SAN FRANCISCO – Prodromal anxiety and depression are common in Parkinson’s disease and may develop years earlier than conventionally thought, according to data presented at the 2016 congress of the International Psychogeriatric Association.

“In some cases, the psychiatric prodrome can appear 25 or more years earlier than the onset of motor symptoms,” said Andrea Seritan, MD, a geriatric psychiatrist at the University of California, San Francisco. Psychiatrists need to keep this fact in mind when treating patients with anxiety or depression, and refer them to a neurologist if they notice or are informed of motor symptoms, she emphasized.

Amy Karon/Frontline Medical News

Patients with Parkinson’s disease often have developed anxiety or depression before the onset of motor symptoms. Historically, this psychiatric prodrome was thought to begin anywhere from 5 to 10 years before motor symptoms, “depending on which expert you ask,” Dr. Seritan said. But after observing that some of her Parkinson’s patients reported decades-long histories of anxiety or depression, she and her colleagues reviewed medical charts for 39 patients aged 50 years or more with confirmed Parkinson’s disease who were referred for psychiatric evaluation at the UCSF Movement Disorder and Neuromodulation Center in 2015 or 2016. A total of 28 patients (72%) were men, mean age at referral was 65 years (standard deviation, 7.6 years), and the patients had been diagnosed with Parkinson’s disease an average of 12 years previously (standard deviation, 6.7 years).

At referral, a total of 34 (87%) patients met DSM-5 criteria for major depressive disorder, dysthymia, or an unspecified depressive disorder, while 68% met DSM-5 criteria for generalized anxiety disorder, panic disorder, social anxiety disorder, other anxiety disorders, Dr. Seritan said. About two-thirds of patients had comorbid depression and anxiety. Other DSM-5 diagnoses included impulse control disorders (15% of patients), substance abuse disorders (13%), and mild (21%) or major (13%) neurocognitive disorders.

Exactly 50% of patients had depression preceding their Parkinson’s disease diagnosis, while 43% of patients had prodromal anxiety, Dr. Seritan and her colleagues determined. The average age of onset of psychiatric symptoms was in the 30s, but this ranged from childhood or adolescence into the 60s. Mean ages of Parkinson’s diagnosis were much later – 58 years for patients whose primary prodrome was anxiety and 56 years for patients whose primary prodrome was depression, with a standard deviation of 9.8 years for each group.

The findings suggest that a decades-long prodrome of anxiety or depression is common in Parkinson’s disease, Dr. Seritan concluded. Psychiatrists should be alert to the possibility of Parkinson’s disease in patients with depression or anxiety, because individuals with movement disorders can be very susceptible to the side effects of antidepressants and antipsychotics, she emphasized.

Dr. Seritan reported no funding sources and had no conflicts of interest.

SAN FRANCISCO – Prodromal anxiety and depression are common in Parkinson’s disease and may develop years earlier than conventionally thought, according to data presented at the 2016 congress of the International Psychogeriatric Association.

“In some cases, the psychiatric prodrome can appear 25 or more years earlier than the onset of motor symptoms,” said Andrea Seritan, MD, a geriatric psychiatrist at the University of California, San Francisco. Psychiatrists need to keep this fact in mind when treating patients with anxiety or depression, and refer them to a neurologist if they notice or are informed of motor symptoms, she emphasized.

Amy Karon/Frontline Medical News

Patients with Parkinson’s disease often have developed anxiety or depression before the onset of motor symptoms. Historically, this psychiatric prodrome was thought to begin anywhere from 5 to 10 years before motor symptoms, “depending on which expert you ask,” Dr. Seritan said. But after observing that some of her Parkinson’s patients reported decades-long histories of anxiety or depression, she and her colleagues reviewed medical charts for 39 patients aged 50 years or more with confirmed Parkinson’s disease who were referred for psychiatric evaluation at the UCSF Movement Disorder and Neuromodulation Center in 2015 or 2016. A total of 28 patients (72%) were men, mean age at referral was 65 years (standard deviation, 7.6 years), and the patients had been diagnosed with Parkinson’s disease an average of 12 years previously (standard deviation, 6.7 years).

At referral, a total of 34 (87%) patients met DSM-5 criteria for major depressive disorder, dysthymia, or an unspecified depressive disorder, while 68% met DSM-5 criteria for generalized anxiety disorder, panic disorder, social anxiety disorder, other anxiety disorders, Dr. Seritan said. About two-thirds of patients had comorbid depression and anxiety. Other DSM-5 diagnoses included impulse control disorders (15% of patients), substance abuse disorders (13%), and mild (21%) or major (13%) neurocognitive disorders.

Exactly 50% of patients had depression preceding their Parkinson’s disease diagnosis, while 43% of patients had prodromal anxiety, Dr. Seritan and her colleagues determined. The average age of onset of psychiatric symptoms was in the 30s, but this ranged from childhood or adolescence into the 60s. Mean ages of Parkinson’s diagnosis were much later – 58 years for patients whose primary prodrome was anxiety and 56 years for patients whose primary prodrome was depression, with a standard deviation of 9.8 years for each group.

The findings suggest that a decades-long prodrome of anxiety or depression is common in Parkinson’s disease, Dr. Seritan concluded. Psychiatrists should be alert to the possibility of Parkinson’s disease in patients with depression or anxiety, because individuals with movement disorders can be very susceptible to the side effects of antidepressants and antipsychotics, she emphasized.

Dr. Seritan reported no funding sources and had no conflicts of interest.

SAN FRANCISCO – Prodromal anxiety and depression are common in Parkinson’s disease and may develop years earlier than conventionally thought, according to data presented at the 2016 congress of the International Psychogeriatric Association.

“In some cases, the psychiatric prodrome can appear 25 or more years earlier than the onset of motor symptoms,” said Andrea Seritan, MD, a geriatric psychiatrist at the University of California, San Francisco. Psychiatrists need to keep this fact in mind when treating patients with anxiety or depression, and refer them to a neurologist if they notice or are informed of motor symptoms, she emphasized.

Amy Karon/Frontline Medical News

Patients with Parkinson’s disease often have developed anxiety or depression before the onset of motor symptoms. Historically, this psychiatric prodrome was thought to begin anywhere from 5 to 10 years before motor symptoms, “depending on which expert you ask,” Dr. Seritan said. But after observing that some of her Parkinson’s patients reported decades-long histories of anxiety or depression, she and her colleagues reviewed medical charts for 39 patients aged 50 years or more with confirmed Parkinson’s disease who were referred for psychiatric evaluation at the UCSF Movement Disorder and Neuromodulation Center in 2015 or 2016. A total of 28 patients (72%) were men, mean age at referral was 65 years (standard deviation, 7.6 years), and the patients had been diagnosed with Parkinson’s disease an average of 12 years previously (standard deviation, 6.7 years).

At referral, a total of 34 (87%) patients met DSM-5 criteria for major depressive disorder, dysthymia, or an unspecified depressive disorder, while 68% met DSM-5 criteria for generalized anxiety disorder, panic disorder, social anxiety disorder, other anxiety disorders, Dr. Seritan said. About two-thirds of patients had comorbid depression and anxiety. Other DSM-5 diagnoses included impulse control disorders (15% of patients), substance abuse disorders (13%), and mild (21%) or major (13%) neurocognitive disorders.

Exactly 50% of patients had depression preceding their Parkinson’s disease diagnosis, while 43% of patients had prodromal anxiety, Dr. Seritan and her colleagues determined. The average age of onset of psychiatric symptoms was in the 30s, but this ranged from childhood or adolescence into the 60s. Mean ages of Parkinson’s diagnosis were much later – 58 years for patients whose primary prodrome was anxiety and 56 years for patients whose primary prodrome was depression, with a standard deviation of 9.8 years for each group.

The findings suggest that a decades-long prodrome of anxiety or depression is common in Parkinson’s disease, Dr. Seritan concluded. Psychiatrists should be alert to the possibility of Parkinson’s disease in patients with depression or anxiety, because individuals with movement disorders can be very susceptible to the side effects of antidepressants and antipsychotics, she emphasized.

Dr. Seritan reported no funding sources and had no conflicts of interest.

SAN FRANCISCO – Autism spectrum disorders often are missed in older adults, even though they cause substantial morbidity; identifying these disorders enables clinicians to teach more effective caregiving strategies and adjust medications, which can substantially reduce distress for all concerned, according to Shabbir Amanullah, MD.

About 1% of adults have an autism spectrum disorder (ASD), and so will about 700,000 U.S. seniors by 2030, said Dr. Amanullah, a geriatric psychiatrist at Woodstock General Hospital in Ontario. Like their younger peers, older patients with ASD show persistent social deficit and rigid thinking, adhere to inflexible routines, and may have perseverative interests. Many also are high-functioning retired professionals with children, belying stereotypes of autism as a severely disabling disorder of childhood, Dr. Amanullah said. These factors can complicate diagnosis of ASD, especially when patients or family members cannot or will not provide a detailed childhood and psychiatric history.

Undetected ASD is especially burdensome in institutional settings, where patients struggle to adjust and “become angry, even violent,” Dr. Amanullah said at the 2016 congress of the International Psychogeriatric Association.

He noted the case of a 72-year-old nursing home resident referred to him for persistently hostile behavior; she “had never really settled in,” slept poorly, and constantly complained about the staff, food, and other residents, whom she “smacked on the bum with her cane.” She also had complained about the facility to local officials, triggering investigations of minor issues. Staff avoided her whenever possible, her children were estranged, and she failed to improve despite therapy with several psychotropic medications.

This is a classic case of autism spectrum disorder, said Dr. Amanullah, also an adjunct professor  Dalhousie University, Halifax, N.S., and at the University of Western Ontario. The patient acted out most in high-stimulus environments such as the crowded nursing home cafeteria, and interpreted promises to help her “in a minute” literally, becoming enraged when staff arrived 5 minutes later instead. When questioned, she reported having always been “disliked” and without friends. But instead of ruminating over past wrongs as patients with paranoia tend to do, she became uncomfortable and looked down when describing having been bullied as a child.

All these clues had gone unrecognized, according to Dr. Amanullah. “Nobody gave importance to the real reason this patient was complaining. Staff were distracted by the fact that she’d been employed and had children, and did not recognize that someone with ASD can meet this description,” he said.

But staff members often did know children with autism, and so their frustration often turned to compassion after they were educated about her diagnosis and connected it with her behaviors, he said. The patient, for her part, stopped complaining as much about the food after she was allowed to avoid the dining room during busy times and eat in her room if she wished. She also became less recalcitrant after staff began reviewing her schedule with her each morning. If she avoided her most severe behaviors, a staff person also sat with her to keep her company at the end of the day.

Such changes can make a tremendous difference in and outside of institutional settings, but patients with ASD often also need treatment for concurrent Axis I disorders, Dr. Amanullah said. This patient met that description, and Dr. Amanullah increased her antidepressant dose while tapering her off an antipsychotic. He said 20 mg citalopram once daily works well but can manifest as inappropriate jokes rather than physical behaviors. "Autistic individuals vary in their expression of sexuality and may make odd remarks that can be misconstrued," he said in an interview. "But generally, they don't act out." All this underscores the need for clinicians to “consider the power of bias” in their thinking, he said. “We have to be willing to change the way we see things, and even more importantly, recognize what the problem was to begin with.”

Dr. Amanullah disclosed no funding sources or relevant financial conflicts.

SAN FRANCISCO – Autism spectrum disorders often are missed in older adults, even though they cause substantial morbidity; identifying these disorders enables clinicians to teach more effective caregiving strategies and adjust medications, which can substantially reduce distress for all concerned, according to Shabbir Amanullah, MD.

About 1% of adults have an autism spectrum disorder (ASD), and so will about 700,000 U.S. seniors by 2030, said Dr. Amanullah, a geriatric psychiatrist at Woodstock General Hospital in Ontario. Like their younger peers, older patients with ASD show persistent social deficit and rigid thinking, adhere to inflexible routines, and may have perseverative interests. Many also are high-functioning retired professionals with children, belying stereotypes of autism as a severely disabling disorder of childhood, Dr. Amanullah said. These factors can complicate diagnosis of ASD, especially when patients or family members cannot or will not provide a detailed childhood and psychiatric history.

Undetected ASD is especially burdensome in institutional settings, where patients struggle to adjust and “become angry, even violent,” Dr. Amanullah said at the 2016 congress of the International Psychogeriatric Association.

He noted the case of a 72-year-old nursing home resident referred to him for persistently hostile behavior; she “had never really settled in,” slept poorly, and constantly complained about the staff, food, and other residents, whom she “smacked on the bum with her cane.” She also had complained about the facility to local officials, triggering investigations of minor issues. Staff avoided her whenever possible, her children were estranged, and she failed to improve despite therapy with several psychotropic medications.

This is a classic case of autism spectrum disorder, said Dr. Amanullah, also an adjunct professor  Dalhousie University, Halifax, N.S., and at the University of Western Ontario. The patient acted out most in high-stimulus environments such as the crowded nursing home cafeteria, and interpreted promises to help her “in a minute” literally, becoming enraged when staff arrived 5 minutes later instead. When questioned, she reported having always been “disliked” and without friends. But instead of ruminating over past wrongs as patients with paranoia tend to do, she became uncomfortable and looked down when describing having been bullied as a child.

All these clues had gone unrecognized, according to Dr. Amanullah. “Nobody gave importance to the real reason this patient was complaining. Staff were distracted by the fact that she’d been employed and had children, and did not recognize that someone with ASD can meet this description,” he said.

But staff members often did know children with autism, and so their frustration often turned to compassion after they were educated about her diagnosis and connected it with her behaviors, he said. The patient, for her part, stopped complaining as much about the food after she was allowed to avoid the dining room during busy times and eat in her room if she wished. She also became less recalcitrant after staff began reviewing her schedule with her each morning. If she avoided her most severe behaviors, a staff person also sat with her to keep her company at the end of the day.

Such changes can make a tremendous difference in and outside of institutional settings, but patients with ASD often also need treatment for concurrent Axis I disorders, Dr. Amanullah said. This patient met that description, and Dr. Amanullah increased her antidepressant dose while tapering her off an antipsychotic. He said 20 mg citalopram once daily works well but can manifest as inappropriate jokes rather than physical behaviors. "Autistic individuals vary in their expression of sexuality and may make odd remarks that can be misconstrued," he said in an interview. "But generally, they don't act out." All this underscores the need for clinicians to “consider the power of bias” in their thinking, he said. “We have to be willing to change the way we see things, and even more importantly, recognize what the problem was to begin with.”

Dr. Amanullah disclosed no funding sources or relevant financial conflicts.

SAN FRANCISCO – Autism spectrum disorders often are missed in older adults, even though they cause substantial morbidity; identifying these disorders enables clinicians to teach more effective caregiving strategies and adjust medications, which can substantially reduce distress for all concerned, according to Shabbir Amanullah, MD.

About 1% of adults have an autism spectrum disorder (ASD), and so will about 700,000 U.S. seniors by 2030, said Dr. Amanullah, a geriatric psychiatrist at Woodstock General Hospital in Ontario. Like their younger peers, older patients with ASD show persistent social deficit and rigid thinking, adhere to inflexible routines, and may have perseverative interests. Many also are high-functioning retired professionals with children, belying stereotypes of autism as a severely disabling disorder of childhood, Dr. Amanullah said. These factors can complicate diagnosis of ASD, especially when patients or family members cannot or will not provide a detailed childhood and psychiatric history.

Undetected ASD is especially burdensome in institutional settings, where patients struggle to adjust and “become angry, even violent,” Dr. Amanullah said at the 2016 congress of the International Psychogeriatric Association.

He noted the case of a 72-year-old nursing home resident referred to him for persistently hostile behavior; she “had never really settled in,” slept poorly, and constantly complained about the staff, food, and other residents, whom she “smacked on the bum with her cane.” She also had complained about the facility to local officials, triggering investigations of minor issues. Staff avoided her whenever possible, her children were estranged, and she failed to improve despite therapy with several psychotropic medications.

This is a classic case of autism spectrum disorder, said Dr. Amanullah, also an adjunct professor  Dalhousie University, Halifax, N.S., and at the University of Western Ontario. The patient acted out most in high-stimulus environments such as the crowded nursing home cafeteria, and interpreted promises to help her “in a minute” literally, becoming enraged when staff arrived 5 minutes later instead. When questioned, she reported having always been “disliked” and without friends. But instead of ruminating over past wrongs as patients with paranoia tend to do, she became uncomfortable and looked down when describing having been bullied as a child.

All these clues had gone unrecognized, according to Dr. Amanullah. “Nobody gave importance to the real reason this patient was complaining. Staff were distracted by the fact that she’d been employed and had children, and did not recognize that someone with ASD can meet this description,” he said.

But staff members often did know children with autism, and so their frustration often turned to compassion after they were educated about her diagnosis and connected it with her behaviors, he said. The patient, for her part, stopped complaining as much about the food after she was allowed to avoid the dining room during busy times and eat in her room if she wished. She also became less recalcitrant after staff began reviewing her schedule with her each morning. If she avoided her most severe behaviors, a staff person also sat with her to keep her company at the end of the day.

Such changes can make a tremendous difference in and outside of institutional settings, but patients with ASD often also need treatment for concurrent Axis I disorders, Dr. Amanullah said. This patient met that description, and Dr. Amanullah increased her antidepressant dose while tapering her off an antipsychotic. He said 20 mg citalopram once daily works well but can manifest as inappropriate jokes rather than physical behaviors. "Autistic individuals vary in their expression of sexuality and may make odd remarks that can be misconstrued," he said in an interview. "But generally, they don't act out." All this underscores the need for clinicians to “consider the power of bias” in their thinking, he said. “We have to be willing to change the way we see things, and even more importantly, recognize what the problem was to begin with.”

Dr. Amanullah disclosed no funding sources or relevant financial conflicts.

There are “no clinically meaningful differences” between Amgen’s biosimilar adalimumab (Amjevita) and AbbVie’s branded product Humira, the Food and Drug Administration noted it its Sept. 23 announcement of Amjevita’s approval.

Although Amjevita (adalimumab-atto) is expected to cost less than Humira, Amgen has not released price information or a launch date pending ongoing litigation with AbbVie over intellectual property rights, an Amgen spokeswoman said.

[email protected]

There are “no clinically meaningful differences” between Amgen’s biosimilar adalimumab (Amjevita) and AbbVie’s branded product Humira, the Food and Drug Administration noted it its Sept. 23 announcement of Amjevita’s approval.

Although Amjevita (adalimumab-atto) is expected to cost less than Humira, Amgen has not released price information or a launch date pending ongoing litigation with AbbVie over intellectual property rights, an Amgen spokeswoman said.

[email protected]

There are “no clinically meaningful differences” between Amgen’s biosimilar adalimumab (Amjevita) and AbbVie’s branded product Humira, the Food and Drug Administration noted it its Sept. 23 announcement of Amjevita’s approval.

Although Amjevita (adalimumab-atto) is expected to cost less than Humira, Amgen has not released price information or a launch date pending ongoing litigation with AbbVie over intellectual property rights, an Amgen spokeswoman said.

[email protected]

VIENNA – The year 2016 has brought answers to two key questions regarding the off-label use of intravenous ketamine in patients with treatment-resistant depression: What’s the optimal dosing schedule? And what’s the likely mechanism of benefit?

Ketamine has generated enormous interest among psychiatrists and patients because the response is so dramatic, with marked improvement seen within hours in a much higher proportion of patients than respond to conventional antidepressants, which target the serotonergic system. But the benefits are not long lasting, and psychiatrists have wondered how often the treatment should be repeated. That question has been answered in a multicenter, double-blind U.S. randomized trial, Eduard Vieta, MD, PhD, noted at the annual congress of the European College of Neuropsychopharmacology.

Investigators randomized 67 patients with treatment-resistant depression to ketamine at 0.5 mg/kg of body weight at either two or three times per week, or to placebo. The mean reduction on the Montgomery-Åsberg Depression Rating Scale at day 15 was 18.4 points with twice-weekly therapy and similar at 17.7 with thrice-weekly therapy, both significantly better than with placebo (Am J Psychiatry. 2016 Aug 1;173[8]:816-26).

“It turns out that two and three times per week were equally effective, so obviously twice per week is enough,” said Dr. Vieta, professor of psychiatry and head of the bipolar disorders program at the University of Barcelona.

Ketamine’s approved indication is as an anesthetic agent. Its long-term safety as an antidepressant remains an open question. The drug has undesirable psychotropic side effects, including dissociation, but related compounds without those issues are speeding through the developmental pipeline. The Food and Drug Administration has granted Janssen Pharmaceuticals “fast track” and “breakthrough therapy” status for intranasal esketamine, the S(+) enantiomer of ketamine, which is now in phase III clinical trials for treatment-resistant depression as well as for depression with suicidal thoughts. The FDA reserves these designations for potential therapies addressing a major unmet need. Allergan has received the same designations from the FDA for its drug rapastinel, which also is now in phase III clinical trials.

“Ketamine is clearly not something to use as first-line therapy. I think there is a problem in certain places: I know in the U.S. there are now plenty of ketamine clinics administering the drug to first comers. That doesn’t make sense to me. But ketamine does open an important new avenue,” he said.

Dr. Vieta asserted that the future of new drug development for mood disorders lies in the glutamatergic system. However, a recent study by investigators at the National Institute of Mental Health – who pioneered the use of ketamine as an antidepressant – and colleagues at the University of Maryland, Baltimore, casts doubt upon the conventional wisdom that ketamine’s mechanism of benefit as an antidepressant involves N-methyl-d-aspartate receptor (NMDA) antagonism.

Instead, they reported, the antidepressant effect is actually exerted by a ketamine metabolite known as HNK, or (2S,6S;2R,6R)-hydroxynorketamine. And HNK’s antidepressant effect is not related to NMDA receptors, but is instead tied to activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. And in mice, at least, HNK lacks the unwelcome psychotomimetic side effects of ketamine (Nature. 2016 May 4;533[7604]:481-6).

“This is a very nice paper and very important. This opens up a new avenue in drug development, looking at agents that act on AMPA receptors to provide rapid relief of depressive symptoms in unipolar depression but probably also in bipolar depression,” said Dr. Vieta.

He reported receiving research grants from numerous pharmaceutical companies having an interest in treatments for mood disorders.

[email protected]

VIENNA – The year 2016 has brought answers to two key questions regarding the off-label use of intravenous ketamine in patients with treatment-resistant depression: What’s the optimal dosing schedule? And what’s the likely mechanism of benefit?

Ketamine has generated enormous interest among psychiatrists and patients because the response is so dramatic, with marked improvement seen within hours in a much higher proportion of patients than respond to conventional antidepressants, which target the serotonergic system. But the benefits are not long lasting, and psychiatrists have wondered how often the treatment should be repeated. That question has been answered in a multicenter, double-blind U.S. randomized trial, Eduard Vieta, MD, PhD, noted at the annual congress of the European College of Neuropsychopharmacology.

Investigators randomized 67 patients with treatment-resistant depression to ketamine at 0.5 mg/kg of body weight at either two or three times per week, or to placebo. The mean reduction on the Montgomery-Åsberg Depression Rating Scale at day 15 was 18.4 points with twice-weekly therapy and similar at 17.7 with thrice-weekly therapy, both significantly better than with placebo (Am J Psychiatry. 2016 Aug 1;173[8]:816-26).

“It turns out that two and three times per week were equally effective, so obviously twice per week is enough,” said Dr. Vieta, professor of psychiatry and head of the bipolar disorders program at the University of Barcelona.

Ketamine’s approved indication is as an anesthetic agent. Its long-term safety as an antidepressant remains an open question. The drug has undesirable psychotropic side effects, including dissociation, but related compounds without those issues are speeding through the developmental pipeline. The Food and Drug Administration has granted Janssen Pharmaceuticals “fast track” and “breakthrough therapy” status for intranasal esketamine, the S(+) enantiomer of ketamine, which is now in phase III clinical trials for treatment-resistant depression as well as for depression with suicidal thoughts. The FDA reserves these designations for potential therapies addressing a major unmet need. Allergan has received the same designations from the FDA for its drug rapastinel, which also is now in phase III clinical trials.

“Ketamine is clearly not something to use as first-line therapy. I think there is a problem in certain places: I know in the U.S. there are now plenty of ketamine clinics administering the drug to first comers. That doesn’t make sense to me. But ketamine does open an important new avenue,” he said.

Dr. Vieta asserted that the future of new drug development for mood disorders lies in the glutamatergic system. However, a recent study by investigators at the National Institute of Mental Health – who pioneered the use of ketamine as an antidepressant – and colleagues at the University of Maryland, Baltimore, casts doubt upon the conventional wisdom that ketamine’s mechanism of benefit as an antidepressant involves N-methyl-d-aspartate receptor (NMDA) antagonism.

Instead, they reported, the antidepressant effect is actually exerted by a ketamine metabolite known as HNK, or (2S,6S;2R,6R)-hydroxynorketamine. And HNK’s antidepressant effect is not related to NMDA receptors, but is instead tied to activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. And in mice, at least, HNK lacks the unwelcome psychotomimetic side effects of ketamine (Nature. 2016 May 4;533[7604]:481-6).

“This is a very nice paper and very important. This opens up a new avenue in drug development, looking at agents that act on AMPA receptors to provide rapid relief of depressive symptoms in unipolar depression but probably also in bipolar depression,” said Dr. Vieta.

He reported receiving research grants from numerous pharmaceutical companies having an interest in treatments for mood disorders.

[email protected]

VIENNA – The year 2016 has brought answers to two key questions regarding the off-label use of intravenous ketamine in patients with treatment-resistant depression: What’s the optimal dosing schedule? And what’s the likely mechanism of benefit?

Ketamine has generated enormous interest among psychiatrists and patients because the response is so dramatic, with marked improvement seen within hours in a much higher proportion of patients than respond to conventional antidepressants, which target the serotonergic system. But the benefits are not long lasting, and psychiatrists have wondered how often the treatment should be repeated. That question has been answered in a multicenter, double-blind U.S. randomized trial, Eduard Vieta, MD, PhD, noted at the annual congress of the European College of Neuropsychopharmacology.

Investigators randomized 67 patients with treatment-resistant depression to ketamine at 0.5 mg/kg of body weight at either two or three times per week, or to placebo. The mean reduction on the Montgomery-Åsberg Depression Rating Scale at day 15 was 18.4 points with twice-weekly therapy and similar at 17.7 with thrice-weekly therapy, both significantly better than with placebo (Am J Psychiatry. 2016 Aug 1;173[8]:816-26).

“It turns out that two and three times per week were equally effective, so obviously twice per week is enough,” said Dr. Vieta, professor of psychiatry and head of the bipolar disorders program at the University of Barcelona.

Ketamine’s approved indication is as an anesthetic agent. Its long-term safety as an antidepressant remains an open question. The drug has undesirable psychotropic side effects, including dissociation, but related compounds without those issues are speeding through the developmental pipeline. The Food and Drug Administration has granted Janssen Pharmaceuticals “fast track” and “breakthrough therapy” status for intranasal esketamine, the S(+) enantiomer of ketamine, which is now in phase III clinical trials for treatment-resistant depression as well as for depression with suicidal thoughts. The FDA reserves these designations for potential therapies addressing a major unmet need. Allergan has received the same designations from the FDA for its drug rapastinel, which also is now in phase III clinical trials.

“Ketamine is clearly not something to use as first-line therapy. I think there is a problem in certain places: I know in the U.S. there are now plenty of ketamine clinics administering the drug to first comers. That doesn’t make sense to me. But ketamine does open an important new avenue,” he said.

Dr. Vieta asserted that the future of new drug development for mood disorders lies in the glutamatergic system. However, a recent study by investigators at the National Institute of Mental Health – who pioneered the use of ketamine as an antidepressant – and colleagues at the University of Maryland, Baltimore, casts doubt upon the conventional wisdom that ketamine’s mechanism of benefit as an antidepressant involves N-methyl-d-aspartate receptor (NMDA) antagonism.

Instead, they reported, the antidepressant effect is actually exerted by a ketamine metabolite known as HNK, or (2S,6S;2R,6R)-hydroxynorketamine. And HNK’s antidepressant effect is not related to NMDA receptors, but is instead tied to activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. And in mice, at least, HNK lacks the unwelcome psychotomimetic side effects of ketamine (Nature. 2016 May 4;533[7604]:481-6).

“This is a very nice paper and very important. This opens up a new avenue in drug development, looking at agents that act on AMPA receptors to provide rapid relief of depressive symptoms in unipolar depression but probably also in bipolar depression,” said Dr. Vieta.

He reported receiving research grants from numerous pharmaceutical companies having an interest in treatments for mood disorders.

[email protected]

ORLANDO – Boys with hemophilia have a better quality of life when they are managed with intensive bleeding prophylaxis with clotting factor concentrates rather than on-demand therapy, results of an international study suggest.

An analysis of pooled data from six studies conducted in eight countries showed that boys with severe hemophilia who received limited on-demand factor replacement had significantly lower health-related quality of life (HRQoL) scores than did boys treated prophylactically, reported Victoria Price, MB, of Dalhousie University, Halifax, N.S., and colleagues.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

“Early initiation of intensive prophylaxis has the greatest impact on HRQoL in boys with severe hemophilia. HRQoL in boys with severe hemophilia exposed to early initiation of intensive prophylaxis is comparable to boys with mild hemophilia receiving on-demand therapy,” they wrote in a scientific poster presented at the World Federation of Hemophilia World Congress.

In countries where patients have access to safe clotting factor concentrates, prophylaxis has become the standard of care for management of hemophilia A and B, because it has been shown to reduce the frequency of bleeds. But because of the small sample sizes in most studies of hemophilia, it has been difficult to determine whether prophylaxis actually has a significant effect on HRQoL, the investigators noted.

To get an answer to that question, they looked at data from six studies in boys younger than 18 that measured HRQoL using the same standard instrument, the Canadian Haemophilia Outcomes–Kids’ Life Assessment Tool (CHO-KLAT). The studies were conducted in Brazil, Canada, China, France, Germany, the Netherlands, Spain, and the United Kingdom.

Patients in the studies were grouped into one of five categories:

• Early initiation with intensive prophylaxis (Germany, the Netherlands, Spain, UK)

• Gradual initiation with intensive prophylaxis (Canada, France)

• Late initiation with limited prophylaxis (Brazil, China)

• On-demand with good access to factor (Canada and European nations)

• On-demand with variable or limited access to factor (Brazil and China).

Data on a total of 254 boys with severe hemophilia were analyzed and compared with estimated scores from boys with mild hemophilia in the pooled dataset.

Of the boys with severe hemophilia, 220 (86.6% had hemophilia A, and 34 (13.4%) had hemophilia B. They ranged in age from 4.4 to 17.9 years; 21 of the boys were younger than 7 years.

The investigators found that in a linear regression model, patients with early initiation and intensive prophylaxis had the highest CHO-KLAT scores, followed by those who had gradual initiation with intensive prophylaxis (P = .003), late initiation/limited prophylaxis (P = .005), on-demand with good access (P = .008) and, lastly, on-demand with limited access to factor (P less than .001)

The authors noted that the differences by treatment group in the analysis were defined by expert consensus, and may not reflect changes in treatment protocols over the last 10 years. The studies were published between 2006 and 2016.

“Despite this limitation, important differences were observed between groups,” they wrote.

The studies were supported by grants from the Canadian Haemophilia Society and the Society of Haemophilia Clinic Directors of Canada, Bayer, Baxalta, and CSL Behring. The authors did not report conflict of interest disclosures.

ORLANDO – Boys with hemophilia have a better quality of life when they are managed with intensive bleeding prophylaxis with clotting factor concentrates rather than on-demand therapy, results of an international study suggest.

An analysis of pooled data from six studies conducted in eight countries showed that boys with severe hemophilia who received limited on-demand factor replacement had significantly lower health-related quality of life (HRQoL) scores than did boys treated prophylactically, reported Victoria Price, MB, of Dalhousie University, Halifax, N.S., and colleagues.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

“Early initiation of intensive prophylaxis has the greatest impact on HRQoL in boys with severe hemophilia. HRQoL in boys with severe hemophilia exposed to early initiation of intensive prophylaxis is comparable to boys with mild hemophilia receiving on-demand therapy,” they wrote in a scientific poster presented at the World Federation of Hemophilia World Congress.

In countries where patients have access to safe clotting factor concentrates, prophylaxis has become the standard of care for management of hemophilia A and B, because it has been shown to reduce the frequency of bleeds. But because of the small sample sizes in most studies of hemophilia, it has been difficult to determine whether prophylaxis actually has a significant effect on HRQoL, the investigators noted.

To get an answer to that question, they looked at data from six studies in boys younger than 18 that measured HRQoL using the same standard instrument, the Canadian Haemophilia Outcomes–Kids’ Life Assessment Tool (CHO-KLAT). The studies were conducted in Brazil, Canada, China, France, Germany, the Netherlands, Spain, and the United Kingdom.

Patients in the studies were grouped into one of five categories:

• Early initiation with intensive prophylaxis (Germany, the Netherlands, Spain, UK)

• Gradual initiation with intensive prophylaxis (Canada, France)

• Late initiation with limited prophylaxis (Brazil, China)

• On-demand with good access to factor (Canada and European nations)

• On-demand with variable or limited access to factor (Brazil and China).

Data on a total of 254 boys with severe hemophilia were analyzed and compared with estimated scores from boys with mild hemophilia in the pooled dataset.

Of the boys with severe hemophilia, 220 (86.6% had hemophilia A, and 34 (13.4%) had hemophilia B. They ranged in age from 4.4 to 17.9 years; 21 of the boys were younger than 7 years.

The investigators found that in a linear regression model, patients with early initiation and intensive prophylaxis had the highest CHO-KLAT scores, followed by those who had gradual initiation with intensive prophylaxis (P = .003), late initiation/limited prophylaxis (P = .005), on-demand with good access (P = .008) and, lastly, on-demand with limited access to factor (P less than .001)

The authors noted that the differences by treatment group in the analysis were defined by expert consensus, and may not reflect changes in treatment protocols over the last 10 years. The studies were published between 2006 and 2016.

“Despite this limitation, important differences were observed between groups,” they wrote.

The studies were supported by grants from the Canadian Haemophilia Society and the Society of Haemophilia Clinic Directors of Canada, Bayer, Baxalta, and CSL Behring. The authors did not report conflict of interest disclosures.

ORLANDO – Boys with hemophilia have a better quality of life when they are managed with intensive bleeding prophylaxis with clotting factor concentrates rather than on-demand therapy, results of an international study suggest.

An analysis of pooled data from six studies conducted in eight countries showed that boys with severe hemophilia who received limited on-demand factor replacement had significantly lower health-related quality of life (HRQoL) scores than did boys treated prophylactically, reported Victoria Price, MB, of Dalhousie University, Halifax, N.S., and colleagues.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

“Early initiation of intensive prophylaxis has the greatest impact on HRQoL in boys with severe hemophilia. HRQoL in boys with severe hemophilia exposed to early initiation of intensive prophylaxis is comparable to boys with mild hemophilia receiving on-demand therapy,” they wrote in a scientific poster presented at the World Federation of Hemophilia World Congress.

In countries where patients have access to safe clotting factor concentrates, prophylaxis has become the standard of care for management of hemophilia A and B, because it has been shown to reduce the frequency of bleeds. But because of the small sample sizes in most studies of hemophilia, it has been difficult to determine whether prophylaxis actually has a significant effect on HRQoL, the investigators noted.

To get an answer to that question, they looked at data from six studies in boys younger than 18 that measured HRQoL using the same standard instrument, the Canadian Haemophilia Outcomes–Kids’ Life Assessment Tool (CHO-KLAT). The studies were conducted in Brazil, Canada, China, France, Germany, the Netherlands, Spain, and the United Kingdom.

Patients in the studies were grouped into one of five categories:

• Early initiation with intensive prophylaxis (Germany, the Netherlands, Spain, UK)

• Gradual initiation with intensive prophylaxis (Canada, France)

• Late initiation with limited prophylaxis (Brazil, China)

• On-demand with good access to factor (Canada and European nations)

• On-demand with variable or limited access to factor (Brazil and China).

Data on a total of 254 boys with severe hemophilia were analyzed and compared with estimated scores from boys with mild hemophilia in the pooled dataset.

Of the boys with severe hemophilia, 220 (86.6% had hemophilia A, and 34 (13.4%) had hemophilia B. They ranged in age from 4.4 to 17.9 years; 21 of the boys were younger than 7 years.

The investigators found that in a linear regression model, patients with early initiation and intensive prophylaxis had the highest CHO-KLAT scores, followed by those who had gradual initiation with intensive prophylaxis (P = .003), late initiation/limited prophylaxis (P = .005), on-demand with good access (P = .008) and, lastly, on-demand with limited access to factor (P less than .001)

The authors noted that the differences by treatment group in the analysis were defined by expert consensus, and may not reflect changes in treatment protocols over the last 10 years. The studies were published between 2006 and 2016.

“Despite this limitation, important differences were observed between groups,” they wrote.

The studies were supported by grants from the Canadian Haemophilia Society and the Society of Haemophilia Clinic Directors of Canada, Bayer, Baxalta, and CSL Behring. The authors did not report conflict of interest disclosures.

Patients with relapsed multiple myeloma treated with carfilzomib, lenalidomide, and dexamethasone (KRd) experienced improved Global Health Status/Quality of Life scale scores, compared with similar patients who received lenalidomide and dexamethasone (Rd) in the open-label, randomized, phase III ASPIRE trial.

In addition to the improved progression-free survival with KRd vs. Rd, which was previously reported (N Engl J Med. 2015 Jan 8;372[3]:142-52), 396 patients randomized to receive KRd had higher scores on the Global Health Status/Quality of Life (GHS/QoL) scale across 18 28-day treatment cycles, as compared with 396 patients randomized to receive Rd. Statistically significant differences were seen at cycle 12 when 25.5% of KRd-treated patients and 17.4% of Rd patients met the responder definition of at least a 5-point improvement on the GHS/QoL scale. At cycle 18, 24.2% vs. 12.9% of patients in the groups, respectively, met the responder definition, A. Keith Stewart, MD, of the Mayo Clinic in Scottsdale, Ariz., and his colleagues reported online ahead of print (J Clin Oncol. 2016 Sep. 6. doi: 10.1200/JCO.2016.66.9648).

At least a 15-point improvement was seen in 19.9% of KRd-treated patients and 12.4% of Rd-treated patients at cycle 12, and in 17.7% and 10.6%, respectively, at cycle 18. The minimal important difference of 5.6 points on the GHS/QoL scale was met at cycle 12 and was approached (4.8) at cycle 18, the researchers said.

The addition of carfilzomib to Rd improved health-related quality of life without negatively affecting patient-reported symptoms or increasing adverse treatment effects, they concluded.

Dr. Stewart reported consulting or advisory roles with several drug companies including Amgen, the maker of carfilzomib. Detailed disclosures for all authors are available with the full text of the article at JCO.org.

[email protected]

Patients with relapsed multiple myeloma treated with carfilzomib, lenalidomide, and dexamethasone (KRd) experienced improved Global Health Status/Quality of Life scale scores, compared with similar patients who received lenalidomide and dexamethasone (Rd) in the open-label, randomized, phase III ASPIRE trial.

In addition to the improved progression-free survival with KRd vs. Rd, which was previously reported (N Engl J Med. 2015 Jan 8;372[3]:142-52), 396 patients randomized to receive KRd had higher scores on the Global Health Status/Quality of Life (GHS/QoL) scale across 18 28-day treatment cycles, as compared with 396 patients randomized to receive Rd. Statistically significant differences were seen at cycle 12 when 25.5% of KRd-treated patients and 17.4% of Rd patients met the responder definition of at least a 5-point improvement on the GHS/QoL scale. At cycle 18, 24.2% vs. 12.9% of patients in the groups, respectively, met the responder definition, A. Keith Stewart, MD, of the Mayo Clinic in Scottsdale, Ariz., and his colleagues reported online ahead of print (J Clin Oncol. 2016 Sep. 6. doi: 10.1200/JCO.2016.66.9648).

At least a 15-point improvement was seen in 19.9% of KRd-treated patients and 12.4% of Rd-treated patients at cycle 12, and in 17.7% and 10.6%, respectively, at cycle 18. The minimal important difference of 5.6 points on the GHS/QoL scale was met at cycle 12 and was approached (4.8) at cycle 18, the researchers said.

The addition of carfilzomib to Rd improved health-related quality of life without negatively affecting patient-reported symptoms or increasing adverse treatment effects, they concluded.

Dr. Stewart reported consulting or advisory roles with several drug companies including Amgen, the maker of carfilzomib. Detailed disclosures for all authors are available with the full text of the article at JCO.org.

[email protected]

Patients with relapsed multiple myeloma treated with carfilzomib, lenalidomide, and dexamethasone (KRd) experienced improved Global Health Status/Quality of Life scale scores, compared with similar patients who received lenalidomide and dexamethasone (Rd) in the open-label, randomized, phase III ASPIRE trial.

In addition to the improved progression-free survival with KRd vs. Rd, which was previously reported (N Engl J Med. 2015 Jan 8;372[3]:142-52), 396 patients randomized to receive KRd had higher scores on the Global Health Status/Quality of Life (GHS/QoL) scale across 18 28-day treatment cycles, as compared with 396 patients randomized to receive Rd. Statistically significant differences were seen at cycle 12 when 25.5% of KRd-treated patients and 17.4% of Rd patients met the responder definition of at least a 5-point improvement on the GHS/QoL scale. At cycle 18, 24.2% vs. 12.9% of patients in the groups, respectively, met the responder definition, A. Keith Stewart, MD, of the Mayo Clinic in Scottsdale, Ariz., and his colleagues reported online ahead of print (J Clin Oncol. 2016 Sep. 6. doi: 10.1200/JCO.2016.66.9648).

At least a 15-point improvement was seen in 19.9% of KRd-treated patients and 12.4% of Rd-treated patients at cycle 12, and in 17.7% and 10.6%, respectively, at cycle 18. The minimal important difference of 5.6 points on the GHS/QoL scale was met at cycle 12 and was approached (4.8) at cycle 18, the researchers said.

The addition of carfilzomib to Rd improved health-related quality of life without negatively affecting patient-reported symptoms or increasing adverse treatment effects, they concluded.

Dr. Stewart reported consulting or advisory roles with several drug companies including Amgen, the maker of carfilzomib. Detailed disclosures for all authors are available with the full text of the article at JCO.org.

[email protected]

The pathophysiology of exercise intolerance in chronic thromboembolic disease (CTED) and mechanism of improvement after pulmonary endarterectomy have not been well understood, but researchers in the Netherlands have identified those key clinical characteristics of exercise intolerance as well as the mechanisms to response of treatment.

This is the first study to identify the pathophysiology of the exercise intolerance—abnormal pulmonary vascular response—and the underlying mechanism for the pulmonary improvement, Coen van Kan, MD, of Our Lady’s Hospital in Amsterdam and colleagues at the University of Amsterdam reported in the September issue of the Journal of Thoracic and Cardiovascular Surgery (2016;152[3]:763-71).

“Our observations point to a hampered pulmonary vascular response and decreased ventilatory efficiency as underlying pathophysiological mechanisms to explain the exercise limitation observed in patients with CTED,” Dr. van Kan and colleagues wrote. “The clinically significant symptomatic improvement after surgery was shown to be related to significant improvements in both circulatory and ventilatory responses indicative for an improved right ventricle stroke volume during exercise and ventilatory efficiency.”

The researchers studied 14 patients with symptomatic CTED but with normal pulmonary pressures at rest. The patients underwent cardiopulmonary exercise testing (CPET) during right heart catheterization and then had noninvasive CPET 1 year later. During exercise the study subjects showed four features of abnormal pulmonary vascular responses:

• Steep mean pulmonary artery pressure/cardiac output (2.7 mm Hg/min per L).

• Low pulmonary vascular compliance (2.8 mL/mm Hg).

• Mean pulmonary artery pressure (mPAP)/cardiac output slope correlated with dead space ventilation (r = 0.586; P = .028).

• Ventilatory equivalents for carbon dioxide slope (r = 0.580; P = .030).

After screening for exercise-induced pulmonary hypertension, nine patients went on to have pulmonary endarterectomy (three patients had mPAP within normal limits during exercise and hence were not candidates, while two others declined surgery). All nine patients who had surgery survived, and a year afterward, their New York Heart Association functional class scores had improved from class II or II to class I in all patients. “Also, mean peak workload and mean oxygen consumption peak had increased, and the improvements observed tended to reach statistical significance,” Dr. van Kan and colleagues said.

After catheterization, improvement in exercise capacity was related to restoration of right ventricle stroke volume response, as measured by oxygen pulse improvement from 11.7 to 13.3 (P = .027) and heart rate response from 80.9 to 72 (P = .003); and a decrease in ventilatory equivalents for carbon dioxide slope from 38.2 to 32.8 (P = .014).

Dr. van Kan and coauthors had no financial relationships to disclose.

The pathophysiology of exercise intolerance in chronic thromboembolic disease (CTED) and mechanism of improvement after pulmonary endarterectomy have not been well understood, but researchers in the Netherlands have identified those key clinical characteristics of exercise intolerance as well as the mechanisms to response of treatment.

This is the first study to identify the pathophysiology of the exercise intolerance—abnormal pulmonary vascular response—and the underlying mechanism for the pulmonary improvement, Coen van Kan, MD, of Our Lady’s Hospital in Amsterdam and colleagues at the University of Amsterdam reported in the September issue of the Journal of Thoracic and Cardiovascular Surgery (2016;152[3]:763-71).

“Our observations point to a hampered pulmonary vascular response and decreased ventilatory efficiency as underlying pathophysiological mechanisms to explain the exercise limitation observed in patients with CTED,” Dr. van Kan and colleagues wrote. “The clinically significant symptomatic improvement after surgery was shown to be related to significant improvements in both circulatory and ventilatory responses indicative for an improved right ventricle stroke volume during exercise and ventilatory efficiency.”

The researchers studied 14 patients with symptomatic CTED but with normal pulmonary pressures at rest. The patients underwent cardiopulmonary exercise testing (CPET) during right heart catheterization and then had noninvasive CPET 1 year later. During exercise the study subjects showed four features of abnormal pulmonary vascular responses:

• Steep mean pulmonary artery pressure/cardiac output (2.7 mm Hg/min per L).

• Low pulmonary vascular compliance (2.8 mL/mm Hg).

• Mean pulmonary artery pressure (mPAP)/cardiac output slope correlated with dead space ventilation (r = 0.586; P = .028).

• Ventilatory equivalents for carbon dioxide slope (r = 0.580; P = .030).

After screening for exercise-induced pulmonary hypertension, nine patients went on to have pulmonary endarterectomy (three patients had mPAP within normal limits during exercise and hence were not candidates, while two others declined surgery). All nine patients who had surgery survived, and a year afterward, their New York Heart Association functional class scores had improved from class II or II to class I in all patients. “Also, mean peak workload and mean oxygen consumption peak had increased, and the improvements observed tended to reach statistical significance,” Dr. van Kan and colleagues said.

After catheterization, improvement in exercise capacity was related to restoration of right ventricle stroke volume response, as measured by oxygen pulse improvement from 11.7 to 13.3 (P = .027) and heart rate response from 80.9 to 72 (P = .003); and a decrease in ventilatory equivalents for carbon dioxide slope from 38.2 to 32.8 (P = .014).

Dr. van Kan and coauthors had no financial relationships to disclose.

The pathophysiology of exercise intolerance in chronic thromboembolic disease (CTED) and mechanism of improvement after pulmonary endarterectomy have not been well understood, but researchers in the Netherlands have identified those key clinical characteristics of exercise intolerance as well as the mechanisms to response of treatment.

This is the first study to identify the pathophysiology of the exercise intolerance—abnormal pulmonary vascular response—and the underlying mechanism for the pulmonary improvement, Coen van Kan, MD, of Our Lady’s Hospital in Amsterdam and colleagues at the University of Amsterdam reported in the September issue of the Journal of Thoracic and Cardiovascular Surgery (2016;152[3]:763-71).

“Our observations point to a hampered pulmonary vascular response and decreased ventilatory efficiency as underlying pathophysiological mechanisms to explain the exercise limitation observed in patients with CTED,” Dr. van Kan and colleagues wrote. “The clinically significant symptomatic improvement after surgery was shown to be related to significant improvements in both circulatory and ventilatory responses indicative for an improved right ventricle stroke volume during exercise and ventilatory efficiency.”

The researchers studied 14 patients with symptomatic CTED but with normal pulmonary pressures at rest. The patients underwent cardiopulmonary exercise testing (CPET) during right heart catheterization and then had noninvasive CPET 1 year later. During exercise the study subjects showed four features of abnormal pulmonary vascular responses:

• Steep mean pulmonary artery pressure/cardiac output (2.7 mm Hg/min per L).

• Low pulmonary vascular compliance (2.8 mL/mm Hg).

• Mean pulmonary artery pressure (mPAP)/cardiac output slope correlated with dead space ventilation (r = 0.586; P = .028).

• Ventilatory equivalents for carbon dioxide slope (r = 0.580; P = .030).

After screening for exercise-induced pulmonary hypertension, nine patients went on to have pulmonary endarterectomy (three patients had mPAP within normal limits during exercise and hence were not candidates, while two others declined surgery). All nine patients who had surgery survived, and a year afterward, their New York Heart Association functional class scores had improved from class II or II to class I in all patients. “Also, mean peak workload and mean oxygen consumption peak had increased, and the improvements observed tended to reach statistical significance,” Dr. van Kan and colleagues said.

After catheterization, improvement in exercise capacity was related to restoration of right ventricle stroke volume response, as measured by oxygen pulse improvement from 11.7 to 13.3 (P = .027) and heart rate response from 80.9 to 72 (P = .003); and a decrease in ventilatory equivalents for carbon dioxide slope from 38.2 to 32.8 (P = .014).

Dr. van Kan and coauthors had no financial relationships to disclose.

The availability of lungs for transplant has been severely limited by usable donors, but organs from so-called extended criteria donors – those aged 65 years or older, had a 20 pack-years or more smoking history or history of diabetes mellitus, or were black – were found to be associated with shorter survival than lungs from standard donor lungs, and recipients with more severe lung disease had the lowest survival rates from extended-criteria organs, an analysis of the national donor database found.

“Matching donor quality to recipient severity is critical to achieve optimal outcomes in lung transplantation,” Matthew J. Mulligan, MD, and his colleagues from the University of Maryland, Baltimore, said in the September issue of the Journal of Thoracic and Cardiovascular Surgery (2016;152:891-8). Dr. Mulligan previously presented the study results in April 2015 at the annual meeting of the American Association for Thoracic Surgery in Seattle.

The researchers analyzed 10,995 patients who received donor lungs between May 2005 and December 2012, 3,792 of whom received extended-criteria donor (ECD) organs. The study population was taken from the Organ Procurement and Transplantation Network/United Network for Organ Sharing database. Dr. Mulligan and his coauthors said this is the largest study examining ECD in lung transplants to date.

The goal of the study was to identify donor factors associated with reduced 1-year survival after transplantation, Dr. Mulligan and his colleagues said. “In the current literature, there is a paucity of data to guide the decision of matching donor quality to recipient severity,” the study authors said.

Recipients of extended-criteria lungs had a 41% increased risk of death, compared with recipients standard donor lungs, but individuals with more severe lung disease were at even greater risk with extended-criterial lungs, Dr. Mulligan and his colleagues said. Those who had a lung allocation score (LAS) less than 70 had a 1-year survival of 87% with standard donor lungs vs. 82% with extended-criteria lungs, while those who had a LAS of 70 or greater had survival rates of 80% and 72%, respectively.

Other donor factors that were inconsequential in recipient survival, Dr. Mulligan and his coauthors reported, included an abnormal chest x-ray, purulent secretions on bronchoscopy, blood type, mechanism of death (stroke, blunt trauma, gunshot, asphyxiation, and so on), or diagnosis of coronary artery disease and hypertension.

The researchers also did a Cox regression analysis, and found that recipients of extended-criteria lungs with a LAS greater than 70 had an 81% greater risk of death, compared with 37% for those with a LAS of 70 or greater who received standard-donor lungs, and 42% with a LAS of 70 or less and an extended-criteria donor lung.

These findings support the idea of not using ECD lungs in high-risk individuals with LAS greater than 70. “More important, ECD lungs were associated with the worst survival when transplanted into high-risk recipients,” Dr. Mulligan and his colleagues said.

The authors did acknowledge the inherent limitations of a retrospective analysis, but the large patient population is a redeeming factor of the study, Dr. Mulligan and his colleagues said. “Notwithstanding these limitations, the current study provides a rigorous analysis of a large number of lung transplants in the modern era, and the results reported will be useful to the lung transplant community,” the study authors said.

Dr. Mulligan and his coauthors had no relationships to disclose.

The availability of lungs for transplant has been severely limited by usable donors, but organs from so-called extended criteria donors – those aged 65 years or older, had a 20 pack-years or more smoking history or history of diabetes mellitus, or were black – were found to be associated with shorter survival than lungs from standard donor lungs, and recipients with more severe lung disease had the lowest survival rates from extended-criteria organs, an analysis of the national donor database found.

“Matching donor quality to recipient severity is critical to achieve optimal outcomes in lung transplantation,” Matthew J. Mulligan, MD, and his colleagues from the University of Maryland, Baltimore, said in the September issue of the Journal of Thoracic and Cardiovascular Surgery (2016;152:891-8). Dr. Mulligan previously presented the study results in April 2015 at the annual meeting of the American Association for Thoracic Surgery in Seattle.

The researchers analyzed 10,995 patients who received donor lungs between May 2005 and December 2012, 3,792 of whom received extended-criteria donor (ECD) organs. The study population was taken from the Organ Procurement and Transplantation Network/United Network for Organ Sharing database. Dr. Mulligan and his coauthors said this is the largest study examining ECD in lung transplants to date.

The goal of the study was to identify donor factors associated with reduced 1-year survival after transplantation, Dr. Mulligan and his colleagues said. “In the current literature, there is a paucity of data to guide the decision of matching donor quality to recipient severity,” the study authors said.

Recipients of extended-criteria lungs had a 41% increased risk of death, compared with recipients standard donor lungs, but individuals with more severe lung disease were at even greater risk with extended-criterial lungs, Dr. Mulligan and his colleagues said. Those who had a lung allocation score (LAS) less than 70 had a 1-year survival of 87% with standard donor lungs vs. 82% with extended-criteria lungs, while those who had a LAS of 70 or greater had survival rates of 80% and 72%, respectively.

Other donor factors that were inconsequential in recipient survival, Dr. Mulligan and his coauthors reported, included an abnormal chest x-ray, purulent secretions on bronchoscopy, blood type, mechanism of death (stroke, blunt trauma, gunshot, asphyxiation, and so on), or diagnosis of coronary artery disease and hypertension.

The researchers also did a Cox regression analysis, and found that recipients of extended-criteria lungs with a LAS greater than 70 had an 81% greater risk of death, compared with 37% for those with a LAS of 70 or greater who received standard-donor lungs, and 42% with a LAS of 70 or less and an extended-criteria donor lung.

These findings support the idea of not using ECD lungs in high-risk individuals with LAS greater than 70. “More important, ECD lungs were associated with the worst survival when transplanted into high-risk recipients,” Dr. Mulligan and his colleagues said.

The authors did acknowledge the inherent limitations of a retrospective analysis, but the large patient population is a redeeming factor of the study, Dr. Mulligan and his colleagues said. “Notwithstanding these limitations, the current study provides a rigorous analysis of a large number of lung transplants in the modern era, and the results reported will be useful to the lung transplant community,” the study authors said.

Dr. Mulligan and his coauthors had no relationships to disclose.

The availability of lungs for transplant has been severely limited by usable donors, but organs from so-called extended criteria donors – those aged 65 years or older, had a 20 pack-years or more smoking history or history of diabetes mellitus, or were black – were found to be associated with shorter survival than lungs from standard donor lungs, and recipients with more severe lung disease had the lowest survival rates from extended-criteria organs, an analysis of the national donor database found.

“Matching donor quality to recipient severity is critical to achieve optimal outcomes in lung transplantation,” Matthew J. Mulligan, MD, and his colleagues from the University of Maryland, Baltimore, said in the September issue of the Journal of Thoracic and Cardiovascular Surgery (2016;152:891-8). Dr. Mulligan previously presented the study results in April 2015 at the annual meeting of the American Association for Thoracic Surgery in Seattle.

The researchers analyzed 10,995 patients who received donor lungs between May 2005 and December 2012, 3,792 of whom received extended-criteria donor (ECD) organs. The study population was taken from the Organ Procurement and Transplantation Network/United Network for Organ Sharing database. Dr. Mulligan and his coauthors said this is the largest study examining ECD in lung transplants to date.

The goal of the study was to identify donor factors associated with reduced 1-year survival after transplantation, Dr. Mulligan and his colleagues said. “In the current literature, there is a paucity of data to guide the decision of matching donor quality to recipient severity,” the study authors said.

Recipients of extended-criteria lungs had a 41% increased risk of death, compared with recipients standard donor lungs, but individuals with more severe lung disease were at even greater risk with extended-criterial lungs, Dr. Mulligan and his colleagues said. Those who had a lung allocation score (LAS) less than 70 had a 1-year survival of 87% with standard donor lungs vs. 82% with extended-criteria lungs, while those who had a LAS of 70 or greater had survival rates of 80% and 72%, respectively.

Other donor factors that were inconsequential in recipient survival, Dr. Mulligan and his coauthors reported, included an abnormal chest x-ray, purulent secretions on bronchoscopy, blood type, mechanism of death (stroke, blunt trauma, gunshot, asphyxiation, and so on), or diagnosis of coronary artery disease and hypertension.

The researchers also did a Cox regression analysis, and found that recipients of extended-criteria lungs with a LAS greater than 70 had an 81% greater risk of death, compared with 37% for those with a LAS of 70 or greater who received standard-donor lungs, and 42% with a LAS of 70 or less and an extended-criteria donor lung.

These findings support the idea of not using ECD lungs in high-risk individuals with LAS greater than 70. “More important, ECD lungs were associated with the worst survival when transplanted into high-risk recipients,” Dr. Mulligan and his colleagues said.

The authors did acknowledge the inherent limitations of a retrospective analysis, but the large patient population is a redeeming factor of the study, Dr. Mulligan and his colleagues said. “Notwithstanding these limitations, the current study provides a rigorous analysis of a large number of lung transplants in the modern era, and the results reported will be useful to the lung transplant community,” the study authors said.

Dr. Mulligan and his coauthors had no relationships to disclose.

The Food and Drug Administration has approved ustekinumab (Stelara) for the treatment of moderately to severely active Crohn’s disease in certain adults.

Specifically, the new approval for the human monoclonal antibody, which was previously approved for the treatment of psoriasis and psoriatic arthritis, is for Crohn’s disease patients aged 18 years or older who fail or cannot tolerate treatment with immunomodulators or corticosteroids but who never failed treatment with a tumor necrosis factor (TNF) blocker, or who fail or cannot tolerate treatment with one or more TNF blockers, according to a statement from the drug’s maker, Janssen Biotech.

The drug is the first biologic agent to target interleukin (IL)-12 and IL-23 in Crohn’s disease, and its approval was based on findings in more than 1,300 patients across three Janssen Biotech–sponsored phase III studies (UNITI-1, UNITI-2, IM-UNITI) demonstrating its efficacy with respect to clinical response and remission rates.

“Crohn’s disease is a complex condition to treat, and not all therapies work for every patient. The FDA approval of Stelara represents an important advancement in treating patients with Crohn’s disease, as this therapy offers an alternate mechanism of action to induce and maintain clinical remission over time,” study investigator William J. Sandborn, MD, of the University of California, San Diego, said in the statement.

[email protected]

The Food and Drug Administration has approved ustekinumab (Stelara) for the treatment of moderately to severely active Crohn’s disease in certain adults.

Specifically, the new approval for the human monoclonal antibody, which was previously approved for the treatment of psoriasis and psoriatic arthritis, is for Crohn’s disease patients aged 18 years or older who fail or cannot tolerate treatment with immunomodulators or corticosteroids but who never failed treatment with a tumor necrosis factor (TNF) blocker, or who fail or cannot tolerate treatment with one or more TNF blockers, according to a statement from the drug’s maker, Janssen Biotech.

The drug is the first biologic agent to target interleukin (IL)-12 and IL-23 in Crohn’s disease, and its approval was based on findings in more than 1,300 patients across three Janssen Biotech–sponsored phase III studies (UNITI-1, UNITI-2, IM-UNITI) demonstrating its efficacy with respect to clinical response and remission rates.

“Crohn’s disease is a complex condition to treat, and not all therapies work for every patient. The FDA approval of Stelara represents an important advancement in treating patients with Crohn’s disease, as this therapy offers an alternate mechanism of action to induce and maintain clinical remission over time,” study investigator William J. Sandborn, MD, of the University of California, San Diego, said in the statement.

[email protected]

The Food and Drug Administration has approved ustekinumab (Stelara) for the treatment of moderately to severely active Crohn’s disease in certain adults.

Specifically, the new approval for the human monoclonal antibody, which was previously approved for the treatment of psoriasis and psoriatic arthritis, is for Crohn’s disease patients aged 18 years or older who fail or cannot tolerate treatment with immunomodulators or corticosteroids but who never failed treatment with a tumor necrosis factor (TNF) blocker, or who fail or cannot tolerate treatment with one or more TNF blockers, according to a statement from the drug’s maker, Janssen Biotech.

The drug is the first biologic agent to target interleukin (IL)-12 and IL-23 in Crohn’s disease, and its approval was based on findings in more than 1,300 patients across three Janssen Biotech–sponsored phase III studies (UNITI-1, UNITI-2, IM-UNITI) demonstrating its efficacy with respect to clinical response and remission rates.

“Crohn’s disease is a complex condition to treat, and not all therapies work for every patient. The FDA approval of Stelara represents an important advancement in treating patients with Crohn’s disease, as this therapy offers an alternate mechanism of action to induce and maintain clinical remission over time,” study investigator William J. Sandborn, MD, of the University of California, San Diego, said in the statement.

[email protected]

New federal regulations aim to strengthen the current requirements on reporting of clinical trial information.

The new rule offers a checklist to help determine which clinical trials are subject to regulations and who is responsible for information that appears on ClinicalTrials.gov. In addition, the rule does the following:

ClinicalTrials.gov

• Expands the scope of trials for which results must be submitted to include Food and Drug Administration–regulated products that have not yet been approved, licensed, or cleared.

• Requires additional information be submitted to ClinicalTrials.gov, including demographic information about trial participants.

• Expands adverse-event reporting.

• Adds potential penalties for noncompliance.

Simultaneously, the National Institutes of Health issued a complimentary policy for all trials it funds, regardless of whether the trials would be subject to the final rule.

Current federal requirements for reporting of clinical trial information were originally enacted as part of the FDA Amendments Act of 2007. However, a 2015 analysis of trials listed on ClinicalTrials.gov from 2007 to 2012 found a woeful lack of compliance: Study results were posted for 13% of trials covered by reporting requirements (N Engl J Med. 2015;372:1031-9).

“Organizations will need to ensure that their systems, procedures, and organizational values all promote complete and timely clinical trial reporting,” wrote Deborah Zarin, MD, of the National Library of Medicine, Bethesda, Md., and her colleagues in a special report on the final rule (N Engl J Med. 2016 Sep 16. doi: 10.1056/NEJMsr1611785). “In the end, the parties responsible for clinical trials will be held accountable by the public.”

The final rule applies to most interventional studies of drugs, biologics, and devices regulated by FDA, but it will not apply to phase I trials of pharmaceuticals or small feasibility studies of devices. It specifies how and when information collected in a clinical trial should be collected and submitted to ClinicalTrials.gov but does not dictate how clinical trials should be designed or conducted.

“Expanding the registration information in ClinicalTrials.gov improves people’s ability to find clinical trials in which they may be able to participate and access investigational therapies,” NIH officials said in a statement. “More information about the scientific results of trials, whether positive or negative, may help inform healthcare providers and patients regarding medical decisions. Additional information will help researchers avoid unnecessary duplication of studies, focus on areas in need of study and improve study design, ultimately advancing the development of clinical interventions.”

“Many U.S. academic medical centers, including those that conduct the most clinical trials, will find that the majority of their clinical trials fall under the [FDA Amendments Act], the NIH policy, or both,” Dr. Zarin and her colleagues wrote. “We hope that sponsors and other relevant entities will go considerably above and beyond the minimum requirements and expectations, making an effort to honor the contributions of all study participants and ensure that others in the scientific community have access to complete and high-quality information about every clinical trial under their stewardship.”

The final rule was published in the Federal Register on Sept. 21 and becomes effective on Jan. 18, 2017.

[email protected]

New federal regulations aim to strengthen the current requirements on reporting of clinical trial information.

The new rule offers a checklist to help determine which clinical trials are subject to regulations and who is responsible for information that appears on ClinicalTrials.gov. In addition, the rule does the following:

ClinicalTrials.gov

• Expands the scope of trials for which results must be submitted to include Food and Drug Administration–regulated products that have not yet been approved, licensed, or cleared.

• Requires additional information be submitted to ClinicalTrials.gov, including demographic information about trial participants.

• Expands adverse-event reporting.

• Adds potential penalties for noncompliance.

Simultaneously, the National Institutes of Health issued a complimentary policy for all trials it funds, regardless of whether the trials would be subject to the final rule.

Current federal requirements for reporting of clinical trial information were originally enacted as part of the FDA Amendments Act of 2007. However, a 2015 analysis of trials listed on ClinicalTrials.gov from 2007 to 2012 found a woeful lack of compliance: Study results were posted for 13% of trials covered by reporting requirements (N Engl J Med. 2015;372:1031-9).

“Organizations will need to ensure that their systems, procedures, and organizational values all promote complete and timely clinical trial reporting,” wrote Deborah Zarin, MD, of the National Library of Medicine, Bethesda, Md., and her colleagues in a special report on the final rule (N Engl J Med. 2016 Sep 16. doi: 10.1056/NEJMsr1611785). “In the end, the parties responsible for clinical trials will be held accountable by the public.”

The final rule applies to most interventional studies of drugs, biologics, and devices regulated by FDA, but it will not apply to phase I trials of pharmaceuticals or small feasibility studies of devices. It specifies how and when information collected in a clinical trial should be collected and submitted to ClinicalTrials.gov but does not dictate how clinical trials should be designed or conducted.

“Expanding the registration information in ClinicalTrials.gov improves people’s ability to find clinical trials in which they may be able to participate and access investigational therapies,” NIH officials said in a statement. “More information about the scientific results of trials, whether positive or negative, may help inform healthcare providers and patients regarding medical decisions. Additional information will help researchers avoid unnecessary duplication of studies, focus on areas in need of study and improve study design, ultimately advancing the development of clinical interventions.”

“Many U.S. academic medical centers, including those that conduct the most clinical trials, will find that the majority of their clinical trials fall under the [FDA Amendments Act], the NIH policy, or both,” Dr. Zarin and her colleagues wrote. “We hope that sponsors and other relevant entities will go considerably above and beyond the minimum requirements and expectations, making an effort to honor the contributions of all study participants and ensure that others in the scientific community have access to complete and high-quality information about every clinical trial under their stewardship.”

The final rule was published in the Federal Register on Sept. 21 and becomes effective on Jan. 18, 2017.

[email protected]

New federal regulations aim to strengthen the current requirements on reporting of clinical trial information.

The new rule offers a checklist to help determine which clinical trials are subject to regulations and who is responsible for information that appears on ClinicalTrials.gov. In addition, the rule does the following:

ClinicalTrials.gov

• Expands the scope of trials for which results must be submitted to include Food and Drug Administration–regulated products that have not yet been approved, licensed, or cleared.

• Requires additional information be submitted to ClinicalTrials.gov, including demographic information about trial participants.

• Expands adverse-event reporting.

• Adds potential penalties for noncompliance.

Simultaneously, the National Institutes of Health issued a complimentary policy for all trials it funds, regardless of whether the trials would be subject to the final rule.

Current federal requirements for reporting of clinical trial information were originally enacted as part of the FDA Amendments Act of 2007. However, a 2015 analysis of trials listed on ClinicalTrials.gov from 2007 to 2012 found a woeful lack of compliance: Study results were posted for 13% of trials covered by reporting requirements (N Engl J Med. 2015;372:1031-9).

“Organizations will need to ensure that their systems, procedures, and organizational values all promote complete and timely clinical trial reporting,” wrote Deborah Zarin, MD, of the National Library of Medicine, Bethesda, Md., and her colleagues in a special report on the final rule (N Engl J Med. 2016 Sep 16. doi: 10.1056/NEJMsr1611785). “In the end, the parties responsible for clinical trials will be held accountable by the public.”

The final rule applies to most interventional studies of drugs, biologics, and devices regulated by FDA, but it will not apply to phase I trials of pharmaceuticals or small feasibility studies of devices. It specifies how and when information collected in a clinical trial should be collected and submitted to ClinicalTrials.gov but does not dictate how clinical trials should be designed or conducted.

“Expanding the registration information in ClinicalTrials.gov improves people’s ability to find clinical trials in which they may be able to participate and access investigational therapies,” NIH officials said in a statement. “More information about the scientific results of trials, whether positive or negative, may help inform healthcare providers and patients regarding medical decisions. Additional information will help researchers avoid unnecessary duplication of studies, focus on areas in need of study and improve study design, ultimately advancing the development of clinical interventions.”

“Many U.S. academic medical centers, including those that conduct the most clinical trials, will find that the majority of their clinical trials fall under the [FDA Amendments Act], the NIH policy, or both,” Dr. Zarin and her colleagues wrote. “We hope that sponsors and other relevant entities will go considerably above and beyond the minimum requirements and expectations, making an effort to honor the contributions of all study participants and ensure that others in the scientific community have access to complete and high-quality information about every clinical trial under their stewardship.”

The final rule was published in the Federal Register on Sept. 21 and becomes effective on Jan. 18, 2017.

[email protected]