Michele G. Sullivan

A cognitive-behavioral couples therapy specially targeted at posttraumatic stress disorder helped improve symptoms and increased patient satisfaction within the relationship.

"There is increasing recognition that intimate relationships play a potent role in recovery from PTSD, its comorbid symptoms, and the psychosocial impairments that accompany it," Candice M. Monson, Ph.D., and her colleagues wrote in the Aug. 15 issue of JAMA. "Cognitive behavioral conjoint therapy may be used to efficiently address individual and relational dimensions of traumatization and might be indicated for individuals with PTSD who have stable relationships and partners who are willing to engage in treatment with them."

DoxaDigital/iStock

Dr. Monson, professor of psychology at Ryerson University in Toronto, examined the efficacy of an intervention called cognitive-behavioral conjoint therapy, which stressed education, communication, and conflict resolution. She and her associates randomized 40 couples to either the 3-month PTSD program or a wait list. The primary end point was change on the CAPS (Clinician-Administered PTSD Scale). Secondary end points included change on the PTSD Checklist, the DAS (Dyadic Adjustment Scale), the BDI (Beck Depression Inventory), and the State-Trait Anxiety Inventory (JAMA 2012;308:700-9).

The participants were a mean of 40 years old and had been married for 5-8 years. Causes of PTSD included adult or childhood sexual trauma, noncombat physical assault, motor vehicle collision, witnessing or learning about death or illness, and combat-related issues. Time since the trauma ranged from 44 years to fewer than 12 months. Many of the partners with PTSD also had at least one comorbid condition, including mood disorder (up to 90%), anxiety disorder (50%), and substance abuse or dependence (45%).

The intervention consisted of 15 sessions covering three psychosocial realms; the sessions were held twice a week. Phase 1 targeted learning about PTSD and its relational effects. Phase 2 focused on enhanced communication. Phase 3 challenged couples to actively improve their relationships by putting these new skills to work. Couples also were followed for an additional 3 months to determine whether improvements could be maintained.

At the conclusion of the treatment period, PTSD symptom severity had decreased almost three times as much as it did in the control arm. Partner relationship satisfaction had improved four times more. There were also gains in the secondary end points of depression, anger, and anxiety.

After the 3-month follow-up period, 81% of couples reported sustained gains in PTSD symptoms and 81% no longer met the criteria for a PTSD diagnosis. All of the couples reported satisfaction with their relationship.

The investigators cautioned, however, that the relatively high partner satisfaction reported at baseline might have skewed the results somewhat. There was "little evidence of differences between the [intervention group] and the wait list in partner-reported relationship satisfaction, and partners’ ratings of PTSD symptom improvements were not as consistent with the clinicians’ ratings," they said.

Past research in this area yielded more partner-rated benefits, which were similar to those observed by clinicians, wrote Dr. Monson and her coauthors.

The study was sponsored by the National Institute of Mental Health. Dr. Monson had no financial declarations. Dr. Najavits reported no financial disclosures.

A cognitive-behavioral couples therapy specially targeted at posttraumatic stress disorder helped improve symptoms and increased patient satisfaction within the relationship.

"There is increasing recognition that intimate relationships play a potent role in recovery from PTSD, its comorbid symptoms, and the psychosocial impairments that accompany it," Candice M. Monson, Ph.D., and her colleagues wrote in the Aug. 15 issue of JAMA. "Cognitive behavioral conjoint therapy may be used to efficiently address individual and relational dimensions of traumatization and might be indicated for individuals with PTSD who have stable relationships and partners who are willing to engage in treatment with them."

DoxaDigital/iStock

Dr. Monson, professor of psychology at Ryerson University in Toronto, examined the efficacy of an intervention called cognitive-behavioral conjoint therapy, which stressed education, communication, and conflict resolution. She and her associates randomized 40 couples to either the 3-month PTSD program or a wait list. The primary end point was change on the CAPS (Clinician-Administered PTSD Scale). Secondary end points included change on the PTSD Checklist, the DAS (Dyadic Adjustment Scale), the BDI (Beck Depression Inventory), and the State-Trait Anxiety Inventory (JAMA 2012;308:700-9).

The participants were a mean of 40 years old and had been married for 5-8 years. Causes of PTSD included adult or childhood sexual trauma, noncombat physical assault, motor vehicle collision, witnessing or learning about death or illness, and combat-related issues. Time since the trauma ranged from 44 years to fewer than 12 months. Many of the partners with PTSD also had at least one comorbid condition, including mood disorder (up to 90%), anxiety disorder (50%), and substance abuse or dependence (45%).

The intervention consisted of 15 sessions covering three psychosocial realms; the sessions were held twice a week. Phase 1 targeted learning about PTSD and its relational effects. Phase 2 focused on enhanced communication. Phase 3 challenged couples to actively improve their relationships by putting these new skills to work. Couples also were followed for an additional 3 months to determine whether improvements could be maintained.

At the conclusion of the treatment period, PTSD symptom severity had decreased almost three times as much as it did in the control arm. Partner relationship satisfaction had improved four times more. There were also gains in the secondary end points of depression, anger, and anxiety.

After the 3-month follow-up period, 81% of couples reported sustained gains in PTSD symptoms and 81% no longer met the criteria for a PTSD diagnosis. All of the couples reported satisfaction with their relationship.

The investigators cautioned, however, that the relatively high partner satisfaction reported at baseline might have skewed the results somewhat. There was "little evidence of differences between the [intervention group] and the wait list in partner-reported relationship satisfaction, and partners’ ratings of PTSD symptom improvements were not as consistent with the clinicians’ ratings," they said.

Past research in this area yielded more partner-rated benefits, which were similar to those observed by clinicians, wrote Dr. Monson and her coauthors.

The study was sponsored by the National Institute of Mental Health. Dr. Monson had no financial declarations. Dr. Najavits reported no financial disclosures.

A cognitive-behavioral couples therapy specially targeted at posttraumatic stress disorder helped improve symptoms and increased patient satisfaction within the relationship.

"There is increasing recognition that intimate relationships play a potent role in recovery from PTSD, its comorbid symptoms, and the psychosocial impairments that accompany it," Candice M. Monson, Ph.D., and her colleagues wrote in the Aug. 15 issue of JAMA. "Cognitive behavioral conjoint therapy may be used to efficiently address individual and relational dimensions of traumatization and might be indicated for individuals with PTSD who have stable relationships and partners who are willing to engage in treatment with them."

DoxaDigital/iStock

Dr. Monson, professor of psychology at Ryerson University in Toronto, examined the efficacy of an intervention called cognitive-behavioral conjoint therapy, which stressed education, communication, and conflict resolution. She and her associates randomized 40 couples to either the 3-month PTSD program or a wait list. The primary end point was change on the CAPS (Clinician-Administered PTSD Scale). Secondary end points included change on the PTSD Checklist, the DAS (Dyadic Adjustment Scale), the BDI (Beck Depression Inventory), and the State-Trait Anxiety Inventory (JAMA 2012;308:700-9).

The participants were a mean of 40 years old and had been married for 5-8 years. Causes of PTSD included adult or childhood sexual trauma, noncombat physical assault, motor vehicle collision, witnessing or learning about death or illness, and combat-related issues. Time since the trauma ranged from 44 years to fewer than 12 months. Many of the partners with PTSD also had at least one comorbid condition, including mood disorder (up to 90%), anxiety disorder (50%), and substance abuse or dependence (45%).

The intervention consisted of 15 sessions covering three psychosocial realms; the sessions were held twice a week. Phase 1 targeted learning about PTSD and its relational effects. Phase 2 focused on enhanced communication. Phase 3 challenged couples to actively improve their relationships by putting these new skills to work. Couples also were followed for an additional 3 months to determine whether improvements could be maintained.

At the conclusion of the treatment period, PTSD symptom severity had decreased almost three times as much as it did in the control arm. Partner relationship satisfaction had improved four times more. There were also gains in the secondary end points of depression, anger, and anxiety.

After the 3-month follow-up period, 81% of couples reported sustained gains in PTSD symptoms and 81% no longer met the criteria for a PTSD diagnosis. All of the couples reported satisfaction with their relationship.

The investigators cautioned, however, that the relatively high partner satisfaction reported at baseline might have skewed the results somewhat. There was "little evidence of differences between the [intervention group] and the wait list in partner-reported relationship satisfaction, and partners’ ratings of PTSD symptom improvements were not as consistent with the clinicians’ ratings," they said.

Past research in this area yielded more partner-rated benefits, which were similar to those observed by clinicians, wrote Dr. Monson and her coauthors.

The study was sponsored by the National Institute of Mental Health. Dr. Monson had no financial declarations. Dr. Najavits reported no financial disclosures.

A proposal for a new way to classify seizures would modify the way they have been discussed and organized since 1989.

But the new system – put forth by a committee specially convened by the International League Against Epilepsy (ILAE) – isn’t finding friends in every corner. Its move away from expert opinion to clinical evidence has ruffled the feathers of some highly respected clinicians, who assert that the current system is well organized, logical, and has long been integrated into both education and practice.

The proposed classification and terminology scheme would follow a Darwinian-like "Tree of Life" organization. Seizures would be broadly grouped into generalized or focal, depending on their origin and propagation over hemispheres; etiology (structural/metabolic, genetic, or unknown); and finally, by diagnostic specificity.

In this new scheme, focal seizures are seen as those that originate within a neuronal network but are limited to one hemisphere. Seizures that rapidly activate bilateral neuronal networks are seen as generalized.

Generalized seizures could be further categorized by their clinical presentation (tonic, clonic, or a combination; atonic; myoclonic; or absence), age at manifestation, and into other symptoms (Epilepsia 2010;51:676-85).

The system also advises dropping some terms that could be confusing or emotionally charged. "Benign" doesn’t recognize that real problems may result from the condition, wrote primary author Anne T. Berg, Ph.D. Both "idiopathic" and "cryptogenic" can now mean "unknown cause," but can also designate highly drug responsive, or symptomatic. "Symptomatic" currently connotes a poor prognosis, while ignoring the concept that all seizures cause symptoms, she wrote in the document.

"In addition to being confusing, these current terms aren’t necessarily true," said Dr. Jeffrey R. Buchhalter, who was a member of the classification writing committee and is a pediatric neurologist at the Phoenix Children’s Hospital. "What this new system is all about is separating what we know is true from what we do not."

The proposed system doesn’t replace diagnostic classifications, Dr. Berg, a research professor at Northwestern University, Chicago, said in an interview.

A diagnosis can be made with the existing terms, like Lennox-Gastaut syndrome or childhood absence epilepsy. Instead, the proposed system attempts to logically organize them according to their fundamental relationships.

"What we propose looks at the individual pieces [of the disorders] separately and then asks ‘How often do these go together?’ The new system would also benefit research, because everyone – no matter what country – would be speaking the same scientific language, she added.

The committee’s proposal is based on scientific evidence, instead of relying heavily on expert opinion, as does the current scheme, which was created in 1989. The current system doesn’t allow for the enormous changes made in understanding what causes epilepsy and how it is best treated, Dr. Hans Luders said in an interview. Any descriptive method needs to include these advances in imaging, genetics, and pharmacotherapy. The new system incorporates those new understandings, but in doing so, it drops some cherished nomenclature.

"What we have now, in many cases, are named syndromes used as diagnostic labels," said Dr. Luders, a neurologist at Case Western Reserve University, Cleveland. "Syndromes are a constellation of clinical signs that tend to uniformly occur together. As we have become more sophisticated, what is a syndrome or not has become debatable. There are so many syndromes now that memorizing them has become quite confusing," both for neurologists and students.

"We’re moving away from consensus opinion of thought leaders, and from whom consensus opinion was derived, to evidence-based ideas. And in any evidence review, expert opinion is the lowest tier. It’s below level 4," Dr. Berg said.

As such, the new proposal is not without its detractors, she said. A March opinion piece in Epilepsia airs some of these issues (Epilepsia 2012;53:399-404). In it, Dr. Chrysostomos P. Panayiotopoulos argues that the proposed classification scheme "does not fulfill its intent to improve the [current] classifications."

Dr. Panayiotopoulos, a neurologist at the John Radcliffe Hospital in Headington, England, is also the first to have described Panayiotopoulos syndrome, a benign childhood epilepsy characterized by autonomic seizures and status epilepticus, and a shifting or multifocal electroencephalogram.

The new classification scheme "has met with considerable protest from several expert epileptologists" and doesn’t incorporate most of the classification changes suggested in the 2010 ILAE report, he wrote. But philosophical arguing hobbled that proposed system, and it was never actually adopted by the ILAE. Because of the field’s inability to agree on the 2010 document, much of the extant classification system is still the same as it was in 1989.

In his editorial, Dr. Panayiotopoulos expressed much concern about the proposed classification of focal seizures according to their manifestations. "Such a proposition defies the essence and the principal of any classification that requires an organization and a common language for communication."

Neglecting to rely upon expert opinion is a large error, he said. "The ILAE Commission could benefit by asking experts in basic and clinical science to provide a concise statement in their field of expertise as, for example, what are focal, myoclonic, or absence seizures, and their subtypes, their manifestations, and their possible pathophysiology."

Areas of disagreement should be "identified and stated clearly, with documentation of the reasons for it."

But this approach could throw the debate back into the turbulent waters of the last decades, Dr. Buchhalter said. The new proposal is just one in a long line of criteria adjustments – some of them accepted into use and many of them not.

"Before 1981, seizure classifications were based on semiology. Beginning then, though, things changed and we started to base classifications on EEG type. Then, as we gained knowledge about genetics and family history, we incorporated that information as well."

This led to an ILAE uproar – members said the system was too bulky and complicated, Dr. Buchhalter said. "A task force met and said this was just getting too confusing and that everything but indicators of focality or generalization should be stripped out. All the data on what the seizures looked like, family history, and genetics were all thrown out."

It wasn’t long before the complaints started. "Within 8 years, ILAE took a lot of heat," because of this oversimplified system. In 1986, there was a "paradigm shift," with the addition of information, such as developmental status, family history, and imaging findings. "We established measurable, objective criteria that recognized seizure types and syndromes as unique entities," Dr. Buchhalter said.

In another failed effort to simplify classification, Dr. Luders proposed a five-faceted semiology-based scheme. Seizures could be classified, he proposed, by localizing the epileptogenic zone and by seizure semiology, etiology, frequency, and medical comorbidities.

"All cases can be classified according to this five-dimensional system, even at an initial encounter when no detailed test results are available," he wrote in the German journal Der Nervenarzt. "Information from clinical tests such as MRI and EEG are translated into the best possible working hypothesis at the time of classification, allowing increased precision of the classification as additional information becomes available" (Nervenarzt 2006;77:961-9).

"I say forget all of these names and syndromes – you don’t have to use them," he said in an interview. "If you’re a general neurologist or psychiatrist who occasionally sees an epilepsy patient, these labels are very confusing. It’s much easier to handle [with the semiologic system], and this is the way we do it [at Case Medical Center]. It’s the same way that we classify any of the neurological diseases."

Dr. Luders’s suggestion was likewise unpopular, said both Dr. Buchhalter and Dr. Berg. And all three agreed on one thing: Change of any kind is difficult in a large group.

"When things like this are proposed, you have to factor in the emotional part," Dr. Buchhalter said. "People get used to concepts and don’t want to let them go."

Dr. Luders, Dr. Berg, Dr. Buchhalter, and Dr. Panayiotopoulos reported having no financial disclosures.

A proposal for a new way to classify seizures would modify the way they have been discussed and organized since 1989.

But the new system – put forth by a committee specially convened by the International League Against Epilepsy (ILAE) – isn’t finding friends in every corner. Its move away from expert opinion to clinical evidence has ruffled the feathers of some highly respected clinicians, who assert that the current system is well organized, logical, and has long been integrated into both education and practice.

The proposed classification and terminology scheme would follow a Darwinian-like "Tree of Life" organization. Seizures would be broadly grouped into generalized or focal, depending on their origin and propagation over hemispheres; etiology (structural/metabolic, genetic, or unknown); and finally, by diagnostic specificity.

In this new scheme, focal seizures are seen as those that originate within a neuronal network but are limited to one hemisphere. Seizures that rapidly activate bilateral neuronal networks are seen as generalized.

Generalized seizures could be further categorized by their clinical presentation (tonic, clonic, or a combination; atonic; myoclonic; or absence), age at manifestation, and into other symptoms (Epilepsia 2010;51:676-85).

The system also advises dropping some terms that could be confusing or emotionally charged. "Benign" doesn’t recognize that real problems may result from the condition, wrote primary author Anne T. Berg, Ph.D. Both "idiopathic" and "cryptogenic" can now mean "unknown cause," but can also designate highly drug responsive, or symptomatic. "Symptomatic" currently connotes a poor prognosis, while ignoring the concept that all seizures cause symptoms, she wrote in the document.

"In addition to being confusing, these current terms aren’t necessarily true," said Dr. Jeffrey R. Buchhalter, who was a member of the classification writing committee and is a pediatric neurologist at the Phoenix Children’s Hospital. "What this new system is all about is separating what we know is true from what we do not."

The proposed system doesn’t replace diagnostic classifications, Dr. Berg, a research professor at Northwestern University, Chicago, said in an interview.

A diagnosis can be made with the existing terms, like Lennox-Gastaut syndrome or childhood absence epilepsy. Instead, the proposed system attempts to logically organize them according to their fundamental relationships.

"What we propose looks at the individual pieces [of the disorders] separately and then asks ‘How often do these go together?’ The new system would also benefit research, because everyone – no matter what country – would be speaking the same scientific language, she added.

The committee’s proposal is based on scientific evidence, instead of relying heavily on expert opinion, as does the current scheme, which was created in 1989. The current system doesn’t allow for the enormous changes made in understanding what causes epilepsy and how it is best treated, Dr. Hans Luders said in an interview. Any descriptive method needs to include these advances in imaging, genetics, and pharmacotherapy. The new system incorporates those new understandings, but in doing so, it drops some cherished nomenclature.

"What we have now, in many cases, are named syndromes used as diagnostic labels," said Dr. Luders, a neurologist at Case Western Reserve University, Cleveland. "Syndromes are a constellation of clinical signs that tend to uniformly occur together. As we have become more sophisticated, what is a syndrome or not has become debatable. There are so many syndromes now that memorizing them has become quite confusing," both for neurologists and students.

"We’re moving away from consensus opinion of thought leaders, and from whom consensus opinion was derived, to evidence-based ideas. And in any evidence review, expert opinion is the lowest tier. It’s below level 4," Dr. Berg said.

As such, the new proposal is not without its detractors, she said. A March opinion piece in Epilepsia airs some of these issues (Epilepsia 2012;53:399-404). In it, Dr. Chrysostomos P. Panayiotopoulos argues that the proposed classification scheme "does not fulfill its intent to improve the [current] classifications."

Dr. Panayiotopoulos, a neurologist at the John Radcliffe Hospital in Headington, England, is also the first to have described Panayiotopoulos syndrome, a benign childhood epilepsy characterized by autonomic seizures and status epilepticus, and a shifting or multifocal electroencephalogram.

The new classification scheme "has met with considerable protest from several expert epileptologists" and doesn’t incorporate most of the classification changes suggested in the 2010 ILAE report, he wrote. But philosophical arguing hobbled that proposed system, and it was never actually adopted by the ILAE. Because of the field’s inability to agree on the 2010 document, much of the extant classification system is still the same as it was in 1989.

In his editorial, Dr. Panayiotopoulos expressed much concern about the proposed classification of focal seizures according to their manifestations. "Such a proposition defies the essence and the principal of any classification that requires an organization and a common language for communication."

Neglecting to rely upon expert opinion is a large error, he said. "The ILAE Commission could benefit by asking experts in basic and clinical science to provide a concise statement in their field of expertise as, for example, what are focal, myoclonic, or absence seizures, and their subtypes, their manifestations, and their possible pathophysiology."

Areas of disagreement should be "identified and stated clearly, with documentation of the reasons for it."

But this approach could throw the debate back into the turbulent waters of the last decades, Dr. Buchhalter said. The new proposal is just one in a long line of criteria adjustments – some of them accepted into use and many of them not.

"Before 1981, seizure classifications were based on semiology. Beginning then, though, things changed and we started to base classifications on EEG type. Then, as we gained knowledge about genetics and family history, we incorporated that information as well."

This led to an ILAE uproar – members said the system was too bulky and complicated, Dr. Buchhalter said. "A task force met and said this was just getting too confusing and that everything but indicators of focality or generalization should be stripped out. All the data on what the seizures looked like, family history, and genetics were all thrown out."

It wasn’t long before the complaints started. "Within 8 years, ILAE took a lot of heat," because of this oversimplified system. In 1986, there was a "paradigm shift," with the addition of information, such as developmental status, family history, and imaging findings. "We established measurable, objective criteria that recognized seizure types and syndromes as unique entities," Dr. Buchhalter said.

In another failed effort to simplify classification, Dr. Luders proposed a five-faceted semiology-based scheme. Seizures could be classified, he proposed, by localizing the epileptogenic zone and by seizure semiology, etiology, frequency, and medical comorbidities.

"All cases can be classified according to this five-dimensional system, even at an initial encounter when no detailed test results are available," he wrote in the German journal Der Nervenarzt. "Information from clinical tests such as MRI and EEG are translated into the best possible working hypothesis at the time of classification, allowing increased precision of the classification as additional information becomes available" (Nervenarzt 2006;77:961-9).

"I say forget all of these names and syndromes – you don’t have to use them," he said in an interview. "If you’re a general neurologist or psychiatrist who occasionally sees an epilepsy patient, these labels are very confusing. It’s much easier to handle [with the semiologic system], and this is the way we do it [at Case Medical Center]. It’s the same way that we classify any of the neurological diseases."

Dr. Luders’s suggestion was likewise unpopular, said both Dr. Buchhalter and Dr. Berg. And all three agreed on one thing: Change of any kind is difficult in a large group.

"When things like this are proposed, you have to factor in the emotional part," Dr. Buchhalter said. "People get used to concepts and don’t want to let them go."

Dr. Luders, Dr. Berg, Dr. Buchhalter, and Dr. Panayiotopoulos reported having no financial disclosures.

A proposal for a new way to classify seizures would modify the way they have been discussed and organized since 1989.

But the new system – put forth by a committee specially convened by the International League Against Epilepsy (ILAE) – isn’t finding friends in every corner. Its move away from expert opinion to clinical evidence has ruffled the feathers of some highly respected clinicians, who assert that the current system is well organized, logical, and has long been integrated into both education and practice.

The proposed classification and terminology scheme would follow a Darwinian-like "Tree of Life" organization. Seizures would be broadly grouped into generalized or focal, depending on their origin and propagation over hemispheres; etiology (structural/metabolic, genetic, or unknown); and finally, by diagnostic specificity.

In this new scheme, focal seizures are seen as those that originate within a neuronal network but are limited to one hemisphere. Seizures that rapidly activate bilateral neuronal networks are seen as generalized.

Generalized seizures could be further categorized by their clinical presentation (tonic, clonic, or a combination; atonic; myoclonic; or absence), age at manifestation, and into other symptoms (Epilepsia 2010;51:676-85).

The system also advises dropping some terms that could be confusing or emotionally charged. "Benign" doesn’t recognize that real problems may result from the condition, wrote primary author Anne T. Berg, Ph.D. Both "idiopathic" and "cryptogenic" can now mean "unknown cause," but can also designate highly drug responsive, or symptomatic. "Symptomatic" currently connotes a poor prognosis, while ignoring the concept that all seizures cause symptoms, she wrote in the document.

"In addition to being confusing, these current terms aren’t necessarily true," said Dr. Jeffrey R. Buchhalter, who was a member of the classification writing committee and is a pediatric neurologist at the Phoenix Children’s Hospital. "What this new system is all about is separating what we know is true from what we do not."

The proposed system doesn’t replace diagnostic classifications, Dr. Berg, a research professor at Northwestern University, Chicago, said in an interview.

A diagnosis can be made with the existing terms, like Lennox-Gastaut syndrome or childhood absence epilepsy. Instead, the proposed system attempts to logically organize them according to their fundamental relationships.

"What we propose looks at the individual pieces [of the disorders] separately and then asks ‘How often do these go together?’ The new system would also benefit research, because everyone – no matter what country – would be speaking the same scientific language, she added.

The committee’s proposal is based on scientific evidence, instead of relying heavily on expert opinion, as does the current scheme, which was created in 1989. The current system doesn’t allow for the enormous changes made in understanding what causes epilepsy and how it is best treated, Dr. Hans Luders said in an interview. Any descriptive method needs to include these advances in imaging, genetics, and pharmacotherapy. The new system incorporates those new understandings, but in doing so, it drops some cherished nomenclature.

"What we have now, in many cases, are named syndromes used as diagnostic labels," said Dr. Luders, a neurologist at Case Western Reserve University, Cleveland. "Syndromes are a constellation of clinical signs that tend to uniformly occur together. As we have become more sophisticated, what is a syndrome or not has become debatable. There are so many syndromes now that memorizing them has become quite confusing," both for neurologists and students.

"We’re moving away from consensus opinion of thought leaders, and from whom consensus opinion was derived, to evidence-based ideas. And in any evidence review, expert opinion is the lowest tier. It’s below level 4," Dr. Berg said.

As such, the new proposal is not without its detractors, she said. A March opinion piece in Epilepsia airs some of these issues (Epilepsia 2012;53:399-404). In it, Dr. Chrysostomos P. Panayiotopoulos argues that the proposed classification scheme "does not fulfill its intent to improve the [current] classifications."

Dr. Panayiotopoulos, a neurologist at the John Radcliffe Hospital in Headington, England, is also the first to have described Panayiotopoulos syndrome, a benign childhood epilepsy characterized by autonomic seizures and status epilepticus, and a shifting or multifocal electroencephalogram.

The new classification scheme "has met with considerable protest from several expert epileptologists" and doesn’t incorporate most of the classification changes suggested in the 2010 ILAE report, he wrote. But philosophical arguing hobbled that proposed system, and it was never actually adopted by the ILAE. Because of the field’s inability to agree on the 2010 document, much of the extant classification system is still the same as it was in 1989.

In his editorial, Dr. Panayiotopoulos expressed much concern about the proposed classification of focal seizures according to their manifestations. "Such a proposition defies the essence and the principal of any classification that requires an organization and a common language for communication."

Neglecting to rely upon expert opinion is a large error, he said. "The ILAE Commission could benefit by asking experts in basic and clinical science to provide a concise statement in their field of expertise as, for example, what are focal, myoclonic, or absence seizures, and their subtypes, their manifestations, and their possible pathophysiology."

Areas of disagreement should be "identified and stated clearly, with documentation of the reasons for it."

But this approach could throw the debate back into the turbulent waters of the last decades, Dr. Buchhalter said. The new proposal is just one in a long line of criteria adjustments – some of them accepted into use and many of them not.

"Before 1981, seizure classifications were based on semiology. Beginning then, though, things changed and we started to base classifications on EEG type. Then, as we gained knowledge about genetics and family history, we incorporated that information as well."

This led to an ILAE uproar – members said the system was too bulky and complicated, Dr. Buchhalter said. "A task force met and said this was just getting too confusing and that everything but indicators of focality or generalization should be stripped out. All the data on what the seizures looked like, family history, and genetics were all thrown out."

It wasn’t long before the complaints started. "Within 8 years, ILAE took a lot of heat," because of this oversimplified system. In 1986, there was a "paradigm shift," with the addition of information, such as developmental status, family history, and imaging findings. "We established measurable, objective criteria that recognized seizure types and syndromes as unique entities," Dr. Buchhalter said.

In another failed effort to simplify classification, Dr. Luders proposed a five-faceted semiology-based scheme. Seizures could be classified, he proposed, by localizing the epileptogenic zone and by seizure semiology, etiology, frequency, and medical comorbidities.

"All cases can be classified according to this five-dimensional system, even at an initial encounter when no detailed test results are available," he wrote in the German journal Der Nervenarzt. "Information from clinical tests such as MRI and EEG are translated into the best possible working hypothesis at the time of classification, allowing increased precision of the classification as additional information becomes available" (Nervenarzt 2006;77:961-9).

"I say forget all of these names and syndromes – you don’t have to use them," he said in an interview. "If you’re a general neurologist or psychiatrist who occasionally sees an epilepsy patient, these labels are very confusing. It’s much easier to handle [with the semiologic system], and this is the way we do it [at Case Medical Center]. It’s the same way that we classify any of the neurological diseases."

Dr. Luders’s suggestion was likewise unpopular, said both Dr. Buchhalter and Dr. Berg. And all three agreed on one thing: Change of any kind is difficult in a large group.

"When things like this are proposed, you have to factor in the emotional part," Dr. Buchhalter said. "People get used to concepts and don’t want to let them go."

Dr. Luders, Dr. Berg, Dr. Buchhalter, and Dr. Panayiotopoulos reported having no financial disclosures.

A subcutaneous injectable form of trastuzumab achieved pharmacokinetic and clinical outcomes that equaled those of intravenous infusion for women with HER2-positive breast cancers in a randomized open-label phase III study.

The international HannaH trial found no significant differences in presurgical serum trough levels at any time during the six-cycle neoadjuvant treatment. At the end of the year-long study, 45% of the subcutaneous group and 41% of the intravenous group had a pathological complete response (pCR).

The subcutaneous form of trastuzumab (Herceptin) takes 5 minutes to administer; patients can self-administer the drug at home. The infusion takes 90 minutes and must be done in the clinic.

If clinical results are equivalent, the injection could become an attractive alternative to intravenous treatment, Dr. Gustavo Ismael of the Hospital Amaral Carvalho, Jaú, Brazil, and his coauthors proposed in the Aug. 9 online issue of the Lancet Oncology (2012 [doi.org/10.1016/S1470-2045(12)70329-7]).*

"The shortened duration of administration with subcutaneous trastuzumab ... suggests the potential for substantial time saving for patients, physicians, and nursing staff," the investigators wrote.

Susan Willson, a spokesperson for Genentech, said the company is looking at the HannaH data, as well as that of other studies, to determine whether the subcutaneous form of trastuzumab will be put forth to the Food and Drug Administration.

Earlier this year, Roche, Genetech’s parent company, submitted a line extension application for subcutaneous trastuzumab to the European Medicines Association. The requested indication is the treatment of HER-2-positive breast cancer.

Trastuzumab Given with Neoadjuvant Chemo

The HannaH (enHANced treatment with NeoAdjuvant Herceptin) trial randomized 596 women with HER-2 positive breast cancer to six cycles of neoadjuvant chemotherapy with either the injections or intravenous infusions; both were administered once every 3 weeks.

The injection was a fixed dose of 600 mg trastuzumab with recombinant hyaluronidase PH-20 delivered to the thigh by study nurses. The enzyme temporarily degrades interstitial hyaluronan, expanding the space to accommodate the volume of the injection.

Women in the subcutaneous group did not take a loading dose of the medication. Those in the intravenous group received an 8 mg/kg loading dose followed by a 6 mg/kg maintenance dose. The follow-up period was 24 months or until disease recurrence

The chemotherapy regimen for both groups consisted of four 3-week cycles of docetaxel (Taxotere) followed by four cycles of fluorouracil and cyclophosphamide. After surgery, all patients continued their trastuzumab regimen for 1 year.

Median patient age was 50 years. About 50% were positive for estrogen receptor tumors. More than half had operable cancer; more than a third had locally advanced cancer; and about 6% had inflammatory breast cancer. Median follow-up in both groups was a little more than 1 year.

The pharmacokinetic profile was similar between the two forms of trastuzumab. After the first cycle, the mean trough serum level was similar between the injectable and intravenous forms (32.7 mcg/mL vs. 34.5 mcg/mL). The levels were also similar before the third cycle (45 and 48 mcg/mL). Almost all patients (98%) reached the therapeutic level of more than 20 micrograms/ml by cycle 8.

The mean presurgical trough level of the subcutaneous form was 58 mcg/mL; for the intravenous form, the mean level was 79 mcg/mL.

Similar Efficacy and Toxicity

The efficacy analysis included 523 patients and showed noninferiority of subcutaneous trastuzumab to intravenous trastuzumab. A pathological complete response occurred in 45% of the subcutaneous group and in 41% of the intravenous group in a per-protocol analysis. An intent-to-treat analysis showed similar numbers, with a complete pathological response in 42% of the subcutaneous group an 37% of the intravenous group.

Overall responses rates, including complete and partial responses, were comparable. Event-free and overall survival data were not yet mature, and have yet to be reported.

The rate of adverse events was similar between the subcutaneous and intravenous groups: alopecia (63% each), nausea (49% each), neutropenia (44% subcutaneous vs. 46% intravenous), diarrhea (34% subcutaneous vs. 37% intravenous), asthenia (25% each), and fatigue (23% subcutaneous vs. 26% intravenous).

The same proportion of patients in each group experienced at least one serious adverse event (52%). The most common were neutropenia, leucopenia, and febrile neutropenia.

Four adverse events lead to death – one in the subcutaneous group and three in the intravenous group during neoadjuvant treatment. These included a fatal acute pneumonia in an obese 66-year-old with pulmonary fibrosis in the subcutaneous group. In the intravenous group, the deaths were a myocardial infarction in an obese patient with a history of hypertension; a sudden death in an overweight patient who with hypertension and diabetes; fatal septic shock in a patient who developed febrile neutropenia. The septic shock and cardiac deaths were attributed to the treatment, the investigators said.

The proportion of grade 3 adverse events was similar in both groups, but the relative percentage of those classified as serious adverse events was 7.7% for the intravenous group and 18% for the subcutaneous group. "A similar finding was made for grade 2 adverse events, of which 0.5% was classed as serous ... in the intravenous group versus 1.5% in the subcutaneous group," they wrote. The investigators could not find an explanation for the imbalance in reporting of serious adverse events, but suggested that they may have been more conservative in assessing the subcutaneous arm of the trial.

Two patients in the subcutaneous group had mild congestive heart failure; both were obese with a history of hypertension. Six patients in the intravenous group and seven in the subcutaneous group had a significant decrease in left ventricular ejection fraction.

Antitrastuzumab antibodies developed in 10 patients in the intravenous group and 20 in the subcutaneous group, but these did not affect serum trough levels.

F. Hoffman-LaRoche funded the study Dr. Ismael disclosed that he has received honoraria from the company. His co-investigators also reported several financial relationships, including travels grants, speakers fees, research support, and employment.

Click here to hear Dr. Ismael discuss the trial in a podcast at the Lancet Oncology website.

*Correction, 08/13/12: This sentence was corrected to state that injectable trastuzumab could become an alternative to intravenous treatment. Weekly treatment was not specified.

A subcutaneous injectable form of trastuzumab achieved pharmacokinetic and clinical outcomes that equaled those of intravenous infusion for women with HER2-positive breast cancers in a randomized open-label phase III study.

The international HannaH trial found no significant differences in presurgical serum trough levels at any time during the six-cycle neoadjuvant treatment. At the end of the year-long study, 45% of the subcutaneous group and 41% of the intravenous group had a pathological complete response (pCR).

The subcutaneous form of trastuzumab (Herceptin) takes 5 minutes to administer; patients can self-administer the drug at home. The infusion takes 90 minutes and must be done in the clinic.

If clinical results are equivalent, the injection could become an attractive alternative to intravenous treatment, Dr. Gustavo Ismael of the Hospital Amaral Carvalho, Jaú, Brazil, and his coauthors proposed in the Aug. 9 online issue of the Lancet Oncology (2012 [doi.org/10.1016/S1470-2045(12)70329-7]).*

"The shortened duration of administration with subcutaneous trastuzumab ... suggests the potential for substantial time saving for patients, physicians, and nursing staff," the investigators wrote.

Susan Willson, a spokesperson for Genentech, said the company is looking at the HannaH data, as well as that of other studies, to determine whether the subcutaneous form of trastuzumab will be put forth to the Food and Drug Administration.

Earlier this year, Roche, Genetech’s parent company, submitted a line extension application for subcutaneous trastuzumab to the European Medicines Association. The requested indication is the treatment of HER-2-positive breast cancer.

Trastuzumab Given with Neoadjuvant Chemo

The HannaH (enHANced treatment with NeoAdjuvant Herceptin) trial randomized 596 women with HER-2 positive breast cancer to six cycles of neoadjuvant chemotherapy with either the injections or intravenous infusions; both were administered once every 3 weeks.

The injection was a fixed dose of 600 mg trastuzumab with recombinant hyaluronidase PH-20 delivered to the thigh by study nurses. The enzyme temporarily degrades interstitial hyaluronan, expanding the space to accommodate the volume of the injection.

Women in the subcutaneous group did not take a loading dose of the medication. Those in the intravenous group received an 8 mg/kg loading dose followed by a 6 mg/kg maintenance dose. The follow-up period was 24 months or until disease recurrence

The chemotherapy regimen for both groups consisted of four 3-week cycles of docetaxel (Taxotere) followed by four cycles of fluorouracil and cyclophosphamide. After surgery, all patients continued their trastuzumab regimen for 1 year.

Median patient age was 50 years. About 50% were positive for estrogen receptor tumors. More than half had operable cancer; more than a third had locally advanced cancer; and about 6% had inflammatory breast cancer. Median follow-up in both groups was a little more than 1 year.

The pharmacokinetic profile was similar between the two forms of trastuzumab. After the first cycle, the mean trough serum level was similar between the injectable and intravenous forms (32.7 mcg/mL vs. 34.5 mcg/mL). The levels were also similar before the third cycle (45 and 48 mcg/mL). Almost all patients (98%) reached the therapeutic level of more than 20 micrograms/ml by cycle 8.

The mean presurgical trough level of the subcutaneous form was 58 mcg/mL; for the intravenous form, the mean level was 79 mcg/mL.

Similar Efficacy and Toxicity

The efficacy analysis included 523 patients and showed noninferiority of subcutaneous trastuzumab to intravenous trastuzumab. A pathological complete response occurred in 45% of the subcutaneous group and in 41% of the intravenous group in a per-protocol analysis. An intent-to-treat analysis showed similar numbers, with a complete pathological response in 42% of the subcutaneous group an 37% of the intravenous group.

Overall responses rates, including complete and partial responses, were comparable. Event-free and overall survival data were not yet mature, and have yet to be reported.

The rate of adverse events was similar between the subcutaneous and intravenous groups: alopecia (63% each), nausea (49% each), neutropenia (44% subcutaneous vs. 46% intravenous), diarrhea (34% subcutaneous vs. 37% intravenous), asthenia (25% each), and fatigue (23% subcutaneous vs. 26% intravenous).

The same proportion of patients in each group experienced at least one serious adverse event (52%). The most common were neutropenia, leucopenia, and febrile neutropenia.

Four adverse events lead to death – one in the subcutaneous group and three in the intravenous group during neoadjuvant treatment. These included a fatal acute pneumonia in an obese 66-year-old with pulmonary fibrosis in the subcutaneous group. In the intravenous group, the deaths were a myocardial infarction in an obese patient with a history of hypertension; a sudden death in an overweight patient who with hypertension and diabetes; fatal septic shock in a patient who developed febrile neutropenia. The septic shock and cardiac deaths were attributed to the treatment, the investigators said.

The proportion of grade 3 adverse events was similar in both groups, but the relative percentage of those classified as serious adverse events was 7.7% for the intravenous group and 18% for the subcutaneous group. "A similar finding was made for grade 2 adverse events, of which 0.5% was classed as serous ... in the intravenous group versus 1.5% in the subcutaneous group," they wrote. The investigators could not find an explanation for the imbalance in reporting of serious adverse events, but suggested that they may have been more conservative in assessing the subcutaneous arm of the trial.

Two patients in the subcutaneous group had mild congestive heart failure; both were obese with a history of hypertension. Six patients in the intravenous group and seven in the subcutaneous group had a significant decrease in left ventricular ejection fraction.

Antitrastuzumab antibodies developed in 10 patients in the intravenous group and 20 in the subcutaneous group, but these did not affect serum trough levels.

F. Hoffman-LaRoche funded the study Dr. Ismael disclosed that he has received honoraria from the company. His co-investigators also reported several financial relationships, including travels grants, speakers fees, research support, and employment.

Click here to hear Dr. Ismael discuss the trial in a podcast at the Lancet Oncology website.

*Correction, 08/13/12: This sentence was corrected to state that injectable trastuzumab could become an alternative to intravenous treatment. Weekly treatment was not specified.

A subcutaneous injectable form of trastuzumab achieved pharmacokinetic and clinical outcomes that equaled those of intravenous infusion for women with HER2-positive breast cancers in a randomized open-label phase III study.

The international HannaH trial found no significant differences in presurgical serum trough levels at any time during the six-cycle neoadjuvant treatment. At the end of the year-long study, 45% of the subcutaneous group and 41% of the intravenous group had a pathological complete response (pCR).

The subcutaneous form of trastuzumab (Herceptin) takes 5 minutes to administer; patients can self-administer the drug at home. The infusion takes 90 minutes and must be done in the clinic.

If clinical results are equivalent, the injection could become an attractive alternative to intravenous treatment, Dr. Gustavo Ismael of the Hospital Amaral Carvalho, Jaú, Brazil, and his coauthors proposed in the Aug. 9 online issue of the Lancet Oncology (2012 [doi.org/10.1016/S1470-2045(12)70329-7]).*

"The shortened duration of administration with subcutaneous trastuzumab ... suggests the potential for substantial time saving for patients, physicians, and nursing staff," the investigators wrote.

Susan Willson, a spokesperson for Genentech, said the company is looking at the HannaH data, as well as that of other studies, to determine whether the subcutaneous form of trastuzumab will be put forth to the Food and Drug Administration.

Earlier this year, Roche, Genetech’s parent company, submitted a line extension application for subcutaneous trastuzumab to the European Medicines Association. The requested indication is the treatment of HER-2-positive breast cancer.

Trastuzumab Given with Neoadjuvant Chemo

The HannaH (enHANced treatment with NeoAdjuvant Herceptin) trial randomized 596 women with HER-2 positive breast cancer to six cycles of neoadjuvant chemotherapy with either the injections or intravenous infusions; both were administered once every 3 weeks.

The injection was a fixed dose of 600 mg trastuzumab with recombinant hyaluronidase PH-20 delivered to the thigh by study nurses. The enzyme temporarily degrades interstitial hyaluronan, expanding the space to accommodate the volume of the injection.

Women in the subcutaneous group did not take a loading dose of the medication. Those in the intravenous group received an 8 mg/kg loading dose followed by a 6 mg/kg maintenance dose. The follow-up period was 24 months or until disease recurrence

The chemotherapy regimen for both groups consisted of four 3-week cycles of docetaxel (Taxotere) followed by four cycles of fluorouracil and cyclophosphamide. After surgery, all patients continued their trastuzumab regimen for 1 year.

Median patient age was 50 years. About 50% were positive for estrogen receptor tumors. More than half had operable cancer; more than a third had locally advanced cancer; and about 6% had inflammatory breast cancer. Median follow-up in both groups was a little more than 1 year.

The pharmacokinetic profile was similar between the two forms of trastuzumab. After the first cycle, the mean trough serum level was similar between the injectable and intravenous forms (32.7 mcg/mL vs. 34.5 mcg/mL). The levels were also similar before the third cycle (45 and 48 mcg/mL). Almost all patients (98%) reached the therapeutic level of more than 20 micrograms/ml by cycle 8.

The mean presurgical trough level of the subcutaneous form was 58 mcg/mL; for the intravenous form, the mean level was 79 mcg/mL.

Similar Efficacy and Toxicity

The efficacy analysis included 523 patients and showed noninferiority of subcutaneous trastuzumab to intravenous trastuzumab. A pathological complete response occurred in 45% of the subcutaneous group and in 41% of the intravenous group in a per-protocol analysis. An intent-to-treat analysis showed similar numbers, with a complete pathological response in 42% of the subcutaneous group an 37% of the intravenous group.

Overall responses rates, including complete and partial responses, were comparable. Event-free and overall survival data were not yet mature, and have yet to be reported.

The rate of adverse events was similar between the subcutaneous and intravenous groups: alopecia (63% each), nausea (49% each), neutropenia (44% subcutaneous vs. 46% intravenous), diarrhea (34% subcutaneous vs. 37% intravenous), asthenia (25% each), and fatigue (23% subcutaneous vs. 26% intravenous).

The same proportion of patients in each group experienced at least one serious adverse event (52%). The most common were neutropenia, leucopenia, and febrile neutropenia.

Four adverse events lead to death – one in the subcutaneous group and three in the intravenous group during neoadjuvant treatment. These included a fatal acute pneumonia in an obese 66-year-old with pulmonary fibrosis in the subcutaneous group. In the intravenous group, the deaths were a myocardial infarction in an obese patient with a history of hypertension; a sudden death in an overweight patient who with hypertension and diabetes; fatal septic shock in a patient who developed febrile neutropenia. The septic shock and cardiac deaths were attributed to the treatment, the investigators said.

The proportion of grade 3 adverse events was similar in both groups, but the relative percentage of those classified as serious adverse events was 7.7% for the intravenous group and 18% for the subcutaneous group. "A similar finding was made for grade 2 adverse events, of which 0.5% was classed as serous ... in the intravenous group versus 1.5% in the subcutaneous group," they wrote. The investigators could not find an explanation for the imbalance in reporting of serious adverse events, but suggested that they may have been more conservative in assessing the subcutaneous arm of the trial.

Two patients in the subcutaneous group had mild congestive heart failure; both were obese with a history of hypertension. Six patients in the intravenous group and seven in the subcutaneous group had a significant decrease in left ventricular ejection fraction.

Antitrastuzumab antibodies developed in 10 patients in the intravenous group and 20 in the subcutaneous group, but these did not affect serum trough levels.

F. Hoffman-LaRoche funded the study Dr. Ismael disclosed that he has received honoraria from the company. His co-investigators also reported several financial relationships, including travels grants, speakers fees, research support, and employment.

Click here to hear Dr. Ismael discuss the trial in a podcast at the Lancet Oncology website.

*Correction, 08/13/12: This sentence was corrected to state that injectable trastuzumab could become an alternative to intravenous treatment. Weekly treatment was not specified.

In the near future, the anesthetic agent ketamine could play an important role in the treatment of patients who are depressed – and even suicidal.

Several recent studies support the drug’s almost immediate and long-lasting effects. Animal trials suggest that ketamine might work by stimulating brain-derived neurotrophic factors (BDNFs), which spur neuronal growth. They also hint that variations in the genes that code for BDNF might confer resistance to ketamine; humans with this allele might be less likely to respond to ketamine’s effects.

"These clues help focus the search for the molecular targets of a future generation of medications that will lift depression within hours instead of weeks," said Dr. Carlos A. Zarate, a primary investigator in some of the studies. "The more precisely we understand how this mechanism works, the more narrowly treatment can be targeted to achieve rapid antidepressant effects and avoid undesirable side effects."

The National Institutes of Health funded all of the ketamine studies, which were published in several journals between December 2011 and June 2012.

A study of 30 patients with treatment-resistant major depressive disorder concluded that ketamine infusions were associated with significant increases in serum BDNF, accompanied by changes in slow-wave activity on electroencephalograms. Dr. Wallace C. Duncan Jr., of the National Institute of Mental Health, found that the changes were directly related to response: Patients who experienced significant improvements in depression had the highest level of change (Int. J. Neuropsychopharmacol. 2012 June 7 [doi: 10.1017/S1461145712000545]).

"The induction of neurotrophic factors may therefore partially underlie the antidepressant effects of ketamine, given that major depressive disorder is associated with low levels of BDNF and that chronic treatment with antidepressants elevates BDNF levels," he said.

BDNF also is important in facilitating synaptic potentiation, he added.

A mouse study, published in the June issue of Biological Psychiatry, shed some additional light on how the drug might work, and in whom. Dr. George Aghajanian of Yale University, Boston, and his colleagues examined mice specifically bred to express two copies of a gene that impairs BDNF signaling – an allele configuration expressed in about 30% of humans (Biol. Psychiatry 2012;71:996-1005).

The researchers compared the brains of these mice to those of mice with a single copy of the gene, and to those that lacked the risk allele completely. The homozygous mice displayed significantly less dendritic complexity in their brain neural networks. The density of individual dendritic spines also was much reduced.

Some of the mice received injections of ketamine. When their brains were examined 24 hours later, the heterozygous and wild-type mice showed significantly more dendritic complexity. The mice that were homozygous for the risk gene, however, had fewer improvements in neural health, showing that the gene blunts ketamine’s neural benefits.

A study in humans supports that idea. Dr. Gonzalo Laje of the National Institute of Mental Health has reported on a series of 62 patients with major depressive disorder who were genotyped for the risk allele and treated with ketamine. The presence of a double copy of the gene accounted for 28% of the difference in patients’ response to the drug (Biol. Psychiatry 2012 July 9 [doi: 10.1016/j.biopsych.2012.05.031]).

Two recent clinical trials of ketamine show the drug’s potential in major depression. Dr. Zarate reported on a series of 15 patients with bipolar I or II depression stabilized on lithium or valproate who received infusions of ketamine or placebo in a crossover design. The investigators rated depressive symptoms at 40, 80, 110, and 230 minutes after the infusions, and also on days 1, 2, 3, 7, 10, and 14 after each phase of treatment (Biol. Psychiatry 2012;71:939-46).

Depressive symptoms significantly decreased in the active group, compared with the placebo group. The difference between groups remained significant through the third day.

The investigators also examined the drug’s effect on suicidal ideation. On two scales, suicidal thoughts decreased significantly by 40 minutes after the infusion and remained significantly decreased for up to 10 days.

"The most intriguing finding ... may be that ketamine exerted measurable, rapid, and continued anti-suicidal effects," the authors said. "To our knowledge, no controlled study of patients with bipolar depression has yet demonstrated this rapidity of onset, robustness of effect, and continued effect on suicidal ideation resulting from a single administration of any intervention."

Dr. Zarate and coinvestigators also published a meta-analysis of ketamine studies, which found strong evidence that the drug offers a rapid, sustained improvement in depressive symptoms. Thus far, 163 patients have been treated in open-label or placebo-controlled trials; response rates have varied from 25% to 85% at 24 hours post infusion, and from 14% to 70% 72 hours afterward. Two open-label and seven randomized controlled trials are currently ongoing (Biol. Psychiatry 2012 June 18 [doi: 10.1016/j.biopsych.2012.05.003]).

Despite encouraging results, questions remain, Dr. Zarate and his coauthors said. "It’s unclear why many patients showing a response at 24 hours relapse less than 48 hours later," they wrote. "It’s also unclear why some patients maintain their response for several weeks."

Although the drug’s adverse event profile is largely acceptable, "there are disadvantages to continuing patients on thrice-weekly or even weekly [intravenous] ketamine infusions."

One option might be to start patients getting a single ketamine dose on an approved monoaminergic antidepressant or mood stabilizer, Dr. Zarate and his colleagues suggested. "Even though patients may have previously not responded to this medication, it might still help maintain an acute response to ketamine."

However, they concluded, "this type of approach, although practical, remains speculative at this point, and future studies are clearly needed."

Dr. Zarate has a patent application for the use of ketamine in major depression. He has assigned his rights to the U.S. government, but will still receive a share of any royalties that might be produced. Dr. Duncan, Dr. Aghajanian, and Dr. Laje declared they had no financial conflicts of interest.

In the near future, the anesthetic agent ketamine could play an important role in the treatment of patients who are depressed – and even suicidal.

Several recent studies support the drug’s almost immediate and long-lasting effects. Animal trials suggest that ketamine might work by stimulating brain-derived neurotrophic factors (BDNFs), which spur neuronal growth. They also hint that variations in the genes that code for BDNF might confer resistance to ketamine; humans with this allele might be less likely to respond to ketamine’s effects.

"These clues help focus the search for the molecular targets of a future generation of medications that will lift depression within hours instead of weeks," said Dr. Carlos A. Zarate, a primary investigator in some of the studies. "The more precisely we understand how this mechanism works, the more narrowly treatment can be targeted to achieve rapid antidepressant effects and avoid undesirable side effects."

The National Institutes of Health funded all of the ketamine studies, which were published in several journals between December 2011 and June 2012.

A study of 30 patients with treatment-resistant major depressive disorder concluded that ketamine infusions were associated with significant increases in serum BDNF, accompanied by changes in slow-wave activity on electroencephalograms. Dr. Wallace C. Duncan Jr., of the National Institute of Mental Health, found that the changes were directly related to response: Patients who experienced significant improvements in depression had the highest level of change (Int. J. Neuropsychopharmacol. 2012 June 7 [doi: 10.1017/S1461145712000545]).

"The induction of neurotrophic factors may therefore partially underlie the antidepressant effects of ketamine, given that major depressive disorder is associated with low levels of BDNF and that chronic treatment with antidepressants elevates BDNF levels," he said.

BDNF also is important in facilitating synaptic potentiation, he added.

A mouse study, published in the June issue of Biological Psychiatry, shed some additional light on how the drug might work, and in whom. Dr. George Aghajanian of Yale University, Boston, and his colleagues examined mice specifically bred to express two copies of a gene that impairs BDNF signaling – an allele configuration expressed in about 30% of humans (Biol. Psychiatry 2012;71:996-1005).

The researchers compared the brains of these mice to those of mice with a single copy of the gene, and to those that lacked the risk allele completely. The homozygous mice displayed significantly less dendritic complexity in their brain neural networks. The density of individual dendritic spines also was much reduced.

Some of the mice received injections of ketamine. When their brains were examined 24 hours later, the heterozygous and wild-type mice showed significantly more dendritic complexity. The mice that were homozygous for the risk gene, however, had fewer improvements in neural health, showing that the gene blunts ketamine’s neural benefits.

A study in humans supports that idea. Dr. Gonzalo Laje of the National Institute of Mental Health has reported on a series of 62 patients with major depressive disorder who were genotyped for the risk allele and treated with ketamine. The presence of a double copy of the gene accounted for 28% of the difference in patients’ response to the drug (Biol. Psychiatry 2012 July 9 [doi: 10.1016/j.biopsych.2012.05.031]).

Two recent clinical trials of ketamine show the drug’s potential in major depression. Dr. Zarate reported on a series of 15 patients with bipolar I or II depression stabilized on lithium or valproate who received infusions of ketamine or placebo in a crossover design. The investigators rated depressive symptoms at 40, 80, 110, and 230 minutes after the infusions, and also on days 1, 2, 3, 7, 10, and 14 after each phase of treatment (Biol. Psychiatry 2012;71:939-46).

Depressive symptoms significantly decreased in the active group, compared with the placebo group. The difference between groups remained significant through the third day.

The investigators also examined the drug’s effect on suicidal ideation. On two scales, suicidal thoughts decreased significantly by 40 minutes after the infusion and remained significantly decreased for up to 10 days.

"The most intriguing finding ... may be that ketamine exerted measurable, rapid, and continued anti-suicidal effects," the authors said. "To our knowledge, no controlled study of patients with bipolar depression has yet demonstrated this rapidity of onset, robustness of effect, and continued effect on suicidal ideation resulting from a single administration of any intervention."

Dr. Zarate and coinvestigators also published a meta-analysis of ketamine studies, which found strong evidence that the drug offers a rapid, sustained improvement in depressive symptoms. Thus far, 163 patients have been treated in open-label or placebo-controlled trials; response rates have varied from 25% to 85% at 24 hours post infusion, and from 14% to 70% 72 hours afterward. Two open-label and seven randomized controlled trials are currently ongoing (Biol. Psychiatry 2012 June 18 [doi: 10.1016/j.biopsych.2012.05.003]).

Despite encouraging results, questions remain, Dr. Zarate and his coauthors said. "It’s unclear why many patients showing a response at 24 hours relapse less than 48 hours later," they wrote. "It’s also unclear why some patients maintain their response for several weeks."

Although the drug’s adverse event profile is largely acceptable, "there are disadvantages to continuing patients on thrice-weekly or even weekly [intravenous] ketamine infusions."

One option might be to start patients getting a single ketamine dose on an approved monoaminergic antidepressant or mood stabilizer, Dr. Zarate and his colleagues suggested. "Even though patients may have previously not responded to this medication, it might still help maintain an acute response to ketamine."

However, they concluded, "this type of approach, although practical, remains speculative at this point, and future studies are clearly needed."

Dr. Zarate has a patent application for the use of ketamine in major depression. He has assigned his rights to the U.S. government, but will still receive a share of any royalties that might be produced. Dr. Duncan, Dr. Aghajanian, and Dr. Laje declared they had no financial conflicts of interest.

In the near future, the anesthetic agent ketamine could play an important role in the treatment of patients who are depressed – and even suicidal.

Several recent studies support the drug’s almost immediate and long-lasting effects. Animal trials suggest that ketamine might work by stimulating brain-derived neurotrophic factors (BDNFs), which spur neuronal growth. They also hint that variations in the genes that code for BDNF might confer resistance to ketamine; humans with this allele might be less likely to respond to ketamine’s effects.

"These clues help focus the search for the molecular targets of a future generation of medications that will lift depression within hours instead of weeks," said Dr. Carlos A. Zarate, a primary investigator in some of the studies. "The more precisely we understand how this mechanism works, the more narrowly treatment can be targeted to achieve rapid antidepressant effects and avoid undesirable side effects."

The National Institutes of Health funded all of the ketamine studies, which were published in several journals between December 2011 and June 2012.

A study of 30 patients with treatment-resistant major depressive disorder concluded that ketamine infusions were associated with significant increases in serum BDNF, accompanied by changes in slow-wave activity on electroencephalograms. Dr. Wallace C. Duncan Jr., of the National Institute of Mental Health, found that the changes were directly related to response: Patients who experienced significant improvements in depression had the highest level of change (Int. J. Neuropsychopharmacol. 2012 June 7 [doi: 10.1017/S1461145712000545]).

"The induction of neurotrophic factors may therefore partially underlie the antidepressant effects of ketamine, given that major depressive disorder is associated with low levels of BDNF and that chronic treatment with antidepressants elevates BDNF levels," he said.

BDNF also is important in facilitating synaptic potentiation, he added.

A mouse study, published in the June issue of Biological Psychiatry, shed some additional light on how the drug might work, and in whom. Dr. George Aghajanian of Yale University, Boston, and his colleagues examined mice specifically bred to express two copies of a gene that impairs BDNF signaling – an allele configuration expressed in about 30% of humans (Biol. Psychiatry 2012;71:996-1005).

The researchers compared the brains of these mice to those of mice with a single copy of the gene, and to those that lacked the risk allele completely. The homozygous mice displayed significantly less dendritic complexity in their brain neural networks. The density of individual dendritic spines also was much reduced.

Some of the mice received injections of ketamine. When their brains were examined 24 hours later, the heterozygous and wild-type mice showed significantly more dendritic complexity. The mice that were homozygous for the risk gene, however, had fewer improvements in neural health, showing that the gene blunts ketamine’s neural benefits.

A study in humans supports that idea. Dr. Gonzalo Laje of the National Institute of Mental Health has reported on a series of 62 patients with major depressive disorder who were genotyped for the risk allele and treated with ketamine. The presence of a double copy of the gene accounted for 28% of the difference in patients’ response to the drug (Biol. Psychiatry 2012 July 9 [doi: 10.1016/j.biopsych.2012.05.031]).

Two recent clinical trials of ketamine show the drug’s potential in major depression. Dr. Zarate reported on a series of 15 patients with bipolar I or II depression stabilized on lithium or valproate who received infusions of ketamine or placebo in a crossover design. The investigators rated depressive symptoms at 40, 80, 110, and 230 minutes after the infusions, and also on days 1, 2, 3, 7, 10, and 14 after each phase of treatment (Biol. Psychiatry 2012;71:939-46).

Depressive symptoms significantly decreased in the active group, compared with the placebo group. The difference between groups remained significant through the third day.

The investigators also examined the drug’s effect on suicidal ideation. On two scales, suicidal thoughts decreased significantly by 40 minutes after the infusion and remained significantly decreased for up to 10 days.

"The most intriguing finding ... may be that ketamine exerted measurable, rapid, and continued anti-suicidal effects," the authors said. "To our knowledge, no controlled study of patients with bipolar depression has yet demonstrated this rapidity of onset, robustness of effect, and continued effect on suicidal ideation resulting from a single administration of any intervention."

Dr. Zarate and coinvestigators also published a meta-analysis of ketamine studies, which found strong evidence that the drug offers a rapid, sustained improvement in depressive symptoms. Thus far, 163 patients have been treated in open-label or placebo-controlled trials; response rates have varied from 25% to 85% at 24 hours post infusion, and from 14% to 70% 72 hours afterward. Two open-label and seven randomized controlled trials are currently ongoing (Biol. Psychiatry 2012 June 18 [doi: 10.1016/j.biopsych.2012.05.003]).

Despite encouraging results, questions remain, Dr. Zarate and his coauthors said. "It’s unclear why many patients showing a response at 24 hours relapse less than 48 hours later," they wrote. "It’s also unclear why some patients maintain their response for several weeks."

Although the drug’s adverse event profile is largely acceptable, "there are disadvantages to continuing patients on thrice-weekly or even weekly [intravenous] ketamine infusions."

One option might be to start patients getting a single ketamine dose on an approved monoaminergic antidepressant or mood stabilizer, Dr. Zarate and his colleagues suggested. "Even though patients may have previously not responded to this medication, it might still help maintain an acute response to ketamine."

However, they concluded, "this type of approach, although practical, remains speculative at this point, and future studies are clearly needed."

Dr. Zarate has a patent application for the use of ketamine in major depression. He has assigned his rights to the U.S. government, but will still receive a share of any royalties that might be produced. Dr. Duncan, Dr. Aghajanian, and Dr. Laje declared they had no financial conflicts of interest.

In the wake of yet another negative trial, Pfizer Inc. has discontinued research on bapineuzumab, a monoclonal antibody designed to target amyloid beta plaques in the brains of patients with Alzheimer’s disease.

The phase III trial failed to meet any of its cognitive or functional endpoints in 1,100 patients who were negative for the high-risk apolipoprotein E4 allele (apo E4). These new results, combined with disappointing outcomes in a separate study of apo E4 carriers, were the knockout punch for bapineuzumab.

Dr. Steven J. Romano, head of the Medicines Development Group at Pfizer’s Global Primary Care Business Unit, said in a written statement that the company was disappointed in the clinical outcomes.

"We are ... saddened by the lost opportunity to provide a meaningful advance for patients afflicted with mild to moderate Alzheimer’s disease and their caregivers."

In July, Pfizer reported negative results in a phase 3 study of the drug’s effect on 1,300 apo E4 carriers with Alzheimer’s disease. The primary endpoints of both studies were changes in the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog), and the Disability Assessment for Dementia (DAD).

There were no new signs of any safety problems in either study. Adverse events, which included pneumonia, syncope, hip fractures, and convulsions, were significantly more common in the active group, compared with the placebo group. Some patients also experienced cerebral vasogenic edema and microhemorrhages.

In the wake of these negative results, Pfizer will also discontinue two other phase III studies in patients with mild to moderate Alzheimer’s, including two follow-up extension studies.

Dr. Romano said that subgroup analyses on the studies will continue. "These data, and the subgroup and biomarker analyses underway, will further inform our understanding of this complex disease and advance research in this field."

In the wake of yet another negative trial, Pfizer Inc. has discontinued research on bapineuzumab, a monoclonal antibody designed to target amyloid beta plaques in the brains of patients with Alzheimer’s disease.

The phase III trial failed to meet any of its cognitive or functional endpoints in 1,100 patients who were negative for the high-risk apolipoprotein E4 allele (apo E4). These new results, combined with disappointing outcomes in a separate study of apo E4 carriers, were the knockout punch for bapineuzumab.

Dr. Steven J. Romano, head of the Medicines Development Group at Pfizer’s Global Primary Care Business Unit, said in a written statement that the company was disappointed in the clinical outcomes.

"We are ... saddened by the lost opportunity to provide a meaningful advance for patients afflicted with mild to moderate Alzheimer’s disease and their caregivers."

In July, Pfizer reported negative results in a phase 3 study of the drug’s effect on 1,300 apo E4 carriers with Alzheimer’s disease. The primary endpoints of both studies were changes in the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog), and the Disability Assessment for Dementia (DAD).

There were no new signs of any safety problems in either study. Adverse events, which included pneumonia, syncope, hip fractures, and convulsions, were significantly more common in the active group, compared with the placebo group. Some patients also experienced cerebral vasogenic edema and microhemorrhages.

In the wake of these negative results, Pfizer will also discontinue two other phase III studies in patients with mild to moderate Alzheimer’s, including two follow-up extension studies.

Dr. Romano said that subgroup analyses on the studies will continue. "These data, and the subgroup and biomarker analyses underway, will further inform our understanding of this complex disease and advance research in this field."

In the wake of yet another negative trial, Pfizer Inc. has discontinued research on bapineuzumab, a monoclonal antibody designed to target amyloid beta plaques in the brains of patients with Alzheimer’s disease.

The phase III trial failed to meet any of its cognitive or functional endpoints in 1,100 patients who were negative for the high-risk apolipoprotein E4 allele (apo E4). These new results, combined with disappointing outcomes in a separate study of apo E4 carriers, were the knockout punch for bapineuzumab.

Dr. Steven J. Romano, head of the Medicines Development Group at Pfizer’s Global Primary Care Business Unit, said in a written statement that the company was disappointed in the clinical outcomes.

"We are ... saddened by the lost opportunity to provide a meaningful advance for patients afflicted with mild to moderate Alzheimer’s disease and their caregivers."

In July, Pfizer reported negative results in a phase 3 study of the drug’s effect on 1,300 apo E4 carriers with Alzheimer’s disease. The primary endpoints of both studies were changes in the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog), and the Disability Assessment for Dementia (DAD).

There were no new signs of any safety problems in either study. Adverse events, which included pneumonia, syncope, hip fractures, and convulsions, were significantly more common in the active group, compared with the placebo group. Some patients also experienced cerebral vasogenic edema and microhemorrhages.

In the wake of these negative results, Pfizer will also discontinue two other phase III studies in patients with mild to moderate Alzheimer’s, including two follow-up extension studies.

Dr. Romano said that subgroup analyses on the studies will continue. "These data, and the subgroup and biomarker analyses underway, will further inform our understanding of this complex disease and advance research in this field."

VANCOUVER, B.C. – Nonpharmacologic interventions bestow clinically meaningful benefits on patients with dementia, a literature review has concluded.

But these aren’t one-size-fits-all activities, Dr. Clive Ballard said at the Alzheimer’s Association International Conference. Different activities improve different problems, leading to the possibility of targeted treatment.

"Reminiscence improves depression but no other neuropsychiatric symptom. Social interaction and pleasant activities improve agitation but not mood," said Dr. Ballard, a professor of age-related diseases at King’s College London. "There is a substantial amount of data emerging that shows not only that these interventions are helpful, but that we can target them to specific symptoms."

Nonpharmacologic interventions have several benefits for patients who are living in an institutional setting: They produce results, they don’t come with the baggage of physical side effects, and – perhaps most importantly – they are simple.

"If you’re going to do something in a nursing home, it has to be easy and practical. If it’s not simple, you can’t implement it."

Dr. Ballard and his colleagues reviewed 56 studies of nondrug interventions designed to improve dementia care in nursing homes; 32 of these have been published since 2008, which he said is "very encouraging."

The studies varied widely in duration, from 1 to 24 weeks. The investigators grouped the interventions into broad categories: social interaction, exercise, personalized care, and person-centered care.

Twelve studies addressed the use of reminiscence. The studies included groups of up to 130 residents, and ran for a median of 7 weeks. "The results were encouraging, and the most consistent outcome was for depression," with the majority of residents showing a significant improvement in that measure, Dr. Ballard said.

"There is increasing controversy about the benefit of antidepressants in the context of dementia, so it’s especially encouraging that there are nondrug interventions" for depression, he said.

Five trials looked at engaging residents in pleasant activities; the median length of intervention was 3.5 weeks. "All four of the trials that looked at agitation as an outcome showed a significant benefit," Dr. Ballard said. "There was less clear-cut evidence of an effect in depression. One trial also reported an improvement in apathy."

Seven studies examined the benefits of exercise; the median study length was 16 weeks. "There was some evidence of improvement in depression, but it was marginal, with two showing a benefit and three not. None of the trials showed that any other neuropsychiatric condition improved." Residents who exercised did, however, show improvements in gait and mobility.

There were 10 studies on personalized music. The results were "not quite as consistent" as those of studies in which patients engaged in pleasant activities, but four of the seven that looked at agitation showed a significant benefit. There wasn’t any benefit for depression. "This one is a really simple thing to do – it can be used as a reminiscence tool or simply having someone sitting with patients and listening together to music the patient likes."

Two trials examined "person-centered care" – care that is individually tailored to the patient’s preferences and goals. These studies compared person-centered care to care as usual. One was a 4-month study of almost 300 patients. There were significant improvements in agitation, but no reduction in antipsychotic use. "The effect on quality of life was marginal," Dr. Ballard said.

The second was a 10-month intervention comparing six facilities that incorporated person-centered care and six having usual care. "These showed a halving in the use of antipsychotic drugs, with no worsening of symptoms. But neither was there an overall improvement in behavior," he said.

However, 42 patients in the active group, who were on antipsychotic drugs at baseline, showed significantly less social withdrawal as the study progressed, Dr. Ballard said. "Their social interaction, activity, and overall well-being significantly increased. It appeared that stopping the antipsychotics led to an improvement in their quality of life, but there was probably not a lot of improvement in those who were not on antipsychotics to start with."

It’s hard to tell why the programs improve behavior and well-being, but Dr. Ballard said one sad fact may hold an answer.

"We have done two studies of dementia care mapping, which involved about 1,000 patients in 30 homes. The residents were observed every 5 minutes over 6 hours of waking time, to ascertain the amount of time spent in social interactions with other residents or staff. It was a total of about 2 minutes. If someone’s life consists of sitting alone all day, with only 2 minutes of interacting with another human, no drug is going to sort that out."

Dr. Ballard disclosed financial relationships with numerous drug companies.

VANCOUVER, B.C. – Nonpharmacologic interventions bestow clinically meaningful benefits on patients with dementia, a literature review has concluded.

But these aren’t one-size-fits-all activities, Dr. Clive Ballard said at the Alzheimer’s Association International Conference. Different activities improve different problems, leading to the possibility of targeted treatment.

"Reminiscence improves depression but no other neuropsychiatric symptom. Social interaction and pleasant activities improve agitation but not mood," said Dr. Ballard, a professor of age-related diseases at King’s College London. "There is a substantial amount of data emerging that shows not only that these interventions are helpful, but that we can target them to specific symptoms."

Nonpharmacologic interventions have several benefits for patients who are living in an institutional setting: They produce results, they don’t come with the baggage of physical side effects, and – perhaps most importantly – they are simple.

"If you’re going to do something in a nursing home, it has to be easy and practical. If it’s not simple, you can’t implement it."

Dr. Ballard and his colleagues reviewed 56 studies of nondrug interventions designed to improve dementia care in nursing homes; 32 of these have been published since 2008, which he said is "very encouraging."

The studies varied widely in duration, from 1 to 24 weeks. The investigators grouped the interventions into broad categories: social interaction, exercise, personalized care, and person-centered care.

Twelve studies addressed the use of reminiscence. The studies included groups of up to 130 residents, and ran for a median of 7 weeks. "The results were encouraging, and the most consistent outcome was for depression," with the majority of residents showing a significant improvement in that measure, Dr. Ballard said.

"There is increasing controversy about the benefit of antidepressants in the context of dementia, so it’s especially encouraging that there are nondrug interventions" for depression, he said.

Five trials looked at engaging residents in pleasant activities; the median length of intervention was 3.5 weeks. "All four of the trials that looked at agitation as an outcome showed a significant benefit," Dr. Ballard said. "There was less clear-cut evidence of an effect in depression. One trial also reported an improvement in apathy."

Seven studies examined the benefits of exercise; the median study length was 16 weeks. "There was some evidence of improvement in depression, but it was marginal, with two showing a benefit and three not. None of the trials showed that any other neuropsychiatric condition improved." Residents who exercised did, however, show improvements in gait and mobility.

There were 10 studies on personalized music. The results were "not quite as consistent" as those of studies in which patients engaged in pleasant activities, but four of the seven that looked at agitation showed a significant benefit. There wasn’t any benefit for depression. "This one is a really simple thing to do – it can be used as a reminiscence tool or simply having someone sitting with patients and listening together to music the patient likes."

Two trials examined "person-centered care" – care that is individually tailored to the patient’s preferences and goals. These studies compared person-centered care to care as usual. One was a 4-month study of almost 300 patients. There were significant improvements in agitation, but no reduction in antipsychotic use. "The effect on quality of life was marginal," Dr. Ballard said.

The second was a 10-month intervention comparing six facilities that incorporated person-centered care and six having usual care. "These showed a halving in the use of antipsychotic drugs, with no worsening of symptoms. But neither was there an overall improvement in behavior," he said.

However, 42 patients in the active group, who were on antipsychotic drugs at baseline, showed significantly less social withdrawal as the study progressed, Dr. Ballard said. "Their social interaction, activity, and overall well-being significantly increased. It appeared that stopping the antipsychotics led to an improvement in their quality of life, but there was probably not a lot of improvement in those who were not on antipsychotics to start with."

It’s hard to tell why the programs improve behavior and well-being, but Dr. Ballard said one sad fact may hold an answer.

"We have done two studies of dementia care mapping, which involved about 1,000 patients in 30 homes. The residents were observed every 5 minutes over 6 hours of waking time, to ascertain the amount of time spent in social interactions with other residents or staff. It was a total of about 2 minutes. If someone’s life consists of sitting alone all day, with only 2 minutes of interacting with another human, no drug is going to sort that out."

Dr. Ballard disclosed financial relationships with numerous drug companies.

VANCOUVER, B.C. – Nonpharmacologic interventions bestow clinically meaningful benefits on patients with dementia, a literature review has concluded.

But these aren’t one-size-fits-all activities, Dr. Clive Ballard said at the Alzheimer’s Association International Conference. Different activities improve different problems, leading to the possibility of targeted treatment.

"Reminiscence improves depression but no other neuropsychiatric symptom. Social interaction and pleasant activities improve agitation but not mood," said Dr. Ballard, a professor of age-related diseases at King’s College London. "There is a substantial amount of data emerging that shows not only that these interventions are helpful, but that we can target them to specific symptoms."

Nonpharmacologic interventions have several benefits for patients who are living in an institutional setting: They produce results, they don’t come with the baggage of physical side effects, and – perhaps most importantly – they are simple.

"If you’re going to do something in a nursing home, it has to be easy and practical. If it’s not simple, you can’t implement it."

Dr. Ballard and his colleagues reviewed 56 studies of nondrug interventions designed to improve dementia care in nursing homes; 32 of these have been published since 2008, which he said is "very encouraging."

The studies varied widely in duration, from 1 to 24 weeks. The investigators grouped the interventions into broad categories: social interaction, exercise, personalized care, and person-centered care.

Twelve studies addressed the use of reminiscence. The studies included groups of up to 130 residents, and ran for a median of 7 weeks. "The results were encouraging, and the most consistent outcome was for depression," with the majority of residents showing a significant improvement in that measure, Dr. Ballard said.

"There is increasing controversy about the benefit of antidepressants in the context of dementia, so it’s especially encouraging that there are nondrug interventions" for depression, he said.

Five trials looked at engaging residents in pleasant activities; the median length of intervention was 3.5 weeks. "All four of the trials that looked at agitation as an outcome showed a significant benefit," Dr. Ballard said. "There was less clear-cut evidence of an effect in depression. One trial also reported an improvement in apathy."

Seven studies examined the benefits of exercise; the median study length was 16 weeks. "There was some evidence of improvement in depression, but it was marginal, with two showing a benefit and three not. None of the trials showed that any other neuropsychiatric condition improved." Residents who exercised did, however, show improvements in gait and mobility.

There were 10 studies on personalized music. The results were "not quite as consistent" as those of studies in which patients engaged in pleasant activities, but four of the seven that looked at agitation showed a significant benefit. There wasn’t any benefit for depression. "This one is a really simple thing to do – it can be used as a reminiscence tool or simply having someone sitting with patients and listening together to music the patient likes."

Two trials examined "person-centered care" – care that is individually tailored to the patient’s preferences and goals. These studies compared person-centered care to care as usual. One was a 4-month study of almost 300 patients. There were significant improvements in agitation, but no reduction in antipsychotic use. "The effect on quality of life was marginal," Dr. Ballard said.

The second was a 10-month intervention comparing six facilities that incorporated person-centered care and six having usual care. "These showed a halving in the use of antipsychotic drugs, with no worsening of symptoms. But neither was there an overall improvement in behavior," he said.

However, 42 patients in the active group, who were on antipsychotic drugs at baseline, showed significantly less social withdrawal as the study progressed, Dr. Ballard said. "Their social interaction, activity, and overall well-being significantly increased. It appeared that stopping the antipsychotics led to an improvement in their quality of life, but there was probably not a lot of improvement in those who were not on antipsychotics to start with."

It’s hard to tell why the programs improve behavior and well-being, but Dr. Ballard said one sad fact may hold an answer.

"We have done two studies of dementia care mapping, which involved about 1,000 patients in 30 homes. The residents were observed every 5 minutes over 6 hours of waking time, to ascertain the amount of time spent in social interactions with other residents or staff. It was a total of about 2 minutes. If someone’s life consists of sitting alone all day, with only 2 minutes of interacting with another human, no drug is going to sort that out."

Dr. Ballard disclosed financial relationships with numerous drug companies.

VANCOUVER, B.C.  – When Alzheimer’s disease patients who took risperidone for psychoses discontinued the drug, they were more than four times more likely to relapse than were those who continued treatment in a randomized, placebo-controlled trial.

The ADAD (Antipsychotic Discontinuation in Alzheimer’s Disease) trial suggests that at least some patients might benefit from a longer course of antipsychotic treatment, Dr. Davangere Devanand said at the Alzheimer’s Association International Conference 2012.

The ADAD trial began with a 16-week, open label phase in which 180 patients with dementia and psychotic symptoms or agitation and aggression received a flexible dose of risperidone. At the end of that period, 110 responders were randomized to one of three 32-week arms: continued risperidone treatment; placebo for 32 weeks; or risperidone for 16 weeks followed by 16 weeks of placebo.

The mean daily dose was small, at 0.97 mg. The primary outcome was relapse to psychotic symptoms. At the end of the run-in period, the average total Neuropsychiatric Inventory score had decreased from 36 to 9.

In the first half of the randomization period, 60% of those on placebo relapsed, compared with 33% of those who continued the drug (hazard ratio, 1.97).

The second 16-week period evaluated the change in those who switched from risperidone to placebo, compared with the continuation group. Relapse occurred in 48% of the switched patients, compared with 15% of those who continued risperidone (HR, 4.33)

"There were no significant interactions predicting who would relapse, even in the baseline measures of psychosis or cognition," said Dr. Devanand, codirector of the memory disorders center and codirector of the late life depression clinic at the New York State Psychiatric Institute, New York.

There were no significant between-group differences in adverse events, he said. There were three deaths in the run-in phase and three in the randomization phase (two on risperidone and one in placebo), but Dr. Devanand said that the sample size wasn’t large enough to draw any conclusions about mortality risks.

He pointed out several factors that could have affected the study’s outcome. "This is a discontinuation trial, so the sample was an enriched population," he said. "This might mean that relapse is more likely in patients who have previously responded to a drug."

Dr. Devanand disclosed financial relationships with Eli Lilly, Novartis, Bristol-Myers Squibb, and Sanofi Aventis. Janssen Pharmaceuticals supplied the risperidone used in the study but had no input in the data compilation. The study was supported by the National Institutes of Health and the National Institute on Aging.

VANCOUVER, B.C.  – When Alzheimer’s disease patients who took risperidone for psychoses discontinued the drug, they were more than four times more likely to relapse than were those who continued treatment in a randomized, placebo-controlled trial.

The ADAD (Antipsychotic Discontinuation in Alzheimer’s Disease) trial suggests that at least some patients might benefit from a longer course of antipsychotic treatment, Dr. Davangere Devanand said at the Alzheimer’s Association International Conference 2012.

The ADAD trial began with a 16-week, open label phase in which 180 patients with dementia and psychotic symptoms or agitation and aggression received a flexible dose of risperidone. At the end of that period, 110 responders were randomized to one of three 32-week arms: continued risperidone treatment; placebo for 32 weeks; or risperidone for 16 weeks followed by 16 weeks of placebo.

The mean daily dose was small, at 0.97 mg. The primary outcome was relapse to psychotic symptoms. At the end of the run-in period, the average total Neuropsychiatric Inventory score had decreased from 36 to 9.

In the first half of the randomization period, 60% of those on placebo relapsed, compared with 33% of those who continued the drug (hazard ratio, 1.97).

The second 16-week period evaluated the change in those who switched from risperidone to placebo, compared with the continuation group. Relapse occurred in 48% of the switched patients, compared with 15% of those who continued risperidone (HR, 4.33)

"There were no significant interactions predicting who would relapse, even in the baseline measures of psychosis or cognition," said Dr. Devanand, codirector of the memory disorders center and codirector of the late life depression clinic at the New York State Psychiatric Institute, New York.

There were no significant between-group differences in adverse events, he said. There were three deaths in the run-in phase and three in the randomization phase (two on risperidone and one in placebo), but Dr. Devanand said that the sample size wasn’t large enough to draw any conclusions about mortality risks.

He pointed out several factors that could have affected the study’s outcome. "This is a discontinuation trial, so the sample was an enriched population," he said. "This might mean that relapse is more likely in patients who have previously responded to a drug."

Dr. Devanand disclosed financial relationships with Eli Lilly, Novartis, Bristol-Myers Squibb, and Sanofi Aventis. Janssen Pharmaceuticals supplied the risperidone used in the study but had no input in the data compilation. The study was supported by the National Institutes of Health and the National Institute on Aging.

VANCOUVER, B.C.  – When Alzheimer’s disease patients who took risperidone for psychoses discontinued the drug, they were more than four times more likely to relapse than were those who continued treatment in a randomized, placebo-controlled trial.

The ADAD (Antipsychotic Discontinuation in Alzheimer’s Disease) trial suggests that at least some patients might benefit from a longer course of antipsychotic treatment, Dr. Davangere Devanand said at the Alzheimer’s Association International Conference 2012.

The ADAD trial began with a 16-week, open label phase in which 180 patients with dementia and psychotic symptoms or agitation and aggression received a flexible dose of risperidone. At the end of that period, 110 responders were randomized to one of three 32-week arms: continued risperidone treatment; placebo for 32 weeks; or risperidone for 16 weeks followed by 16 weeks of placebo.

The mean daily dose was small, at 0.97 mg. The primary outcome was relapse to psychotic symptoms. At the end of the run-in period, the average total Neuropsychiatric Inventory score had decreased from 36 to 9.

In the first half of the randomization period, 60% of those on placebo relapsed, compared with 33% of those who continued the drug (hazard ratio, 1.97).

The second 16-week period evaluated the change in those who switched from risperidone to placebo, compared with the continuation group. Relapse occurred in 48% of the switched patients, compared with 15% of those who continued risperidone (HR, 4.33)

"There were no significant interactions predicting who would relapse, even in the baseline measures of psychosis or cognition," said Dr. Devanand, codirector of the memory disorders center and codirector of the late life depression clinic at the New York State Psychiatric Institute, New York.

There were no significant between-group differences in adverse events, he said. There were three deaths in the run-in phase and three in the randomization phase (two on risperidone and one in placebo), but Dr. Devanand said that the sample size wasn’t large enough to draw any conclusions about mortality risks.

He pointed out several factors that could have affected the study’s outcome. "This is a discontinuation trial, so the sample was an enriched population," he said. "This might mean that relapse is more likely in patients who have previously responded to a drug."

Dr. Devanand disclosed financial relationships with Eli Lilly, Novartis, Bristol-Myers Squibb, and Sanofi Aventis. Janssen Pharmaceuticals supplied the risperidone used in the study but had no input in the data compilation. The study was supported by the National Institutes of Health and the National Institute on Aging.

Depression does more than strike at the heart; it can compromise survival for patients with metastatic kidney cancer.

Researchers from the University of Texas M.D. Anderson Cancer Center in Houston found that patients with higher levels of cortisol – a stress hormone linked with depression – died significantly sooner than those with lower cortisol levels (hazard ratio, 1.9; P = .002).

The prospective study accrued 217 patients with newly diagnosed metastatic renal cell carcinoma (RCC) from 2000 to 2007. Participants completed psychosocial questionnaires; saliva and blood samples also were collected.

Nearly a quarter (23%) of the population had a score of 16 or greater on the CES-D (Centers for Epidemiologic StudiesDepression) scale, which met criteria for depressive symptoms and was also associated with shorter survival, compared with lower scores (HR, 1.5; P = .05).

Genomic analysis suggested a biological underpinning for the observed link, reported Lorenzo Cohen, Ph.D., a professor in M.D. Anderson’s departments of general oncology and behavioral science and director of the integrative medicine program, and his coauthors. Patients with high cortisol levels had marked up-regulation of proinflammatory genes.

"Collectively, the present data suggest that the association between RCC patient psychological condition and survival time may stem from systemic dysregulation of inflammatory biology resulting from blunted cortisol rhythmicity and subsequent de-repression of pro-inflammatory signaling pathways within the tumor microenvironment that subsequently contribute to disease progression and metastasis," wrote the investigators. (PLoS ONE 2012 Aug. 1 [doi:10.1371/journal.pone.0042324]).

Grants from the Dana Foundation, the Mary and David Wolff Family Foundation, the U.S. Department of Health and Human Services, the National Institutes of Health, and the M.D. Anderson Cancer Center supported the research.

Depression does more than strike at the heart; it can compromise survival for patients with metastatic kidney cancer.

Researchers from the University of Texas M.D. Anderson Cancer Center in Houston found that patients with higher levels of cortisol – a stress hormone linked with depression – died significantly sooner than those with lower cortisol levels (hazard ratio, 1.9; P = .002).

The prospective study accrued 217 patients with newly diagnosed metastatic renal cell carcinoma (RCC) from 2000 to 2007. Participants completed psychosocial questionnaires; saliva and blood samples also were collected.

Nearly a quarter (23%) of the population had a score of 16 or greater on the CES-D (Centers for Epidemiologic StudiesDepression) scale, which met criteria for depressive symptoms and was also associated with shorter survival, compared with lower scores (HR, 1.5; P = .05).

Genomic analysis suggested a biological underpinning for the observed link, reported Lorenzo Cohen, Ph.D., a professor in M.D. Anderson’s departments of general oncology and behavioral science and director of the integrative medicine program, and his coauthors. Patients with high cortisol levels had marked up-regulation of proinflammatory genes.

"Collectively, the present data suggest that the association between RCC patient psychological condition and survival time may stem from systemic dysregulation of inflammatory biology resulting from blunted cortisol rhythmicity and subsequent de-repression of pro-inflammatory signaling pathways within the tumor microenvironment that subsequently contribute to disease progression and metastasis," wrote the investigators. (PLoS ONE 2012 Aug. 1 [doi:10.1371/journal.pone.0042324]).

Grants from the Dana Foundation, the Mary and David Wolff Family Foundation, the U.S. Department of Health and Human Services, the National Institutes of Health, and the M.D. Anderson Cancer Center supported the research.

Depression does more than strike at the heart; it can compromise survival for patients with metastatic kidney cancer.

Researchers from the University of Texas M.D. Anderson Cancer Center in Houston found that patients with higher levels of cortisol – a stress hormone linked with depression – died significantly sooner than those with lower cortisol levels (hazard ratio, 1.9; P = .002).

The prospective study accrued 217 patients with newly diagnosed metastatic renal cell carcinoma (RCC) from 2000 to 2007. Participants completed psychosocial questionnaires; saliva and blood samples also were collected.

Nearly a quarter (23%) of the population had a score of 16 or greater on the CES-D (Centers for Epidemiologic StudiesDepression) scale, which met criteria for depressive symptoms and was also associated with shorter survival, compared with lower scores (HR, 1.5; P = .05).

Genomic analysis suggested a biological underpinning for the observed link, reported Lorenzo Cohen, Ph.D., a professor in M.D. Anderson’s departments of general oncology and behavioral science and director of the integrative medicine program, and his coauthors. Patients with high cortisol levels had marked up-regulation of proinflammatory genes.

"Collectively, the present data suggest that the association between RCC patient psychological condition and survival time may stem from systemic dysregulation of inflammatory biology resulting from blunted cortisol rhythmicity and subsequent de-repression of pro-inflammatory signaling pathways within the tumor microenvironment that subsequently contribute to disease progression and metastasis," wrote the investigators. (PLoS ONE 2012 Aug. 1 [doi:10.1371/journal.pone.0042324]).

Grants from the Dana Foundation, the Mary and David Wolff Family Foundation, the U.S. Department of Health and Human Services, the National Institutes of Health, and the M.D. Anderson Cancer Center supported the research.

PHILADELPHIA – An elevated postpartum fasting blood sugar does not predict type 2 diabetes in women who had gestational diabetes.

Out of nine women with an elevated fasting glucose after giving birth, only two went on to a diagnosis of type 2 diabetes 6 weeks later, Dr. Hilary Roeder said at the annual scientific sessions of the American Diabetes Association.

"That means that if we had used the postpartum glucose value as a diagnostic tool, seven women would have been misdiagnosed," Dr. Roeder, an ob.gyn. at Scripps Health in San Diego, said in an interview. "We still have no good way to know specifically which women with gestational diabetes will subsequently develop type 2 diabetes."

For women with gestational diabetes, an oral glucose tolerance test should be done 6 weeks after delivery, the American Diabetes Association recommends. But some new mothers don’t make it back to the doctor at that time, Dr. Roeder said.

"We still have no good way to know specifically which women with gestational diabetes will subsequently develop type 2 diabetes."

"The problem with formal screening at the 6-week postpartum appointment is that patients don’t always come back for this visit," she said. "They get busy with the new baby or have already gone back to work and they don’t follow up. Or if they do, they often are not fasting – a requirement to perform formal screening for type 2 diabetes. Our thought was that if we could diagnose them prior to discharge from the hospital, we could set up a follow-up visit with a primary care physician or an endocrinologist so they can get proper care."

She employed a retrospective cohort study to determine whether postpartum glucose on the day of delivery was associated with a later type 2 diabetes diagnosis. Although there were 545 patients with gestational diabetes in the records, only 165 (30%) had a formal diabetes screen at 6 weeks – illustrating the poor rate of follow-up in the cohort.

Of those who were tested at 6 weeks, 111 also had a postpartum fasting glucose available for review. The patients had a mean age of 32 years, with a mean body mass index of 31 kg/m². They had a mean gestation of 25 weeks when diagnosed with gestational diabetes.

Nine of those with a postpartum test had glucose levels above 126 mg/dL. But 6 weeks later, only two of those women were found to have type 2 diabetes.

When Dr. Roeder compared the postpartum glucose levels between patients, she found no significant difference between those who developed type 2 diabetes and those who did not. In fact, had the diagnosis been made immediately post partum, six additional women who did develop diabetes would have been missed, as their blood sugar was less than 126 mg/dL after delivery.

Overall, postpartum blood glucose levels were significantly higher than 6-week levels (mean 101 mg/dL vs. 93 mg/dL). Dr. Roeder said she believes human placental lactogen and other placentally-derived hormones could be responsible for this in part. The hormones keep glucose in the maternal bloodstream, making it more available for fetal metabolism. This results in higher maternal glucose levels, which take some time after birth to decline.

"Even though the placenta has been removed, the hormones are still circulating for an indefinite time after birth," she said.

Because immediate postpartum testing does not appear helpful, Dr. Roeder said it’s critical that women with gestational diabetes attend their 6-week checkup and have a full diabetes screen.

"We really need to impress upon our patients how important this visit is to their future health."

Dr. Roeder had no financial disclosures.

PHILADELPHIA – An elevated postpartum fasting blood sugar does not predict type 2 diabetes in women who had gestational diabetes.

Out of nine women with an elevated fasting glucose after giving birth, only two went on to a diagnosis of type 2 diabetes 6 weeks later, Dr. Hilary Roeder said at the annual scientific sessions of the American Diabetes Association.

"That means that if we had used the postpartum glucose value as a diagnostic tool, seven women would have been misdiagnosed," Dr. Roeder, an ob.gyn. at Scripps Health in San Diego, said in an interview. "We still have no good way to know specifically which women with gestational diabetes will subsequently develop type 2 diabetes."

For women with gestational diabetes, an oral glucose tolerance test should be done 6 weeks after delivery, the American Diabetes Association recommends. But some new mothers don’t make it back to the doctor at that time, Dr. Roeder said.

"We still have no good way to know specifically which women with gestational diabetes will subsequently develop type 2 diabetes."

"The problem with formal screening at the 6-week postpartum appointment is that patients don’t always come back for this visit," she said. "They get busy with the new baby or have already gone back to work and they don’t follow up. Or if they do, they often are not fasting – a requirement to perform formal screening for type 2 diabetes. Our thought was that if we could diagnose them prior to discharge from the hospital, we could set up a follow-up visit with a primary care physician or an endocrinologist so they can get proper care."

She employed a retrospective cohort study to determine whether postpartum glucose on the day of delivery was associated with a later type 2 diabetes diagnosis. Although there were 545 patients with gestational diabetes in the records, only 165 (30%) had a formal diabetes screen at 6 weeks – illustrating the poor rate of follow-up in the cohort.

Of those who were tested at 6 weeks, 111 also had a postpartum fasting glucose available for review. The patients had a mean age of 32 years, with a mean body mass index of 31 kg/m². They had a mean gestation of 25 weeks when diagnosed with gestational diabetes.

Nine of those with a postpartum test had glucose levels above 126 mg/dL. But 6 weeks later, only two of those women were found to have type 2 diabetes.

When Dr. Roeder compared the postpartum glucose levels between patients, she found no significant difference between those who developed type 2 diabetes and those who did not. In fact, had the diagnosis been made immediately post partum, six additional women who did develop diabetes would have been missed, as their blood sugar was less than 126 mg/dL after delivery.

Overall, postpartum blood glucose levels were significantly higher than 6-week levels (mean 101 mg/dL vs. 93 mg/dL). Dr. Roeder said she believes human placental lactogen and other placentally-derived hormones could be responsible for this in part. The hormones keep glucose in the maternal bloodstream, making it more available for fetal metabolism. This results in higher maternal glucose levels, which take some time after birth to decline.

"Even though the placenta has been removed, the hormones are still circulating for an indefinite time after birth," she said.

Because immediate postpartum testing does not appear helpful, Dr. Roeder said it’s critical that women with gestational diabetes attend their 6-week checkup and have a full diabetes screen.

"We really need to impress upon our patients how important this visit is to their future health."

Dr. Roeder had no financial disclosures.

PHILADELPHIA – An elevated postpartum fasting blood sugar does not predict type 2 diabetes in women who had gestational diabetes.

Out of nine women with an elevated fasting glucose after giving birth, only two went on to a diagnosis of type 2 diabetes 6 weeks later, Dr. Hilary Roeder said at the annual scientific sessions of the American Diabetes Association.

"That means that if we had used the postpartum glucose value as a diagnostic tool, seven women would have been misdiagnosed," Dr. Roeder, an ob.gyn. at Scripps Health in San Diego, said in an interview. "We still have no good way to know specifically which women with gestational diabetes will subsequently develop type 2 diabetes."

For women with gestational diabetes, an oral glucose tolerance test should be done 6 weeks after delivery, the American Diabetes Association recommends. But some new mothers don’t make it back to the doctor at that time, Dr. Roeder said.

"We still have no good way to know specifically which women with gestational diabetes will subsequently develop type 2 diabetes."

"The problem with formal screening at the 6-week postpartum appointment is that patients don’t always come back for this visit," she said. "They get busy with the new baby or have already gone back to work and they don’t follow up. Or if they do, they often are not fasting – a requirement to perform formal screening for type 2 diabetes. Our thought was that if we could diagnose them prior to discharge from the hospital, we could set up a follow-up visit with a primary care physician or an endocrinologist so they can get proper care."

She employed a retrospective cohort study to determine whether postpartum glucose on the day of delivery was associated with a later type 2 diabetes diagnosis. Although there were 545 patients with gestational diabetes in the records, only 165 (30%) had a formal diabetes screen at 6 weeks – illustrating the poor rate of follow-up in the cohort.

Of those who were tested at 6 weeks, 111 also had a postpartum fasting glucose available for review. The patients had a mean age of 32 years, with a mean body mass index of 31 kg/m². They had a mean gestation of 25 weeks when diagnosed with gestational diabetes.

Nine of those with a postpartum test had glucose levels above 126 mg/dL. But 6 weeks later, only two of those women were found to have type 2 diabetes.

When Dr. Roeder compared the postpartum glucose levels between patients, she found no significant difference between those who developed type 2 diabetes and those who did not. In fact, had the diagnosis been made immediately post partum, six additional women who did develop diabetes would have been missed, as their blood sugar was less than 126 mg/dL after delivery.

Overall, postpartum blood glucose levels were significantly higher than 6-week levels (mean 101 mg/dL vs. 93 mg/dL). Dr. Roeder said she believes human placental lactogen and other placentally-derived hormones could be responsible for this in part. The hormones keep glucose in the maternal bloodstream, making it more available for fetal metabolism. This results in higher maternal glucose levels, which take some time after birth to decline.

"Even though the placenta has been removed, the hormones are still circulating for an indefinite time after birth," she said.

Because immediate postpartum testing does not appear helpful, Dr. Roeder said it’s critical that women with gestational diabetes attend their 6-week checkup and have a full diabetes screen.

"We really need to impress upon our patients how important this visit is to their future health."

Dr. Roeder had no financial disclosures.