (HAM-D-24) after 1 week, while remission was defined as scoring 10 or less on the HAM-D-24 at two consecutive follow-up points each week. After two treatments, 8% of responders achieved remission, and nearly 18% remitted after a full week.

Meanwhile, patients who did not complete the study or meet the response and remission criteria still benefited, Dr. Kellner said. “Nonremitters [about 28% of the study] and dropouts [about 10%] get considerably better from whatever ECT they are able to have.”

ECT with a pulse width of less than 0.5 milliseconds is considered ultrabrief pulse ECT. Pulse widths of 0.5 msec or higher are considered standard ECT. Seizures induced by any pulse width are the theorized mechanism of action for reducing depression with ECT, but correlates between higher levels of energy and greater levels of negative cognitive effects are well established in the literature. Presenter Dr. Pascal Sienaert, a psychiatrist and director of the ECT program at the Catholic University of Leuven (Belgium), said that because the “ideal stimulus to depolarize a group of neurons would be 0.1 or 0.2 milliseconds,” ultrabrief pulse ECT should “theoretically” be the most effective with the least cognitive burden.

Whitney McKnight/Frontline Medical News

In the PRIDE study, nearly 85% of participants seized at the lowest stimulus dose during their first treatment when ultralow doses were used to determine each patient’s seizure threshold. Given the age of the cohort, this was a fortunate surprise, Dr. Kellner said, since it allowed subsequent dosing at six times the seizure threshold at low absolute stimulus charges. “This is a very efficient form of ECT for inducing a seizure,” Dr. Kellner said in his presentation.

About 10% of responders in the study experienced more than a 50% drop in their HAM-D scores after one treatment at the ultralow dose, which has created some debate over whether it was a placebo response. Dr. Kellner rejected this theory. “I think ECT is such a powerful biological treatment, it’s very hard to ascribe this to placebo.”

Rates of remission varied greatly in the PRIDE study, ranging from 20% remitting after 4 treatments, to 26% remitting after 10 treatments. “This speaks to the point that you can’t tell a patient how long their treatment will be. Some need fewer treatments; some need prolonged courses.”

But Dr. Sienaert’s own findings cast doubt on the ability of ultrabrief pulse ECT to ensure fewer cognitive burdens than standard ECT.

In a randomized comparison of ultrabrief bifrontal and unilateral ECT for patients with refractory depression, no significant differences were found in response and remission rates. However, the cohort treated with right unilateral ultrabrief pulse ECT required fewer treatments to reach response and remission (J Affect Disord. 2010 Apr;122[1-2]:60-7. doi: 10.1016/j.jad.2009.06.011).

Although all patients had baseline deficits across the cognitive domains, Dr. Sienaert’s study did not find any additional declines in cognition following ECT in either arm. Because the entire study group overall remained cognitively impaired, Dr. Sienaert theorized the sample was either previously cognitively scarred, putting them at risk for depression, or that the inverse was true: their depression left them vulnerable to cognitive deficits.

Taken with the results of a second study by Dr. Sienaert, there doesn’t seem to be any notable cognitive advantage to ultrabrief pulse ECT.

In the second study, a randomized, controlled comparison of right unilateral ultrabrief pulse ECT with right unilateral standard pulse ECT in 116 patients, standard pulse ECT performed significantly better than did ultrabrief pulse ECT, and had similar relapse rates at 3 and 6 months. Most of the patients in the study were women in their early 60s who were taking medication for their depression (J Affect Disord. 2015 Sep 15;184:137-44. doi: 10.1016/j.jad.2015.05.22).

Remission rates in both those who dropped out (58%) of the standard group and those who completed the standard ECT treatments (68.4%) were higher, compared with the ultrabrief intention-to-treat (41.4%) and completion (49%) groups. The standard ECT group also needed, on average, two fewer treatments to reach remission (7 vs. 9). Cognitive burdens in the two therapies were comparable.

However, a recently published meta-analysis of both standard and ultrabrief pulse ECT found that while ultrabrief pulse ECT has lower remission rates than standard ECT, it is associated with having less of a cognitive impact (J Clin Psychiatry. 2015 Jul 21).

Even though, according to Dr. Sienaert, many clinicians have changed their practice, adopting ultrabrief pulse ECT for all patients, he told the audience: “I don’t think it should be the standard of care. There is not one single technique that should be ... the data give us possibilities to tailor treatment to our patients.”

Having a range of treatments also helps to persuade patients who might be put off by near sadistic depictions of “shock therapy” in popular culture such as in the movie “One Flew Over the Cuckoo’s Nest” based on the novel by Ken Kesey and released in 1975. “It’s still responsible for the vast majority of stigma surrounding ECT,” Dr. Kellner said.

In an interview, Dr. Sienaert said having more options means, “You can choose treatments with less cognitive side effects for patients who are either afraid of [experiencing cognitive deficits] or who already have cognitive issues, such as might be in the elderly.”

Data presented by Dr. Declan McLoughlin, a research professor of psychiatry at Trinity College Dublin, considered the question of whether a specific ECT treatment’s efficacy might be outweighed by a lack of effectiveness.

Whitney McKnight/Frontline Medical News

Previous trials have tested whether standard bitemporal ECT has better efficacy than that of high-dose unilateral ECT, but whether a cognitive impact was too great proved unclear.

In a currently unpublished study, Dr. McLoughlin and his associates showed that both forms of treatment were efficacious and effective. The upshot was that high-dose ECT was not inferior and offered some cognitive advantages, “Particularly if cognitive side effects are an issue to begin with,” he said.

The study randomly assigned 138 patients with severe depression, two-thirds of whom were women primarily in their late 50s, to receive standard bitemporal ECT at 1.5 times the patient’s established seizure threshold twice weekly, or high-dose right unilateral ECT at 6.0 times the patient’s seizure threshold twice weekly. Patients received up to 12 sessions depending upon the treatment recommended by the individual clinician. All participants, except for the clinicians administering the treatments, were blinded. Patients were rated for their response and remission rates after every second ECT treatment and were followed for 12 months after their last treatment.

Nearly 51% of patients in the low-dose group met the primary clinical outcome with a 60% or greater change from baseline on their HAM-D-24, scoring 16 or less. Just under 61% of patients met the response criteria in the high-dose group.

Forty-two percent of patients in the low-dose group met remission criteria of at least a 60% decrease in their baseline HAM-D with a score of 10 or less on two consecutive rating sessions, while just over 46% did in the high-dose group.

“Over time, the unilateral group did slightly better, including at 6 months’ follow-up,” Dr. McLoughlin said.

The higher dose group outperformed the lower-dose group by just over 1 point on the HAM-D scores, within the noninferiority threshold.

At 6 months, nearly a third of remitters in each group had relapsed with a 10-point or higher increase from their HAM-D taken at the end of their treatment.

The high-dose patients also experienced less impairment to their autobiographical memory (details they told the clinician before receiving ECT) directly after treatment and at 6-month follow-up. The low-dose patients overall recalled about 60% of their autobiographical memory, compared with the high dose group’s 70%. However, Dr. McLoughlin noted that this is normal in the general population, “but it’s probably a bit worse in depressed patients.”

An as yet unpublished meta-analysis Dr. McLoughlin and his colleagues conducted of the six previous trials comparing the efficacy of these two forms of ECT also found no significant difference between the two regarding response or remission, and that higher doses of ECT offered better reorientation times, and better retrograde autobiographical memory, with no differences in global cognition, complex figure tests, or verbal learning.

While cognitive data from the PRIDE phase I and efficacy data from the study’s phase II are forthcoming, according to Dr. Kellner, he agreed with Dr. McLoughlin that overall, bilateral treatments were better, although the unilateral treatments approach the same efficacy levels. Ultimately, however, group data are irrelevant if they fail to jibe with what is happening in front of a clinician treating a patient.

“For an individual patient who doesn’t respond to right unilateral ECT, it’s imperative they be switched over to a different form of ECT,” said Dr. Kellner, since many right unilateral nonresponders will do well with bilateral ECT. “Particularly if patients are urgently ill, one should consider using bilateral ECT from the outset. I still believe that is a true clinical dictum.”

The lineup of international ECT experts drew roughly 200 audience members, the largest such ECT audiences Dr. Kellner and Dr. Sienaert said they’d ever seen.

“The biggest problem is ECT remains stigmatized,” Dr. Kellner said. “It needs to be said at any ECT gathering.”

Dr. Kellner is a consultant to Luitpold Pharmaceuticals. Dr. Sienaert noted he had received travel expenses in the past year from MECTA, and Dr. McLoughlin had no relevant disclosures.

[email protected]

On Twitter @whitneymcknight

AMSTERDAM – Despite persistent stigma, electroconvulsive therapy endures as an effective treatment for depression, particularly when applied with a patient-specific approach, according to several study results presented at the annual congress of the European College of Neuropsychopharmacology.

Dr. Charles Kellner, professor of psychiatry at the Icahn School of Medicine at Mount Sinai, New York, said ECT is well established as effective in elderly populations with depression and is notable for its ability to rapidly curb suicidal ideation, as shown by unpublished data from his PRIDE study (Prolonging Remission in Depressed Elderly, NCT01028508). That study showed an 85% drop in suicidality in patients by the end of their ECT treatment course.

“ECT would be one of the very best treatments in all of medicine” if not for several factors, Dr. Kellner said. ECT cannot prevent relapse in depression unless it is used as maintenance therapy, and varying degrees of negative cognitive impact can come with the procedure, he said. In addition, ECT has been stigmatized by the popular media and others in the profession, and by the antipsychiatry movement, he said.

Despite all this, burgeoning data indicate clinicians have a variety of effective and efficacious ECT methods from which to choose. The overall calculus for which ECT method is best in a specific case “is severity of illness,” Dr. Kellner said in an interview. “It’s usually driven by suicidality and how dysfunctional the patient has become.”

In Dr. Kellner’s PRIDE phase I study, data indicated that 40% of 240 consenting patients with a mean age of 70 years and unipolar depression, given ultrabrief pulse right unilateral ECT three times weekly until remission, and augmented by a low dose of the selective serotonin reuptake inhibitor venlafaxine (up to 225 mg per day after any previous medication washout), were successfully treated for their depression after 1 week.

The response criteria was a 50% or greater reduction from baseline in at least 21 of 24 items on the Hamilton Rating Scale for Depression (HAM-D-24) after 1 week, while remission was defined as scoring 10 or less on the HAM-D-24 at two consecutive follow-up points each week. After two treatments, 8% of responders achieved remission, and nearly 18% remitted after a full week.

Meanwhile, patients who did not complete the study or meet the response and remission criteria still benefited, Dr. Kellner said. “Nonremitters [about 28% of the study] and dropouts [about 10%] get considerably better from whatever ECT they are able to have.”

ECT with a pulse width of less than 0.5 milliseconds is considered ultrabrief pulse ECT. Pulse widths of 0.5 msec or higher are considered standard ECT. Seizures induced by any pulse width are the theorized mechanism of action for reducing depression with ECT, but correlates between higher levels of energy and greater levels of negative cognitive effects are well established in the literature. Presenter Dr. Pascal Sienaert, a psychiatrist and director of the ECT program at the Catholic University of Leuven (Belgium), said that because the “ideal stimulus to depolarize a group of neurons would be 0.1 or 0.2 milliseconds,” ultrabrief pulse ECT should “theoretically” be the most effective with the least cognitive burden.

Whitney McKnight/Frontline Medical News

In the PRIDE study, nearly 85% of participants seized at the lowest stimulus dose during their first treatment when ultralow doses were used to determine each patient’s seizure threshold. Given the age of the cohort, this was a fortunate surprise, Dr. Kellner said, since it allowed subsequent dosing at six times the seizure threshold at low absolute stimulus charges. “This is a very efficient form of ECT for inducing a seizure,” Dr. Kellner said in his presentation.

About 10% of responders in the study experienced more than a 50% drop in their HAM-D scores after one treatment at the ultralow dose, which has created some debate over whether it was a placebo response. Dr. Kellner rejected this theory. “I think ECT is such a powerful biological treatment, it’s very hard to ascribe this to placebo.”

Rates of remission varied greatly in the PRIDE study, ranging from 20% remitting after 4 treatments, to 26% remitting after 10 treatments. “This speaks to the point that you can’t tell a patient how long their treatment will be. Some need fewer treatments; some need prolonged courses.”

But Dr. Sienaert’s own findings cast doubt on the ability of ultrabrief pulse ECT to ensure fewer cognitive burdens than standard ECT.

In a randomized comparison of ultrabrief bifrontal and unilateral ECT for patients with refractory depression, no significant differences were found in response and remission rates. However, the cohort treated with right unilateral ultrabrief pulse ECT required fewer treatments to reach response and remission (J Affect Disord. 2010 Apr;122[1-2]:60-7. doi: 10.1016/j.jad.2009.06.011).

Although all patients had baseline deficits across the cognitive domains, Dr. Sienaert’s study did not find any additional declines in cognition following ECT in either arm. Because the entire study group overall remained cognitively impaired, Dr. Sienaert theorized the sample was either previously cognitively scarred, putting them at risk for depression, or that the inverse was true: their depression left them vulnerable to cognitive deficits.

Taken with the results of a second study by Dr. Sienaert, there doesn’t seem to be any notable cognitive advantage to ultrabrief pulse ECT.

In the second study, a randomized, controlled comparison of right unilateral ultrabrief pulse ECT with right unilateral standard pulse ECT in 116 patients, standard pulse ECT performed significantly better than did ultrabrief pulse ECT, and had similar relapse rates at 3 and 6 months. Most of the patients in the study were women in their early 60s who were taking medication for their depression (J Affect Disord. 2015 Sep 15;184:137-44. doi: 10.1016/j.jad.2015.05.22).

Remission rates in both those who dropped out (58%) of the standard group and those who completed the standard ECT treatments (68.4%) were higher, compared with the ultrabrief intention-to-treat (41.4%) and completion (49%) groups. The standard ECT group also needed, on average, two fewer treatments to reach remission (7 vs. 9). Cognitive burdens in the two therapies were comparable.

However, a recently published meta-analysis of both standard and ultrabrief pulse ECT found that while ultrabrief pulse ECT has lower remission rates than standard ECT, it is associated with having less of a cognitive impact (J Clin Psychiatry. 2015 Jul 21).

Even though, according to Dr. Sienaert, many clinicians have changed their practice, adopting ultrabrief pulse ECT for all patients, he told the audience: “I don’t think it should be the standard of care. There is not one single technique that should be ... the data give us possibilities to tailor treatment to our patients.”

Having a range of treatments also helps to persuade patients who might be put off by near sadistic depictions of “shock therapy” in popular culture such as in the movie “One Flew Over the Cuckoo’s Nest” based on the novel by Ken Kesey and released in 1975. “It’s still responsible for the vast majority of stigma surrounding ECT,” Dr. Kellner said.

In an interview, Dr. Sienaert said having more options means, “You can choose treatments with less cognitive side effects for patients who are either afraid of [experiencing cognitive deficits] or who already have cognitive issues, such as might be in the elderly.”

Data presented by Dr. Declan McLoughlin, a research professor of psychiatry at Trinity College Dublin, considered the question of whether a specific ECT treatment’s efficacy might be outweighed by a lack of effectiveness.

Whitney McKnight/Frontline Medical News

Previous trials have tested whether standard bitemporal ECT has better efficacy than that of high-dose unilateral ECT, but whether a cognitive impact was too great proved unclear.

In a currently unpublished study, Dr. McLoughlin and his associates showed that both forms of treatment were efficacious and effective. The upshot was that high-dose ECT was not inferior and offered some cognitive advantages, “Particularly if cognitive side effects are an issue to begin with,” he said.

The study randomly assigned 138 patients with severe depression, two-thirds of whom were women primarily in their late 50s, to receive standard bitemporal ECT at 1.5 times the patient’s established seizure threshold twice weekly, or high-dose right unilateral ECT at 6.0 times the patient’s seizure threshold twice weekly. Patients received up to 12 sessions depending upon the treatment recommended by the individual clinician. All participants, except for the clinicians administering the treatments, were blinded. Patients were rated for their response and remission rates after every second ECT treatment and were followed for 12 months after their last treatment.

Nearly 51% of patients in the low-dose group met the primary clinical outcome with a 60% or greater change from baseline on their HAM-D-24, scoring 16 or less. Just under 61% of patients met the response criteria in the high-dose group.

Forty-two percent of patients in the low-dose group met remission criteria of at least a 60% decrease in their baseline HAM-D with a score of 10 or less on two consecutive rating sessions, while just over 46% did in the high-dose group.

“Over time, the unilateral group did slightly better, including at 6 months’ follow-up,” Dr. McLoughlin said.

The higher dose group outperformed the lower-dose group by just over 1 point on the HAM-D scores, within the noninferiority threshold.

At 6 months, nearly a third of remitters in each group had relapsed with a 10-point or higher increase from their HAM-D taken at the end of their treatment.

The high-dose patients also experienced less impairment to their autobiographical memory (details they told the clinician before receiving ECT) directly after treatment and at 6-month follow-up. The low-dose patients overall recalled about 60% of their autobiographical memory, compared with the high dose group’s 70%. However, Dr. McLoughlin noted that this is normal in the general population, “but it’s probably a bit worse in depressed patients.”

An as yet unpublished meta-analysis Dr. McLoughlin and his colleagues conducted of the six previous trials comparing the efficacy of these two forms of ECT also found no significant difference between the two regarding response or remission, and that higher doses of ECT offered better reorientation times, and better retrograde autobiographical memory, with no differences in global cognition, complex figure tests, or verbal learning.

While cognitive data from the PRIDE phase I and efficacy data from the study’s phase II are forthcoming, according to Dr. Kellner, he agreed with Dr. McLoughlin that overall, bilateral treatments were better, although the unilateral treatments approach the same efficacy levels. Ultimately, however, group data are irrelevant if they fail to jibe with what is happening in front of a clinician treating a patient.

“For an individual patient who doesn’t respond to right unilateral ECT, it’s imperative they be switched over to a different form of ECT,” said Dr. Kellner, since many right unilateral nonresponders will do well with bilateral ECT. “Particularly if patients are urgently ill, one should consider using bilateral ECT from the outset. I still believe that is a true clinical dictum.”

The lineup of international ECT experts drew roughly 200 audience members, the largest such ECT audiences Dr. Kellner and Dr. Sienaert said they’d ever seen.

“The biggest problem is ECT remains stigmatized,” Dr. Kellner said. “It needs to be said at any ECT gathering.”

Dr. Kellner is a consultant to Luitpold Pharmaceuticals. Dr. Sienaert noted he had received travel expenses in the past year from MECTA, and Dr. McLoughlin had no relevant disclosures.

[email protected]

On Twitter @whitneymcknight