Kate Johnson

MONTREAL — The addition of d-cycloserine to cognitive-behavioral therapy for the treatment of posttraumatic stress disorder showed little or no benefit over placebo, based on several studies presented at the meeting.

The presentations sparked some heated debate and dampened hopes for the drug in treating posttraumatic stress disorder (PTSD), given that it has already shown promise in the treatment of social anxiety disorder, panic disorder, and some phobias – and might have potential in the treatment of obsessive-compulsive disorder and addictions.

“The early results are not as positive as we [had] hoped,” commented Dr. Charles Marmar, professor and chair of the department of psychiatry at New York University, when asked to comment after the session. “We didn't see much evidence today that

But Dr. Pitman cautioned against dismissing the potential of

“It's fair to conclude that DCS has the capability of bolstering cognitive-behavioral therapy by enhancing retention, but maybe PTSD is a tougher nut to crack.”

In animal laboratory work, DCS been shown to reduce fear in mice. Its positive effect in the treatment of human anxiety and phobia studies is believed to stem from the drug's ability to enhance learning of new responses to stressful stimuli.

“Maybe for PTSD, the neurobiological mechanisms that are associated with maintenance of this disorder are more complex than those associated with less complex disorders such as social anxiety,” suggested Stéphane Guay, Ph.D., director of the trauma study center at Louis-H. Lafontaine Hospital in Montreal, who presented one of the negative DCS studies at the meeting, cosponsored by Boston University.

His randomized, double-blind placebo-controlled trial included 45 adult PTSD patients, with moderate to severe symptoms. All patients received 11 or 12 sessions (duration, 90 minutes) of CBT combined with either placebo (n = 23) or DCS (n = 22) 50 mg, administered 1 hour prior to the session for sessions 4 through 11.

The idea behind administration of the drug is that cognitive-behavioral therapy is based on learning, and DCS can enhance learning, he explained. CBT was manualized, and included psychoeducation about posttraumatic stress disorder, prolonged imaginal exposure, and breathing retraining.

The main outcomes were PTSD symptoms, measured with the Clinician-Administered PTSD Scale (CAPS) and the Structured Clinical Interview for DSM-IV Disorders (SCID), and depression, measured by the Beck Depression Inventory (BDI).

Remission rates were roughly equivalent in both groups at 55% for the placebo group and 48% for the treated group immediately following the treatment, and 59% and 44% at the 6-month follow-up.

“We found that DCS didn't seem to improve or increase or accelerate the treatment,” he said in an interview. “In fact, those who received DCS did worse in general.”

The researchers analyzed a subgroup of patients who were depressed at baseline and found that while CAPS scores dropped for nondepressed patients, they remained almost the same in the depressed group. “These data do not support the use of DCS as an adjunct to CBT in PTSD and show a negative interaction between PTSD, major depression, and DCS,” he concluded. “The mechanism of major depression and PTSD may be different.”

Two other studies presented during the session had not yet been unblinded, so no reliable conclusions could be drawn, and a third study of 20 patients randomized to CBT plus placebo or CBT plus

Asked to comment on the presentations, Rachel Yehuda, Ph.D., professor of psychiatry at Mount Sinai School of Medicine and director of mental health at the James J. Peters VA Medical Center, both in New York, expressed concern that there was too much unfounded optimism in the face of the underwhelming findings.

“I am challenging my clinical colleagues to not get too excited because the basic scientists are staying more sober,” she said, referring to the earlier session that presented findings of this therapy in mice.

“They're not presenting the negatives of the data with adequate emphasis – it's as simple as that,” added Dr. Alexander McFarlane, director of the Centre for Military and Veterans' Health and professor of psychiatry at the University of Adelaide (Australia). “You can see there's a real desire to bring the world of psychotherapy and the world of pharmacology together. There's tremendous investment in this idea.

“The trouble is, you always have inconvenient truths, and it's about not running away from them. Good science is to face those inconsistencies.”

But Dr. Pitman was more optimistic. “The goal of DCS is to facilitate the consolidation of extinction learning. It's called extinction retention. We've published data that extinction retention is deficient in posttraumatic stress disorder, so the idea that extinction retention could be boosted by an agent like DCS is very attractive,” he said.

The field is still very new, and gaps in knowledge are numerous, both at the basic science and clinical level, said Dr. Marmar, urging patience.

“The fact that DCS has been shown to accelerate or improve the effectiveness of behavioral treatments for other disorders, like phobia, social anxiety, and some others suggests we should continue to work on this drug with PTSD – and try to refine it and try to determine the optimal parameters in dosing and scheduling.”

MONTREAL — The addition of d-cycloserine to cognitive-behavioral therapy for the treatment of posttraumatic stress disorder showed little or no benefit over placebo, based on several studies presented at the meeting.

The presentations sparked some heated debate and dampened hopes for the drug in treating posttraumatic stress disorder (PTSD), given that it has already shown promise in the treatment of social anxiety disorder, panic disorder, and some phobias – and might have potential in the treatment of obsessive-compulsive disorder and addictions.

“The early results are not as positive as we [had] hoped,” commented Dr. Charles Marmar, professor and chair of the department of psychiatry at New York University, when asked to comment after the session. “We didn't see much evidence today that

But Dr. Pitman cautioned against dismissing the potential of

“It's fair to conclude that DCS has the capability of bolstering cognitive-behavioral therapy by enhancing retention, but maybe PTSD is a tougher nut to crack.”

In animal laboratory work, DCS been shown to reduce fear in mice. Its positive effect in the treatment of human anxiety and phobia studies is believed to stem from the drug's ability to enhance learning of new responses to stressful stimuli.

“Maybe for PTSD, the neurobiological mechanisms that are associated with maintenance of this disorder are more complex than those associated with less complex disorders such as social anxiety,” suggested Stéphane Guay, Ph.D., director of the trauma study center at Louis-H. Lafontaine Hospital in Montreal, who presented one of the negative DCS studies at the meeting, cosponsored by Boston University.

His randomized, double-blind placebo-controlled trial included 45 adult PTSD patients, with moderate to severe symptoms. All patients received 11 or 12 sessions (duration, 90 minutes) of CBT combined with either placebo (n = 23) or DCS (n = 22) 50 mg, administered 1 hour prior to the session for sessions 4 through 11.

The idea behind administration of the drug is that cognitive-behavioral therapy is based on learning, and DCS can enhance learning, he explained. CBT was manualized, and included psychoeducation about posttraumatic stress disorder, prolonged imaginal exposure, and breathing retraining.

The main outcomes were PTSD symptoms, measured with the Clinician-Administered PTSD Scale (CAPS) and the Structured Clinical Interview for DSM-IV Disorders (SCID), and depression, measured by the Beck Depression Inventory (BDI).

Remission rates were roughly equivalent in both groups at 55% for the placebo group and 48% for the treated group immediately following the treatment, and 59% and 44% at the 6-month follow-up.

“We found that DCS didn't seem to improve or increase or accelerate the treatment,” he said in an interview. “In fact, those who received DCS did worse in general.”

The researchers analyzed a subgroup of patients who were depressed at baseline and found that while CAPS scores dropped for nondepressed patients, they remained almost the same in the depressed group. “These data do not support the use of DCS as an adjunct to CBT in PTSD and show a negative interaction between PTSD, major depression, and DCS,” he concluded. “The mechanism of major depression and PTSD may be different.”

Two other studies presented during the session had not yet been unblinded, so no reliable conclusions could be drawn, and a third study of 20 patients randomized to CBT plus placebo or CBT plus

Asked to comment on the presentations, Rachel Yehuda, Ph.D., professor of psychiatry at Mount Sinai School of Medicine and director of mental health at the James J. Peters VA Medical Center, both in New York, expressed concern that there was too much unfounded optimism in the face of the underwhelming findings.

“I am challenging my clinical colleagues to not get too excited because the basic scientists are staying more sober,” she said, referring to the earlier session that presented findings of this therapy in mice.

“They're not presenting the negatives of the data with adequate emphasis – it's as simple as that,” added Dr. Alexander McFarlane, director of the Centre for Military and Veterans' Health and professor of psychiatry at the University of Adelaide (Australia). “You can see there's a real desire to bring the world of psychotherapy and the world of pharmacology together. There's tremendous investment in this idea.

“The trouble is, you always have inconvenient truths, and it's about not running away from them. Good science is to face those inconsistencies.”

But Dr. Pitman was more optimistic. “The goal of DCS is to facilitate the consolidation of extinction learning. It's called extinction retention. We've published data that extinction retention is deficient in posttraumatic stress disorder, so the idea that extinction retention could be boosted by an agent like DCS is very attractive,” he said.

The field is still very new, and gaps in knowledge are numerous, both at the basic science and clinical level, said Dr. Marmar, urging patience.

“The fact that DCS has been shown to accelerate or improve the effectiveness of behavioral treatments for other disorders, like phobia, social anxiety, and some others suggests we should continue to work on this drug with PTSD – and try to refine it and try to determine the optimal parameters in dosing and scheduling.”

MONTREAL — The addition of d-cycloserine to cognitive-behavioral therapy for the treatment of posttraumatic stress disorder showed little or no benefit over placebo, based on several studies presented at the meeting.

The presentations sparked some heated debate and dampened hopes for the drug in treating posttraumatic stress disorder (PTSD), given that it has already shown promise in the treatment of social anxiety disorder, panic disorder, and some phobias – and might have potential in the treatment of obsessive-compulsive disorder and addictions.

“The early results are not as positive as we [had] hoped,” commented Dr. Charles Marmar, professor and chair of the department of psychiatry at New York University, when asked to comment after the session. “We didn't see much evidence today that

But Dr. Pitman cautioned against dismissing the potential of

“It's fair to conclude that DCS has the capability of bolstering cognitive-behavioral therapy by enhancing retention, but maybe PTSD is a tougher nut to crack.”

In animal laboratory work, DCS been shown to reduce fear in mice. Its positive effect in the treatment of human anxiety and phobia studies is believed to stem from the drug's ability to enhance learning of new responses to stressful stimuli.

“Maybe for PTSD, the neurobiological mechanisms that are associated with maintenance of this disorder are more complex than those associated with less complex disorders such as social anxiety,” suggested Stéphane Guay, Ph.D., director of the trauma study center at Louis-H. Lafontaine Hospital in Montreal, who presented one of the negative DCS studies at the meeting, cosponsored by Boston University.

His randomized, double-blind placebo-controlled trial included 45 adult PTSD patients, with moderate to severe symptoms. All patients received 11 or 12 sessions (duration, 90 minutes) of CBT combined with either placebo (n = 23) or DCS (n = 22) 50 mg, administered 1 hour prior to the session for sessions 4 through 11.

The idea behind administration of the drug is that cognitive-behavioral therapy is based on learning, and DCS can enhance learning, he explained. CBT was manualized, and included psychoeducation about posttraumatic stress disorder, prolonged imaginal exposure, and breathing retraining.

The main outcomes were PTSD symptoms, measured with the Clinician-Administered PTSD Scale (CAPS) and the Structured Clinical Interview for DSM-IV Disorders (SCID), and depression, measured by the Beck Depression Inventory (BDI).

Remission rates were roughly equivalent in both groups at 55% for the placebo group and 48% for the treated group immediately following the treatment, and 59% and 44% at the 6-month follow-up.

“We found that DCS didn't seem to improve or increase or accelerate the treatment,” he said in an interview. “In fact, those who received DCS did worse in general.”

The researchers analyzed a subgroup of patients who were depressed at baseline and found that while CAPS scores dropped for nondepressed patients, they remained almost the same in the depressed group. “These data do not support the use of DCS as an adjunct to CBT in PTSD and show a negative interaction between PTSD, major depression, and DCS,” he concluded. “The mechanism of major depression and PTSD may be different.”

Two other studies presented during the session had not yet been unblinded, so no reliable conclusions could be drawn, and a third study of 20 patients randomized to CBT plus placebo or CBT plus

Asked to comment on the presentations, Rachel Yehuda, Ph.D., professor of psychiatry at Mount Sinai School of Medicine and director of mental health at the James J. Peters VA Medical Center, both in New York, expressed concern that there was too much unfounded optimism in the face of the underwhelming findings.

“I am challenging my clinical colleagues to not get too excited because the basic scientists are staying more sober,” she said, referring to the earlier session that presented findings of this therapy in mice.

“They're not presenting the negatives of the data with adequate emphasis – it's as simple as that,” added Dr. Alexander McFarlane, director of the Centre for Military and Veterans' Health and professor of psychiatry at the University of Adelaide (Australia). “You can see there's a real desire to bring the world of psychotherapy and the world of pharmacology together. There's tremendous investment in this idea.

“The trouble is, you always have inconvenient truths, and it's about not running away from them. Good science is to face those inconsistencies.”

But Dr. Pitman was more optimistic. “The goal of DCS is to facilitate the consolidation of extinction learning. It's called extinction retention. We've published data that extinction retention is deficient in posttraumatic stress disorder, so the idea that extinction retention could be boosted by an agent like DCS is very attractive,” he said.

The field is still very new, and gaps in knowledge are numerous, both at the basic science and clinical level, said Dr. Marmar, urging patience.

“The fact that DCS has been shown to accelerate or improve the effectiveness of behavioral treatments for other disorders, like phobia, social anxiety, and some others suggests we should continue to work on this drug with PTSD – and try to refine it and try to determine the optimal parameters in dosing and scheduling.”

MONTREAL – Treatment of posttraumatic stress disorder with the beta-blocker propranolol might interrupt memory reconsolidation by inhibiting protein synthesis in the brain, reported researchers at the International Society for Traumatic Stress Studies.

“It does not erase memories; this is a misnomer,” clarified Alain Brunet, Ph.D., of the department of psychiatry at McGill University and a researcher at the Douglas Mental Health Institute, both in Montreal.

Dr. Brunet presented several studies conducted by his group that suggest this pharmacologic interruption of memory might dampen emotional response to the information, presenting a promising treatment opportunity for posttraumatic stress disorder (PTSD).

Current treatment for PTSD is centered on psychotherapy that focuses on exposure to the traumatic memory and learning new responses to it, Dr. Brunet said. But a recent analysis found that only about one-third of patients treated this way experience a lasting, clinically meaningful improvement, he said.

Propranolol treatment takes a different approach. It is based on the notion that memories, once they are consolidated, can be retrieved, and they exist in a labile state during which they are susceptible to modification until they are reconsolidated. During the labile window of opportunity, which is believed to be several hours, administration of propranolol can strip the memory of its emotional meaning, making it less stressful, he said.

In a randomized, controlled trial involving 19 chronic PTSD patients with an average symptom of duration 10 years (J. Psychiatr. Res. 2008;42:503–6), Dr. Brunet and his colleagues asked the patients to recall their memory by writing a trauma script and outlining the details of their traumatic experience and the emotions they felt.

Nine patients were then given a two-dose regimen of fast-acting propranolol (40 mg) immediately after memory recall, followed by an extended-release propanolol dose (60 mg) 75 minutes later, and the other 10 patients received placebo. One week later, after reviewing their trauma script, patients' physiologic responses to the memories were compared, using heart rate, skin conductivity, and corrugator electromyography (EMG) measurements.

Dr. Brunet reported significant differences between the placebo and treatment groups on heart rate and skin conductivity tests but not on EMG. There was a trend toward decreased symptoms, measured on the self-report Impact of Event Scale-Revised (IES-R).

The field of memory reconsolidation blockade is young when it comes to human studies, but there is substantial animal research to support it, commented Dr. Charles Marmar, professor and chair in the department of psychiatry at New York University Medical Center, who chaired a panel discussion after the session.

“The notion of building a pipeline from basic science, to translational studies in humans, to new treatments is very, very important in psychiatry,” he said in an interview. “This work is pioneering. We should have some patience about this and appreciate that this is a new paradigm in mental health research.”

MONTREAL – Treatment of posttraumatic stress disorder with the beta-blocker propranolol might interrupt memory reconsolidation by inhibiting protein synthesis in the brain, reported researchers at the International Society for Traumatic Stress Studies.

“It does not erase memories; this is a misnomer,” clarified Alain Brunet, Ph.D., of the department of psychiatry at McGill University and a researcher at the Douglas Mental Health Institute, both in Montreal.

Dr. Brunet presented several studies conducted by his group that suggest this pharmacologic interruption of memory might dampen emotional response to the information, presenting a promising treatment opportunity for posttraumatic stress disorder (PTSD).

Current treatment for PTSD is centered on psychotherapy that focuses on exposure to the traumatic memory and learning new responses to it, Dr. Brunet said. But a recent analysis found that only about one-third of patients treated this way experience a lasting, clinically meaningful improvement, he said.

Propranolol treatment takes a different approach. It is based on the notion that memories, once they are consolidated, can be retrieved, and they exist in a labile state during which they are susceptible to modification until they are reconsolidated. During the labile window of opportunity, which is believed to be several hours, administration of propranolol can strip the memory of its emotional meaning, making it less stressful, he said.

In a randomized, controlled trial involving 19 chronic PTSD patients with an average symptom of duration 10 years (J. Psychiatr. Res. 2008;42:503–6), Dr. Brunet and his colleagues asked the patients to recall their memory by writing a trauma script and outlining the details of their traumatic experience and the emotions they felt.

Nine patients were then given a two-dose regimen of fast-acting propranolol (40 mg) immediately after memory recall, followed by an extended-release propanolol dose (60 mg) 75 minutes later, and the other 10 patients received placebo. One week later, after reviewing their trauma script, patients' physiologic responses to the memories were compared, using heart rate, skin conductivity, and corrugator electromyography (EMG) measurements.

Dr. Brunet reported significant differences between the placebo and treatment groups on heart rate and skin conductivity tests but not on EMG. There was a trend toward decreased symptoms, measured on the self-report Impact of Event Scale-Revised (IES-R).

The field of memory reconsolidation blockade is young when it comes to human studies, but there is substantial animal research to support it, commented Dr. Charles Marmar, professor and chair in the department of psychiatry at New York University Medical Center, who chaired a panel discussion after the session.

“The notion of building a pipeline from basic science, to translational studies in humans, to new treatments is very, very important in psychiatry,” he said in an interview. “This work is pioneering. We should have some patience about this and appreciate that this is a new paradigm in mental health research.”

MONTREAL – Treatment of posttraumatic stress disorder with the beta-blocker propranolol might interrupt memory reconsolidation by inhibiting protein synthesis in the brain, reported researchers at the International Society for Traumatic Stress Studies.

“It does not erase memories; this is a misnomer,” clarified Alain Brunet, Ph.D., of the department of psychiatry at McGill University and a researcher at the Douglas Mental Health Institute, both in Montreal.

Dr. Brunet presented several studies conducted by his group that suggest this pharmacologic interruption of memory might dampen emotional response to the information, presenting a promising treatment opportunity for posttraumatic stress disorder (PTSD).

Current treatment for PTSD is centered on psychotherapy that focuses on exposure to the traumatic memory and learning new responses to it, Dr. Brunet said. But a recent analysis found that only about one-third of patients treated this way experience a lasting, clinically meaningful improvement, he said.

Propranolol treatment takes a different approach. It is based on the notion that memories, once they are consolidated, can be retrieved, and they exist in a labile state during which they are susceptible to modification until they are reconsolidated. During the labile window of opportunity, which is believed to be several hours, administration of propranolol can strip the memory of its emotional meaning, making it less stressful, he said.

In a randomized, controlled trial involving 19 chronic PTSD patients with an average symptom of duration 10 years (J. Psychiatr. Res. 2008;42:503–6), Dr. Brunet and his colleagues asked the patients to recall their memory by writing a trauma script and outlining the details of their traumatic experience and the emotions they felt.

Nine patients were then given a two-dose regimen of fast-acting propranolol (40 mg) immediately after memory recall, followed by an extended-release propanolol dose (60 mg) 75 minutes later, and the other 10 patients received placebo. One week later, after reviewing their trauma script, patients' physiologic responses to the memories were compared, using heart rate, skin conductivity, and corrugator electromyography (EMG) measurements.

Dr. Brunet reported significant differences between the placebo and treatment groups on heart rate and skin conductivity tests but not on EMG. There was a trend toward decreased symptoms, measured on the self-report Impact of Event Scale-Revised (IES-R).

The field of memory reconsolidation blockade is young when it comes to human studies, but there is substantial animal research to support it, commented Dr. Charles Marmar, professor and chair in the department of psychiatry at New York University Medical Center, who chaired a panel discussion after the session.

“The notion of building a pipeline from basic science, to translational studies in humans, to new treatments is very, very important in psychiatry,” he said in an interview. “This work is pioneering. We should have some patience about this and appreciate that this is a new paradigm in mental health research.”

MONTREAL – Predisposition is an important factor, but a traumatic event remains the necessary trigger in the development of posttraumatic stress disorder, a new study of identical twins indicates.

“Embedded within the diagnostic criteria of PTSD is a presumed causal event, but this assumption has come under scrutiny, as a recent study suggested that the symptoms of PTSD may merely represent general psychiatric symptoms that would have developed even in the absence of a trauma (J. Anxiety Disord. 2007;21:176–82), explained Dr. Roger Pitman, director of the PTSD and psychophysiology laboratory at Massachusetts General Hospital and professor of psychiatry at Harvard Medical School, both in Boston.

Speaking at the meeting Dr. Pitman launched new evidence to support the widely held theory that trauma is central to the development of PTSD.

The study comprised 104 Vietnam combat veterans and their nonveteran identical twins. Of the veterans, 50 had PTSD and 54 did not, whereas none of the nonveteran identical twins had the disorder (J. Clin. Psychiatry 2010;71:1324–30).

“If the PTSD-affected veterans had predisposing vulnerability to psychopathology on a genetic or environmental basis, then that ought to be shared by their twins,” he explained.

Psychometric measures – including the Symptom Checklist-90-Revised, the Clinician-Administered PTSD Scale (CAPS), and the Mississippi Scale for Combat-Related PTSD – were used to assess symptoms for all veterans and their twins. For the nonveterans, questions about combat trauma were replaced with questions about their most traumatic experience.

As expected, the evaluations revealed higher scores on all measures for the PTSD-affected veterans, compared with their identical twins. All nonveteran twins had scores similar to those of the veterans without PTSD.

“These results do not support the idea that the people with PTSD would have been symptomatic even without the traumatic event,” Dr. Pitman said. “They do support the conclusion that the mental disorders found in PTSD result from a trauma.”

About one-third of individuals who were exposed to a traumatic event will go on to develop PTSD.

This suggests that certain people might have an underlying predisposition to developing the disorder, Dr. Pitman said.

“We called the twins of the PTSD-affected veterans 'high risk' because they had a shared familial environment and shared genes,” he noted.

Indeed, further analysis revealed certain “neurological soft signs” in these twins. “We found subtle abnormalities of the nervous system that were elevated in the veterans with PTSD, [compared with] the veterans without PTSD, and these were also elevated in the identical twins of the PTSD veterans,” he reported.

“The nonveterans were not symptomatic; we infer [that] the increased presence of these subtle abnormalities could make them more vulnerable to developing PTSD, but in order for this to occur, there would have to be a traumatic exposure.”

When Dr. Harrison G. Pope Jr., coauthor of the 2007 paper that questioned the trauma-PTSD connection, was reached for comment, he said that Dr. Pitman's study was not contradictory to that of Dr. Pope's group. “[Our paper] showed that the symptom cluster of PTSD is not unique to victims of trauma, but can occur commonly in patients seeking treatment for depression, even if these patients have not experienced a trauma,” said Dr. Pope, professor of psychiatry at Harvard Medical School, Boston, and director of the biological psychiatry laboratory at McLean Hospital in Belmont, Mass.

Specifically, Dr. Pope and his colleagues concluded that “the symptom cluster traditionally associated with PTSD may be nonspecific, in that it may frequently occur in the absence of trauma.”

By comparison, Dr. Pitman's study “simply showed that trauma can cause these symptoms, to a much greater degree.”

From a clinical perspective this means that “one should not automatically assume that all so-called PTSD symptoms are necessarily attributable to trauma. Therefore, when treating a patient who is a trauma victim and who also exhibits symptoms, one should reasonably consider both of these possibilities,” he said.

MONTREAL – Predisposition is an important factor, but a traumatic event remains the necessary trigger in the development of posttraumatic stress disorder, a new study of identical twins indicates.

“Embedded within the diagnostic criteria of PTSD is a presumed causal event, but this assumption has come under scrutiny, as a recent study suggested that the symptoms of PTSD may merely represent general psychiatric symptoms that would have developed even in the absence of a trauma (J. Anxiety Disord. 2007;21:176–82), explained Dr. Roger Pitman, director of the PTSD and psychophysiology laboratory at Massachusetts General Hospital and professor of psychiatry at Harvard Medical School, both in Boston.

Speaking at the meeting Dr. Pitman launched new evidence to support the widely held theory that trauma is central to the development of PTSD.

The study comprised 104 Vietnam combat veterans and their nonveteran identical twins. Of the veterans, 50 had PTSD and 54 did not, whereas none of the nonveteran identical twins had the disorder (J. Clin. Psychiatry 2010;71:1324–30).

“If the PTSD-affected veterans had predisposing vulnerability to psychopathology on a genetic or environmental basis, then that ought to be shared by their twins,” he explained.

Psychometric measures – including the Symptom Checklist-90-Revised, the Clinician-Administered PTSD Scale (CAPS), and the Mississippi Scale for Combat-Related PTSD – were used to assess symptoms for all veterans and their twins. For the nonveterans, questions about combat trauma were replaced with questions about their most traumatic experience.

As expected, the evaluations revealed higher scores on all measures for the PTSD-affected veterans, compared with their identical twins. All nonveteran twins had scores similar to those of the veterans without PTSD.

“These results do not support the idea that the people with PTSD would have been symptomatic even without the traumatic event,” Dr. Pitman said. “They do support the conclusion that the mental disorders found in PTSD result from a trauma.”

About one-third of individuals who were exposed to a traumatic event will go on to develop PTSD.

This suggests that certain people might have an underlying predisposition to developing the disorder, Dr. Pitman said.

“We called the twins of the PTSD-affected veterans 'high risk' because they had a shared familial environment and shared genes,” he noted.

Indeed, further analysis revealed certain “neurological soft signs” in these twins. “We found subtle abnormalities of the nervous system that were elevated in the veterans with PTSD, [compared with] the veterans without PTSD, and these were also elevated in the identical twins of the PTSD veterans,” he reported.

“The nonveterans were not symptomatic; we infer [that] the increased presence of these subtle abnormalities could make them more vulnerable to developing PTSD, but in order for this to occur, there would have to be a traumatic exposure.”

When Dr. Harrison G. Pope Jr., coauthor of the 2007 paper that questioned the trauma-PTSD connection, was reached for comment, he said that Dr. Pitman's study was not contradictory to that of Dr. Pope's group. “[Our paper] showed that the symptom cluster of PTSD is not unique to victims of trauma, but can occur commonly in patients seeking treatment for depression, even if these patients have not experienced a trauma,” said Dr. Pope, professor of psychiatry at Harvard Medical School, Boston, and director of the biological psychiatry laboratory at McLean Hospital in Belmont, Mass.

Specifically, Dr. Pope and his colleagues concluded that “the symptom cluster traditionally associated with PTSD may be nonspecific, in that it may frequently occur in the absence of trauma.”

By comparison, Dr. Pitman's study “simply showed that trauma can cause these symptoms, to a much greater degree.”

From a clinical perspective this means that “one should not automatically assume that all so-called PTSD symptoms are necessarily attributable to trauma. Therefore, when treating a patient who is a trauma victim and who also exhibits symptoms, one should reasonably consider both of these possibilities,” he said.

MONTREAL – Predisposition is an important factor, but a traumatic event remains the necessary trigger in the development of posttraumatic stress disorder, a new study of identical twins indicates.

“Embedded within the diagnostic criteria of PTSD is a presumed causal event, but this assumption has come under scrutiny, as a recent study suggested that the symptoms of PTSD may merely represent general psychiatric symptoms that would have developed even in the absence of a trauma (J. Anxiety Disord. 2007;21:176–82), explained Dr. Roger Pitman, director of the PTSD and psychophysiology laboratory at Massachusetts General Hospital and professor of psychiatry at Harvard Medical School, both in Boston.

Speaking at the meeting Dr. Pitman launched new evidence to support the widely held theory that trauma is central to the development of PTSD.

The study comprised 104 Vietnam combat veterans and their nonveteran identical twins. Of the veterans, 50 had PTSD and 54 did not, whereas none of the nonveteran identical twins had the disorder (J. Clin. Psychiatry 2010;71:1324–30).

“If the PTSD-affected veterans had predisposing vulnerability to psychopathology on a genetic or environmental basis, then that ought to be shared by their twins,” he explained.

Psychometric measures – including the Symptom Checklist-90-Revised, the Clinician-Administered PTSD Scale (CAPS), and the Mississippi Scale for Combat-Related PTSD – were used to assess symptoms for all veterans and their twins. For the nonveterans, questions about combat trauma were replaced with questions about their most traumatic experience.

As expected, the evaluations revealed higher scores on all measures for the PTSD-affected veterans, compared with their identical twins. All nonveteran twins had scores similar to those of the veterans without PTSD.

“These results do not support the idea that the people with PTSD would have been symptomatic even without the traumatic event,” Dr. Pitman said. “They do support the conclusion that the mental disorders found in PTSD result from a trauma.”

About one-third of individuals who were exposed to a traumatic event will go on to develop PTSD.

This suggests that certain people might have an underlying predisposition to developing the disorder, Dr. Pitman said.

“We called the twins of the PTSD-affected veterans 'high risk' because they had a shared familial environment and shared genes,” he noted.

Indeed, further analysis revealed certain “neurological soft signs” in these twins. “We found subtle abnormalities of the nervous system that were elevated in the veterans with PTSD, [compared with] the veterans without PTSD, and these were also elevated in the identical twins of the PTSD veterans,” he reported.

“The nonveterans were not symptomatic; we infer [that] the increased presence of these subtle abnormalities could make them more vulnerable to developing PTSD, but in order for this to occur, there would have to be a traumatic exposure.”

When Dr. Harrison G. Pope Jr., coauthor of the 2007 paper that questioned the trauma-PTSD connection, was reached for comment, he said that Dr. Pitman's study was not contradictory to that of Dr. Pope's group. “[Our paper] showed that the symptom cluster of PTSD is not unique to victims of trauma, but can occur commonly in patients seeking treatment for depression, even if these patients have not experienced a trauma,” said Dr. Pope, professor of psychiatry at Harvard Medical School, Boston, and director of the biological psychiatry laboratory at McLean Hospital in Belmont, Mass.

Specifically, Dr. Pope and his colleagues concluded that “the symptom cluster traditionally associated with PTSD may be nonspecific, in that it may frequently occur in the absence of trauma.”

By comparison, Dr. Pitman's study “simply showed that trauma can cause these symptoms, to a much greater degree.”

From a clinical perspective this means that “one should not automatically assume that all so-called PTSD symptoms are necessarily attributable to trauma. Therefore, when treating a patient who is a trauma victim and who also exhibits symptoms, one should reasonably consider both of these possibilities,” he said.

MONTREAL - Bevacizumab-containing regimens continued to show efficacy against glioblastoma in phase II trials presented at the annual meeting of the Society for Neuro-Oncology.

Adding bevacizumab (Avastin) and irinotecan (Camptosar) to a standard temozolomide (Temodar)–based chemoradiation regimen for newly diagnosed glioblastoma increased progression-free and overall survival by about 6 months, compared with historical controls, in a study reported by investigators from Duke University in Durham, N.C.

In a separate RTOG (Radiation Therapy Oncology Group) study, investigators defined efficacy as a progression-free survival rate of 35% at 6 months in patients with recurrent glioblastoma. Both regimens in the noncomparative trial – bevacizumab with dose-dense temozolomide and bevacizumab with irinotecan – cleared the mark at 40% and 39%, respectively. Median overall survival was longer with the temozolomide partnership (9.4 months vs. 7.7. months with irinotecan), but the difference was not significant.

In 2009, the Food and Drug Administration approved bevacizumab as a single agent for the second-line treatment of glioblastoma, based on objective response rates in two single-arm trials.

Newly Diagnosed in Duke Study

The Genentech-sponsored study from Duke began with 125 patients (mean age, 56 years; 59% male) with newly diagnosed grade IV malignant glioblastoma multiforme (GBM), reported Dr. Annick Desjardins of the university’s brain tumor center. Most (70%) had Karnofsky performance scores greater than 90%.

Between 2 and 4 weeks after resection, patients started 6 weeks of radiotherapy and daily temozolomide at 75 mg/m2. At a minimum of 28 days post craniotomy, bevacizumab was added at a dose of 10 mg/kg once every 2 weeks.

In the second phase of the trial, 113 patients went on to receive 6-12 more weeks of bevacizumab at the same dosage, combined with temozolomide at 200 mg/m2 on days 1-5 of each month, and irinotecan dosed according to whether patients were or were not taking enzyme-inducing antiepileptic drugs (340 mg/m2 or 125 mg/m2, respectively, on days 1 and 15 of each month).

The first phase of treatment was associated with minimal toxicity, the investigators recently reported (Int. J. Radiat. Oncol. Biol. Phys. 2010 Oct 30 [doi:10.1016/j.ijrobp.2010.08.058]). Grade 4 thrombocytopenia occurred in 2.4%, neutropenia in 0.8%, central nervous system hemorrhage in 0.8%, and deep vein thrombosis and pulmonary embolism in 1.6%, said Dr. Desjardins.

Five patients did not complete the first phase (one patient with grade 2 CNS hemorrhage, two with pulmonary emboli, one with grade 4 pancytopenia, and one with wound dehiscence). Seven other patients did not go on to the second phase (three with tumor progression, two withdrawing because of fatigue, and one each with a bowel perforation and a rectal abscess). Patients in the second phase have been followed for a median of 28 months, said Dr. Desjardins.

A final analysis for the original cohort of 125 shows that median progression-free survival reached 14.2 months and median overall survival was 21.3 months. This compares with medians of 6.9 months and 15.9 months, respectively, that had been reported in the literature, she said.

Additionally, progression-free survival rates were 88% at 6 months, 64% at 1 year, and 16% at 2 years in the Duke cohort; overall survival rates were 94%, 82%, and 44%, respectively.

For all 125 patients enrolled, the overall serious toxicities included 1 CNS hemorrhage, 9 VTEs, 2 wound dehiscences, 1 bowel perforation, 17 grade 4 hematologic toxicities, 1 secondary malignancy, and 2 cases of pneumocystis pneumonia. There were four toxicity-related deaths.

RTOG Trial in Recurrent GBM

The noncomparative RTOG study enrolled patients with recurrent glioblastoma who had failed previous chemoradiation with temozolomide. In all, 57 patients were assigned to bevacizumab 10 mg/kg IV plus irinotecan 200 mg/kg every 2 weeks, and 58 were assigned to the same bevacizumab dose plus dose-dense temozolomide 75-100 mg/m2 daily on the first 3 weeks of a 28-day cycle (Neuro. Oncol. 2010;12[suppl. 4; abstract NO-14, RTOG 0625]:iv36-57 [doi:10.1093/neuonc/noq116.s6]).

The two arms had different end points: safety with temozolomide and efficacy in the irinotecan arm, noted the presenter, Dr. Mark Gilbert, a professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston.

Hematologic toxicities were seen more in the temozolomide arm, whereas gastrointestinal toxicities predominated in the irinotecan arm, said Dr. Gilbert. One case of gastrointestinal perforation resulted in death.

"The primary objectives were met," he reported. "We found that administering bevacizumab regimens in a cooperative group setting was feasible. We had acceptable toxicity with the combination of bevacizumab and dose-dense temozolomide, and it supported our use of this type of regimen in the up-front setting. And, in fact, the efficacy of both arms reached our target."

Trials’ Protocols Criticized

Both study designs were challenged at the meeting.

Session moderator Dr. Martin van den Bent contended that exposing all patients to the bevacizumab/irinotecan regimen in the Duke study – rather than randomizing patients to one agent or the other – makes it impossible to know which drug is preferable.

"It’s flatly outrageous. It should not have been done," Dr. van den Bent elaborated in an interview after the session. "What I find very disturbing is they did a very big study of 120 patients ... but by doing it in an uncontrolled fashion, they ended up with an impossible interpretation of whether the irinotecan added to the bevacizumab made any difference."

Dr. van den Bent, professor of neuro-oncology at the cancer center of Erasmus University in Rotterdam, the Netherlands, charged that Duke has a history of doing uncontrolled trials, but he also criticized the field’s eagerness to embrace bevacizumab based on such trials.

"The use of bevacizumab at present is based on uncontrolled studies; it’s been FDA approved on a scientifically not valid end point," said Dr. van den Bent, a past chair of the EORTC (European Organization of Research and Treatment) Brain Tumor Group.

Study design also triggered a complaint with the RTOG trial. Dr. Gilbert cautioned that randomization was not consistent because of safety concerns with the temozolomide regimen. Until these were resolved, the initial 90 patients were randomized 2:1 favoring irinotecan. Consequently, the final 30 temozolomide patients were assigned to that arm without randomization.

For these reasons, "we cannot on the basis of this study tell which of the two treatments" is better, "or in fact whether a combination of chemotherapy with bevacizumab is better than bevacizumab alone," he said, stressing that the study was not powered for comparison.

A member of the audience asked whether this wasn’t "kind of a charade," since comparisons were being made anyway.

"It’s not a charade," Dr. Gilbert replied, reiterating that the investigators had two separate goals: safety with temozolomide and efficacy with irinotecan. "It is what it is," he said. "We certainly weren’t going to power it, because we weren’t interested particularly in the question of which was the better regimen."

Genentech sponsored the study from Duke University. Dr. Desjardins reported no conflicts of interest. Dr. Gilbert disclosed research support from Merck and Genentech, and honoraria/advisory board participation with Merck and Genentech. Dr. van den Bent said he is a consultant for eight companies, including F. Hoffmann-La Roche, the parent company of Genentech.

MONTREAL - Bevacizumab-containing regimens continued to show efficacy against glioblastoma in phase II trials presented at the annual meeting of the Society for Neuro-Oncology.

Adding bevacizumab (Avastin) and irinotecan (Camptosar) to a standard temozolomide (Temodar)–based chemoradiation regimen for newly diagnosed glioblastoma increased progression-free and overall survival by about 6 months, compared with historical controls, in a study reported by investigators from Duke University in Durham, N.C.

In a separate RTOG (Radiation Therapy Oncology Group) study, investigators defined efficacy as a progression-free survival rate of 35% at 6 months in patients with recurrent glioblastoma. Both regimens in the noncomparative trial – bevacizumab with dose-dense temozolomide and bevacizumab with irinotecan – cleared the mark at 40% and 39%, respectively. Median overall survival was longer with the temozolomide partnership (9.4 months vs. 7.7. months with irinotecan), but the difference was not significant.

In 2009, the Food and Drug Administration approved bevacizumab as a single agent for the second-line treatment of glioblastoma, based on objective response rates in two single-arm trials.

Newly Diagnosed in Duke Study

The Genentech-sponsored study from Duke began with 125 patients (mean age, 56 years; 59% male) with newly diagnosed grade IV malignant glioblastoma multiforme (GBM), reported Dr. Annick Desjardins of the university’s brain tumor center. Most (70%) had Karnofsky performance scores greater than 90%.

Between 2 and 4 weeks after resection, patients started 6 weeks of radiotherapy and daily temozolomide at 75 mg/m2. At a minimum of 28 days post craniotomy, bevacizumab was added at a dose of 10 mg/kg once every 2 weeks.

In the second phase of the trial, 113 patients went on to receive 6-12 more weeks of bevacizumab at the same dosage, combined with temozolomide at 200 mg/m2 on days 1-5 of each month, and irinotecan dosed according to whether patients were or were not taking enzyme-inducing antiepileptic drugs (340 mg/m2 or 125 mg/m2, respectively, on days 1 and 15 of each month).

The first phase of treatment was associated with minimal toxicity, the investigators recently reported (Int. J. Radiat. Oncol. Biol. Phys. 2010 Oct 30 [doi:10.1016/j.ijrobp.2010.08.058]). Grade 4 thrombocytopenia occurred in 2.4%, neutropenia in 0.8%, central nervous system hemorrhage in 0.8%, and deep vein thrombosis and pulmonary embolism in 1.6%, said Dr. Desjardins.

Five patients did not complete the first phase (one patient with grade 2 CNS hemorrhage, two with pulmonary emboli, one with grade 4 pancytopenia, and one with wound dehiscence). Seven other patients did not go on to the second phase (three with tumor progression, two withdrawing because of fatigue, and one each with a bowel perforation and a rectal abscess). Patients in the second phase have been followed for a median of 28 months, said Dr. Desjardins.

A final analysis for the original cohort of 125 shows that median progression-free survival reached 14.2 months and median overall survival was 21.3 months. This compares with medians of 6.9 months and 15.9 months, respectively, that had been reported in the literature, she said.

Additionally, progression-free survival rates were 88% at 6 months, 64% at 1 year, and 16% at 2 years in the Duke cohort; overall survival rates were 94%, 82%, and 44%, respectively.

For all 125 patients enrolled, the overall serious toxicities included 1 CNS hemorrhage, 9 VTEs, 2 wound dehiscences, 1 bowel perforation, 17 grade 4 hematologic toxicities, 1 secondary malignancy, and 2 cases of pneumocystis pneumonia. There were four toxicity-related deaths.

RTOG Trial in Recurrent GBM

The noncomparative RTOG study enrolled patients with recurrent glioblastoma who had failed previous chemoradiation with temozolomide. In all, 57 patients were assigned to bevacizumab 10 mg/kg IV plus irinotecan 200 mg/kg every 2 weeks, and 58 were assigned to the same bevacizumab dose plus dose-dense temozolomide 75-100 mg/m2 daily on the first 3 weeks of a 28-day cycle (Neuro. Oncol. 2010;12[suppl. 4; abstract NO-14, RTOG 0625]:iv36-57 [doi:10.1093/neuonc/noq116.s6]).

The two arms had different end points: safety with temozolomide and efficacy in the irinotecan arm, noted the presenter, Dr. Mark Gilbert, a professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston.

Hematologic toxicities were seen more in the temozolomide arm, whereas gastrointestinal toxicities predominated in the irinotecan arm, said Dr. Gilbert. One case of gastrointestinal perforation resulted in death.

"The primary objectives were met," he reported. "We found that administering bevacizumab regimens in a cooperative group setting was feasible. We had acceptable toxicity with the combination of bevacizumab and dose-dense temozolomide, and it supported our use of this type of regimen in the up-front setting. And, in fact, the efficacy of both arms reached our target."

Trials’ Protocols Criticized

Both study designs were challenged at the meeting.

Session moderator Dr. Martin van den Bent contended that exposing all patients to the bevacizumab/irinotecan regimen in the Duke study – rather than randomizing patients to one agent or the other – makes it impossible to know which drug is preferable.

"It’s flatly outrageous. It should not have been done," Dr. van den Bent elaborated in an interview after the session. "What I find very disturbing is they did a very big study of 120 patients ... but by doing it in an uncontrolled fashion, they ended up with an impossible interpretation of whether the irinotecan added to the bevacizumab made any difference."

Dr. van den Bent, professor of neuro-oncology at the cancer center of Erasmus University in Rotterdam, the Netherlands, charged that Duke has a history of doing uncontrolled trials, but he also criticized the field’s eagerness to embrace bevacizumab based on such trials.

"The use of bevacizumab at present is based on uncontrolled studies; it’s been FDA approved on a scientifically not valid end point," said Dr. van den Bent, a past chair of the EORTC (European Organization of Research and Treatment) Brain Tumor Group.

Study design also triggered a complaint with the RTOG trial. Dr. Gilbert cautioned that randomization was not consistent because of safety concerns with the temozolomide regimen. Until these were resolved, the initial 90 patients were randomized 2:1 favoring irinotecan. Consequently, the final 30 temozolomide patients were assigned to that arm without randomization.

For these reasons, "we cannot on the basis of this study tell which of the two treatments" is better, "or in fact whether a combination of chemotherapy with bevacizumab is better than bevacizumab alone," he said, stressing that the study was not powered for comparison.

A member of the audience asked whether this wasn’t "kind of a charade," since comparisons were being made anyway.

"It’s not a charade," Dr. Gilbert replied, reiterating that the investigators had two separate goals: safety with temozolomide and efficacy with irinotecan. "It is what it is," he said. "We certainly weren’t going to power it, because we weren’t interested particularly in the question of which was the better regimen."

Genentech sponsored the study from Duke University. Dr. Desjardins reported no conflicts of interest. Dr. Gilbert disclosed research support from Merck and Genentech, and honoraria/advisory board participation with Merck and Genentech. Dr. van den Bent said he is a consultant for eight companies, including F. Hoffmann-La Roche, the parent company of Genentech.

MONTREAL - Bevacizumab-containing regimens continued to show efficacy against glioblastoma in phase II trials presented at the annual meeting of the Society for Neuro-Oncology.

Adding bevacizumab (Avastin) and irinotecan (Camptosar) to a standard temozolomide (Temodar)–based chemoradiation regimen for newly diagnosed glioblastoma increased progression-free and overall survival by about 6 months, compared with historical controls, in a study reported by investigators from Duke University in Durham, N.C.

In a separate RTOG (Radiation Therapy Oncology Group) study, investigators defined efficacy as a progression-free survival rate of 35% at 6 months in patients with recurrent glioblastoma. Both regimens in the noncomparative trial – bevacizumab with dose-dense temozolomide and bevacizumab with irinotecan – cleared the mark at 40% and 39%, respectively. Median overall survival was longer with the temozolomide partnership (9.4 months vs. 7.7. months with irinotecan), but the difference was not significant.

In 2009, the Food and Drug Administration approved bevacizumab as a single agent for the second-line treatment of glioblastoma, based on objective response rates in two single-arm trials.

Newly Diagnosed in Duke Study

The Genentech-sponsored study from Duke began with 125 patients (mean age, 56 years; 59% male) with newly diagnosed grade IV malignant glioblastoma multiforme (GBM), reported Dr. Annick Desjardins of the university’s brain tumor center. Most (70%) had Karnofsky performance scores greater than 90%.

Between 2 and 4 weeks after resection, patients started 6 weeks of radiotherapy and daily temozolomide at 75 mg/m2. At a minimum of 28 days post craniotomy, bevacizumab was added at a dose of 10 mg/kg once every 2 weeks.

In the second phase of the trial, 113 patients went on to receive 6-12 more weeks of bevacizumab at the same dosage, combined with temozolomide at 200 mg/m2 on days 1-5 of each month, and irinotecan dosed according to whether patients were or were not taking enzyme-inducing antiepileptic drugs (340 mg/m2 or 125 mg/m2, respectively, on days 1 and 15 of each month).

The first phase of treatment was associated with minimal toxicity, the investigators recently reported (Int. J. Radiat. Oncol. Biol. Phys. 2010 Oct 30 [doi:10.1016/j.ijrobp.2010.08.058]). Grade 4 thrombocytopenia occurred in 2.4%, neutropenia in 0.8%, central nervous system hemorrhage in 0.8%, and deep vein thrombosis and pulmonary embolism in 1.6%, said Dr. Desjardins.

Five patients did not complete the first phase (one patient with grade 2 CNS hemorrhage, two with pulmonary emboli, one with grade 4 pancytopenia, and one with wound dehiscence). Seven other patients did not go on to the second phase (three with tumor progression, two withdrawing because of fatigue, and one each with a bowel perforation and a rectal abscess). Patients in the second phase have been followed for a median of 28 months, said Dr. Desjardins.

A final analysis for the original cohort of 125 shows that median progression-free survival reached 14.2 months and median overall survival was 21.3 months. This compares with medians of 6.9 months and 15.9 months, respectively, that had been reported in the literature, she said.

Additionally, progression-free survival rates were 88% at 6 months, 64% at 1 year, and 16% at 2 years in the Duke cohort; overall survival rates were 94%, 82%, and 44%, respectively.

For all 125 patients enrolled, the overall serious toxicities included 1 CNS hemorrhage, 9 VTEs, 2 wound dehiscences, 1 bowel perforation, 17 grade 4 hematologic toxicities, 1 secondary malignancy, and 2 cases of pneumocystis pneumonia. There were four toxicity-related deaths.

RTOG Trial in Recurrent GBM

The noncomparative RTOG study enrolled patients with recurrent glioblastoma who had failed previous chemoradiation with temozolomide. In all, 57 patients were assigned to bevacizumab 10 mg/kg IV plus irinotecan 200 mg/kg every 2 weeks, and 58 were assigned to the same bevacizumab dose plus dose-dense temozolomide 75-100 mg/m2 daily on the first 3 weeks of a 28-day cycle (Neuro. Oncol. 2010;12[suppl. 4; abstract NO-14, RTOG 0625]:iv36-57 [doi:10.1093/neuonc/noq116.s6]).

The two arms had different end points: safety with temozolomide and efficacy in the irinotecan arm, noted the presenter, Dr. Mark Gilbert, a professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston.

Hematologic toxicities were seen more in the temozolomide arm, whereas gastrointestinal toxicities predominated in the irinotecan arm, said Dr. Gilbert. One case of gastrointestinal perforation resulted in death.

"The primary objectives were met," he reported. "We found that administering bevacizumab regimens in a cooperative group setting was feasible. We had acceptable toxicity with the combination of bevacizumab and dose-dense temozolomide, and it supported our use of this type of regimen in the up-front setting. And, in fact, the efficacy of both arms reached our target."

Trials’ Protocols Criticized

Both study designs were challenged at the meeting.

Session moderator Dr. Martin van den Bent contended that exposing all patients to the bevacizumab/irinotecan regimen in the Duke study – rather than randomizing patients to one agent or the other – makes it impossible to know which drug is preferable.

"It’s flatly outrageous. It should not have been done," Dr. van den Bent elaborated in an interview after the session. "What I find very disturbing is they did a very big study of 120 patients ... but by doing it in an uncontrolled fashion, they ended up with an impossible interpretation of whether the irinotecan added to the bevacizumab made any difference."

Dr. van den Bent, professor of neuro-oncology at the cancer center of Erasmus University in Rotterdam, the Netherlands, charged that Duke has a history of doing uncontrolled trials, but he also criticized the field’s eagerness to embrace bevacizumab based on such trials.

"The use of bevacizumab at present is based on uncontrolled studies; it’s been FDA approved on a scientifically not valid end point," said Dr. van den Bent, a past chair of the EORTC (European Organization of Research and Treatment) Brain Tumor Group.

Study design also triggered a complaint with the RTOG trial. Dr. Gilbert cautioned that randomization was not consistent because of safety concerns with the temozolomide regimen. Until these were resolved, the initial 90 patients were randomized 2:1 favoring irinotecan. Consequently, the final 30 temozolomide patients were assigned to that arm without randomization.

For these reasons, "we cannot on the basis of this study tell which of the two treatments" is better, "or in fact whether a combination of chemotherapy with bevacizumab is better than bevacizumab alone," he said, stressing that the study was not powered for comparison.

A member of the audience asked whether this wasn’t "kind of a charade," since comparisons were being made anyway.

"It’s not a charade," Dr. Gilbert replied, reiterating that the investigators had two separate goals: safety with temozolomide and efficacy with irinotecan. "It is what it is," he said. "We certainly weren’t going to power it, because we weren’t interested particularly in the question of which was the better regimen."

Genentech sponsored the study from Duke University. Dr. Desjardins reported no conflicts of interest. Dr. Gilbert disclosed research support from Merck and Genentech, and honoraria/advisory board participation with Merck and Genentech. Dr. van den Bent said he is a consultant for eight companies, including F. Hoffmann-La Roche, the parent company of Genentech.

MONTREAL – The novel tyrosine kinase inhibitor cediranib performed short of expectations in REGAL, a randomized, parallel-group, multicenter phase III study in patients with recurrent glioblastoma.

Whether paired with lomustine or given as monotherapy, cediranib (Recentin) failed to improve progression-free survival, the study’s primary end point, or overall survival, a secondary end point, in comparisons with lomustine plus placebo.

"Our initial study was a 45-mg-per-day dose, and there is a dose-response curve with this agent," said Dr. Tracy T. Batchelor, who reported the findings at the annual meeting of the Society for Neuro-Oncology. "If there’s one thing I could go back and do [with this study], I might start with a higher dose."

The study randomized 325 patients with recurrent glioblastoma on a 2:2:1 ratio to three all-oral regimens: cediranib monotherapy, 30 mg/day (131 patients); a combination of cediranib, 20 mg/day, and lomustine, 110 mg/m2 once every 6 weeks (129 patients); or a control group of lomustine at the same dose and a cediranib-matched placebo, 20 mg/day (65 patients).

Participants came from 10 countries and had to have at least one prior regimen containing temozolomide (Temodar), but no prior treatment with an agent inhibiting vascular endothelial growth factor (VEGF) signaling.

Progression-free survival was determined by a centralized, independent review by a radiologist who was blinded to treatment status. For this outcome, the study found no statistically significant advantage of cediranib monotherapy (median, 92 days; P = .889) or combination therapy (median, 125 days; P = .162) compared with controls (median, 82 days).

"Although the trend was in the right direction, the P values were not statistically significant," said Dr. Batchelor, executive director of the Stephen E. and Catherine Pappas Center for Neuro-Oncology at Massachusetts General Hospital, Boston. "There is a suggestion of an early separation of the curves by about 3 months, but then they begin converging, and eventually cross over."

Similarly, there was no statistical difference between groups for overall survival, which ranged from 8 to 9.8 months, he said.

Two other secondary end points, steroid use and time to neurologic decline, did favor cediranib, either alone or in combination, reported Dr. Batchelor. There was a statistically significant reduction in steroid use in the cediranib monotherapy group (P = .006) and in the combination arm (P = .012) compared with controls. And time to neurologic decline was significantly prolonged in the combination therapy group compared with controls (P = .009).

Cediranib fell short, however, on the APF6 (the proportion of patients alive and progression free at 6 months), with a rate of 16%, vs. 34.5% in the combination group and 24.5% in the control group. Dr. Batchelor’s previously published, nonrandomized, noncontrolled study of cediranib monotherapy in a similar patient population reported a much higher APF6 of 25.8% (J. Clin. Oncol. 2010;28:2817-23).

"I think the dosing in that study – 45mg compared with 30 mg – is a contributing factor to this difference," he said in an interview.

Cediranib is an oral, pan-VEGF receptor tyrosine kinase inhibitor (TKI), and "the concern with TKIs is that the toxicities you see with this classic drug may compromise dose intensity or the agent or of chemotherapy combined with it," explained Dr. Batchelor. Trial sponsor AstraZeneca recommended the lower dose, he explained.

Adverse events occurred at a similar rate across all arms, 60.9% with monotherapy, 79.7% with combination therapy, and 60.9% with controls. The profile of toxicities with cediranib was consistent with what has been previously reported and included fatigue (16.4%), hypertension (14.1%), and diarrhea (6.3%). However, of note, was that "there was no compromise of cediranib dose intensity based on toxicity," he said. "In fact the cediranib dose intensity was maintained in 95% of patients, while in those who received more than one dose of lomustine, about half had a reduction in dose in the control arm, and 70% required some reduction in the combination arm."

When asked to comment on the findings, Dr. Kenneth D. Aldape, conference chair, said, "It is a negative study and these initial results were somewhat disappointing; however I don’t think we want to throw in the towel for this particular drug." "Higher doses could be considered, and I think in current and future trials, [investigators] will be using higher doses in the hopes of increasing efficacy of this agent," said Dr. Aldape, professor of pathology at the University of Texas M.D. Anderson Cancer Center in Houston.

Dr. Aldape also noted that the trial enrolled patients with recurrent glioblastoma for whom previous treatments had failed. "Newer trials will look at newly diagnosed patients who are treatment naive. So it’s possible that a drug that doesn’t work in recurrent disease might have some efficacy in newly diagnosed patients, especially if the dose is increased."

Dr. Batchelor has received research funding and honoraria from AstraZeneca, which sponsored the trial and is developing cediranib.

MONTREAL – The novel tyrosine kinase inhibitor cediranib performed short of expectations in REGAL, a randomized, parallel-group, multicenter phase III study in patients with recurrent glioblastoma.

Whether paired with lomustine or given as monotherapy, cediranib (Recentin) failed to improve progression-free survival, the study’s primary end point, or overall survival, a secondary end point, in comparisons with lomustine plus placebo.

"Our initial study was a 45-mg-per-day dose, and there is a dose-response curve with this agent," said Dr. Tracy T. Batchelor, who reported the findings at the annual meeting of the Society for Neuro-Oncology. "If there’s one thing I could go back and do [with this study], I might start with a higher dose."

The study randomized 325 patients with recurrent glioblastoma on a 2:2:1 ratio to three all-oral regimens: cediranib monotherapy, 30 mg/day (131 patients); a combination of cediranib, 20 mg/day, and lomustine, 110 mg/m2 once every 6 weeks (129 patients); or a control group of lomustine at the same dose and a cediranib-matched placebo, 20 mg/day (65 patients).

Participants came from 10 countries and had to have at least one prior regimen containing temozolomide (Temodar), but no prior treatment with an agent inhibiting vascular endothelial growth factor (VEGF) signaling.

Progression-free survival was determined by a centralized, independent review by a radiologist who was blinded to treatment status. For this outcome, the study found no statistically significant advantage of cediranib monotherapy (median, 92 days; P = .889) or combination therapy (median, 125 days; P = .162) compared with controls (median, 82 days).

"Although the trend was in the right direction, the P values were not statistically significant," said Dr. Batchelor, executive director of the Stephen E. and Catherine Pappas Center for Neuro-Oncology at Massachusetts General Hospital, Boston. "There is a suggestion of an early separation of the curves by about 3 months, but then they begin converging, and eventually cross over."

Similarly, there was no statistical difference between groups for overall survival, which ranged from 8 to 9.8 months, he said.

Two other secondary end points, steroid use and time to neurologic decline, did favor cediranib, either alone or in combination, reported Dr. Batchelor. There was a statistically significant reduction in steroid use in the cediranib monotherapy group (P = .006) and in the combination arm (P = .012) compared with controls. And time to neurologic decline was significantly prolonged in the combination therapy group compared with controls (P = .009).

Cediranib fell short, however, on the APF6 (the proportion of patients alive and progression free at 6 months), with a rate of 16%, vs. 34.5% in the combination group and 24.5% in the control group. Dr. Batchelor’s previously published, nonrandomized, noncontrolled study of cediranib monotherapy in a similar patient population reported a much higher APF6 of 25.8% (J. Clin. Oncol. 2010;28:2817-23).

"I think the dosing in that study – 45mg compared with 30 mg – is a contributing factor to this difference," he said in an interview.

Cediranib is an oral, pan-VEGF receptor tyrosine kinase inhibitor (TKI), and "the concern with TKIs is that the toxicities you see with this classic drug may compromise dose intensity or the agent or of chemotherapy combined with it," explained Dr. Batchelor. Trial sponsor AstraZeneca recommended the lower dose, he explained.

Adverse events occurred at a similar rate across all arms, 60.9% with monotherapy, 79.7% with combination therapy, and 60.9% with controls. The profile of toxicities with cediranib was consistent with what has been previously reported and included fatigue (16.4%), hypertension (14.1%), and diarrhea (6.3%). However, of note, was that "there was no compromise of cediranib dose intensity based on toxicity," he said. "In fact the cediranib dose intensity was maintained in 95% of patients, while in those who received more than one dose of lomustine, about half had a reduction in dose in the control arm, and 70% required some reduction in the combination arm."

When asked to comment on the findings, Dr. Kenneth D. Aldape, conference chair, said, "It is a negative study and these initial results were somewhat disappointing; however I don’t think we want to throw in the towel for this particular drug." "Higher doses could be considered, and I think in current and future trials, [investigators] will be using higher doses in the hopes of increasing efficacy of this agent," said Dr. Aldape, professor of pathology at the University of Texas M.D. Anderson Cancer Center in Houston.

Dr. Aldape also noted that the trial enrolled patients with recurrent glioblastoma for whom previous treatments had failed. "Newer trials will look at newly diagnosed patients who are treatment naive. So it’s possible that a drug that doesn’t work in recurrent disease might have some efficacy in newly diagnosed patients, especially if the dose is increased."

Dr. Batchelor has received research funding and honoraria from AstraZeneca, which sponsored the trial and is developing cediranib.

MONTREAL – The novel tyrosine kinase inhibitor cediranib performed short of expectations in REGAL, a randomized, parallel-group, multicenter phase III study in patients with recurrent glioblastoma.

Whether paired with lomustine or given as monotherapy, cediranib (Recentin) failed to improve progression-free survival, the study’s primary end point, or overall survival, a secondary end point, in comparisons with lomustine plus placebo.

"Our initial study was a 45-mg-per-day dose, and there is a dose-response curve with this agent," said Dr. Tracy T. Batchelor, who reported the findings at the annual meeting of the Society for Neuro-Oncology. "If there’s one thing I could go back and do [with this study], I might start with a higher dose."

The study randomized 325 patients with recurrent glioblastoma on a 2:2:1 ratio to three all-oral regimens: cediranib monotherapy, 30 mg/day (131 patients); a combination of cediranib, 20 mg/day, and lomustine, 110 mg/m2 once every 6 weeks (129 patients); or a control group of lomustine at the same dose and a cediranib-matched placebo, 20 mg/day (65 patients).

Participants came from 10 countries and had to have at least one prior regimen containing temozolomide (Temodar), but no prior treatment with an agent inhibiting vascular endothelial growth factor (VEGF) signaling.

Progression-free survival was determined by a centralized, independent review by a radiologist who was blinded to treatment status. For this outcome, the study found no statistically significant advantage of cediranib monotherapy (median, 92 days; P = .889) or combination therapy (median, 125 days; P = .162) compared with controls (median, 82 days).

"Although the trend was in the right direction, the P values were not statistically significant," said Dr. Batchelor, executive director of the Stephen E. and Catherine Pappas Center for Neuro-Oncology at Massachusetts General Hospital, Boston. "There is a suggestion of an early separation of the curves by about 3 months, but then they begin converging, and eventually cross over."

Similarly, there was no statistical difference between groups for overall survival, which ranged from 8 to 9.8 months, he said.

Two other secondary end points, steroid use and time to neurologic decline, did favor cediranib, either alone or in combination, reported Dr. Batchelor. There was a statistically significant reduction in steroid use in the cediranib monotherapy group (P = .006) and in the combination arm (P = .012) compared with controls. And time to neurologic decline was significantly prolonged in the combination therapy group compared with controls (P = .009).

Cediranib fell short, however, on the APF6 (the proportion of patients alive and progression free at 6 months), with a rate of 16%, vs. 34.5% in the combination group and 24.5% in the control group. Dr. Batchelor’s previously published, nonrandomized, noncontrolled study of cediranib monotherapy in a similar patient population reported a much higher APF6 of 25.8% (J. Clin. Oncol. 2010;28:2817-23).

"I think the dosing in that study – 45mg compared with 30 mg – is a contributing factor to this difference," he said in an interview.

Cediranib is an oral, pan-VEGF receptor tyrosine kinase inhibitor (TKI), and "the concern with TKIs is that the toxicities you see with this classic drug may compromise dose intensity or the agent or of chemotherapy combined with it," explained Dr. Batchelor. Trial sponsor AstraZeneca recommended the lower dose, he explained.

Adverse events occurred at a similar rate across all arms, 60.9% with monotherapy, 79.7% with combination therapy, and 60.9% with controls. The profile of toxicities with cediranib was consistent with what has been previously reported and included fatigue (16.4%), hypertension (14.1%), and diarrhea (6.3%). However, of note, was that "there was no compromise of cediranib dose intensity based on toxicity," he said. "In fact the cediranib dose intensity was maintained in 95% of patients, while in those who received more than one dose of lomustine, about half had a reduction in dose in the control arm, and 70% required some reduction in the combination arm."

When asked to comment on the findings, Dr. Kenneth D. Aldape, conference chair, said, "It is a negative study and these initial results were somewhat disappointing; however I don’t think we want to throw in the towel for this particular drug." "Higher doses could be considered, and I think in current and future trials, [investigators] will be using higher doses in the hopes of increasing efficacy of this agent," said Dr. Aldape, professor of pathology at the University of Texas M.D. Anderson Cancer Center in Houston.

Dr. Aldape also noted that the trial enrolled patients with recurrent glioblastoma for whom previous treatments had failed. "Newer trials will look at newly diagnosed patients who are treatment naive. So it’s possible that a drug that doesn’t work in recurrent disease might have some efficacy in newly diagnosed patients, especially if the dose is increased."

Dr. Batchelor has received research funding and honoraria from AstraZeneca, which sponsored the trial and is developing cediranib.

MONTREAL – Cognitive, behavioral, and physical problems still persist today in a group of children exposed to prenatal stress during the Quebec ice storm of January 1998, according to research presented at the annual meeting of the International Society for Traumatic Stress Studies.

"The fetus is not immune to a certain amount of stress, which can be transmitted – probably biologically – from the mother, with resulting cognitive, emotional, physical, and motor development problems," reported Suzanne King, Ph.D., associate professor of psychiatry at McGill University and director of the psychosocial research division of the Douglas Hospital, both in Montreal.

The study measured subjective stress and objective hardship in 150 women during the ice storm, which was described as "the worst natural disaster in Canadian history" by the Insurance Bureau of Canada.

During the midwinter storm, 3 million people were left with no electricity, some for as long as 45 days, and 454 shelters were set up to house more than 17,000 people.

The study is the first prospective analysis of the effects of stress from a natural disaster on pregnant women and their children, said Dr. King. It used questionnaires to measure subjective and objective maternal stress during the storm, and then followed the offspring at 6 months, 2 years, 5.5 years, and 11.5 years.

From a sample of 1,440 women, only 224 responded (15%), and 150 completed the study. "Our resulting sample ended up being a highly educated group with a higher socioeconomic standard than average, which adds significance to the findings," she said.

On average, women in the study were without electricity for 15 days (range, 0-45) and without telephone contact for 4 days (range, 0-34). Two-thirds of them were forced to leave their homes during the storm, and possible posttraumatic stress disorder was present in 4%-17%, said Dr. King.

Although the rates of postpartum depression and premature birth (before 37 weeks) were within normal ranges at 17% and 8%, respectively, there was evidence of compromised cognitive development in the offspring at 2 years, with an odds ratio of 4.4 for delayed development in offspring exposed to high versus low levels of maternal objective stress. "This was controlling for subjective stress, which did not have a significant impact on this outcome. This was objective stress – just the facts – what happened to them," she said.

Additionally, at 2 years, there was a 10-point difference in IQ levels between these two sets of offspring, and these differences persisted at 8.5 years, the most recent data available.

In terms of subjective stress, high levels of maternal subjective stress were associated with increasing levels of offspring internalizing problems such as anxiety and depression, and externalizing problems such as aggression, she added.

"The kids are doing very well because they are from such highly resourced families – their IQs are still quite high, they’re above average – but even in these families we see this significant effect."

Additionally, an analysis of autisticlike symptoms at 6.5 years showed an interaction between both maternal stress and trimester of pregnancy. "For kids who were exposed to stress during the first trimester only, there were increasingly severe autisticlike symptoms with increasing objective stress. None of these kids are autistic, or even close, but in terms of these types of traits we are seeing an effect."

The researchers also examined dermatoglyphic asymmetry of fingertip ridges, a characteristic found more commonly in schizophrenia than in healthy individuals, which may reflect fetal disruptions in development between weeks 14 and 26. This finding was more common among offspring of mothers exposed during this period of their pregnancy, compared with children of mothers exposed during a different period (Dev. Psychopathol. 2009;21:343-53).

Dr. King and her group believe that much of the effect of maternal prenatal stress on an offspring’s cognition and emotional development is a result of direct effects on the fetal brain. In fact, when computational analysis of high-resolution structural magnetic resonance images was used to assess individual and group differences in brain structure, there was a decrease in hippocampal volume observed in boys, but not in girls. "The hippocampus is the part of the brain that is involved in stress reaction, memory, and emotions," she explained.

Similarly, an analysis of breastfed versus nonbreastfed infants during and after the ice storm showed a link between breastfeeding and decreased hippocampal volume, decreased salivary cortisol stress response, and increased internalizing problems in offspring aged 11.5 years, the group reported in a poster at the meeting.

Session chair Yael Danieli, Ph.D., said Dr. King’s study underscores the necessity of taking a full family history when assessing cognitive and psychological problems. "For a complete assessment of a human being’s state of health, one has to know a full history of trauma of prior generations," Dr. Danieli, a New York clinical psychologist, past president of the ISTSS, and editor of the International Handbook of Multigenerational Legacies of Trauma (1988), said in an interview.

But another presenter in the session urged caution. "I do believe fetuses are sensitive to maternal stress but in a complex way," said Cécile Rousseau, M.D., associate professor of psychiatry at McGill. "In some studies, the more a family has been exposed to stress, the better the kids are doing. We should build complex models because these are huge stresses. Let’s look for links for autism and schizophrenia, but let’s be very, very careful. My gut feeling is there are relationships but this is utterly complex."

The investigators have no commercial relationships.

MONTREAL – Cognitive, behavioral, and physical problems still persist today in a group of children exposed to prenatal stress during the Quebec ice storm of January 1998, according to research presented at the annual meeting of the International Society for Traumatic Stress Studies.

"The fetus is not immune to a certain amount of stress, which can be transmitted – probably biologically – from the mother, with resulting cognitive, emotional, physical, and motor development problems," reported Suzanne King, Ph.D., associate professor of psychiatry at McGill University and director of the psychosocial research division of the Douglas Hospital, both in Montreal.

The study measured subjective stress and objective hardship in 150 women during the ice storm, which was described as "the worst natural disaster in Canadian history" by the Insurance Bureau of Canada.

During the midwinter storm, 3 million people were left with no electricity, some for as long as 45 days, and 454 shelters were set up to house more than 17,000 people.

The study is the first prospective analysis of the effects of stress from a natural disaster on pregnant women and their children, said Dr. King. It used questionnaires to measure subjective and objective maternal stress during the storm, and then followed the offspring at 6 months, 2 years, 5.5 years, and 11.5 years.

From a sample of 1,440 women, only 224 responded (15%), and 150 completed the study. "Our resulting sample ended up being a highly educated group with a higher socioeconomic standard than average, which adds significance to the findings," she said.

On average, women in the study were without electricity for 15 days (range, 0-45) and without telephone contact for 4 days (range, 0-34). Two-thirds of them were forced to leave their homes during the storm, and possible posttraumatic stress disorder was present in 4%-17%, said Dr. King.

Although the rates of postpartum depression and premature birth (before 37 weeks) were within normal ranges at 17% and 8%, respectively, there was evidence of compromised cognitive development in the offspring at 2 years, with an odds ratio of 4.4 for delayed development in offspring exposed to high versus low levels of maternal objective stress. "This was controlling for subjective stress, which did not have a significant impact on this outcome. This was objective stress – just the facts – what happened to them," she said.

Additionally, at 2 years, there was a 10-point difference in IQ levels between these two sets of offspring, and these differences persisted at 8.5 years, the most recent data available.

In terms of subjective stress, high levels of maternal subjective stress were associated with increasing levels of offspring internalizing problems such as anxiety and depression, and externalizing problems such as aggression, she added.

"The kids are doing very well because they are from such highly resourced families – their IQs are still quite high, they’re above average – but even in these families we see this significant effect."

Additionally, an analysis of autisticlike symptoms at 6.5 years showed an interaction between both maternal stress and trimester of pregnancy. "For kids who were exposed to stress during the first trimester only, there were increasingly severe autisticlike symptoms with increasing objective stress. None of these kids are autistic, or even close, but in terms of these types of traits we are seeing an effect."

The researchers also examined dermatoglyphic asymmetry of fingertip ridges, a characteristic found more commonly in schizophrenia than in healthy individuals, which may reflect fetal disruptions in development between weeks 14 and 26. This finding was more common among offspring of mothers exposed during this period of their pregnancy, compared with children of mothers exposed during a different period (Dev. Psychopathol. 2009;21:343-53).

Dr. King and her group believe that much of the effect of maternal prenatal stress on an offspring’s cognition and emotional development is a result of direct effects on the fetal brain. In fact, when computational analysis of high-resolution structural magnetic resonance images was used to assess individual and group differences in brain structure, there was a decrease in hippocampal volume observed in boys, but not in girls. "The hippocampus is the part of the brain that is involved in stress reaction, memory, and emotions," she explained.

Similarly, an analysis of breastfed versus nonbreastfed infants during and after the ice storm showed a link between breastfeeding and decreased hippocampal volume, decreased salivary cortisol stress response, and increased internalizing problems in offspring aged 11.5 years, the group reported in a poster at the meeting.

Session chair Yael Danieli, Ph.D., said Dr. King’s study underscores the necessity of taking a full family history when assessing cognitive and psychological problems. "For a complete assessment of a human being’s state of health, one has to know a full history of trauma of prior generations," Dr. Danieli, a New York clinical psychologist, past president of the ISTSS, and editor of the International Handbook of Multigenerational Legacies of Trauma (1988), said in an interview.

But another presenter in the session urged caution. "I do believe fetuses are sensitive to maternal stress but in a complex way," said Cécile Rousseau, M.D., associate professor of psychiatry at McGill. "In some studies, the more a family has been exposed to stress, the better the kids are doing. We should build complex models because these are huge stresses. Let’s look for links for autism and schizophrenia, but let’s be very, very careful. My gut feeling is there are relationships but this is utterly complex."

The investigators have no commercial relationships.

MONTREAL – Cognitive, behavioral, and physical problems still persist today in a group of children exposed to prenatal stress during the Quebec ice storm of January 1998, according to research presented at the annual meeting of the International Society for Traumatic Stress Studies.

"The fetus is not immune to a certain amount of stress, which can be transmitted – probably biologically – from the mother, with resulting cognitive, emotional, physical, and motor development problems," reported Suzanne King, Ph.D., associate professor of psychiatry at McGill University and director of the psychosocial research division of the Douglas Hospital, both in Montreal.

The study measured subjective stress and objective hardship in 150 women during the ice storm, which was described as "the worst natural disaster in Canadian history" by the Insurance Bureau of Canada.

During the midwinter storm, 3 million people were left with no electricity, some for as long as 45 days, and 454 shelters were set up to house more than 17,000 people.

The study is the first prospective analysis of the effects of stress from a natural disaster on pregnant women and their children, said Dr. King. It used questionnaires to measure subjective and objective maternal stress during the storm, and then followed the offspring at 6 months, 2 years, 5.5 years, and 11.5 years.

From a sample of 1,440 women, only 224 responded (15%), and 150 completed the study. "Our resulting sample ended up being a highly educated group with a higher socioeconomic standard than average, which adds significance to the findings," she said.

On average, women in the study were without electricity for 15 days (range, 0-45) and without telephone contact for 4 days (range, 0-34). Two-thirds of them were forced to leave their homes during the storm, and possible posttraumatic stress disorder was present in 4%-17%, said Dr. King.

Although the rates of postpartum depression and premature birth (before 37 weeks) were within normal ranges at 17% and 8%, respectively, there was evidence of compromised cognitive development in the offspring at 2 years, with an odds ratio of 4.4 for delayed development in offspring exposed to high versus low levels of maternal objective stress. "This was controlling for subjective stress, which did not have a significant impact on this outcome. This was objective stress – just the facts – what happened to them," she said.

Additionally, at 2 years, there was a 10-point difference in IQ levels between these two sets of offspring, and these differences persisted at 8.5 years, the most recent data available.

In terms of subjective stress, high levels of maternal subjective stress were associated with increasing levels of offspring internalizing problems such as anxiety and depression, and externalizing problems such as aggression, she added.

"The kids are doing very well because they are from such highly resourced families – their IQs are still quite high, they’re above average – but even in these families we see this significant effect."

Additionally, an analysis of autisticlike symptoms at 6.5 years showed an interaction between both maternal stress and trimester of pregnancy. "For kids who were exposed to stress during the first trimester only, there were increasingly severe autisticlike symptoms with increasing objective stress. None of these kids are autistic, or even close, but in terms of these types of traits we are seeing an effect."

The researchers also examined dermatoglyphic asymmetry of fingertip ridges, a characteristic found more commonly in schizophrenia than in healthy individuals, which may reflect fetal disruptions in development between weeks 14 and 26. This finding was more common among offspring of mothers exposed during this period of their pregnancy, compared with children of mothers exposed during a different period (Dev. Psychopathol. 2009;21:343-53).

Dr. King and her group believe that much of the effect of maternal prenatal stress on an offspring’s cognition and emotional development is a result of direct effects on the fetal brain. In fact, when computational analysis of high-resolution structural magnetic resonance images was used to assess individual and group differences in brain structure, there was a decrease in hippocampal volume observed in boys, but not in girls. "The hippocampus is the part of the brain that is involved in stress reaction, memory, and emotions," she explained.

Similarly, an analysis of breastfed versus nonbreastfed infants during and after the ice storm showed a link between breastfeeding and decreased hippocampal volume, decreased salivary cortisol stress response, and increased internalizing problems in offspring aged 11.5 years, the group reported in a poster at the meeting.

Session chair Yael Danieli, Ph.D., said Dr. King’s study underscores the necessity of taking a full family history when assessing cognitive and psychological problems. "For a complete assessment of a human being’s state of health, one has to know a full history of trauma of prior generations," Dr. Danieli, a New York clinical psychologist, past president of the ISTSS, and editor of the International Handbook of Multigenerational Legacies of Trauma (1988), said in an interview.

But another presenter in the session urged caution. "I do believe fetuses are sensitive to maternal stress but in a complex way," said Cécile Rousseau, M.D., associate professor of psychiatry at McGill. "In some studies, the more a family has been exposed to stress, the better the kids are doing. We should build complex models because these are huge stresses. Let’s look for links for autism and schizophrenia, but let’s be very, very careful. My gut feeling is there are relationships but this is utterly complex."

The investigators have no commercial relationships.

MONTREAL – The addition of d-cycloserine to cognitive-behavioral therapy for the treatment of posttraumatic stress disorder showed little or no benefit over placebo, based on several studies presented at the annual meeting of the International Society for Traumatic Stress Studies.

The presentations sparked some heated debate and dampened hopes for the drug in treating posttraumatic stress disorder (PTSD), given that it has already shown promise in the treatment of social anxiety disorder, panic disorder, and some phobias – and might have potential in the treatment of obsessive-compulsive disorder and addictions.

"The early results are not as positive as we [had] hoped," commented Dr. Charles Marmar, professor and chair of the department of psychiatry at New York University, when asked to comment after the session. "We didn’t see much evidence today that d-cycloserine boosts the therapeutic benefit of cognitive-behavioral therapy [CBT] in PTSD," agreed Dr. Roger Pitman, director of the Massachusetts General Hospital posttraumatic stress disorder and psychophysiology laboratory and professor of psychiatry at Harvard Medical School, both in Boston.

But Dr. Pitman cautioned against dismissing the potential of d-cycloserine (DCS) in psychiatry. "There are several published studies now in social phobia, panic disorder, and height phobia that you can’t simply dismiss," he said in an interview. "It’s fair to conclude that DCS has the capability of bolstering cognitive-behavioral therapy by enhancing retention, but maybe PTSD is a tougher nut to crack."

d-cycloserine, a broad-spectrum antibiotic that has been used for decades in the treatment of tuberculosis and urinary tract infections, also is known to be a cognitive enhancer. In animal laboratory work, DCS been shown to reduce fear in mice. Its positive effect in the treatment of human anxiety and phobia studies is believed to stem from the drug’s ability to enhance learning of new responses to stressful stimuli.

"Maybe for PTSD, the neurobiological mechanisms that are associated with maintenance of this disorder are more complex than those associated with less complex disorders such as social anxiety," suggested St?phane Guay, Ph.D., director of the trauma study center at Louis-H. Lafontaine Hospital in Montreal, who presented one of the negative DCS studies at the meeting, cosponsored by Boston University.

His randomized, double-blind placebo-controlled trial included 45 adult PTSD patients, with moderate to severe symptoms. All patients received 11 or 12 sessions (duration, 90 minutes) of CBT combined with either placebo (n = 23) or DCS (n = 22) 50 mg, administered 1 hour prior to the session for sessions 4 through 11.

The idea behind administration of the drug is that cognitive-behavioral therapy is based on learning, and DCS can enhance learning, he explained. CBT was manualized, and included psychoeducation about posttraumatic stress disorder, prolonged imaginal exposure, and breathing retraining.

The main outcomes were PTSD symptoms, measured with the Clinician-Administered PTSD Scale (CAPS) and the Structured Clinical Interview for DSM-IV Disorders (SCID), and depression, measured by the Beck Depression Inventory (BDI).

Remission rates were roughly equivalent in both groups at 55% for the placebo group and 48% for the treated group immediately following the treatment, and 59% and 44% at the 6-month follow-up. "We found that DCS didn’t seem to improve or increase or accelerate the treatment," he said in an interview. "In fact, those who received DCS did worse in general."

The researchers analyzed a subgroup of patients who were depressed at baseline and found that while CAPS scores dropped for nondepressed patients, they remained almost the same in the depressed group. "These data do not support the use of DCS as an adjunct to CBT in PTSD and show a negative interaction between PTSD, major depression, and DCS," he concluded. "The mechanism of major depression and PTSD may be different."

Two other studies presented during the session had not yet been unblinded, so no reliable conclusions could be drawn, and a third study of 20 patients randomized to CBT plus placebo or CBT plus d-cycloserine showed little difference between groups except a slightly more rapid onset of improvement in the DCS group, reported Clare Henn-Haase, Psy.D., a research psychologist at the San Francisco VA Medical Center.

Asked to comment on the presentations, Rachel Yehuda, Ph.D., professor of psychiatry at Mount Sinai School of Medicine and director of mental health at the James J. Peters VA Medical Center, both in New York, expressed concern that there was too much unfounded optimism in the face of the underwhelming findings.

"I am challenging my clinical colleagues to not get too excited because the basic scientists are staying more sober," she said, referring to the earlier session that presented findings of this therapy in mice.

"They’re not presenting the negatives of the data with adequate emphasis – it’s as simple as that," added Dr. Alexander McFarlane, director of the Centre for Military and Veterans’ Health and professor of psychiatry at the University of Adelaide (Australia). "You can see there’s a real desire to bring the world of psychotherapy and the world of pharmacology together. There’s tremendous investment in this idea. The trouble is, you always have inconvenient truths, and it’s about not running away from them. Good science is to face those inconsistencies."

But Dr. Pitman was more optimistic. "The goal of DCS is to facilitate the consolidation of extinction learning. It’s called extinction retention. We’ve published data that extinction retention is deficient in posttraumatic stress disorder, so the idea that extinction retention could be boosted by an agent like DCS is very attractive," he said.

The field is still very new, and gaps in knowledge are numerous, both at the basic science and clinical level, said Dr. Marmar, urging patience.

"The fact that DCS has been shown to accelerate or improve the effectiveness of behavioral treatments for other disorders, like phobia, social anxiety, and some others suggests we should continue to work on this drug with PTSD – and try to refine it and try to determine the optimal parameters in dosing and scheduling."

None of the presenters reported having conflicts of interest.

MONTREAL – The addition of d-cycloserine to cognitive-behavioral therapy for the treatment of posttraumatic stress disorder showed little or no benefit over placebo, based on several studies presented at the annual meeting of the International Society for Traumatic Stress Studies.

The presentations sparked some heated debate and dampened hopes for the drug in treating posttraumatic stress disorder (PTSD), given that it has already shown promise in the treatment of social anxiety disorder, panic disorder, and some phobias – and might have potential in the treatment of obsessive-compulsive disorder and addictions.

"The early results are not as positive as we [had] hoped," commented Dr. Charles Marmar, professor and chair of the department of psychiatry at New York University, when asked to comment after the session. "We didn’t see much evidence today that d-cycloserine boosts the therapeutic benefit of cognitive-behavioral therapy [CBT] in PTSD," agreed Dr. Roger Pitman, director of the Massachusetts General Hospital posttraumatic stress disorder and psychophysiology laboratory and professor of psychiatry at Harvard Medical School, both in Boston.

But Dr. Pitman cautioned against dismissing the potential of d-cycloserine (DCS) in psychiatry. "There are several published studies now in social phobia, panic disorder, and height phobia that you can’t simply dismiss," he said in an interview. "It’s fair to conclude that DCS has the capability of bolstering cognitive-behavioral therapy by enhancing retention, but maybe PTSD is a tougher nut to crack."

d-cycloserine, a broad-spectrum antibiotic that has been used for decades in the treatment of tuberculosis and urinary tract infections, also is known to be a cognitive enhancer. In animal laboratory work, DCS been shown to reduce fear in mice. Its positive effect in the treatment of human anxiety and phobia studies is believed to stem from the drug’s ability to enhance learning of new responses to stressful stimuli.

"Maybe for PTSD, the neurobiological mechanisms that are associated with maintenance of this disorder are more complex than those associated with less complex disorders such as social anxiety," suggested St?phane Guay, Ph.D., director of the trauma study center at Louis-H. Lafontaine Hospital in Montreal, who presented one of the negative DCS studies at the meeting, cosponsored by Boston University.

His randomized, double-blind placebo-controlled trial included 45 adult PTSD patients, with moderate to severe symptoms. All patients received 11 or 12 sessions (duration, 90 minutes) of CBT combined with either placebo (n = 23) or DCS (n = 22) 50 mg, administered 1 hour prior to the session for sessions 4 through 11.

The idea behind administration of the drug is that cognitive-behavioral therapy is based on learning, and DCS can enhance learning, he explained. CBT was manualized, and included psychoeducation about posttraumatic stress disorder, prolonged imaginal exposure, and breathing retraining.

The main outcomes were PTSD symptoms, measured with the Clinician-Administered PTSD Scale (CAPS) and the Structured Clinical Interview for DSM-IV Disorders (SCID), and depression, measured by the Beck Depression Inventory (BDI).

Remission rates were roughly equivalent in both groups at 55% for the placebo group and 48% for the treated group immediately following the treatment, and 59% and 44% at the 6-month follow-up. "We found that DCS didn’t seem to improve or increase or accelerate the treatment," he said in an interview. "In fact, those who received DCS did worse in general."

The researchers analyzed a subgroup of patients who were depressed at baseline and found that while CAPS scores dropped for nondepressed patients, they remained almost the same in the depressed group. "These data do not support the use of DCS as an adjunct to CBT in PTSD and show a negative interaction between PTSD, major depression, and DCS," he concluded. "The mechanism of major depression and PTSD may be different."

Two other studies presented during the session had not yet been unblinded, so no reliable conclusions could be drawn, and a third study of 20 patients randomized to CBT plus placebo or CBT plus d-cycloserine showed little difference between groups except a slightly more rapid onset of improvement in the DCS group, reported Clare Henn-Haase, Psy.D., a research psychologist at the San Francisco VA Medical Center.

Asked to comment on the presentations, Rachel Yehuda, Ph.D., professor of psychiatry at Mount Sinai School of Medicine and director of mental health at the James J. Peters VA Medical Center, both in New York, expressed concern that there was too much unfounded optimism in the face of the underwhelming findings.

"I am challenging my clinical colleagues to not get too excited because the basic scientists are staying more sober," she said, referring to the earlier session that presented findings of this therapy in mice.

"They’re not presenting the negatives of the data with adequate emphasis – it’s as simple as that," added Dr. Alexander McFarlane, director of the Centre for Military and Veterans’ Health and professor of psychiatry at the University of Adelaide (Australia). "You can see there’s a real desire to bring the world of psychotherapy and the world of pharmacology together. There’s tremendous investment in this idea. The trouble is, you always have inconvenient truths, and it’s about not running away from them. Good science is to face those inconsistencies."

But Dr. Pitman was more optimistic. "The goal of DCS is to facilitate the consolidation of extinction learning. It’s called extinction retention. We’ve published data that extinction retention is deficient in posttraumatic stress disorder, so the idea that extinction retention could be boosted by an agent like DCS is very attractive," he said.

The field is still very new, and gaps in knowledge are numerous, both at the basic science and clinical level, said Dr. Marmar, urging patience.

"The fact that DCS has been shown to accelerate or improve the effectiveness of behavioral treatments for other disorders, like phobia, social anxiety, and some others suggests we should continue to work on this drug with PTSD – and try to refine it and try to determine the optimal parameters in dosing and scheduling."

None of the presenters reported having conflicts of interest.

MONTREAL – The addition of d-cycloserine to cognitive-behavioral therapy for the treatment of posttraumatic stress disorder showed little or no benefit over placebo, based on several studies presented at the annual meeting of the International Society for Traumatic Stress Studies.

The presentations sparked some heated debate and dampened hopes for the drug in treating posttraumatic stress disorder (PTSD), given that it has already shown promise in the treatment of social anxiety disorder, panic disorder, and some phobias – and might have potential in the treatment of obsessive-compulsive disorder and addictions.

"The early results are not as positive as we [had] hoped," commented Dr. Charles Marmar, professor and chair of the department of psychiatry at New York University, when asked to comment after the session. "We didn’t see much evidence today that d-cycloserine boosts the therapeutic benefit of cognitive-behavioral therapy [CBT] in PTSD," agreed Dr. Roger Pitman, director of the Massachusetts General Hospital posttraumatic stress disorder and psychophysiology laboratory and professor of psychiatry at Harvard Medical School, both in Boston.

But Dr. Pitman cautioned against dismissing the potential of d-cycloserine (DCS) in psychiatry. "There are several published studies now in social phobia, panic disorder, and height phobia that you can’t simply dismiss," he said in an interview. "It’s fair to conclude that DCS has the capability of bolstering cognitive-behavioral therapy by enhancing retention, but maybe PTSD is a tougher nut to crack."

d-cycloserine, a broad-spectrum antibiotic that has been used for decades in the treatment of tuberculosis and urinary tract infections, also is known to be a cognitive enhancer. In animal laboratory work, DCS been shown to reduce fear in mice. Its positive effect in the treatment of human anxiety and phobia studies is believed to stem from the drug’s ability to enhance learning of new responses to stressful stimuli.

"Maybe for PTSD, the neurobiological mechanisms that are associated with maintenance of this disorder are more complex than those associated with less complex disorders such as social anxiety," suggested St?phane Guay, Ph.D., director of the trauma study center at Louis-H. Lafontaine Hospital in Montreal, who presented one of the negative DCS studies at the meeting, cosponsored by Boston University.

His randomized, double-blind placebo-controlled trial included 45 adult PTSD patients, with moderate to severe symptoms. All patients received 11 or 12 sessions (duration, 90 minutes) of CBT combined with either placebo (n = 23) or DCS (n = 22) 50 mg, administered 1 hour prior to the session for sessions 4 through 11.

The idea behind administration of the drug is that cognitive-behavioral therapy is based on learning, and DCS can enhance learning, he explained. CBT was manualized, and included psychoeducation about posttraumatic stress disorder, prolonged imaginal exposure, and breathing retraining.

The main outcomes were PTSD symptoms, measured with the Clinician-Administered PTSD Scale (CAPS) and the Structured Clinical Interview for DSM-IV Disorders (SCID), and depression, measured by the Beck Depression Inventory (BDI).

Remission rates were roughly equivalent in both groups at 55% for the placebo group and 48% for the treated group immediately following the treatment, and 59% and 44% at the 6-month follow-up. "We found that DCS didn’t seem to improve or increase or accelerate the treatment," he said in an interview. "In fact, those who received DCS did worse in general."

The researchers analyzed a subgroup of patients who were depressed at baseline and found that while CAPS scores dropped for nondepressed patients, they remained almost the same in the depressed group. "These data do not support the use of DCS as an adjunct to CBT in PTSD and show a negative interaction between PTSD, major depression, and DCS," he concluded. "The mechanism of major depression and PTSD may be different."

Two other studies presented during the session had not yet been unblinded, so no reliable conclusions could be drawn, and a third study of 20 patients randomized to CBT plus placebo or CBT plus d-cycloserine showed little difference between groups except a slightly more rapid onset of improvement in the DCS group, reported Clare Henn-Haase, Psy.D., a research psychologist at the San Francisco VA Medical Center.

Asked to comment on the presentations, Rachel Yehuda, Ph.D., professor of psychiatry at Mount Sinai School of Medicine and director of mental health at the James J. Peters VA Medical Center, both in New York, expressed concern that there was too much unfounded optimism in the face of the underwhelming findings.

"I am challenging my clinical colleagues to not get too excited because the basic scientists are staying more sober," she said, referring to the earlier session that presented findings of this therapy in mice.

"They’re not presenting the negatives of the data with adequate emphasis – it’s as simple as that," added Dr. Alexander McFarlane, director of the Centre for Military and Veterans’ Health and professor of psychiatry at the University of Adelaide (Australia). "You can see there’s a real desire to bring the world of psychotherapy and the world of pharmacology together. There’s tremendous investment in this idea. The trouble is, you always have inconvenient truths, and it’s about not running away from them. Good science is to face those inconsistencies."

But Dr. Pitman was more optimistic. "The goal of DCS is to facilitate the consolidation of extinction learning. It’s called extinction retention. We’ve published data that extinction retention is deficient in posttraumatic stress disorder, so the idea that extinction retention could be boosted by an agent like DCS is very attractive," he said.

The field is still very new, and gaps in knowledge are numerous, both at the basic science and clinical level, said Dr. Marmar, urging patience.

"The fact that DCS has been shown to accelerate or improve the effectiveness of behavioral treatments for other disorders, like phobia, social anxiety, and some others suggests we should continue to work on this drug with PTSD – and try to refine it and try to determine the optimal parameters in dosing and scheduling."

None of the presenters reported having conflicts of interest.

MONTREAL - The physical burden of psychological trauma remains largely underrecognized from both a public health and clinical perspective, a panel of experts explained at the annual meeting of the International Society for Traumatic Stress Studies. And the interplay of mental and physical health should be a central consideration in prevention and treatment programs, they said.

"I think we are just beginning to peel apart the onion" of the extent to which physical illness and mental illness are comorbid, said Dr. Sandro Galea, a physician and epidemiologist affiliated with the school of public health at Columbia University, New York. Mental illness "is a key component in the onset, progression, and severity of a full range of physical illnesses, which, if factored in properly, would illustrate a dramatically greater burden of mental illness than we have currently accepted," he said.

In several ongoing studies across a wide variety of populations, Dr. Galea and his colleagues have documented "an extraordinary relationship" between posttraumatic stress disorder (PTSD) and health disorders such as vascular problems, respiratory and lung problems (including chronic obstructive pulmonary disease, tuberculosis, and emphysema), and other major illnesses such as arthritis, cancer, and diabetes, he reported.

"With few exceptions, it is pretty consistent across the board" that there is a clear association of physical health, functioning, and disability according to the presence or absence of current or lifetime PTSD, he said.

For example, recent evidence from the Detroit Neighborhood Health Study shows evidence of epigenetic and immune system dysfunction among individuals with depression and/or PTSD, compared with unaffected individuals (Proc. Natl. Acad. Sci. 2010;10720:9470-5).

"As providers, we need to be aware of this association and should think about screening for trauma in many of our patients, particularly those with chronic illness," said Dr. Beth E. Cohen of the University of California, San Francisco, and an internal medicine specialist at the San Francisco VA Medical Center. "There’s a lot of data showing [that] people do not actually get diagnosed and treated for things like PTSD for years or even decades after they start to experience these symptoms. If we were able to treat people more aggressively up front, perhaps we could prevent a lot of this."

As coinvestigator on the Heart and Soul Study, Dr. Cohen and her colleagues have documented an increased rate of cardiovascular (CVD) events among heart disease patients with a history of psychological trauma vs. those without (Arch. Gen. Psychiatry 2010;67:750-8). Over a mean of 6 years’ follow-up, there was a 44% rate of CVD events in subjects in the highest quartile of psychological trauma, compared with 36% among those in the lowest quartile, she said.

"Psychological trauma was common in this cohort of patients with heart disease," she said. In addition, greater lifetime trauma was prospectively associated with an increased risk of cardiac events, independent of psychiatric comorbidities, health behaviors, and conventional cardiac risk factors, she explained.

"Cumulative psychological trauma is a very real risk factor for cardiac disease, and patients do not have to either develop a psychiatric disorder or engage in a negative health behavior for this cardiac risk to emerge."

Both Dr. Cohen and Dr. Galea noted the importance of communication between providers of mental and medical health care.

Psychiatrists need to be aware that the psychological trauma they treat is "part of a much greater constellation of symptoms," said Dr. Galea in an interview. "One of the big challenges of medicine is that we are trained in silos. The rheumatologist doesn’t think about PTSD, and the psychiatrist doesn’t think about arthritis. I think we need to be profoundly aware that mental illness does not exist in isolation and, in fact, is linked to an inextricable part of physical function. We need to make sure that the physicians in charge of the physical symptoms realize the centrality of mental illness in that presentation."

Conversely, mental health practitioners need to be aware of their patients’ increased risk for physical illness, Dr. Cohen said. "We need to think of efforts to reduce cardiac risk in patients with psychological trauma, but given that this doesn’t seem to be driven simply by things like cholesterol or blood pressure, we really need to think outside the box in terms of what’s going on here and how we can approach it," she said in an interview.

Neither Dr. Cohen nor Dr. Galea reported any conflicts of interest.

MONTREAL - The physical burden of psychological trauma remains largely underrecognized from both a public health and clinical perspective, a panel of experts explained at the annual meeting of the International Society for Traumatic Stress Studies. And the interplay of mental and physical health should be a central consideration in prevention and treatment programs, they said.

"I think we are just beginning to peel apart the onion" of the extent to which physical illness and mental illness are comorbid, said Dr. Sandro Galea, a physician and epidemiologist affiliated with the school of public health at Columbia University, New York. Mental illness "is a key component in the onset, progression, and severity of a full range of physical illnesses, which, if factored in properly, would illustrate a dramatically greater burden of mental illness than we have currently accepted," he said.

In several ongoing studies across a wide variety of populations, Dr. Galea and his colleagues have documented "an extraordinary relationship" between posttraumatic stress disorder (PTSD) and health disorders such as vascular problems, respiratory and lung problems (including chronic obstructive pulmonary disease, tuberculosis, and emphysema), and other major illnesses such as arthritis, cancer, and diabetes, he reported.

"With few exceptions, it is pretty consistent across the board" that there is a clear association of physical health, functioning, and disability according to the presence or absence of current or lifetime PTSD, he said.

For example, recent evidence from the Detroit Neighborhood Health Study shows evidence of epigenetic and immune system dysfunction among individuals with depression and/or PTSD, compared with unaffected individuals (Proc. Natl. Acad. Sci. 2010;10720:9470-5).

"As providers, we need to be aware of this association and should think about screening for trauma in many of our patients, particularly those with chronic illness," said Dr. Beth E. Cohen of the University of California, San Francisco, and an internal medicine specialist at the San Francisco VA Medical Center. "There’s a lot of data showing [that] people do not actually get diagnosed and treated for things like PTSD for years or even decades after they start to experience these symptoms. If we were able to treat people more aggressively up front, perhaps we could prevent a lot of this."

As coinvestigator on the Heart and Soul Study, Dr. Cohen and her colleagues have documented an increased rate of cardiovascular (CVD) events among heart disease patients with a history of psychological trauma vs. those without (Arch. Gen. Psychiatry 2010;67:750-8). Over a mean of 6 years’ follow-up, there was a 44% rate of CVD events in subjects in the highest quartile of psychological trauma, compared with 36% among those in the lowest quartile, she said.

"Psychological trauma was common in this cohort of patients with heart disease," she said. In addition, greater lifetime trauma was prospectively associated with an increased risk of cardiac events, independent of psychiatric comorbidities, health behaviors, and conventional cardiac risk factors, she explained.

"Cumulative psychological trauma is a very real risk factor for cardiac disease, and patients do not have to either develop a psychiatric disorder or engage in a negative health behavior for this cardiac risk to emerge."

Both Dr. Cohen and Dr. Galea noted the importance of communication between providers of mental and medical health care.

Psychiatrists need to be aware that the psychological trauma they treat is "part of a much greater constellation of symptoms," said Dr. Galea in an interview. "One of the big challenges of medicine is that we are trained in silos. The rheumatologist doesn’t think about PTSD, and the psychiatrist doesn’t think about arthritis. I think we need to be profoundly aware that mental illness does not exist in isolation and, in fact, is linked to an inextricable part of physical function. We need to make sure that the physicians in charge of the physical symptoms realize the centrality of mental illness in that presentation."

Conversely, mental health practitioners need to be aware of their patients’ increased risk for physical illness, Dr. Cohen said. "We need to think of efforts to reduce cardiac risk in patients with psychological trauma, but given that this doesn’t seem to be driven simply by things like cholesterol or blood pressure, we really need to think outside the box in terms of what’s going on here and how we can approach it," she said in an interview.

Neither Dr. Cohen nor Dr. Galea reported any conflicts of interest.

MONTREAL - The physical burden of psychological trauma remains largely underrecognized from both a public health and clinical perspective, a panel of experts explained at the annual meeting of the International Society for Traumatic Stress Studies. And the interplay of mental and physical health should be a central consideration in prevention and treatment programs, they said.

"I think we are just beginning to peel apart the onion" of the extent to which physical illness and mental illness are comorbid, said Dr. Sandro Galea, a physician and epidemiologist affiliated with the school of public health at Columbia University, New York. Mental illness "is a key component in the onset, progression, and severity of a full range of physical illnesses, which, if factored in properly, would illustrate a dramatically greater burden of mental illness than we have currently accepted," he said.

In several ongoing studies across a wide variety of populations, Dr. Galea and his colleagues have documented "an extraordinary relationship" between posttraumatic stress disorder (PTSD) and health disorders such as vascular problems, respiratory and lung problems (including chronic obstructive pulmonary disease, tuberculosis, and emphysema), and other major illnesses such as arthritis, cancer, and diabetes, he reported.

"With few exceptions, it is pretty consistent across the board" that there is a clear association of physical health, functioning, and disability according to the presence or absence of current or lifetime PTSD, he said.

For example, recent evidence from the Detroit Neighborhood Health Study shows evidence of epigenetic and immune system dysfunction among individuals with depression and/or PTSD, compared with unaffected individuals (Proc. Natl. Acad. Sci. 2010;10720:9470-5).

"As providers, we need to be aware of this association and should think about screening for trauma in many of our patients, particularly those with chronic illness," said Dr. Beth E. Cohen of the University of California, San Francisco, and an internal medicine specialist at the San Francisco VA Medical Center. "There’s a lot of data showing [that] people do not actually get diagnosed and treated for things like PTSD for years or even decades after they start to experience these symptoms. If we were able to treat people more aggressively up front, perhaps we could prevent a lot of this."

As coinvestigator on the Heart and Soul Study, Dr. Cohen and her colleagues have documented an increased rate of cardiovascular (CVD) events among heart disease patients with a history of psychological trauma vs. those without (Arch. Gen. Psychiatry 2010;67:750-8). Over a mean of 6 years’ follow-up, there was a 44% rate of CVD events in subjects in the highest quartile of psychological trauma, compared with 36% among those in the lowest quartile, she said.

"Psychological trauma was common in this cohort of patients with heart disease," she said. In addition, greater lifetime trauma was prospectively associated with an increased risk of cardiac events, independent of psychiatric comorbidities, health behaviors, and conventional cardiac risk factors, she explained.

"Cumulative psychological trauma is a very real risk factor for cardiac disease, and patients do not have to either develop a psychiatric disorder or engage in a negative health behavior for this cardiac risk to emerge."

Both Dr. Cohen and Dr. Galea noted the importance of communication between providers of mental and medical health care.

Psychiatrists need to be aware that the psychological trauma they treat is "part of a much greater constellation of symptoms," said Dr. Galea in an interview. "One of the big challenges of medicine is that we are trained in silos. The rheumatologist doesn’t think about PTSD, and the psychiatrist doesn’t think about arthritis. I think we need to be profoundly aware that mental illness does not exist in isolation and, in fact, is linked to an inextricable part of physical function. We need to make sure that the physicians in charge of the physical symptoms realize the centrality of mental illness in that presentation."

Conversely, mental health practitioners need to be aware of their patients’ increased risk for physical illness, Dr. Cohen said. "We need to think of efforts to reduce cardiac risk in patients with psychological trauma, but given that this doesn’t seem to be driven simply by things like cholesterol or blood pressure, we really need to think outside the box in terms of what’s going on here and how we can approach it," she said in an interview.

Neither Dr. Cohen nor Dr. Galea reported any conflicts of interest.

MONTREAL - The physical burden of psychological trauma remains largely underrecognized from both a public health and clinical perspective, a panel of experts explained at the annual meeting of the International Society for Traumatic Stress Studies. And the interplay of mental and physical health should be a central consideration in prevention and treatment programs, they said.

"I think we are just beginning to peel apart the onion" of the extent to which physical illness and mental illness are comorbid, said Dr. Sandro Galea, a physician and epidemiologist affiliated with the school of public health at Columbia University, New York. Mental illness "is a key component in the onset, progression, and severity of a full range of physical illnesses, which, if factored in properly, would illustrate a dramatically greater burden of mental illness than we have currently accepted," he said.

In several ongoing studies across a wide variety of populations, Dr. Galea and his colleagues have documented "an extraordinary relationship" between posttraumatic stress disorder (PTSD) and health disorders such as vascular problems, respiratory and lung problems (including chronic obstructive pulmonary disease, tuberculosis, and emphysema), and other major illnesses such as arthritis, cancer, and diabetes, he reported.

"With few exceptions, it is pretty consistent across the board" that there is a clear association of physical health, functioning, and disability according to the presence or absence of current or lifetime PTSD, he said.

For example, recent evidence from the Detroit Neighborhood Health Study shows evidence of epigenetic and immune system dysfunction among individuals with depression and/or PTSD, compared with unaffected individuals (Proc. Natl. Acad. Sci. 2010;10720:9470-5).

"As providers, we need to be aware of this association and should think about screening for trauma in many of our patients, particularly those with chronic illness," said Dr. Beth E. Cohen of the University of California, San Francisco, and an internal medicine specialist at the San Francisco VA Medical Center. "There’s a lot of data showing [that] people do not actually get diagnosed and treated for things like PTSD for years or even decades after they start to experience these symptoms. If we were able to treat people more aggressively up front, perhaps we could prevent a lot of this."

As coinvestigator on the Heart and Soul Study, Dr. Cohen and her colleagues have documented an increased rate of cardiovascular (CVD) events among heart disease patients with a history of psychological trauma vs. those without (Arch. Gen. Psychiatry 2010;67:750-8). Over a mean of 6 years’ follow-up, there was a 44% rate of CVD events in subjects in the highest quartile of psychological trauma, compared with 36% among those in the lowest quartile, she said.

"Psychological trauma was common in this cohort of patients with heart disease," she said. In addition, greater lifetime trauma was prospectively associated with an increased risk of cardiac events, independent of psychiatric comorbidities, health behaviors, and conventional cardiac risk factors, she explained.

"Cumulative psychological trauma is a very real risk factor for cardiac disease, and patients do not have to either develop a psychiatric disorder or engage in a negative health behavior for this cardiac risk to emerge."

Both Dr. Cohen and Dr. Galea noted the importance of communication between providers of mental and medical health care.

Psychiatrists need to be aware that the psychological trauma they treat is "part of a much greater constellation of symptoms," said Dr. Galea in an interview. "One of the big challenges of medicine is that we are trained in silos. The rheumatologist doesn’t think about PTSD, and the psychiatrist doesn’t think about arthritis. I think we need to be profoundly aware that mental illness does not exist in isolation and, in fact, is linked to an inextricable part of physical function. We need to make sure that the physicians in charge of the physical symptoms realize the centrality of mental illness in that presentation."

Conversely, mental health practitioners need to be aware of their patients’ increased risk for physical illness, Dr. Cohen said. "We need to think of efforts to reduce cardiac risk in patients with psychological trauma, but given that this doesn’t seem to be driven simply by things like cholesterol or blood pressure, we really need to think outside the box in terms of what’s going on here and how we can approach it," she said in an interview.

Neither Dr. Cohen nor Dr. Galea reported any conflicts of interest.

MONTREAL - The physical burden of psychological trauma remains largely underrecognized from both a public health and clinical perspective, a panel of experts explained at the annual meeting of the International Society for Traumatic Stress Studies. And the interplay of mental and physical health should be a central consideration in prevention and treatment programs, they said.

"I think we are just beginning to peel apart the onion" of the extent to which physical illness and mental illness are comorbid, said Dr. Sandro Galea, a physician and epidemiologist affiliated with the school of public health at Columbia University, New York. Mental illness "is a key component in the onset, progression, and severity of a full range of physical illnesses, which, if factored in properly, would illustrate a dramatically greater burden of mental illness than we have currently accepted," he said.

In several ongoing studies across a wide variety of populations, Dr. Galea and his colleagues have documented "an extraordinary relationship" between posttraumatic stress disorder (PTSD) and health disorders such as vascular problems, respiratory and lung problems (including chronic obstructive pulmonary disease, tuberculosis, and emphysema), and other major illnesses such as arthritis, cancer, and diabetes, he reported.

"With few exceptions, it is pretty consistent across the board" that there is a clear association of physical health, functioning, and disability according to the presence or absence of current or lifetime PTSD, he said.

For example, recent evidence from the Detroit Neighborhood Health Study shows evidence of epigenetic and immune system dysfunction among individuals with depression and/or PTSD, compared with unaffected individuals (Proc. Natl. Acad. Sci. 2010;10720:9470-5).

"As providers, we need to be aware of this association and should think about screening for trauma in many of our patients, particularly those with chronic illness," said Dr. Beth E. Cohen of the University of California, San Francisco, and an internal medicine specialist at the San Francisco VA Medical Center. "There’s a lot of data showing [that] people do not actually get diagnosed and treated for things like PTSD for years or even decades after they start to experience these symptoms. If we were able to treat people more aggressively up front, perhaps we could prevent a lot of this."

As coinvestigator on the Heart and Soul Study, Dr. Cohen and her colleagues have documented an increased rate of cardiovascular (CVD) events among heart disease patients with a history of psychological trauma vs. those without (Arch. Gen. Psychiatry 2010;67:750-8). Over a mean of 6 years’ follow-up, there was a 44% rate of CVD events in subjects in the highest quartile of psychological trauma, compared with 36% among those in the lowest quartile, she said.

"Psychological trauma was common in this cohort of patients with heart disease," she said. In addition, greater lifetime trauma was prospectively associated with an increased risk of cardiac events, independent of psychiatric comorbidities, health behaviors, and conventional cardiac risk factors, she explained.

"Cumulative psychological trauma is a very real risk factor for cardiac disease, and patients do not have to either develop a psychiatric disorder or engage in a negative health behavior for this cardiac risk to emerge."

Both Dr. Cohen and Dr. Galea noted the importance of communication between providers of mental and medical health care.

Psychiatrists need to be aware that the psychological trauma they treat is "part of a much greater constellation of symptoms," said Dr. Galea in an interview. "One of the big challenges of medicine is that we are trained in silos. The rheumatologist doesn’t think about PTSD, and the psychiatrist doesn’t think about arthritis. I think we need to be profoundly aware that mental illness does not exist in isolation and, in fact, is linked to an inextricable part of physical function. We need to make sure that the physicians in charge of the physical symptoms realize the centrality of mental illness in that presentation."

Conversely, mental health practitioners need to be aware of their patients’ increased risk for physical illness, Dr. Cohen said. "We need to think of efforts to reduce cardiac risk in patients with psychological trauma, but given that this doesn’t seem to be driven simply by things like cholesterol or blood pressure, we really need to think outside the box in terms of what’s going on here and how we can approach it," she said in an interview.

Neither Dr. Cohen nor Dr. Galea reported any conflicts of interest.

MONTREAL - The physical burden of psychological trauma remains largely underrecognized from both a public health and clinical perspective, a panel of experts explained at the annual meeting of the International Society for Traumatic Stress Studies. And the interplay of mental and physical health should be a central consideration in prevention and treatment programs, they said.

"I think we are just beginning to peel apart the onion" of the extent to which physical illness and mental illness are comorbid, said Dr. Sandro Galea, a physician and epidemiologist affiliated with the school of public health at Columbia University, New York. Mental illness "is a key component in the onset, progression, and severity of a full range of physical illnesses, which, if factored in properly, would illustrate a dramatically greater burden of mental illness than we have currently accepted," he said.

In several ongoing studies across a wide variety of populations, Dr. Galea and his colleagues have documented "an extraordinary relationship" between posttraumatic stress disorder (PTSD) and health disorders such as vascular problems, respiratory and lung problems (including chronic obstructive pulmonary disease, tuberculosis, and emphysema), and other major illnesses such as arthritis, cancer, and diabetes, he reported.

"With few exceptions, it is pretty consistent across the board" that there is a clear association of physical health, functioning, and disability according to the presence or absence of current or lifetime PTSD, he said.

For example, recent evidence from the Detroit Neighborhood Health Study shows evidence of epigenetic and immune system dysfunction among individuals with depression and/or PTSD, compared with unaffected individuals (Proc. Natl. Acad. Sci. 2010;10720:9470-5).

"As providers, we need to be aware of this association and should think about screening for trauma in many of our patients, particularly those with chronic illness," said Dr. Beth E. Cohen of the University of California, San Francisco, and an internal medicine specialist at the San Francisco VA Medical Center. "There’s a lot of data showing [that] people do not actually get diagnosed and treated for things like PTSD for years or even decades after they start to experience these symptoms. If we were able to treat people more aggressively up front, perhaps we could prevent a lot of this."

As coinvestigator on the Heart and Soul Study, Dr. Cohen and her colleagues have documented an increased rate of cardiovascular (CVD) events among heart disease patients with a history of psychological trauma vs. those without (Arch. Gen. Psychiatry 2010;67:750-8). Over a mean of 6 years’ follow-up, there was a 44% rate of CVD events in subjects in the highest quartile of psychological trauma, compared with 36% among those in the lowest quartile, she said.

"Psychological trauma was common in this cohort of patients with heart disease," she said. In addition, greater lifetime trauma was prospectively associated with an increased risk of cardiac events, independent of psychiatric comorbidities, health behaviors, and conventional cardiac risk factors, she explained.

"Cumulative psychological trauma is a very real risk factor for cardiac disease, and patients do not have to either develop a psychiatric disorder or engage in a negative health behavior for this cardiac risk to emerge."

Both Dr. Cohen and Dr. Galea noted the importance of communication between providers of mental and medical health care.

Psychiatrists need to be aware that the psychological trauma they treat is "part of a much greater constellation of symptoms," said Dr. Galea in an interview. "One of the big challenges of medicine is that we are trained in silos. The rheumatologist doesn’t think about PTSD, and the psychiatrist doesn’t think about arthritis. I think we need to be profoundly aware that mental illness does not exist in isolation and, in fact, is linked to an inextricable part of physical function. We need to make sure that the physicians in charge of the physical symptoms realize the centrality of mental illness in that presentation."

Conversely, mental health practitioners need to be aware of their patients’ increased risk for physical illness, Dr. Cohen said. "We need to think of efforts to reduce cardiac risk in patients with psychological trauma, but given that this doesn’t seem to be driven simply by things like cholesterol or blood pressure, we really need to think outside the box in terms of what’s going on here and how we can approach it," she said in an interview.

Neither Dr. Cohen nor Dr. Galea reported any conflicts of interest.

MONTREAL – Sleep problems are very common among individuals exposed to terrorist attacks, and new evidence suggests that sleep deficits are contributing to obesity in this traumatized population, researchers reported at the annual meeting of the International Society for Traumatic Stress Studies.

Disturbed sleep and traumatic nightmares are hallmark features of posttraumatic stress disorder (PTSD), said Brian Hall, a doctoral candidate at Kent (Ohio) State University and a clinical psychology intern at the Medical University of South Carolina, Charleston. "Sleep is a treatment-refractory target in PTSD. In folks who respond well to treatments for PTSD, sleep problems tend to be a residual issue."

In a study of 501 Israeli Jews living along the Gaza strip, Mr. Hall and his colleagues found that 47% had had at least one direct terrorist exposure involving the death of a relative, personal injury, the injury of a relative or close friend, or witnessing a rocket or terrorist attack with injuries or fatalities.

PTSD was present in 5.5% of this highly exposed cohort, and depression, in an additional 3.8%. Clinical sleep disturbance, assessed using the 18-item Pittsburgh Sleep Quality Index (PSQI), was present in 37.4% of the cohort, but reached 82% among those identified with PTSD, and 79% among those who were depressed. Overweight, assessed by body mass index (BMI), was present in 45% of the entire cohort, with 11% of the overweight group meeting criteria for obesity, he said at the meeting, cosponsored by Boston University.

Statistical analysis showed that although there was no direct effect of PTSD on BMI, sleep mediated this effect.

Further analysis of the same data revealed that females in the cohort were more prone to sleep problems than males (odds ratio, 1.45), as were individuals aged 50-64 years (OR, 2.07) and those older than age 65 years (OR, 4.45), reported Stevan Hobfoll, Ph.D., of Rush University Medical Center in Chicago, in a separate presentation about the same data.

Sleep problems can worsen the symptoms of PTSD and might exacerbate physical health problems such as cardiovascular disease, stroke, and diabetes, said Mr. Hall in an interview. "What I am trying to emphasize from a public health perspective is that interventions targeting sleep problems are important in PTSD."

Asked to comment on the findings, Jeffrey Knight, Ph.D., raised questions about them. "These things are all related, but to what degree and in what order? What do you do with the person in front of you?" said Dr. Knight, a clinical neuropsychologist at the National Center for PTSD, VA Boston Healthcare System, and Boston University. "What you have is a ball of symptoms traveling together as a unit – it’s like a soccer ball – and at any particular time it rolls over and you see certain facets, but the other parts are still operative. Sleep is a piece of the protocol, but whether it’s driven by anxiety or depression or nightmares, you need to address it differently."

None of the presenters reported having conflicts of interest.

MONTREAL – Sleep problems are very common among individuals exposed to terrorist attacks, and new evidence suggests that sleep deficits are contributing to obesity in this traumatized population, researchers reported at the annual meeting of the International Society for Traumatic Stress Studies.

Disturbed sleep and traumatic nightmares are hallmark features of posttraumatic stress disorder (PTSD), said Brian Hall, a doctoral candidate at Kent (Ohio) State University and a clinical psychology intern at the Medical University of South Carolina, Charleston. "Sleep is a treatment-refractory target in PTSD. In folks who respond well to treatments for PTSD, sleep problems tend to be a residual issue."

In a study of 501 Israeli Jews living along the Gaza strip, Mr. Hall and his colleagues found that 47% had had at least one direct terrorist exposure involving the death of a relative, personal injury, the injury of a relative or close friend, or witnessing a rocket or terrorist attack with injuries or fatalities.

PTSD was present in 5.5% of this highly exposed cohort, and depression, in an additional 3.8%. Clinical sleep disturbance, assessed using the 18-item Pittsburgh Sleep Quality Index (PSQI), was present in 37.4% of the cohort, but reached 82% among those identified with PTSD, and 79% among those who were depressed. Overweight, assessed by body mass index (BMI), was present in 45% of the entire cohort, with 11% of the overweight group meeting criteria for obesity, he said at the meeting, cosponsored by Boston University.

Statistical analysis showed that although there was no direct effect of PTSD on BMI, sleep mediated this effect.

Further analysis of the same data revealed that females in the cohort were more prone to sleep problems than males (odds ratio, 1.45), as were individuals aged 50-64 years (OR, 2.07) and those older than age 65 years (OR, 4.45), reported Stevan Hobfoll, Ph.D., of Rush University Medical Center in Chicago, in a separate presentation about the same data.

Sleep problems can worsen the symptoms of PTSD and might exacerbate physical health problems such as cardiovascular disease, stroke, and diabetes, said Mr. Hall in an interview. "What I am trying to emphasize from a public health perspective is that interventions targeting sleep problems are important in PTSD."

Asked to comment on the findings, Jeffrey Knight, Ph.D., raised questions about them. "These things are all related, but to what degree and in what order? What do you do with the person in front of you?" said Dr. Knight, a clinical neuropsychologist at the National Center for PTSD, VA Boston Healthcare System, and Boston University. "What you have is a ball of symptoms traveling together as a unit – it’s like a soccer ball – and at any particular time it rolls over and you see certain facets, but the other parts are still operative. Sleep is a piece of the protocol, but whether it’s driven by anxiety or depression or nightmares, you need to address it differently."

None of the presenters reported having conflicts of interest.

MONTREAL – Sleep problems are very common among individuals exposed to terrorist attacks, and new evidence suggests that sleep deficits are contributing to obesity in this traumatized population, researchers reported at the annual meeting of the International Society for Traumatic Stress Studies.

Disturbed sleep and traumatic nightmares are hallmark features of posttraumatic stress disorder (PTSD), said Brian Hall, a doctoral candidate at Kent (Ohio) State University and a clinical psychology intern at the Medical University of South Carolina, Charleston. "Sleep is a treatment-refractory target in PTSD. In folks who respond well to treatments for PTSD, sleep problems tend to be a residual issue."

In a study of 501 Israeli Jews living along the Gaza strip, Mr. Hall and his colleagues found that 47% had had at least one direct terrorist exposure involving the death of a relative, personal injury, the injury of a relative or close friend, or witnessing a rocket or terrorist attack with injuries or fatalities.

PTSD was present in 5.5% of this highly exposed cohort, and depression, in an additional 3.8%. Clinical sleep disturbance, assessed using the 18-item Pittsburgh Sleep Quality Index (PSQI), was present in 37.4% of the cohort, but reached 82% among those identified with PTSD, and 79% among those who were depressed. Overweight, assessed by body mass index (BMI), was present in 45% of the entire cohort, with 11% of the overweight group meeting criteria for obesity, he said at the meeting, cosponsored by Boston University.

Statistical analysis showed that although there was no direct effect of PTSD on BMI, sleep mediated this effect.

Further analysis of the same data revealed that females in the cohort were more prone to sleep problems than males (odds ratio, 1.45), as were individuals aged 50-64 years (OR, 2.07) and those older than age 65 years (OR, 4.45), reported Stevan Hobfoll, Ph.D., of Rush University Medical Center in Chicago, in a separate presentation about the same data.

Sleep problems can worsen the symptoms of PTSD and might exacerbate physical health problems such as cardiovascular disease, stroke, and diabetes, said Mr. Hall in an interview. "What I am trying to emphasize from a public health perspective is that interventions targeting sleep problems are important in PTSD."

Asked to comment on the findings, Jeffrey Knight, Ph.D., raised questions about them. "These things are all related, but to what degree and in what order? What do you do with the person in front of you?" said Dr. Knight, a clinical neuropsychologist at the National Center for PTSD, VA Boston Healthcare System, and Boston University. "What you have is a ball of symptoms traveling together as a unit – it’s like a soccer ball – and at any particular time it rolls over and you see certain facets, but the other parts are still operative. Sleep is a piece of the protocol, but whether it’s driven by anxiety or depression or nightmares, you need to address it differently."

None of the presenters reported having conflicts of interest.