Randy Dotinga

SAN DIEGO – Findings from the landmark 3-year REMOVAL trial find that metformin could hold potential as a tool to reduce cardiovascular disease (CVD) risk in patients with type 1 diabetes. But – in a challenge to current British and American guidelines – findings from the study suggest that the drug doesn’t meaningfully improve glycemic control.

“The CVD benefit is suggestive, but it’s by no means conclusive,” Naveed Sattar, MD, PhD, of the University of Glasgow said in a presentation at the scientific meetings of the American Diabetic Association. As for glycemic control, “you should not prescribe metformin if you want a clinical change in hemoglobin A1c,” he said.

The findings don’t examine CVD outcomes, and researchers bemoaned their inability to launch such a project because of limitations in funding. Still, the study, funded by the Juvenile Diabetes Research Foundation, is the largest to examine metformin in type 1 diabetes.

The Food and Drug Administration has not approved metformin for type 1 diabetes. However, the American Diabetes Association’s 2017 Standard of Care guidelines note that “adding metformin to insulin therapy may reduce insulin requirements and improve metabolic control in overweight/obese patients with poorly controlled type 1 diabetes” (Diabetes Care. 2017 Jan;40[Suppl 1]).

“Metformin has known efficacy for reducing HbA1c, and, at the time we did this, it was one of few diabetes drugs with indications of an effect on cardiovascular disease risk,” study coauthor Helen M. Colhoun, MD, of the University of Edinburgh said during the discussion following the presentation.

The REMOVAL (cardiovascular and metabolic effects of metformin in patients with type 1 diabetes) trial took place from 2011 to 2014. Involved researchers at 23 hospital diabetes clinics around the world randomly assigned 428 patients to metformin (n = 219) and placebo (n = 209) arms.

The patients were all 40 years or older, with a mean age of 55 years. All patients had been diagnosed with type 1 diabetes at least five years prior to the study and met at least 3 of 10 criteria for high risk of cardiovascular disease. Men accounted for 59% of the patients, about 98% were white, and about 79% were obese or overweight. Patients had high levels of use of statins (73%), blood pressure medications (73%), and antiplatelet drugs (39%).

Participants took oral metformin 1,000 mg twice daily or placebo. The results were reported at the ADA meeting and simultaneously online on June 11, 2017 in Lancet Diabetes Endocrinology (2017 Jun 11. doi: 10.1016/S2213-8587[17]30194-8).

In regard to CVD indicators, the researchers did not find significant reduction in the progression of average common carotid artery intima-media thickness (cIMT) (–0.005 mm per year; 95% confidence interval, –0.012-0.002; P = .1664) in metformin, vs. placebo.

There was, however, a significant reduction in maximal cIMT (–0.013 mm per year; 95% CI, –0.024 to –0.003; P = .0093). The study describes this as a surrogate measure for atherosclerosis progression, although it’s a tertiary rather than primary outcome.

Researchers saw a slight decline in HbA1c in the metformin group (–0.13%; 95% CI, –0.22 to –0.037; P = .0060), but researchers say this occurred early and was not sustained.

In the metformin group, compared with placebo, researchers also found reductions in body weight (–1.17 kg; 95% CI,–1.66 to –0.69; p less than .0001) and LDL cholesterol (–0.13 mmol/L; 95% CI, –0.24 to –0.03; P = .0117) on average.

Researchers didn’t find a significant average reduction in insulin use in the metformin group, compared with placebo (–0.005 units per kg; 95% CI, –0.022-0.012, P = .545), although they did notice “a small but sustained reduction in patients allocated to metformin (estimated in post-hoc analyses as –0.023 units per kg; 95% CI, –0.045 to –0.0005; P = .045).”

Rates of gastrointestinal problems were higher in the metformin group, and 27% of these patients discontinued treatment, compared with 12% of placebo patients (P = .0002). Five of the metformin patients died (as did two of the placebo patients), but researchers didn’t link the deaths to medication.

The findings were clearly disappointing. “We’re certainly not claiming that this is a positive trial,” said study coauthor Dr. Colhoun.

A member of the audience at the AAD meeting asked another coauthor, Irene Hramiak, MD, of the University of Western Ontario, London, whether she would prescribe metformin to a patient with type 1 diabetes and a high risk of CVD. “Probably not,” she said, but she added that it may have value in adolescents with weight issues. In those cases, she said, there may be a benefit to improving weight control and lowering insulin doses.

In light of the study findings, the authors recommend revising guidelines that suggest the use of metformin in type 1 diabetes: “We identified a transient improvement in glycemia that reverted to baseline with insulin dose reduction and identified no suggestion of greater benefit in overweight or obese patients.”

The study adds, “Rather than a role in glycemic control, our findings suggest that long-term use of metformin in type 1 diabetes might reduce the long-term risk of cardiovascular disease via small but sustained reductions in bodyweight and LDL cholesterol.”

The Juvenile Diabetes Research Foundation funded the study. Merck Germany KGaA provided medication and shipping for free. Itamar Medical donated equipment and services. Dr. Sataar reported consulting fees and/or research support from Amgen, Boehringer Ingelheim, Eli Lilly, Janssen, and Novo Nordisk. Dr. Colhoun and Dr. Hramiak reported multiple disclosures, including advisory panel, research support, and speaker’s bureau and stock/shareholder relationships.

This article was updated June 19, 2017.

SAN DIEGO – Findings from the landmark 3-year REMOVAL trial find that metformin could hold potential as a tool to reduce cardiovascular disease (CVD) risk in patients with type 1 diabetes. But – in a challenge to current British and American guidelines – findings from the study suggest that the drug doesn’t meaningfully improve glycemic control.

“The CVD benefit is suggestive, but it’s by no means conclusive,” Naveed Sattar, MD, PhD, of the University of Glasgow said in a presentation at the scientific meetings of the American Diabetic Association. As for glycemic control, “you should not prescribe metformin if you want a clinical change in hemoglobin A1c,” he said.

The findings don’t examine CVD outcomes, and researchers bemoaned their inability to launch such a project because of limitations in funding. Still, the study, funded by the Juvenile Diabetes Research Foundation, is the largest to examine metformin in type 1 diabetes.

The Food and Drug Administration has not approved metformin for type 1 diabetes. However, the American Diabetes Association’s 2017 Standard of Care guidelines note that “adding metformin to insulin therapy may reduce insulin requirements and improve metabolic control in overweight/obese patients with poorly controlled type 1 diabetes” (Diabetes Care. 2017 Jan;40[Suppl 1]).

“Metformin has known efficacy for reducing HbA1c, and, at the time we did this, it was one of few diabetes drugs with indications of an effect on cardiovascular disease risk,” study coauthor Helen M. Colhoun, MD, of the University of Edinburgh said during the discussion following the presentation.

The REMOVAL (cardiovascular and metabolic effects of metformin in patients with type 1 diabetes) trial took place from 2011 to 2014. Involved researchers at 23 hospital diabetes clinics around the world randomly assigned 428 patients to metformin (n = 219) and placebo (n = 209) arms.

The patients were all 40 years or older, with a mean age of 55 years. All patients had been diagnosed with type 1 diabetes at least five years prior to the study and met at least 3 of 10 criteria for high risk of cardiovascular disease. Men accounted for 59% of the patients, about 98% were white, and about 79% were obese or overweight. Patients had high levels of use of statins (73%), blood pressure medications (73%), and antiplatelet drugs (39%).

Participants took oral metformin 1,000 mg twice daily or placebo. The results were reported at the ADA meeting and simultaneously online on June 11, 2017 in Lancet Diabetes Endocrinology (2017 Jun 11. doi: 10.1016/S2213-8587[17]30194-8).

In regard to CVD indicators, the researchers did not find significant reduction in the progression of average common carotid artery intima-media thickness (cIMT) (–0.005 mm per year; 95% confidence interval, –0.012-0.002; P = .1664) in metformin, vs. placebo.

There was, however, a significant reduction in maximal cIMT (–0.013 mm per year; 95% CI, –0.024 to –0.003; P = .0093). The study describes this as a surrogate measure for atherosclerosis progression, although it’s a tertiary rather than primary outcome.

Researchers saw a slight decline in HbA1c in the metformin group (–0.13%; 95% CI, –0.22 to –0.037; P = .0060), but researchers say this occurred early and was not sustained.

In the metformin group, compared with placebo, researchers also found reductions in body weight (–1.17 kg; 95% CI,–1.66 to –0.69; p less than .0001) and LDL cholesterol (–0.13 mmol/L; 95% CI, –0.24 to –0.03; P = .0117) on average.

Researchers didn’t find a significant average reduction in insulin use in the metformin group, compared with placebo (–0.005 units per kg; 95% CI, –0.022-0.012, P = .545), although they did notice “a small but sustained reduction in patients allocated to metformin (estimated in post-hoc analyses as –0.023 units per kg; 95% CI, –0.045 to –0.0005; P = .045).”

Rates of gastrointestinal problems were higher in the metformin group, and 27% of these patients discontinued treatment, compared with 12% of placebo patients (P = .0002). Five of the metformin patients died (as did two of the placebo patients), but researchers didn’t link the deaths to medication.

The findings were clearly disappointing. “We’re certainly not claiming that this is a positive trial,” said study coauthor Dr. Colhoun.

A member of the audience at the AAD meeting asked another coauthor, Irene Hramiak, MD, of the University of Western Ontario, London, whether she would prescribe metformin to a patient with type 1 diabetes and a high risk of CVD. “Probably not,” she said, but she added that it may have value in adolescents with weight issues. In those cases, she said, there may be a benefit to improving weight control and lowering insulin doses.

In light of the study findings, the authors recommend revising guidelines that suggest the use of metformin in type 1 diabetes: “We identified a transient improvement in glycemia that reverted to baseline with insulin dose reduction and identified no suggestion of greater benefit in overweight or obese patients.”

The study adds, “Rather than a role in glycemic control, our findings suggest that long-term use of metformin in type 1 diabetes might reduce the long-term risk of cardiovascular disease via small but sustained reductions in bodyweight and LDL cholesterol.”

The Juvenile Diabetes Research Foundation funded the study. Merck Germany KGaA provided medication and shipping for free. Itamar Medical donated equipment and services. Dr. Sataar reported consulting fees and/or research support from Amgen, Boehringer Ingelheim, Eli Lilly, Janssen, and Novo Nordisk. Dr. Colhoun and Dr. Hramiak reported multiple disclosures, including advisory panel, research support, and speaker’s bureau and stock/shareholder relationships.

This article was updated June 19, 2017.

SAN DIEGO – Findings from the landmark 3-year REMOVAL trial find that metformin could hold potential as a tool to reduce cardiovascular disease (CVD) risk in patients with type 1 diabetes. But – in a challenge to current British and American guidelines – findings from the study suggest that the drug doesn’t meaningfully improve glycemic control.

“The CVD benefit is suggestive, but it’s by no means conclusive,” Naveed Sattar, MD, PhD, of the University of Glasgow said in a presentation at the scientific meetings of the American Diabetic Association. As for glycemic control, “you should not prescribe metformin if you want a clinical change in hemoglobin A1c,” he said.

The findings don’t examine CVD outcomes, and researchers bemoaned their inability to launch such a project because of limitations in funding. Still, the study, funded by the Juvenile Diabetes Research Foundation, is the largest to examine metformin in type 1 diabetes.

The Food and Drug Administration has not approved metformin for type 1 diabetes. However, the American Diabetes Association’s 2017 Standard of Care guidelines note that “adding metformin to insulin therapy may reduce insulin requirements and improve metabolic control in overweight/obese patients with poorly controlled type 1 diabetes” (Diabetes Care. 2017 Jan;40[Suppl 1]).

“Metformin has known efficacy for reducing HbA1c, and, at the time we did this, it was one of few diabetes drugs with indications of an effect on cardiovascular disease risk,” study coauthor Helen M. Colhoun, MD, of the University of Edinburgh said during the discussion following the presentation.

The REMOVAL (cardiovascular and metabolic effects of metformin in patients with type 1 diabetes) trial took place from 2011 to 2014. Involved researchers at 23 hospital diabetes clinics around the world randomly assigned 428 patients to metformin (n = 219) and placebo (n = 209) arms.

The patients were all 40 years or older, with a mean age of 55 years. All patients had been diagnosed with type 1 diabetes at least five years prior to the study and met at least 3 of 10 criteria for high risk of cardiovascular disease. Men accounted for 59% of the patients, about 98% were white, and about 79% were obese or overweight. Patients had high levels of use of statins (73%), blood pressure medications (73%), and antiplatelet drugs (39%).

Participants took oral metformin 1,000 mg twice daily or placebo. The results were reported at the ADA meeting and simultaneously online on June 11, 2017 in Lancet Diabetes Endocrinology (2017 Jun 11. doi: 10.1016/S2213-8587[17]30194-8).

In regard to CVD indicators, the researchers did not find significant reduction in the progression of average common carotid artery intima-media thickness (cIMT) (–0.005 mm per year; 95% confidence interval, –0.012-0.002; P = .1664) in metformin, vs. placebo.

There was, however, a significant reduction in maximal cIMT (–0.013 mm per year; 95% CI, –0.024 to –0.003; P = .0093). The study describes this as a surrogate measure for atherosclerosis progression, although it’s a tertiary rather than primary outcome.

Researchers saw a slight decline in HbA1c in the metformin group (–0.13%; 95% CI, –0.22 to –0.037; P = .0060), but researchers say this occurred early and was not sustained.

In the metformin group, compared with placebo, researchers also found reductions in body weight (–1.17 kg; 95% CI,–1.66 to –0.69; p less than .0001) and LDL cholesterol (–0.13 mmol/L; 95% CI, –0.24 to –0.03; P = .0117) on average.

Researchers didn’t find a significant average reduction in insulin use in the metformin group, compared with placebo (–0.005 units per kg; 95% CI, –0.022-0.012, P = .545), although they did notice “a small but sustained reduction in patients allocated to metformin (estimated in post-hoc analyses as –0.023 units per kg; 95% CI, –0.045 to –0.0005; P = .045).”

Rates of gastrointestinal problems were higher in the metformin group, and 27% of these patients discontinued treatment, compared with 12% of placebo patients (P = .0002). Five of the metformin patients died (as did two of the placebo patients), but researchers didn’t link the deaths to medication.

The findings were clearly disappointing. “We’re certainly not claiming that this is a positive trial,” said study coauthor Dr. Colhoun.

A member of the audience at the AAD meeting asked another coauthor, Irene Hramiak, MD, of the University of Western Ontario, London, whether she would prescribe metformin to a patient with type 1 diabetes and a high risk of CVD. “Probably not,” she said, but she added that it may have value in adolescents with weight issues. In those cases, she said, there may be a benefit to improving weight control and lowering insulin doses.

In light of the study findings, the authors recommend revising guidelines that suggest the use of metformin in type 1 diabetes: “We identified a transient improvement in glycemia that reverted to baseline with insulin dose reduction and identified no suggestion of greater benefit in overweight or obese patients.”

The study adds, “Rather than a role in glycemic control, our findings suggest that long-term use of metformin in type 1 diabetes might reduce the long-term risk of cardiovascular disease via small but sustained reductions in bodyweight and LDL cholesterol.”

The Juvenile Diabetes Research Foundation funded the study. Merck Germany KGaA provided medication and shipping for free. Itamar Medical donated equipment and services. Dr. Sataar reported consulting fees and/or research support from Amgen, Boehringer Ingelheim, Eli Lilly, Janssen, and Novo Nordisk. Dr. Colhoun and Dr. Hramiak reported multiple disclosures, including advisory panel, research support, and speaker’s bureau and stock/shareholder relationships.

This article was updated June 19, 2017.

SAN DIEGO – As quality measures in health care continue to grow in importance, it behooves endocrinologists to pay more attention to the mental as well as physical well-being of patients with diabetic foot conditions before and after treatment.

“We’re on a path from volume-based practice to really showing that what we’re doing actually works, and diabetic foot is going to be caught up in there. It’s really important that we understand how [the diabetic foot] is affecting our patients physically and mentally. We’ll have to measure what we do and see it if improves,” said Dane K. Wukich, MD, professor and Dr. Charles F. Gregory distinguished chair of the department of orthopedic surgery at University of Texas Southwestern Medical Center, Dallas, in a presentation at the annual scientific sessions of the American Diabetes Association.

Courtesy Dr. Dane K. Wukich

cenews@frontlinemedcom.com

SAN DIEGO – As quality measures in health care continue to grow in importance, it behooves endocrinologists to pay more attention to the mental as well as physical well-being of patients with diabetic foot conditions before and after treatment.

“We’re on a path from volume-based practice to really showing that what we’re doing actually works, and diabetic foot is going to be caught up in there. It’s really important that we understand how [the diabetic foot] is affecting our patients physically and mentally. We’ll have to measure what we do and see it if improves,” said Dane K. Wukich, MD, professor and Dr. Charles F. Gregory distinguished chair of the department of orthopedic surgery at University of Texas Southwestern Medical Center, Dallas, in a presentation at the annual scientific sessions of the American Diabetes Association.

Courtesy Dr. Dane K. Wukich

cenews@frontlinemedcom.com

SAN DIEGO – As quality measures in health care continue to grow in importance, it behooves endocrinologists to pay more attention to the mental as well as physical well-being of patients with diabetic foot conditions before and after treatment.

“We’re on a path from volume-based practice to really showing that what we’re doing actually works, and diabetic foot is going to be caught up in there. It’s really important that we understand how [the diabetic foot] is affecting our patients physically and mentally. We’ll have to measure what we do and see it if improves,” said Dane K. Wukich, MD, professor and Dr. Charles F. Gregory distinguished chair of the department of orthopedic surgery at University of Texas Southwestern Medical Center, Dallas, in a presentation at the annual scientific sessions of the American Diabetes Association.

Courtesy Dr. Dane K. Wukich

cenews@frontlinemedcom.com

SAN DIEGO – Should a man with a distant history of pedophilia be allowed to get a penile prosthetic implant to treat his erectile dysfunction? Mental health professionals at a Veterans Affairs medical center in San Diego recently faced this question and decided the risk was too great. They denied his request.

“This kind of dilemma occurs throughout all health systems, and it’s very challenging. It obviously puts the physician in a very ethically challenging situation,” said Kristin Beizai, MD, a psychiatrist and coauthor of a case report presented at the annual meeting of the American Psychiatric Association.

Yash B. Joshi, MD, PhD, and Dr. Beizai, both psychiatrists at the University of California, San Diego, and the VA San Diego Healthcare System, reported the penile prosthetic implant case in a poster at APA.

According to them, a married veteran sought treatment for erectile dysfunction (ED) from VA hospital urologists after oral treatment had failed. The elderly man, who had been imprisoned for 3 years some 25-30 years previously, sought a penile prosthetic implant – an alternative to treatments for ED when drugs have failed. Other options include self-injections and vacuum devices.

Men with the implants trigger erections by squeezing a pump in the scrotum that allows fluid to flow from a reservoir into the cylinder.

The man had been imprisoned in his 40s for 3 years because of a single incident of sexually abusing a toddler. According to the case report, his primary care doctors previously had offered him ED treatments “without acknowledging this history in their clinical-decision making process.”

A psychologist determined the man to be at low risk of committing a sexual offense again and cleared him for an implant. But his urologists requested an ethics consultation, which was provided by a team that included representatives from the fields of psychiatry, internal medicine, nursing, and social work.

“The ethics team determined that the most appropriate course of action hinged on a thorough and individualized risk-benefit assessment to determine if providing the treatment was ethically justifiable,” Dr. Beizai said in an interview.

An on-site psychologist and an outside expert evaluated the patient using a tool known as the Violence Risk Assessment Instrument–Sexual and determined the man was at moderate to severe risk of committing a sexual offense again.

“It was also discovered that the patient never completed treatment for pedophilia in the community as previously recommended,” the psychiatrists reported. “He was offered a plan for reevaluation and rehabilitation by subspecialists but declined this option.”

The man subsequently died of natural causes.

Dr. Beizai said those kinds of cases present numerous challenges. “This case involves surgery/urology, but this is an issue with primary care as well, and they likely do not have the time, resources, or protocol to address fully, particularly when legal information may be withheld and there are confidentiality issues.”

In regard to a risk-benefit analysis, she said, “a general mental health practitioner may not be comfortable completing this kind of assessment, and there may be an indication to refer to a forensic psychiatrist or psychologist. But this can be an expensive and scarce resource.”

There’s also the potential for political storms if the news gets out that a convicted sex offender received ED treatment. News reports in the mid-2000s about this kind of care persuaded several states to ban government payments for ED treatment for convicted sex offenders, and Medicaid funding was eliminated.

Two researchers who study pedophilia said in an interview that these decisions are far from simple and must take several factors into account.

Fred S. Berlin, MD, PhD, director of the Sexual Behavior Consultation Unit, and associate professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, said a sexual offense background isn’t necessarily enough of a reason to deny ED treatment to a patient. Important factors for decision making, he said, include the nature of the previous offenses (such as whether they involved penile penetration, or the use of drugs or alcohol) and the state of an offender’s current relationship.

He added that it’s important to understand that the lack of functioning genitals isn’t a barrier to sexual abuse. “There shouldn’t be a narrow focus on the capacity of the penis to have an erection,” he said.

Treatment for ED in convicted sex offenders can be helpful in some cases, said Richard B. Krueger, MD, an associate clinical professor of psychiatry at Columbia University, New York, and medical director of the Sexual Behavior Clinic at New York State Psychiatric Institute. “The general sense is that it would be a benefit to enable an appropriate, peer-related relationship with a spouse, significant other, or adults,” Dr. Krueger said.

Red flags regarding ED treatment in sex offenders, he said, include high scores on predictive tests, a history of extreme sadism or sociopathy, and challenges regarding monitoring of the offender.

Dr. Beizai, Dr. Joshi, Dr. Krueger, and Dr. Berlin reported no relevant disclosures.

[polldaddy:9767052]

SAN DIEGO – Should a man with a distant history of pedophilia be allowed to get a penile prosthetic implant to treat his erectile dysfunction? Mental health professionals at a Veterans Affairs medical center in San Diego recently faced this question and decided the risk was too great. They denied his request.

“This kind of dilemma occurs throughout all health systems, and it’s very challenging. It obviously puts the physician in a very ethically challenging situation,” said Kristin Beizai, MD, a psychiatrist and coauthor of a case report presented at the annual meeting of the American Psychiatric Association.

Yash B. Joshi, MD, PhD, and Dr. Beizai, both psychiatrists at the University of California, San Diego, and the VA San Diego Healthcare System, reported the penile prosthetic implant case in a poster at APA.

According to them, a married veteran sought treatment for erectile dysfunction (ED) from VA hospital urologists after oral treatment had failed. The elderly man, who had been imprisoned for 3 years some 25-30 years previously, sought a penile prosthetic implant – an alternative to treatments for ED when drugs have failed. Other options include self-injections and vacuum devices.

Men with the implants trigger erections by squeezing a pump in the scrotum that allows fluid to flow from a reservoir into the cylinder.

The man had been imprisoned in his 40s for 3 years because of a single incident of sexually abusing a toddler. According to the case report, his primary care doctors previously had offered him ED treatments “without acknowledging this history in their clinical-decision making process.”

A psychologist determined the man to be at low risk of committing a sexual offense again and cleared him for an implant. But his urologists requested an ethics consultation, which was provided by a team that included representatives from the fields of psychiatry, internal medicine, nursing, and social work.

“The ethics team determined that the most appropriate course of action hinged on a thorough and individualized risk-benefit assessment to determine if providing the treatment was ethically justifiable,” Dr. Beizai said in an interview.

An on-site psychologist and an outside expert evaluated the patient using a tool known as the Violence Risk Assessment Instrument–Sexual and determined the man was at moderate to severe risk of committing a sexual offense again.

“It was also discovered that the patient never completed treatment for pedophilia in the community as previously recommended,” the psychiatrists reported. “He was offered a plan for reevaluation and rehabilitation by subspecialists but declined this option.”

The man subsequently died of natural causes.

Dr. Beizai said those kinds of cases present numerous challenges. “This case involves surgery/urology, but this is an issue with primary care as well, and they likely do not have the time, resources, or protocol to address fully, particularly when legal information may be withheld and there are confidentiality issues.”

In regard to a risk-benefit analysis, she said, “a general mental health practitioner may not be comfortable completing this kind of assessment, and there may be an indication to refer to a forensic psychiatrist or psychologist. But this can be an expensive and scarce resource.”

There’s also the potential for political storms if the news gets out that a convicted sex offender received ED treatment. News reports in the mid-2000s about this kind of care persuaded several states to ban government payments for ED treatment for convicted sex offenders, and Medicaid funding was eliminated.

Two researchers who study pedophilia said in an interview that these decisions are far from simple and must take several factors into account.

Fred S. Berlin, MD, PhD, director of the Sexual Behavior Consultation Unit, and associate professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, said a sexual offense background isn’t necessarily enough of a reason to deny ED treatment to a patient. Important factors for decision making, he said, include the nature of the previous offenses (such as whether they involved penile penetration, or the use of drugs or alcohol) and the state of an offender’s current relationship.

He added that it’s important to understand that the lack of functioning genitals isn’t a barrier to sexual abuse. “There shouldn’t be a narrow focus on the capacity of the penis to have an erection,” he said.

Treatment for ED in convicted sex offenders can be helpful in some cases, said Richard B. Krueger, MD, an associate clinical professor of psychiatry at Columbia University, New York, and medical director of the Sexual Behavior Clinic at New York State Psychiatric Institute. “The general sense is that it would be a benefit to enable an appropriate, peer-related relationship with a spouse, significant other, or adults,” Dr. Krueger said.

Red flags regarding ED treatment in sex offenders, he said, include high scores on predictive tests, a history of extreme sadism or sociopathy, and challenges regarding monitoring of the offender.

Dr. Beizai, Dr. Joshi, Dr. Krueger, and Dr. Berlin reported no relevant disclosures.

[polldaddy:9767052]

SAN DIEGO – Should a man with a distant history of pedophilia be allowed to get a penile prosthetic implant to treat his erectile dysfunction? Mental health professionals at a Veterans Affairs medical center in San Diego recently faced this question and decided the risk was too great. They denied his request.

“This kind of dilemma occurs throughout all health systems, and it’s very challenging. It obviously puts the physician in a very ethically challenging situation,” said Kristin Beizai, MD, a psychiatrist and coauthor of a case report presented at the annual meeting of the American Psychiatric Association.

Yash B. Joshi, MD, PhD, and Dr. Beizai, both psychiatrists at the University of California, San Diego, and the VA San Diego Healthcare System, reported the penile prosthetic implant case in a poster at APA.

According to them, a married veteran sought treatment for erectile dysfunction (ED) from VA hospital urologists after oral treatment had failed. The elderly man, who had been imprisoned for 3 years some 25-30 years previously, sought a penile prosthetic implant – an alternative to treatments for ED when drugs have failed. Other options include self-injections and vacuum devices.

Men with the implants trigger erections by squeezing a pump in the scrotum that allows fluid to flow from a reservoir into the cylinder.

The man had been imprisoned in his 40s for 3 years because of a single incident of sexually abusing a toddler. According to the case report, his primary care doctors previously had offered him ED treatments “without acknowledging this history in their clinical-decision making process.”

A psychologist determined the man to be at low risk of committing a sexual offense again and cleared him for an implant. But his urologists requested an ethics consultation, which was provided by a team that included representatives from the fields of psychiatry, internal medicine, nursing, and social work.

“The ethics team determined that the most appropriate course of action hinged on a thorough and individualized risk-benefit assessment to determine if providing the treatment was ethically justifiable,” Dr. Beizai said in an interview.

An on-site psychologist and an outside expert evaluated the patient using a tool known as the Violence Risk Assessment Instrument–Sexual and determined the man was at moderate to severe risk of committing a sexual offense again.

“It was also discovered that the patient never completed treatment for pedophilia in the community as previously recommended,” the psychiatrists reported. “He was offered a plan for reevaluation and rehabilitation by subspecialists but declined this option.”

The man subsequently died of natural causes.

Dr. Beizai said those kinds of cases present numerous challenges. “This case involves surgery/urology, but this is an issue with primary care as well, and they likely do not have the time, resources, or protocol to address fully, particularly when legal information may be withheld and there are confidentiality issues.”

In regard to a risk-benefit analysis, she said, “a general mental health practitioner may not be comfortable completing this kind of assessment, and there may be an indication to refer to a forensic psychiatrist or psychologist. But this can be an expensive and scarce resource.”

There’s also the potential for political storms if the news gets out that a convicted sex offender received ED treatment. News reports in the mid-2000s about this kind of care persuaded several states to ban government payments for ED treatment for convicted sex offenders, and Medicaid funding was eliminated.

Two researchers who study pedophilia said in an interview that these decisions are far from simple and must take several factors into account.

Fred S. Berlin, MD, PhD, director of the Sexual Behavior Consultation Unit, and associate professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, said a sexual offense background isn’t necessarily enough of a reason to deny ED treatment to a patient. Important factors for decision making, he said, include the nature of the previous offenses (such as whether they involved penile penetration, or the use of drugs or alcohol) and the state of an offender’s current relationship.

He added that it’s important to understand that the lack of functioning genitals isn’t a barrier to sexual abuse. “There shouldn’t be a narrow focus on the capacity of the penis to have an erection,” he said.

Treatment for ED in convicted sex offenders can be helpful in some cases, said Richard B. Krueger, MD, an associate clinical professor of psychiatry at Columbia University, New York, and medical director of the Sexual Behavior Clinic at New York State Psychiatric Institute. “The general sense is that it would be a benefit to enable an appropriate, peer-related relationship with a spouse, significant other, or adults,” Dr. Krueger said.

Red flags regarding ED treatment in sex offenders, he said, include high scores on predictive tests, a history of extreme sadism or sociopathy, and challenges regarding monitoring of the offender.

Dr. Beizai, Dr. Joshi, Dr. Krueger, and Dr. Berlin reported no relevant disclosures.

[polldaddy:9767052]

BOSTON – Two phase III trials of the investigational monoclonal antibody erenumab show promising results in reducing – but not eliminating – days affected by migraines and related disruptions in daily life with limited side effects, representing “an entirely new way forward” in migraine prevention, according to Peter Goadsby, MD.

In May, shortly after the results were released at the annual meeting of the American Academy of Neurology, Amgen filed regulatory documents for erenumab with the Food and Drug Administration.

Erenumab, also known as AMG 334, “is going to be the first mechanism-specific, migraine-targeted preventive treatment approach ever,” Dr. Goadsby, a University of California, San Francisco, neurologist, predicted at the annual meeting of the American Academy of Neurology. Erenumab is a fully human monoclonal antibody that is designed to block the calcitonin gene-related peptide (CGRP) receptor, which is linked to migraine.

Several drug makers are investigating CGRP-modulating treatments for migraine. Results suggest that the medications are “effective for episodic and migraine patients,” said Amaal Starling, MD, of the Mayo Clinic, Scottsdale, Ariz., who spoke about the drugs in a plenary session at the meeting. “They have rapid onset of efficacy, minimal side effects, and infrequent administration. All of these things may improve adherence.”

Dr. Goadsby is the lead author of the study reporting phase III results from the 24-week STRIVE trial, which tested two monthly subcutaneous doses of erenumab (70 mg and 140 mg) against placebo in a 1:1:1 ratio in 955 patients. The patients all had suffered from episodic migraine for at least a year.

“STRIVE has shown that the 70-mg and 140-mg doses are better than placebo at the regulatory endpoint and clinically relevant endpoints,” Dr. Goadsby said, “and there are improvements in function, everyday activities, and physical impairment. The overall frequency of adverse and serious events were comparable, even the same.”

The participants reported an average of 8.3 monthly migraine days (MMDs) at the beginning of the study. At the end, the number declined significantly by an average of 3.2 days (70-mg dose), 3.7 days (140-mg dose), and 1.8 days (placebo; P less than .001).

Half of those in the 140-mg group achieved at least a 50% reduction in MMDs, compared with 43% and 27% for the 70-mg and placebo groups, respectively (P less than .001).

The researchers also examined changes in scores regarding Physical Impairment (PI) and Impact on Everyday Activities (EA) as determined by the Migraine Physical Function Impact Diary. PI scores improved by 4.2, 4.8, and 2.4 points in the 70-mg, 140-mg, and placebo groups, respectively. EA scores improved by 5.5, 5.9, and 3.3 points, respectively (P less than .001).

The study authors reported that tolerability was similar for placebo and the drug. The most common adverse events were nasopharyngitis, upper respiratory tract infection, and sinusitis.

The researchers at the AAN meeting also released the results of a second study known as ARISE, led by David W. Dodick, MD, of the Mayo Clinic, Phoenix, Ariz. This double-blind, 12-week trial randomly assigned 577 adults with episodic migraine to a monthly subcutaneous dose of a placebo or 70 mg of erenumab.

The patients reported an average of 8.3 MMDs at the beginning of the trial. Those who took the medication reported an average 2.9 fewer MMDs while those who took the placebo reported 1.8 fewer MMDs (P less than .001) at 9-12 weeks.

Forty percent of those who took the drug saw a decrease of at least half in MMDs, compared with 30% of those who took placebo (odds ratio, 1.6; P = .010).

The PI levels declined by at least 5 points in 27% of placebo patients and 33% of erenumab patients (P = .13). EA levels declined by at least 5 points in 36% of placebo patients and 40% of erenumab patients (P = .26)

There were similar levels of adverse events in both drug and placebo groups, led by upper respiratory tract infection, injection site pain, and nasopharyngitis.

The Mayo Clinic’s Dr. Starling said anti-CGRP medications may dramatically improve the world of preventive migraine treatments, which are recommended for a third of migraine patients. Only about 3%-13% use them, she said.

In the future, it may be possible to be able to identify and target “super-responders” whose MMDs dip by 75% or more in some cases.

But there are questions, she said. The drugs’ specific mechanism for blocking migraine is not yet clear, and it’s also not clear if the CGRP antagonists could push patients at risk of TIA or cardiac angina to have a stroke instead.

Dr. Starling discussed some of the implications of the CGRP antagonists in development in a video interview.

Both studies were funded by Amgen. Dr. Goadsby reported numerous grants and personal fees from multiple drug makers, including Amgen. Dr. Starling reported support from Amgen, eNeura, and Eli Lilly. Dr. Dodick disclosed many relationships with pharmaceutical companies developing or marketing drugs for headache and migraine, including Amgen.

BOSTON – Two phase III trials of the investigational monoclonal antibody erenumab show promising results in reducing – but not eliminating – days affected by migraines and related disruptions in daily life with limited side effects, representing “an entirely new way forward” in migraine prevention, according to Peter Goadsby, MD.

In May, shortly after the results were released at the annual meeting of the American Academy of Neurology, Amgen filed regulatory documents for erenumab with the Food and Drug Administration.

Erenumab, also known as AMG 334, “is going to be the first mechanism-specific, migraine-targeted preventive treatment approach ever,” Dr. Goadsby, a University of California, San Francisco, neurologist, predicted at the annual meeting of the American Academy of Neurology. Erenumab is a fully human monoclonal antibody that is designed to block the calcitonin gene-related peptide (CGRP) receptor, which is linked to migraine.

Several drug makers are investigating CGRP-modulating treatments for migraine. Results suggest that the medications are “effective for episodic and migraine patients,” said Amaal Starling, MD, of the Mayo Clinic, Scottsdale, Ariz., who spoke about the drugs in a plenary session at the meeting. “They have rapid onset of efficacy, minimal side effects, and infrequent administration. All of these things may improve adherence.”

Dr. Goadsby is the lead author of the study reporting phase III results from the 24-week STRIVE trial, which tested two monthly subcutaneous doses of erenumab (70 mg and 140 mg) against placebo in a 1:1:1 ratio in 955 patients. The patients all had suffered from episodic migraine for at least a year.

“STRIVE has shown that the 70-mg and 140-mg doses are better than placebo at the regulatory endpoint and clinically relevant endpoints,” Dr. Goadsby said, “and there are improvements in function, everyday activities, and physical impairment. The overall frequency of adverse and serious events were comparable, even the same.”

The participants reported an average of 8.3 monthly migraine days (MMDs) at the beginning of the study. At the end, the number declined significantly by an average of 3.2 days (70-mg dose), 3.7 days (140-mg dose), and 1.8 days (placebo; P less than .001).

Half of those in the 140-mg group achieved at least a 50% reduction in MMDs, compared with 43% and 27% for the 70-mg and placebo groups, respectively (P less than .001).

The researchers also examined changes in scores regarding Physical Impairment (PI) and Impact on Everyday Activities (EA) as determined by the Migraine Physical Function Impact Diary. PI scores improved by 4.2, 4.8, and 2.4 points in the 70-mg, 140-mg, and placebo groups, respectively. EA scores improved by 5.5, 5.9, and 3.3 points, respectively (P less than .001).

The study authors reported that tolerability was similar for placebo and the drug. The most common adverse events were nasopharyngitis, upper respiratory tract infection, and sinusitis.

The researchers at the AAN meeting also released the results of a second study known as ARISE, led by David W. Dodick, MD, of the Mayo Clinic, Phoenix, Ariz. This double-blind, 12-week trial randomly assigned 577 adults with episodic migraine to a monthly subcutaneous dose of a placebo or 70 mg of erenumab.

The patients reported an average of 8.3 MMDs at the beginning of the trial. Those who took the medication reported an average 2.9 fewer MMDs while those who took the placebo reported 1.8 fewer MMDs (P less than .001) at 9-12 weeks.

Forty percent of those who took the drug saw a decrease of at least half in MMDs, compared with 30% of those who took placebo (odds ratio, 1.6; P = .010).

The PI levels declined by at least 5 points in 27% of placebo patients and 33% of erenumab patients (P = .13). EA levels declined by at least 5 points in 36% of placebo patients and 40% of erenumab patients (P = .26)

There were similar levels of adverse events in both drug and placebo groups, led by upper respiratory tract infection, injection site pain, and nasopharyngitis.

The Mayo Clinic’s Dr. Starling said anti-CGRP medications may dramatically improve the world of preventive migraine treatments, which are recommended for a third of migraine patients. Only about 3%-13% use them, she said.

In the future, it may be possible to be able to identify and target “super-responders” whose MMDs dip by 75% or more in some cases.

But there are questions, she said. The drugs’ specific mechanism for blocking migraine is not yet clear, and it’s also not clear if the CGRP antagonists could push patients at risk of TIA or cardiac angina to have a stroke instead.

Dr. Starling discussed some of the implications of the CGRP antagonists in development in a video interview.

Both studies were funded by Amgen. Dr. Goadsby reported numerous grants and personal fees from multiple drug makers, including Amgen. Dr. Starling reported support from Amgen, eNeura, and Eli Lilly. Dr. Dodick disclosed many relationships with pharmaceutical companies developing or marketing drugs for headache and migraine, including Amgen.

BOSTON – Two phase III trials of the investigational monoclonal antibody erenumab show promising results in reducing – but not eliminating – days affected by migraines and related disruptions in daily life with limited side effects, representing “an entirely new way forward” in migraine prevention, according to Peter Goadsby, MD.

In May, shortly after the results were released at the annual meeting of the American Academy of Neurology, Amgen filed regulatory documents for erenumab with the Food and Drug Administration.

Erenumab, also known as AMG 334, “is going to be the first mechanism-specific, migraine-targeted preventive treatment approach ever,” Dr. Goadsby, a University of California, San Francisco, neurologist, predicted at the annual meeting of the American Academy of Neurology. Erenumab is a fully human monoclonal antibody that is designed to block the calcitonin gene-related peptide (CGRP) receptor, which is linked to migraine.

Several drug makers are investigating CGRP-modulating treatments for migraine. Results suggest that the medications are “effective for episodic and migraine patients,” said Amaal Starling, MD, of the Mayo Clinic, Scottsdale, Ariz., who spoke about the drugs in a plenary session at the meeting. “They have rapid onset of efficacy, minimal side effects, and infrequent administration. All of these things may improve adherence.”

Dr. Goadsby is the lead author of the study reporting phase III results from the 24-week STRIVE trial, which tested two monthly subcutaneous doses of erenumab (70 mg and 140 mg) against placebo in a 1:1:1 ratio in 955 patients. The patients all had suffered from episodic migraine for at least a year.

“STRIVE has shown that the 70-mg and 140-mg doses are better than placebo at the regulatory endpoint and clinically relevant endpoints,” Dr. Goadsby said, “and there are improvements in function, everyday activities, and physical impairment. The overall frequency of adverse and serious events were comparable, even the same.”

The participants reported an average of 8.3 monthly migraine days (MMDs) at the beginning of the study. At the end, the number declined significantly by an average of 3.2 days (70-mg dose), 3.7 days (140-mg dose), and 1.8 days (placebo; P less than .001).

Half of those in the 140-mg group achieved at least a 50% reduction in MMDs, compared with 43% and 27% for the 70-mg and placebo groups, respectively (P less than .001).

The researchers also examined changes in scores regarding Physical Impairment (PI) and Impact on Everyday Activities (EA) as determined by the Migraine Physical Function Impact Diary. PI scores improved by 4.2, 4.8, and 2.4 points in the 70-mg, 140-mg, and placebo groups, respectively. EA scores improved by 5.5, 5.9, and 3.3 points, respectively (P less than .001).

The study authors reported that tolerability was similar for placebo and the drug. The most common adverse events were nasopharyngitis, upper respiratory tract infection, and sinusitis.

The researchers at the AAN meeting also released the results of a second study known as ARISE, led by David W. Dodick, MD, of the Mayo Clinic, Phoenix, Ariz. This double-blind, 12-week trial randomly assigned 577 adults with episodic migraine to a monthly subcutaneous dose of a placebo or 70 mg of erenumab.

The patients reported an average of 8.3 MMDs at the beginning of the trial. Those who took the medication reported an average 2.9 fewer MMDs while those who took the placebo reported 1.8 fewer MMDs (P less than .001) at 9-12 weeks.

Forty percent of those who took the drug saw a decrease of at least half in MMDs, compared with 30% of those who took placebo (odds ratio, 1.6; P = .010).

The PI levels declined by at least 5 points in 27% of placebo patients and 33% of erenumab patients (P = .13). EA levels declined by at least 5 points in 36% of placebo patients and 40% of erenumab patients (P = .26)

There were similar levels of adverse events in both drug and placebo groups, led by upper respiratory tract infection, injection site pain, and nasopharyngitis.

The Mayo Clinic’s Dr. Starling said anti-CGRP medications may dramatically improve the world of preventive migraine treatments, which are recommended for a third of migraine patients. Only about 3%-13% use them, she said.

In the future, it may be possible to be able to identify and target “super-responders” whose MMDs dip by 75% or more in some cases.

But there are questions, she said. The drugs’ specific mechanism for blocking migraine is not yet clear, and it’s also not clear if the CGRP antagonists could push patients at risk of TIA or cardiac angina to have a stroke instead.

Dr. Starling discussed some of the implications of the CGRP antagonists in development in a video interview.

Both studies were funded by Amgen. Dr. Goadsby reported numerous grants and personal fees from multiple drug makers, including Amgen. Dr. Starling reported support from Amgen, eNeura, and Eli Lilly. Dr. Dodick disclosed many relationships with pharmaceutical companies developing or marketing drugs for headache and migraine, including Amgen.

SAN DIEGO – A new meta-analysis suggests that second-generation long-acting injectable antipsychotics (LAIs) are slightly better than oral antipsychotics at preventing relapse after a first psychotic incident.

The meta-analysis, released at the annual meeting of the American Psychiatric Association, is limited because it looks at only three studies. Still, study lead author Christine Tran-Boynes, DO, said the findings are useful for psychiatrists.

“For a long time, LAIs were associated with severely ill psychotic patients who were frequently hospitalized and not compliant with their oral meds,” Dr. Tran-Boynes, a resident at the University of Maryland, Baltimore, said in an interview. “The purpose of this paper is to change the perception of LAIs. They are not just a medication of last resort in those with severe, chronic psychosis but, instead, can be used in the early stages of psychosis as prophylaxis against relapse.”

Injectable antipsychotics are more commonly used in Europe, where “there also seemed to be a greater willingness among patients to receive this treatment,” said Peter F. Buckley, MD, dean of the medical school at Virginia Commonwealth University, Richmond.

The APA’s schizophrenia treatment guidelines recommend LAIs for patients with “recurrent relapses related to nonadherence” and patients who prefer the shots. Dr. Tran-Boynes notes that “the most common cause of relapse in patients with schizophrenia is partial adherence or nonadherence to oral antipsychotics. If LAIs can improve adherence in patients and monitoring of adherence for clinicians, they could have a role in preventing relapse during this critical period in psychosis.”

The meta-analysis examines three randomized controlled studies – two from 2015 and one from 2013 – that compare second-generation LAIs to first- and second-generation oral antipsychotics after first episodes of psychosis. Dr. Tran-Boynes said researchers could not find any studies comparing first-generation long-acting antipsychotics to oral antipsychotics.

The largest study had 769 participants; the others had 85 and 86. The subjects, all adults, had diagnoses of schizophrenia, schizoaffective disorder, or schizophreniform disorder. Their diagnoses must have been made within the previous 5 years.

According to the meta-analysis, relapses after first-episode psychosis were more likely (relative risk, 1.078; 95% confidence interval, 1.007-1.154; P = 0.012) in patients taking first- or second-generation oral antipsychotics, compared with those on second-generation LAIs.

“There was an 8% greater efficacy for LAIs preventing relapse after early psychosis, compared to oral antipsychotics,” Dr. Tran-Boynes said. She calculated the number needed to treat as 14.

The percentages of patients who did not relapse while taking second-generation LAIs ranged from 73% (31 of 42 patients randomized to an injectable risperidone arm over 24 months) to 95% (38 of 40 patients over a 12-month study, also of injectable risperidone), Dr. Tran-Boynes said.

When asked about the meta-analysis, Robert Rosenheck, MD, expressed concern.

“While well done, it is based on too few studies to give useful guidance to practice,” said Dr. Rosenheck, professor of psychiatry, epidemiology and public health at Yale University, New Haven, Conn.

Dr. Buckley also noted that the meta-analysis includes a small number of studies. “The effect is sizable for a first-episode population, but other studies to date are more mixed,” he added. “For instance, in a study among a more chronic schizophrenic population, we found no difference between a group receiving long-acting injectable risperidone and oral second-generation antipsychotics” (Schizophr Bull. 2015 Mar;41[2]:449-59).

What should psychiatrists know when they consider prescribing LAIs to prevent psychotic relapse? “If a patient expresses willingness to take an oral antipsychotic on a daily basis and/or has someone to monitor his medication intake, then prescribing an oral antipsychotic would be the ideal route,” Dr. Tran-Boynes said. “However, I would recommend LAIs to patients who have demonstrated poor compliance with previous medications in general, poor awareness of psychosis, poor awareness of need for treatment, poor availability of social support to ensure that the patient will take his/her medication daily, and/or if a patient expresses preference for LAIs.”

She cautioned that LAIs have disadvantages. Compared with oral antipsychotics, it’s harder to adjust patients’ dosages in response to side effects or when they improve, she said. LAIs are also more expensive in the short term, she said.

However, LAIs also may have produced fewer side effects, and there aren’t any questions about compliance, she said. In addition, “there’s less pain at the injection site with second-generation LAIs, compared to first-generation LAIs, due to the water-based solution of the former. The oil-based solutions that are characteristic of first-generation LAIs have been shown in studies to be very painful.”

Dr. Tran-Boynes and Dr. Rosenheck reported no relevant disclosures. Dr. Buckley disclosed that he is a research consultant for the National Institute of Mental Health.

SAN DIEGO – A new meta-analysis suggests that second-generation long-acting injectable antipsychotics (LAIs) are slightly better than oral antipsychotics at preventing relapse after a first psychotic incident.

The meta-analysis, released at the annual meeting of the American Psychiatric Association, is limited because it looks at only three studies. Still, study lead author Christine Tran-Boynes, DO, said the findings are useful for psychiatrists.

“For a long time, LAIs were associated with severely ill psychotic patients who were frequently hospitalized and not compliant with their oral meds,” Dr. Tran-Boynes, a resident at the University of Maryland, Baltimore, said in an interview. “The purpose of this paper is to change the perception of LAIs. They are not just a medication of last resort in those with severe, chronic psychosis but, instead, can be used in the early stages of psychosis as prophylaxis against relapse.”

Injectable antipsychotics are more commonly used in Europe, where “there also seemed to be a greater willingness among patients to receive this treatment,” said Peter F. Buckley, MD, dean of the medical school at Virginia Commonwealth University, Richmond.

The APA’s schizophrenia treatment guidelines recommend LAIs for patients with “recurrent relapses related to nonadherence” and patients who prefer the shots. Dr. Tran-Boynes notes that “the most common cause of relapse in patients with schizophrenia is partial adherence or nonadherence to oral antipsychotics. If LAIs can improve adherence in patients and monitoring of adherence for clinicians, they could have a role in preventing relapse during this critical period in psychosis.”

The meta-analysis examines three randomized controlled studies – two from 2015 and one from 2013 – that compare second-generation LAIs to first- and second-generation oral antipsychotics after first episodes of psychosis. Dr. Tran-Boynes said researchers could not find any studies comparing first-generation long-acting antipsychotics to oral antipsychotics.

The largest study had 769 participants; the others had 85 and 86. The subjects, all adults, had diagnoses of schizophrenia, schizoaffective disorder, or schizophreniform disorder. Their diagnoses must have been made within the previous 5 years.

According to the meta-analysis, relapses after first-episode psychosis were more likely (relative risk, 1.078; 95% confidence interval, 1.007-1.154; P = 0.012) in patients taking first- or second-generation oral antipsychotics, compared with those on second-generation LAIs.

“There was an 8% greater efficacy for LAIs preventing relapse after early psychosis, compared to oral antipsychotics,” Dr. Tran-Boynes said. She calculated the number needed to treat as 14.

The percentages of patients who did not relapse while taking second-generation LAIs ranged from 73% (31 of 42 patients randomized to an injectable risperidone arm over 24 months) to 95% (38 of 40 patients over a 12-month study, also of injectable risperidone), Dr. Tran-Boynes said.

When asked about the meta-analysis, Robert Rosenheck, MD, expressed concern.

“While well done, it is based on too few studies to give useful guidance to practice,” said Dr. Rosenheck, professor of psychiatry, epidemiology and public health at Yale University, New Haven, Conn.

Dr. Buckley also noted that the meta-analysis includes a small number of studies. “The effect is sizable for a first-episode population, but other studies to date are more mixed,” he added. “For instance, in a study among a more chronic schizophrenic population, we found no difference between a group receiving long-acting injectable risperidone and oral second-generation antipsychotics” (Schizophr Bull. 2015 Mar;41[2]:449-59).

What should psychiatrists know when they consider prescribing LAIs to prevent psychotic relapse? “If a patient expresses willingness to take an oral antipsychotic on a daily basis and/or has someone to monitor his medication intake, then prescribing an oral antipsychotic would be the ideal route,” Dr. Tran-Boynes said. “However, I would recommend LAIs to patients who have demonstrated poor compliance with previous medications in general, poor awareness of psychosis, poor awareness of need for treatment, poor availability of social support to ensure that the patient will take his/her medication daily, and/or if a patient expresses preference for LAIs.”

She cautioned that LAIs have disadvantages. Compared with oral antipsychotics, it’s harder to adjust patients’ dosages in response to side effects or when they improve, she said. LAIs are also more expensive in the short term, she said.

However, LAIs also may have produced fewer side effects, and there aren’t any questions about compliance, she said. In addition, “there’s less pain at the injection site with second-generation LAIs, compared to first-generation LAIs, due to the water-based solution of the former. The oil-based solutions that are characteristic of first-generation LAIs have been shown in studies to be very painful.”

Dr. Tran-Boynes and Dr. Rosenheck reported no relevant disclosures. Dr. Buckley disclosed that he is a research consultant for the National Institute of Mental Health.

SAN DIEGO – A new meta-analysis suggests that second-generation long-acting injectable antipsychotics (LAIs) are slightly better than oral antipsychotics at preventing relapse after a first psychotic incident.

The meta-analysis, released at the annual meeting of the American Psychiatric Association, is limited because it looks at only three studies. Still, study lead author Christine Tran-Boynes, DO, said the findings are useful for psychiatrists.

“For a long time, LAIs were associated with severely ill psychotic patients who were frequently hospitalized and not compliant with their oral meds,” Dr. Tran-Boynes, a resident at the University of Maryland, Baltimore, said in an interview. “The purpose of this paper is to change the perception of LAIs. They are not just a medication of last resort in those with severe, chronic psychosis but, instead, can be used in the early stages of psychosis as prophylaxis against relapse.”

Injectable antipsychotics are more commonly used in Europe, where “there also seemed to be a greater willingness among patients to receive this treatment,” said Peter F. Buckley, MD, dean of the medical school at Virginia Commonwealth University, Richmond.

The APA’s schizophrenia treatment guidelines recommend LAIs for patients with “recurrent relapses related to nonadherence” and patients who prefer the shots. Dr. Tran-Boynes notes that “the most common cause of relapse in patients with schizophrenia is partial adherence or nonadherence to oral antipsychotics. If LAIs can improve adherence in patients and monitoring of adherence for clinicians, they could have a role in preventing relapse during this critical period in psychosis.”

The meta-analysis examines three randomized controlled studies – two from 2015 and one from 2013 – that compare second-generation LAIs to first- and second-generation oral antipsychotics after first episodes of psychosis. Dr. Tran-Boynes said researchers could not find any studies comparing first-generation long-acting antipsychotics to oral antipsychotics.

The largest study had 769 participants; the others had 85 and 86. The subjects, all adults, had diagnoses of schizophrenia, schizoaffective disorder, or schizophreniform disorder. Their diagnoses must have been made within the previous 5 years.

According to the meta-analysis, relapses after first-episode psychosis were more likely (relative risk, 1.078; 95% confidence interval, 1.007-1.154; P = 0.012) in patients taking first- or second-generation oral antipsychotics, compared with those on second-generation LAIs.

“There was an 8% greater efficacy for LAIs preventing relapse after early psychosis, compared to oral antipsychotics,” Dr. Tran-Boynes said. She calculated the number needed to treat as 14.

The percentages of patients who did not relapse while taking second-generation LAIs ranged from 73% (31 of 42 patients randomized to an injectable risperidone arm over 24 months) to 95% (38 of 40 patients over a 12-month study, also of injectable risperidone), Dr. Tran-Boynes said.

When asked about the meta-analysis, Robert Rosenheck, MD, expressed concern.

“While well done, it is based on too few studies to give useful guidance to practice,” said Dr. Rosenheck, professor of psychiatry, epidemiology and public health at Yale University, New Haven, Conn.

Dr. Buckley also noted that the meta-analysis includes a small number of studies. “The effect is sizable for a first-episode population, but other studies to date are more mixed,” he added. “For instance, in a study among a more chronic schizophrenic population, we found no difference between a group receiving long-acting injectable risperidone and oral second-generation antipsychotics” (Schizophr Bull. 2015 Mar;41[2]:449-59).

What should psychiatrists know when they consider prescribing LAIs to prevent psychotic relapse? “If a patient expresses willingness to take an oral antipsychotic on a daily basis and/or has someone to monitor his medication intake, then prescribing an oral antipsychotic would be the ideal route,” Dr. Tran-Boynes said. “However, I would recommend LAIs to patients who have demonstrated poor compliance with previous medications in general, poor awareness of psychosis, poor awareness of need for treatment, poor availability of social support to ensure that the patient will take his/her medication daily, and/or if a patient expresses preference for LAIs.”

She cautioned that LAIs have disadvantages. Compared with oral antipsychotics, it’s harder to adjust patients’ dosages in response to side effects or when they improve, she said. LAIs are also more expensive in the short term, she said.

However, LAIs also may have produced fewer side effects, and there aren’t any questions about compliance, she said. In addition, “there’s less pain at the injection site with second-generation LAIs, compared to first-generation LAIs, due to the water-based solution of the former. The oil-based solutions that are characteristic of first-generation LAIs have been shown in studies to be very painful.”

Dr. Tran-Boynes and Dr. Rosenheck reported no relevant disclosures. Dr. Buckley disclosed that he is a research consultant for the National Institute of Mental Health.

SAN DIEGO – Injuries and lawsuits related to laser cosmetic surgery are increasing and potential legal threats are not always easy to predict, according to two dermatologists who spoke at the annual meeting of the American Society for Laser Medicine and Surgery (ASLMS).

A laser procedure could go smoothly, for example, but the patient might be able to successfully sue if he or she is allowed to drive home after receiving a sedative. Or a physician might get sued because his or her nurse set a laser at the wrong setting and singed a patient.

The risk of a lawsuit is high, H. Ray Jalian, MD, a dermatologist in Los Angeles, said at the meeting. “The reality is that we’re all at some point going to face this.”

• You may have a duty to protect your patient from bad choices.

Physicians aren’t expected to keep patients from making certain bad decisions such as sunbathing after a traditional resurfacing procedure, said Dr. Avram, of the department of dermatology, Harvard Medical School, Boston, and the ASLMS president. But in some cases, he said, the law may expect the physician to step in to prevent harm. For example, he said, a patient who has undergone a fractional ablative laser procedure and has received a sedative should not be allowed to drive home.

• You may get sued even if your employee is at fault.

The 2013 study found physicians were often sued even when they did not perform the laser procedure in question. Nonphysicians such as physician assistants and nurses often perform laser operations, and many states allow them to do so. “Nonphysicians were less likely to be sued even if they were the operators,” Dr. Jalian said. In the study, almost 38% of the 174 analyzed cases involved nonphysician operators, but they were sued in just 26% of the cases. In 33 of the 174 cases in the study, plaintiffs alleged failure to properly hire, train, or supervise staff.

He recommended looking at state laws, which differ greatly in their regulations – or lack of them – regarding the operation of medical lasers. In some cases, physicians must supervise laser use, he said. “But what are the requirements? Can you be available by phone down the street or in the Caribbean?”

Dr. Jalian, Dr. Avram, and a colleague followed up the 2013 study with another study that tracked 175 legal cases from 1999 to 2012 involving alleged injuries from cutaneous laser surgery. During this time period, 75 (43%) involved a nonphysician operating a laser, increasing from 36% in 2008 to 78% in 2012.

In almost two-thirds of cases, the procedures in question were done by nonphysicians outside a “traditional medical setting” such as a salon or spa (JAMA Dermatol. 2014 Apr;150[4]:407-11).

• Delayed side effects could mean delayed lawsuits.

According to Dr. Avram, statutes of limitations – the length of time in which a patient can file a lawsuit – typically last for 2-3 years in malpractice cases. But he said that the period begins when the physician is alleged to have made a mistake or when the patient becomes aware of – or should reasonably be aware of – an injury. Therefore, physicians could face legal trouble over delayed hypopigmentation that appears 6 months after a laser resurfacing treatment, or granulomas that appear years after a filler treatment, he said.

• A signed form is not a cure-all.

It is wise to make patients sign an extensive informed consent form, but this will not protect a physician against a claim of negligence, Dr. Avram said. And the reverse is also true: If a patient did not sign a proper consent form, he or she could still sue even if the procedure went perfectly, he noted.

• Your instincts are worth trusting.

When it comes to lawsuit prevention, Dr. Avram said, “by far the most important thing you can do happens within a minute of when you see the patient. Assess and trust your own intuition and your staff’s intuition. For elective, cosmetic treatments, don’t be afraid to say no. There’s no legal obligation to perform a cosmetic treatment on a patient.”

If you do choose to treat a patient, he advised, be open about the procedure and “maybe even tell them some of the tougher, worse-case scenarios.” If a procedure goes poorly, he said, consider how to fix it. “Many complications can be significantly improved or cleared with timely and appropriate intervention,” he said.

In some cases, refunding the patient’s money can be considered, with the patient signing a release, he said. “Document that you are refunding the money in order to preserve the doctor-patient relationship, not to avoid negligence.”

Dr. Jalian and Dr. Avram reported no relevant disclosures.

SAN DIEGO – Injuries and lawsuits related to laser cosmetic surgery are increasing and potential legal threats are not always easy to predict, according to two dermatologists who spoke at the annual meeting of the American Society for Laser Medicine and Surgery (ASLMS).

A laser procedure could go smoothly, for example, but the patient might be able to successfully sue if he or she is allowed to drive home after receiving a sedative. Or a physician might get sued because his or her nurse set a laser at the wrong setting and singed a patient.

The risk of a lawsuit is high, H. Ray Jalian, MD, a dermatologist in Los Angeles, said at the meeting. “The reality is that we’re all at some point going to face this.”

• You may have a duty to protect your patient from bad choices.

Physicians aren’t expected to keep patients from making certain bad decisions such as sunbathing after a traditional resurfacing procedure, said Dr. Avram, of the department of dermatology, Harvard Medical School, Boston, and the ASLMS president. But in some cases, he said, the law may expect the physician to step in to prevent harm. For example, he said, a patient who has undergone a fractional ablative laser procedure and has received a sedative should not be allowed to drive home.

• You may get sued even if your employee is at fault.

The 2013 study found physicians were often sued even when they did not perform the laser procedure in question. Nonphysicians such as physician assistants and nurses often perform laser operations, and many states allow them to do so. “Nonphysicians were less likely to be sued even if they were the operators,” Dr. Jalian said. In the study, almost 38% of the 174 analyzed cases involved nonphysician operators, but they were sued in just 26% of the cases. In 33 of the 174 cases in the study, plaintiffs alleged failure to properly hire, train, or supervise staff.

He recommended looking at state laws, which differ greatly in their regulations – or lack of them – regarding the operation of medical lasers. In some cases, physicians must supervise laser use, he said. “But what are the requirements? Can you be available by phone down the street or in the Caribbean?”

Dr. Jalian, Dr. Avram, and a colleague followed up the 2013 study with another study that tracked 175 legal cases from 1999 to 2012 involving alleged injuries from cutaneous laser surgery. During this time period, 75 (43%) involved a nonphysician operating a laser, increasing from 36% in 2008 to 78% in 2012.

In almost two-thirds of cases, the procedures in question were done by nonphysicians outside a “traditional medical setting” such as a salon or spa (JAMA Dermatol. 2014 Apr;150[4]:407-11).

• Delayed side effects could mean delayed lawsuits.

According to Dr. Avram, statutes of limitations – the length of time in which a patient can file a lawsuit – typically last for 2-3 years in malpractice cases. But he said that the period begins when the physician is alleged to have made a mistake or when the patient becomes aware of – or should reasonably be aware of – an injury. Therefore, physicians could face legal trouble over delayed hypopigmentation that appears 6 months after a laser resurfacing treatment, or granulomas that appear years after a filler treatment, he said.

• A signed form is not a cure-all.

It is wise to make patients sign an extensive informed consent form, but this will not protect a physician against a claim of negligence, Dr. Avram said. And the reverse is also true: If a patient did not sign a proper consent form, he or she could still sue even if the procedure went perfectly, he noted.

• Your instincts are worth trusting.

When it comes to lawsuit prevention, Dr. Avram said, “by far the most important thing you can do happens within a minute of when you see the patient. Assess and trust your own intuition and your staff’s intuition. For elective, cosmetic treatments, don’t be afraid to say no. There’s no legal obligation to perform a cosmetic treatment on a patient.”

If you do choose to treat a patient, he advised, be open about the procedure and “maybe even tell them some of the tougher, worse-case scenarios.” If a procedure goes poorly, he said, consider how to fix it. “Many complications can be significantly improved or cleared with timely and appropriate intervention,” he said.

In some cases, refunding the patient’s money can be considered, with the patient signing a release, he said. “Document that you are refunding the money in order to preserve the doctor-patient relationship, not to avoid negligence.”

Dr. Jalian and Dr. Avram reported no relevant disclosures.

SAN DIEGO – Injuries and lawsuits related to laser cosmetic surgery are increasing and potential legal threats are not always easy to predict, according to two dermatologists who spoke at the annual meeting of the American Society for Laser Medicine and Surgery (ASLMS).

A laser procedure could go smoothly, for example, but the patient might be able to successfully sue if he or she is allowed to drive home after receiving a sedative. Or a physician might get sued because his or her nurse set a laser at the wrong setting and singed a patient.

The risk of a lawsuit is high, H. Ray Jalian, MD, a dermatologist in Los Angeles, said at the meeting. “The reality is that we’re all at some point going to face this.”

• You may have a duty to protect your patient from bad choices.

Physicians aren’t expected to keep patients from making certain bad decisions such as sunbathing after a traditional resurfacing procedure, said Dr. Avram, of the department of dermatology, Harvard Medical School, Boston, and the ASLMS president. But in some cases, he said, the law may expect the physician to step in to prevent harm. For example, he said, a patient who has undergone a fractional ablative laser procedure and has received a sedative should not be allowed to drive home.

• You may get sued even if your employee is at fault.

The 2013 study found physicians were often sued even when they did not perform the laser procedure in question. Nonphysicians such as physician assistants and nurses often perform laser operations, and many states allow them to do so. “Nonphysicians were less likely to be sued even if they were the operators,” Dr. Jalian said. In the study, almost 38% of the 174 analyzed cases involved nonphysician operators, but they were sued in just 26% of the cases. In 33 of the 174 cases in the study, plaintiffs alleged failure to properly hire, train, or supervise staff.

He recommended looking at state laws, which differ greatly in their regulations – or lack of them – regarding the operation of medical lasers. In some cases, physicians must supervise laser use, he said. “But what are the requirements? Can you be available by phone down the street or in the Caribbean?”

Dr. Jalian, Dr. Avram, and a colleague followed up the 2013 study with another study that tracked 175 legal cases from 1999 to 2012 involving alleged injuries from cutaneous laser surgery. During this time period, 75 (43%) involved a nonphysician operating a laser, increasing from 36% in 2008 to 78% in 2012.

In almost two-thirds of cases, the procedures in question were done by nonphysicians outside a “traditional medical setting” such as a salon or spa (JAMA Dermatol. 2014 Apr;150[4]:407-11).

• Delayed side effects could mean delayed lawsuits.

According to Dr. Avram, statutes of limitations – the length of time in which a patient can file a lawsuit – typically last for 2-3 years in malpractice cases. But he said that the period begins when the physician is alleged to have made a mistake or when the patient becomes aware of – or should reasonably be aware of – an injury. Therefore, physicians could face legal trouble over delayed hypopigmentation that appears 6 months after a laser resurfacing treatment, or granulomas that appear years after a filler treatment, he said.

• A signed form is not a cure-all.

It is wise to make patients sign an extensive informed consent form, but this will not protect a physician against a claim of negligence, Dr. Avram said. And the reverse is also true: If a patient did not sign a proper consent form, he or she could still sue even if the procedure went perfectly, he noted.

• Your instincts are worth trusting.

When it comes to lawsuit prevention, Dr. Avram said, “by far the most important thing you can do happens within a minute of when you see the patient. Assess and trust your own intuition and your staff’s intuition. For elective, cosmetic treatments, don’t be afraid to say no. There’s no legal obligation to perform a cosmetic treatment on a patient.”

If you do choose to treat a patient, he advised, be open about the procedure and “maybe even tell them some of the tougher, worse-case scenarios.” If a procedure goes poorly, he said, consider how to fix it. “Many complications can be significantly improved or cleared with timely and appropriate intervention,” he said.

In some cases, refunding the patient’s money can be considered, with the patient signing a release, he said. “Document that you are refunding the money in order to preserve the doctor-patient relationship, not to avoid negligence.”

Dr. Jalian and Dr. Avram reported no relevant disclosures.

BOSTON – Last December, the Food and Drug Administration approved nusinersen (Spinraza) as the only treatment for spinal muscular atrophy (SMA) based in part on startling interim results from a study in infants that ended early so all participants could get access to the drug.

Now the final study results are in, and they’re even more impressive: Patients who took the drug were less than half as likely to die as were those in a sham control group, and motor function improved in more than half of infants who took the medication, compared with none in the sham group.

The findings are “incredibly exciting,” said Charlotte J. Sumner, MD, in a discussant presentation at the annual meeting of the American Academy of Neurology. “The data teaches us that this drug is efficacious.”

However, Dr. Sumner, professor of neurology and neuroscience at Johns Hopkins University, Baltimore, cautioned that the drug is tremendously expensive, challenging to administer, and there are several questions about its use that remain unanswered.

SMA is most often caused by mutations in the SMN1 gene, leading to a loss of the protein called survival motor neuron (SMN), which is essential for the survival of motor neurons, except for a small amount produced from the SMN2 gene. The loss of motor neurons in the spinal cord and brainstem leads to weakness and atrophy of muscles used for crawling, walking, sitting up, controlling head movement, and in severe cases, breathing and swallowing. It affects an estimated 1 in 6,000 newborns and is the most common genetic cause of death in infants. Nusinersen is a antisense oligonucleotide that promotes transcription of the full-length SMN protein from the SMN2 gene.

At the AAN meeting, investigators presented the final results of two nusinersen phase III studies as well as interim data from a separate phase II trial.

The ENDEAR trial, a randomized, double-blind, sham-procedure controlled study, assigned 80 patients to 12-mg scaled equivalent doses of nusinersen delivered intrathecally (four doses over 2 months, then one every 4 months) and 41 to a sham procedure (a needle prick in the lower back). The subjects, aged 30-252 days at first dose, underwent 13 months of treatment and follow-up.

Researchers presented an end-of-study analysis of 110 subjects. They found that 51% of those who received the drug were “motor milestone responders” – meaning they had more modified Hammersmith Infant Neurological Examination Section 2 categories with improvement than worsening – compared with 41% at the interim analysis (P less than .0001). None of the sham group patients improved.

The patients treated with nusinersen lived longer: 39% of those in the sham procedure group died, compared with 16% of those in the nusinersen group (hazard ratio, 0.372; P = .0041). Event-free survival (survival without permanent ventilation) was also better in those who received the drugs: 61% in those who took nusinersen, compared with 32% in those who did not (HR, 0.53; P = .0046)

Also, 71% of those treated with the drug were considered responders at day 183 onward based on an improvement of 4 or more points on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale, whereas the response rate was only 3% in the sham group (P less than .0001).

The study authors report that nusinersen was well tolerated with adverse events that “were consistent with those expected in the general population of infants with SMA.” No adverse events were linked to the nusinersen treatment.

Researchers also presented the end-of-study results of the phase III CHERISH trial of 126 patients aged 2-12 years with later-onset SMA who could sit up but not walk. All participants were believed to have a life expectancy of at least 2 years.

The trial is a multicenter, randomized, double-blind, sham-procedure controlled study. The 84 subjects who received the drug improved an average of 3.9 points by the end of study (15 months) on the Hammersmith Functional Motor Scale Expanded score, a measurement of motor function in children with SMA (P = .0000001). The 42 children who received the sham treatment (a small needle prick on the lower back) declined by an average of 1.0 point.

Researchers report that children taking the drug had fewer adverse events, and most were not related to the drug itself.

All surviving participants who completed nusinersen investigational studies are being enrolled in the SHINE open-label extension trial.

Also at the AAN meeting, researchers released interim phase II results from the NURTURE trial, an open-label study of nusinersen in patients with diagnosed but presymptomatic SMA. The study, which is expected to be completed in 2022, recruited participants up to the age of 6 weeks.

The 20 enrolled infants were all alive at a median study period of 317.5 days, and none required assistance with respiration.

In terms of motor function and growth, most were making gains “generally consistent with normal development such as head control, independent sitting, standing and walking independently, as measured by validated scales,” according to a statement released by Biogen.

Three patients developed adverse events that may have been drug related, but the events were resolved and they remained in the trial.

In Dr. Sumner’s discussant presentation on the ENDEAR study, she cautioned that it’s still not known how much older patients with SMA will benefit from the drug treatment. It’s possible that younger patients may gain motor function while older patients will maintain what they have, she said.

In addition, it seems that “certain body segments may respond more robustly than some others. It’s possible that an infant may improve limb strength quite robustly but not lumbar strength.”

She pointed out other questions: Can the drug, which is difficult to administer, be stopped at some point? “We do think of SMA as a disease of development,” she said. “Maybe after development is finished we can withdraw the drug.”

Then there’s the issue of cost and whether insurers are willing to cover the drug. As Dr. Sumner pointed out, the drug is $125,000 per dose and $750,000 over the first year, then $325,000 a year.

It is clear, however, that “the early and efficient diagnosis of SMA is really important, particularly for infantile SMA,” she said. “Time is motor function.”

The studies were funded by Ionis Pharmaceuticals and Biogen. Dr. Sumner reports serving as a consultant for Biogen, Ionis, Avexis, and Roche. She has served on scientific advisory boards for the Cure SMA, SMA Foundation, and Muscular Dystrophy Association nonprofit foundations.

cnnews@frontlinemedcom.com

BOSTON – Last December, the Food and Drug Administration approved nusinersen (Spinraza) as the only treatment for spinal muscular atrophy (SMA) based in part on startling interim results from a study in infants that ended early so all participants could get access to the drug.

Now the final study results are in, and they’re even more impressive: Patients who took the drug were less than half as likely to die as were those in a sham control group, and motor function improved in more than half of infants who took the medication, compared with none in the sham group.

The findings are “incredibly exciting,” said Charlotte J. Sumner, MD, in a discussant presentation at the annual meeting of the American Academy of Neurology. “The data teaches us that this drug is efficacious.”

However, Dr. Sumner, professor of neurology and neuroscience at Johns Hopkins University, Baltimore, cautioned that the drug is tremendously expensive, challenging to administer, and there are several questions about its use that remain unanswered.

SMA is most often caused by mutations in the SMN1 gene, leading to a loss of the protein called survival motor neuron (SMN), which is essential for the survival of motor neurons, except for a small amount produced from the SMN2 gene. The loss of motor neurons in the spinal cord and brainstem leads to weakness and atrophy of muscles used for crawling, walking, sitting up, controlling head movement, and in severe cases, breathing and swallowing. It affects an estimated 1 in 6,000 newborns and is the most common genetic cause of death in infants. Nusinersen is a antisense oligonucleotide that promotes transcription of the full-length SMN protein from the SMN2 gene.

At the AAN meeting, investigators presented the final results of two nusinersen phase III studies as well as interim data from a separate phase II trial.

The ENDEAR trial, a randomized, double-blind, sham-procedure controlled study, assigned 80 patients to 12-mg scaled equivalent doses of nusinersen delivered intrathecally (four doses over 2 months, then one every 4 months) and 41 to a sham procedure (a needle prick in the lower back). The subjects, aged 30-252 days at first dose, underwent 13 months of treatment and follow-up.

Researchers presented an end-of-study analysis of 110 subjects. They found that 51% of those who received the drug were “motor milestone responders” – meaning they had more modified Hammersmith Infant Neurological Examination Section 2 categories with improvement than worsening – compared with 41% at the interim analysis (P less than .0001). None of the sham group patients improved.

The patients treated with nusinersen lived longer: 39% of those in the sham procedure group died, compared with 16% of those in the nusinersen group (hazard ratio, 0.372; P = .0041). Event-free survival (survival without permanent ventilation) was also better in those who received the drugs: 61% in those who took nusinersen, compared with 32% in those who did not (HR, 0.53; P = .0046)

Also, 71% of those treated with the drug were considered responders at day 183 onward based on an improvement of 4 or more points on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale, whereas the response rate was only 3% in the sham group (P less than .0001).

The study authors report that nusinersen was well tolerated with adverse events that “were consistent with those expected in the general population of infants with SMA.” No adverse events were linked to the nusinersen treatment.

Researchers also presented the end-of-study results of the phase III CHERISH trial of 126 patients aged 2-12 years with later-onset SMA who could sit up but not walk. All participants were believed to have a life expectancy of at least 2 years.

The trial is a multicenter, randomized, double-blind, sham-procedure controlled study. The 84 subjects who received the drug improved an average of 3.9 points by the end of study (15 months) on the Hammersmith Functional Motor Scale Expanded score, a measurement of motor function in children with SMA (P = .0000001). The 42 children who received the sham treatment (a small needle prick on the lower back) declined by an average of 1.0 point.

Researchers report that children taking the drug had fewer adverse events, and most were not related to the drug itself.

All surviving participants who completed nusinersen investigational studies are being enrolled in the SHINE open-label extension trial.

Also at the AAN meeting, researchers released interim phase II results from the NURTURE trial, an open-label study of nusinersen in patients with diagnosed but presymptomatic SMA. The study, which is expected to be completed in 2022, recruited participants up to the age of 6 weeks.

The 20 enrolled infants were all alive at a median study period of 317.5 days, and none required assistance with respiration.

In terms of motor function and growth, most were making gains “generally consistent with normal development such as head control, independent sitting, standing and walking independently, as measured by validated scales,” according to a statement released by Biogen.

Three patients developed adverse events that may have been drug related, but the events were resolved and they remained in the trial.

In Dr. Sumner’s discussant presentation on the ENDEAR study, she cautioned that it’s still not known how much older patients with SMA will benefit from the drug treatment. It’s possible that younger patients may gain motor function while older patients will maintain what they have, she said.

In addition, it seems that “certain body segments may respond more robustly than some others. It’s possible that an infant may improve limb strength quite robustly but not lumbar strength.”

She pointed out other questions: Can the drug, which is difficult to administer, be stopped at some point? “We do think of SMA as a disease of development,” she said. “Maybe after development is finished we can withdraw the drug.”

Then there’s the issue of cost and whether insurers are willing to cover the drug. As Dr. Sumner pointed out, the drug is $125,000 per dose and $750,000 over the first year, then $325,000 a year.

It is clear, however, that “the early and efficient diagnosis of SMA is really important, particularly for infantile SMA,” she said. “Time is motor function.”

The studies were funded by Ionis Pharmaceuticals and Biogen. Dr. Sumner reports serving as a consultant for Biogen, Ionis, Avexis, and Roche. She has served on scientific advisory boards for the Cure SMA, SMA Foundation, and Muscular Dystrophy Association nonprofit foundations.

cnnews@frontlinemedcom.com

BOSTON – Last December, the Food and Drug Administration approved nusinersen (Spinraza) as the only treatment for spinal muscular atrophy (SMA) based in part on startling interim results from a study in infants that ended early so all participants could get access to the drug.

Now the final study results are in, and they’re even more impressive: Patients who took the drug were less than half as likely to die as were those in a sham control group, and motor function improved in more than half of infants who took the medication, compared with none in the sham group.

The findings are “incredibly exciting,” said Charlotte J. Sumner, MD, in a discussant presentation at the annual meeting of the American Academy of Neurology. “The data teaches us that this drug is efficacious.”

However, Dr. Sumner, professor of neurology and neuroscience at Johns Hopkins University, Baltimore, cautioned that the drug is tremendously expensive, challenging to administer, and there are several questions about its use that remain unanswered.

SMA is most often caused by mutations in the SMN1 gene, leading to a loss of the protein called survival motor neuron (SMN), which is essential for the survival of motor neurons, except for a small amount produced from the SMN2 gene. The loss of motor neurons in the spinal cord and brainstem leads to weakness and atrophy of muscles used for crawling, walking, sitting up, controlling head movement, and in severe cases, breathing and swallowing. It affects an estimated 1 in 6,000 newborns and is the most common genetic cause of death in infants. Nusinersen is a antisense oligonucleotide that promotes transcription of the full-length SMN protein from the SMN2 gene.

At the AAN meeting, investigators presented the final results of two nusinersen phase III studies as well as interim data from a separate phase II trial.

The ENDEAR trial, a randomized, double-blind, sham-procedure controlled study, assigned 80 patients to 12-mg scaled equivalent doses of nusinersen delivered intrathecally (four doses over 2 months, then one every 4 months) and 41 to a sham procedure (a needle prick in the lower back). The subjects, aged 30-252 days at first dose, underwent 13 months of treatment and follow-up.

Researchers presented an end-of-study analysis of 110 subjects. They found that 51% of those who received the drug were “motor milestone responders” – meaning they had more modified Hammersmith Infant Neurological Examination Section 2 categories with improvement than worsening – compared with 41% at the interim analysis (P less than .0001). None of the sham group patients improved.

The patients treated with nusinersen lived longer: 39% of those in the sham procedure group died, compared with 16% of those in the nusinersen group (hazard ratio, 0.372; P = .0041). Event-free survival (survival without permanent ventilation) was also better in those who received the drugs: 61% in those who took nusinersen, compared with 32% in those who did not (HR, 0.53; P = .0046)

Also, 71% of those treated with the drug were considered responders at day 183 onward based on an improvement of 4 or more points on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scale, whereas the response rate was only 3% in the sham group (P less than .0001).

The study authors report that nusinersen was well tolerated with adverse events that “were consistent with those expected in the general population of infants with SMA.” No adverse events were linked to the nusinersen treatment.

Researchers also presented the end-of-study results of the phase III CHERISH trial of 126 patients aged 2-12 years with later-onset SMA who could sit up but not walk. All participants were believed to have a life expectancy of at least 2 years.

The trial is a multicenter, randomized, double-blind, sham-procedure controlled study. The 84 subjects who received the drug improved an average of 3.9 points by the end of study (15 months) on the Hammersmith Functional Motor Scale Expanded score, a measurement of motor function in children with SMA (P = .0000001). The 42 children who received the sham treatment (a small needle prick on the lower back) declined by an average of 1.0 point.

Researchers report that children taking the drug had fewer adverse events, and most were not related to the drug itself.

All surviving participants who completed nusinersen investigational studies are being enrolled in the SHINE open-label extension trial.

Also at the AAN meeting, researchers released interim phase II results from the NURTURE trial, an open-label study of nusinersen in patients with diagnosed but presymptomatic SMA. The study, which is expected to be completed in 2022, recruited participants up to the age of 6 weeks.

The 20 enrolled infants were all alive at a median study period of 317.5 days, and none required assistance with respiration.

In terms of motor function and growth, most were making gains “generally consistent with normal development such as head control, independent sitting, standing and walking independently, as measured by validated scales,” according to a statement released by Biogen.

Three patients developed adverse events that may have been drug related, but the events were resolved and they remained in the trial.

In Dr. Sumner’s discussant presentation on the ENDEAR study, she cautioned that it’s still not known how much older patients with SMA will benefit from the drug treatment. It’s possible that younger patients may gain motor function while older patients will maintain what they have, she said.

In addition, it seems that “certain body segments may respond more robustly than some others. It’s possible that an infant may improve limb strength quite robustly but not lumbar strength.”

She pointed out other questions: Can the drug, which is difficult to administer, be stopped at some point? “We do think of SMA as a disease of development,” she said. “Maybe after development is finished we can withdraw the drug.”

Then there’s the issue of cost and whether insurers are willing to cover the drug. As Dr. Sumner pointed out, the drug is $125,000 per dose and $750,000 over the first year, then $325,000 a year.

It is clear, however, that “the early and efficient diagnosis of SMA is really important, particularly for infantile SMA,” she said. “Time is motor function.”

The studies were funded by Ionis Pharmaceuticals and Biogen. Dr. Sumner reports serving as a consultant for Biogen, Ionis, Avexis, and Roche. She has served on scientific advisory boards for the Cure SMA, SMA Foundation, and Muscular Dystrophy Association nonprofit foundations.

cnnews@frontlinemedcom.com

SAN DIEGO – Over the past year, the American Psychiatric Association has reasserted its commitment to the Goldwater Rule, yet many psychiatrists have questioned – some publicly – whether the rule needs to be revisited based on their concerns about Donald Trump’s mental fitness to be president.

[polldaddy:9767626]Both sides of the issue got a hearing during a pro and con discussion of the Goldwater Rule at the annual meeting of the American Psychiatric Association. A trio of leading psychiatrists called for the Goldwater Rule to be revised and APA past leadership defended the ethical standards of the existing rule. One past-president of the APA remarked that psychiatrists who object to the rule can choose to quit the APA, a comment that one audience member said harkened back to the Vietnam War–era rebuttal to protesters: “Love it or leave it.”

Several news stories in recent months have highlighted the Trump-spawned debate over the Goldwater Rule, which states that “it is unethical for a psychiatrist to offer a professional opinion unless he or she has conducted an examination and has been granted proper authorization for such a statement.”

The APA created the rule in 1973 after a backlash over the hundreds of U.S. psychiatrists who responded to a magazine survey by diagnosing 1964 GOP presidential candidate Barry Goldwater. He later won a libel suit against the magazine.
Prior to last year’s presidential election, the APA stood by its rule. Then, in March 2017, the APA’s Ethics Committee affirmed that “the rule applies to all professional opinions offered by psychiatrists, not just diagnoses. For example, saying an individual does not have a mental disorder would also constitute a professional opinion.”

During the pro and con discussion at the annual meeting, Paul S. Appelbaum, MD, professor of psychiatry, medicine, and law at Columbia University in New York, called the Goldwater incident “a major embarrassment for psychiatry.”

But, he added, “there are more important justifications than whether we’re embarrassed or not. Part of [the rule] is to protect persons who may be harmed by our blithe speculation to the media. We’re also interested in avoiding an impact on people who may be in need of psychiatric care but are discouraged by what they see and hear about psychiatry in the media,” he said.

“A diagnosis based on casual encounters with a person through the media is necessarily inadequate as a basis for a psychiatric diagnosis or formulation of any reliable sort,” he pointed out.

Claire Pouncey, MD, PhD, a psychiatrist who practices in Philadelphia, questioned why speaking publicly about a public figure is inherently harmful.

“How does it threaten my integrity or integrity of the profession for me to choose to speak publicly about a public figure? The APA seems to not trust its members or recognize us as moral agents who are the arbiters of our own integrity. I wish the APA would trust me,” Dr. Pouncey said.

Last year, she outlined her concerns in an article written with Jerome Kroll, MD, and published in the Journal of the American Academy of Psychiatry and the Law (June 2016;44[2]:226-35).

As for concerns about the adequacy of information, she added, “we never have complete information. And I know we don’t always have a full consent of the person being evaluated. Anyone who’s been in an emergency room knows that in their heart and soul.”

Nassir Ghaemi, MD, MPH, who chaired the session and is professor and director of the mood disorders program at Tufts University in Boston, said that strictly abiding by the Goldwater Rule is “sending out the message that the world’s psychiatrists think it’s bad to get diagnosed with a psychiatric illness. … You are not going to harm patients by talking about psychiatric illness. You help them. We know that.”

[polldaddy:9767626]

SAN DIEGO – Over the past year, the American Psychiatric Association has reasserted its commitment to the Goldwater Rule, yet many psychiatrists have questioned – some publicly – whether the rule needs to be revisited based on their concerns about Donald Trump’s mental fitness to be president.

[polldaddy:9767626]Both sides of the issue got a hearing during a pro and con discussion of the Goldwater Rule at the annual meeting of the American Psychiatric Association. A trio of leading psychiatrists called for the Goldwater Rule to be revised and APA past leadership defended the ethical standards of the existing rule. One past-president of the APA remarked that psychiatrists who object to the rule can choose to quit the APA, a comment that one audience member said harkened back to the Vietnam War–era rebuttal to protesters: “Love it or leave it.”

Several news stories in recent months have highlighted the Trump-spawned debate over the Goldwater Rule, which states that “it is unethical for a psychiatrist to offer a professional opinion unless he or she has conducted an examination and has been granted proper authorization for such a statement.”

The APA created the rule in 1973 after a backlash over the hundreds of U.S. psychiatrists who responded to a magazine survey by diagnosing 1964 GOP presidential candidate Barry Goldwater. He later won a libel suit against the magazine.
Prior to last year’s presidential election, the APA stood by its rule. Then, in March 2017, the APA’s Ethics Committee affirmed that “the rule applies to all professional opinions offered by psychiatrists, not just diagnoses. For example, saying an individual does not have a mental disorder would also constitute a professional opinion.”

During the pro and con discussion at the annual meeting, Paul S. Appelbaum, MD, professor of psychiatry, medicine, and law at Columbia University in New York, called the Goldwater incident “a major embarrassment for psychiatry.”

But, he added, “there are more important justifications than whether we’re embarrassed or not. Part of [the rule] is to protect persons who may be harmed by our blithe speculation to the media. We’re also interested in avoiding an impact on people who may be in need of psychiatric care but are discouraged by what they see and hear about psychiatry in the media,” he said.

“A diagnosis based on casual encounters with a person through the media is necessarily inadequate as a basis for a psychiatric diagnosis or formulation of any reliable sort,” he pointed out.

Claire Pouncey, MD, PhD, a psychiatrist who practices in Philadelphia, questioned why speaking publicly about a public figure is inherently harmful.

“How does it threaten my integrity or integrity of the profession for me to choose to speak publicly about a public figure? The APA seems to not trust its members or recognize us as moral agents who are the arbiters of our own integrity. I wish the APA would trust me,” Dr. Pouncey said.

Last year, she outlined her concerns in an article written with Jerome Kroll, MD, and published in the Journal of the American Academy of Psychiatry and the Law (June 2016;44[2]:226-35).

As for concerns about the adequacy of information, she added, “we never have complete information. And I know we don’t always have a full consent of the person being evaluated. Anyone who’s been in an emergency room knows that in their heart and soul.”

Nassir Ghaemi, MD, MPH, who chaired the session and is professor and director of the mood disorders program at Tufts University in Boston, said that strictly abiding by the Goldwater Rule is “sending out the message that the world’s psychiatrists think it’s bad to get diagnosed with a psychiatric illness. … You are not going to harm patients by talking about psychiatric illness. You help them. We know that.”

[polldaddy:9767626]

SAN DIEGO – Over the past year, the American Psychiatric Association has reasserted its commitment to the Goldwater Rule, yet many psychiatrists have questioned – some publicly – whether the rule needs to be revisited based on their concerns about Donald Trump’s mental fitness to be president.

[polldaddy:9767626]Both sides of the issue got a hearing during a pro and con discussion of the Goldwater Rule at the annual meeting of the American Psychiatric Association. A trio of leading psychiatrists called for the Goldwater Rule to be revised and APA past leadership defended the ethical standards of the existing rule. One past-president of the APA remarked that psychiatrists who object to the rule can choose to quit the APA, a comment that one audience member said harkened back to the Vietnam War–era rebuttal to protesters: “Love it or leave it.”

Several news stories in recent months have highlighted the Trump-spawned debate over the Goldwater Rule, which states that “it is unethical for a psychiatrist to offer a professional opinion unless he or she has conducted an examination and has been granted proper authorization for such a statement.”

The APA created the rule in 1973 after a backlash over the hundreds of U.S. psychiatrists who responded to a magazine survey by diagnosing 1964 GOP presidential candidate Barry Goldwater. He later won a libel suit against the magazine.
Prior to last year’s presidential election, the APA stood by its rule. Then, in March 2017, the APA’s Ethics Committee affirmed that “the rule applies to all professional opinions offered by psychiatrists, not just diagnoses. For example, saying an individual does not have a mental disorder would also constitute a professional opinion.”

During the pro and con discussion at the annual meeting, Paul S. Appelbaum, MD, professor of psychiatry, medicine, and law at Columbia University in New York, called the Goldwater incident “a major embarrassment for psychiatry.”

But, he added, “there are more important justifications than whether we’re embarrassed or not. Part of [the rule] is to protect persons who may be harmed by our blithe speculation to the media. We’re also interested in avoiding an impact on people who may be in need of psychiatric care but are discouraged by what they see and hear about psychiatry in the media,” he said.

“A diagnosis based on casual encounters with a person through the media is necessarily inadequate as a basis for a psychiatric diagnosis or formulation of any reliable sort,” he pointed out.

Claire Pouncey, MD, PhD, a psychiatrist who practices in Philadelphia, questioned why speaking publicly about a public figure is inherently harmful.

“How does it threaten my integrity or integrity of the profession for me to choose to speak publicly about a public figure? The APA seems to not trust its members or recognize us as moral agents who are the arbiters of our own integrity. I wish the APA would trust me,” Dr. Pouncey said.

Last year, she outlined her concerns in an article written with Jerome Kroll, MD, and published in the Journal of the American Academy of Psychiatry and the Law (June 2016;44[2]:226-35).

As for concerns about the adequacy of information, she added, “we never have complete information. And I know we don’t always have a full consent of the person being evaluated. Anyone who’s been in an emergency room knows that in their heart and soul.”

Nassir Ghaemi, MD, MPH, who chaired the session and is professor and director of the mood disorders program at Tufts University in Boston, said that strictly abiding by the Goldwater Rule is “sending out the message that the world’s psychiatrists think it’s bad to get diagnosed with a psychiatric illness. … You are not going to harm patients by talking about psychiatric illness. You help them. We know that.”

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BOSTON – U.S. physicians chose to withdraw life-sustaining care from critically ill ischemic stroke patients at much higher rates in 2011 than in 2006, according to results of a new study, although overall percentages remain low.

The trend was bolstered by big jumps in “withdrawal of care” among patients who underwent thrombolysis or both thrombolysis and endovascular treatment: Over the 5-year period, their likelihood of having care withdrawn increased fivefold.

The study authors don’t know whether the trends have continued over the past 6 years, and it’s not clear why the rates rose so much from 2006 to 2011. The researchers speculate that the increase could be linked to disease severity and the preferences of patients and their families.

Whatever the case, study lead author Malik Muhammad Adil, MD, a neurology resident at the Ochsner Clinic Foundation in New Orleans, cautioned that prematurely withdrawing care can throw off stroke prognostication estimates that are already fuzzy. In an interview, he said this can then lead to “significant consequences, including suboptimal outcomes and higher risk of short-term mortality.”

Dr. Adil defines withdrawal of care as “discontinuation of life-sustaining interventions from a patient who is expected to die without this support.” These interventions include such treatments as intubation, mechanical ventilation, feeding tubes, antibiotics, and brain surgery, he said.

For the new study, researchers examined the Nationwide Inpatient Survey database for the years 2006-2011. They reported their findings at the annual meeting of the American Academy of Neurology.

The study reports the following regarding withdrawal of care among ischemic stroke patients:

• The rate grew in those who received neither thrombolysis nor endovascular treatment from 0.8% in 2006 to 3.0% in 2011 (P less than or equal to .0001).
• In those who received thrombolysis alone, the rate rose from 0.9% to 5.5% (P less than or equal to .0001).
• In those who received endovascular treatment alone, the rate increased from 2.8% to 9.0% (P = .0006).
• In patients who received both thrombolysis and endovascular treatment, the rate grew from 2.0% to 10.3% (P = .0009).

Dr. Adil said several factors can affect rates of withdrawal of care in ischemic stroke patients, such as the level of illness (patients receiving aggressive treatment are sicker), advance directives, and the decisions of family members. Some institutions may be more likely to push for withdrawal of care, too, he said. “At my institution, we are not aggressive with withdrawal of care, and I have seen a few better outcomes than expected,” he said.

Also, the lack of useful data regarding prognosis for these patients may lead to premature decisions regarding withdrawal of care, he said.

“We have few prognostic models/scores that predict mortality, and these models are not very sensitive and specific,” Dr. Adil said. “Often, physicians make these decisions based on their previous experiences. All of this leads to premature withdrawal of care. On the other hand, because of premature withdrawal of care, we do not have the data on long-term outcomes on these patients, leading to errors in prognostication.”

In an interview, Adam G. Kelly, MD, a neurologist at the University of Rochester (N.Y.) and chief of neurology at Highland Hospital in Rochester, said the study is important but lacks crucial information such as the circumstances surrounding the care decisions. He hasn’t noticed trends in withdrawal of care among his patients.

“It’s possible that providers have become better at documenting discussions with patients and families which allowed this information to be better captured,” he said. “As the authors mention, it’s also possible that providers are consciously or unconsciously delivering prognoses that are biased towards negative outcomes, leading patients and families to be more apt to choose a palliative approach.”

Dr. Kelly added that neurologists need to objectively offer prognoses in stroke cases. “When the outcome is in doubt, I recommend time-limited trials of interventions of mechanical ventilation, artificial feeding, and other high-intensity interventions to allow patients and families to make the decision they feel is best,” he said.

What about trends in the years since 2011? Dr. Adil said information regarding the years since 2011 wasn’t available to him, but he hopes to analyze the period from 2012 to 2016.

Dr. Adil discussed his study and its implications in a video interview.

No funding is reported. Dr. Adil reports no relevant disclosures.

cnnews@frontlinemedcom.com

BOSTON – U.S. physicians chose to withdraw life-sustaining care from critically ill ischemic stroke patients at much higher rates in 2011 than in 2006, according to results of a new study, although overall percentages remain low.

The trend was bolstered by big jumps in “withdrawal of care” among patients who underwent thrombolysis or both thrombolysis and endovascular treatment: Over the 5-year period, their likelihood of having care withdrawn increased fivefold.

The study authors don’t know whether the trends have continued over the past 6 years, and it’s not clear why the rates rose so much from 2006 to 2011. The researchers speculate that the increase could be linked to disease severity and the preferences of patients and their families.

Whatever the case, study lead author Malik Muhammad Adil, MD, a neurology resident at the Ochsner Clinic Foundation in New Orleans, cautioned that prematurely withdrawing care can throw off stroke prognostication estimates that are already fuzzy. In an interview, he said this can then lead to “significant consequences, including suboptimal outcomes and higher risk of short-term mortality.”

Dr. Adil defines withdrawal of care as “discontinuation of life-sustaining interventions from a patient who is expected to die without this support.” These interventions include such treatments as intubation, mechanical ventilation, feeding tubes, antibiotics, and brain surgery, he said.

For the new study, researchers examined the Nationwide Inpatient Survey database for the years 2006-2011. They reported their findings at the annual meeting of the American Academy of Neurology.

The study reports the following regarding withdrawal of care among ischemic stroke patients:

• The rate grew in those who received neither thrombolysis nor endovascular treatment from 0.8% in 2006 to 3.0% in 2011 (P less than or equal to .0001).
• In those who received thrombolysis alone, the rate rose from 0.9% to 5.5% (P less than or equal to .0001).
• In those who received endovascular treatment alone, the rate increased from 2.8% to 9.0% (P = .0006).
• In patients who received both thrombolysis and endovascular treatment, the rate grew from 2.0% to 10.3% (P = .0009).

Dr. Adil said several factors can affect rates of withdrawal of care in ischemic stroke patients, such as the level of illness (patients receiving aggressive treatment are sicker), advance directives, and the decisions of family members. Some institutions may be more likely to push for withdrawal of care, too, he said. “At my institution, we are not aggressive with withdrawal of care, and I have seen a few better outcomes than expected,” he said.

Also, the lack of useful data regarding prognosis for these patients may lead to premature decisions regarding withdrawal of care, he said.

“We have few prognostic models/scores that predict mortality, and these models are not very sensitive and specific,” Dr. Adil said. “Often, physicians make these decisions based on their previous experiences. All of this leads to premature withdrawal of care. On the other hand, because of premature withdrawal of care, we do not have the data on long-term outcomes on these patients, leading to errors in prognostication.”

In an interview, Adam G. Kelly, MD, a neurologist at the University of Rochester (N.Y.) and chief of neurology at Highland Hospital in Rochester, said the study is important but lacks crucial information such as the circumstances surrounding the care decisions. He hasn’t noticed trends in withdrawal of care among his patients.

“It’s possible that providers have become better at documenting discussions with patients and families which allowed this information to be better captured,” he said. “As the authors mention, it’s also possible that providers are consciously or unconsciously delivering prognoses that are biased towards negative outcomes, leading patients and families to be more apt to choose a palliative approach.”

Dr. Kelly added that neurologists need to objectively offer prognoses in stroke cases. “When the outcome is in doubt, I recommend time-limited trials of interventions of mechanical ventilation, artificial feeding, and other high-intensity interventions to allow patients and families to make the decision they feel is best,” he said.

What about trends in the years since 2011? Dr. Adil said information regarding the years since 2011 wasn’t available to him, but he hopes to analyze the period from 2012 to 2016.

Dr. Adil discussed his study and its implications in a video interview.

No funding is reported. Dr. Adil reports no relevant disclosures.

cnnews@frontlinemedcom.com

BOSTON – U.S. physicians chose to withdraw life-sustaining care from critically ill ischemic stroke patients at much higher rates in 2011 than in 2006, according to results of a new study, although overall percentages remain low.

The trend was bolstered by big jumps in “withdrawal of care” among patients who underwent thrombolysis or both thrombolysis and endovascular treatment: Over the 5-year period, their likelihood of having care withdrawn increased fivefold.

The study authors don’t know whether the trends have continued over the past 6 years, and it’s not clear why the rates rose so much from 2006 to 2011. The researchers speculate that the increase could be linked to disease severity and the preferences of patients and their families.

Whatever the case, study lead author Malik Muhammad Adil, MD, a neurology resident at the Ochsner Clinic Foundation in New Orleans, cautioned that prematurely withdrawing care can throw off stroke prognostication estimates that are already fuzzy. In an interview, he said this can then lead to “significant consequences, including suboptimal outcomes and higher risk of short-term mortality.”

Dr. Adil defines withdrawal of care as “discontinuation of life-sustaining interventions from a patient who is expected to die without this support.” These interventions include such treatments as intubation, mechanical ventilation, feeding tubes, antibiotics, and brain surgery, he said.

For the new study, researchers examined the Nationwide Inpatient Survey database for the years 2006-2011. They reported their findings at the annual meeting of the American Academy of Neurology.

The study reports the following regarding withdrawal of care among ischemic stroke patients:

• The rate grew in those who received neither thrombolysis nor endovascular treatment from 0.8% in 2006 to 3.0% in 2011 (P less than or equal to .0001).
• In those who received thrombolysis alone, the rate rose from 0.9% to 5.5% (P less than or equal to .0001).
• In those who received endovascular treatment alone, the rate increased from 2.8% to 9.0% (P = .0006).
• In patients who received both thrombolysis and endovascular treatment, the rate grew from 2.0% to 10.3% (P = .0009).

Dr. Adil said several factors can affect rates of withdrawal of care in ischemic stroke patients, such as the level of illness (patients receiving aggressive treatment are sicker), advance directives, and the decisions of family members. Some institutions may be more likely to push for withdrawal of care, too, he said. “At my institution, we are not aggressive with withdrawal of care, and I have seen a few better outcomes than expected,” he said.

Also, the lack of useful data regarding prognosis for these patients may lead to premature decisions regarding withdrawal of care, he said.

“We have few prognostic models/scores that predict mortality, and these models are not very sensitive and specific,” Dr. Adil said. “Often, physicians make these decisions based on their previous experiences. All of this leads to premature withdrawal of care. On the other hand, because of premature withdrawal of care, we do not have the data on long-term outcomes on these patients, leading to errors in prognostication.”

In an interview, Adam G. Kelly, MD, a neurologist at the University of Rochester (N.Y.) and chief of neurology at Highland Hospital in Rochester, said the study is important but lacks crucial information such as the circumstances surrounding the care decisions. He hasn’t noticed trends in withdrawal of care among his patients.

“It’s possible that providers have become better at documenting discussions with patients and families which allowed this information to be better captured,” he said. “As the authors mention, it’s also possible that providers are consciously or unconsciously delivering prognoses that are biased towards negative outcomes, leading patients and families to be more apt to choose a palliative approach.”

Dr. Kelly added that neurologists need to objectively offer prognoses in stroke cases. “When the outcome is in doubt, I recommend time-limited trials of interventions of mechanical ventilation, artificial feeding, and other high-intensity interventions to allow patients and families to make the decision they feel is best,” he said.

What about trends in the years since 2011? Dr. Adil said information regarding the years since 2011 wasn’t available to him, but he hopes to analyze the period from 2012 to 2016.

Dr. Adil discussed his study and its implications in a video interview.

No funding is reported. Dr. Adil reports no relevant disclosures.

cnnews@frontlinemedcom.com

Mental health researchers like to say a half-century has passed since the last major advance in schizophrenia treatment came along. Gavin P. Reynolds, PhD, a schizophrenia researcher, says that’s wrong. In fact, he says, “it’s more like 60-plus!”

Yes, there have been advances in drug treatment since the early 1950s, when chlorpromazine (Thorazine) was introduced. Available are new types of antipsychotics, a whole bunch in fact, and they’ve helped many patients. “But these have been incremental, rather than the much-needed quantum leap,” said Dr. Reynolds in an interview. “We still need improved treatments. About one-third of patients do not respond to standard drug treatment. And of those who do respond, the negative symptoms and cognitive problems caused by schizophrenia may still be very limiting.”

Thorazine: A pioneer with major limits

Like every person, each illness has a history. But schizophrenia’s past is fuzzier than that of many diseases, and this lack of clarity continues into the present as researchers try to understand exactly what it is – a single disorder? a collection of conditions? – and what it isn’t.

“Schizophrenia is a serious mental illness with a remarkably short recorded history. Unlike depression and mania, which are recognizable in ancient texts, schizophrenia-like disorder appeared rather suddenly in the early 19th century,” wrote R. Walter Heinrichs, PhD, a psychologist at Toronto’s York University (J Hist Behav Sci. 2003 Fall;39[4]:349-63). “This could mean that the illness is a recent disease that was largely unknown in earlier times. But perhaps schizophrenia existed, embedded and disguised within more general concepts of madness, and within the arcane languages and cultures of remote times,” he wrote.

As Dr. Heinrichs noted, schizophrenia’s history has spawned at least three theories: It’s a fairly new disease that just popped up in recent centuries. It has been around a long time but just didn’t get identified. It’s not a real disease but a product of modern thought.

Psychiatrists and researchers have rejected the latter possibility and its implications that psychotherapy could be the best treatment. Instead, they have tried to adjust the workings of the schizophrenic brain via medication.

The main breakthrough came in the 1950s through the development of the antipsychotic chlorpromazine. Its success “was instrumental in the reintegration of psychiatry with the other medical disciplines,” wrote Thomas A. Ban, MD, an emeritus professor at Vanderbilt University, Nashville, Tenn. “It turned psychiatrists from caregivers to full-fledged physicians who can help their patients and not only listen to their problems” (Neuropsychiatr Dis Treat. 2007 Aug; 3[4]:495-500).

Since chlorpromazine, however, medical treatment for schizophrenia has barely evolved, said Dr. Reynolds, professor emeritus at Queen’s University Belfast (Northern Ireland) and honorary professor at Sheffield (England) Hallam University. “The two most important developments have been the introduction of clozapine (Clozaril) for patients who don’t respond to other treatments and aripiprazole (Abilify), which has a somewhat different pharmacological action from other antipsychotics and thereby avoids some of the side effects.”

Negative symptoms fail to crumble

But, he said, side effects such as severe weight gain still can hamper the use of antipsychotics. And antipsychotics don’t fare well at treating the negative symptoms of schizophrenia.

As one overview puts it, “negative symptoms, e.g., social withdrawal, reduced initiative, anhedonia, and affective flattening, are notoriously difficult to treat.” Nonmedical treatments have shown some promise, the overview authors write: “Some positive findings have been reported, with the most robust improvements observed for social skills training. Although cognitive-behavior therapy shows significant effects for negative symptoms as a secondary outcome measure, there is a lack of data to allow for definite conclusions of its effectiveness for patients with predominant negative symptoms.”

As for medications, “antipsychotics have been shown to improve negative symptoms, but this seems to be limited to secondary negative symptoms in acute patients. It has also been suggested that antipsychotics may aggravate negative symptoms” (Schizophr Res. 2016 Jun 9. doi: 10.1016/j.schres.2016.05.015).

Looking to dopamine... and beyond

One solution to the vexing schizophrenia treatment gap is to develop a new medication that does a better job of adjusting the brain’s processing of dopamine.

Some researchers have found evidence that dopamine levels rise in the brains of people with schizophrenia, potentially explaining why chlorpromazine – which blocks receptors that process dopamine – is so effective. There also are signs that genes linked to dopamine play a role in schizophrenia.

But chlorpromazine is not effective enough to help many patients. Some gain no benefit, while others only see improvement in positive schizophrenia symptoms, those that are considered to be brought on – added – such as hallucinations and delusions.

And chlorpromazine isn’t believed to improve cognitive symptoms of schizophrenia like disorganized thoughts and concentration difficulties.

Atypical antipsychotics like clozapine (Clozaril) and risperidone (Risperdal), add the blocking of serotonin receptors to their dopamine focus. But they have serious limitations just like chlorpromazine.

The conclusion to take from the failure of dopamine-based drugs to fully combat schizophrenia, Dr. Kantrowitz and a colleague wrote, is that “dopaminergic dysfunction appears to account for only a part of schizophrenia’s symptomatic and neurocognitive profile.” Something else must be going on.

Enter the neurotransmitter known as glutamate.

The angel dust connection

Children who grew up in the 1970s and 1980s were flooded plenty of media messages about the dangers of illegal drugs. But one drug, “angel dust,” also known as phencyclidine or PCP, stood apart from the rest.

Using PCP, television shows and films suggested, led to consequences that could be deadly in ways that were entirely unlike the usual causes of death by drug use – a car accident, say, or a heroin overdose. Taking PCP, it seemed, was tied to crazed misadventure.

Consider a 1982 TV movie, “Desperate Lives,” starring a young actress named Helen Hunt. In a startling scene, she takes the drug and promptly jumps through a second-story window before screeching and cutting herself with jagged glass. The portrayal of PCP users as vividly unhinged – detached from reality and willing to hurt themselves or others – reflected a real phenomenon. As scientists had discovered, angel dust could made people act as if they were psychotic.

In the 1960s, “people started observing that drugs like PCP and ketamine produced schizophrenia-like symptoms,” Dr. Kantrowitz said. “But these observations were mostly ignored until the 1980s and 1990s.”

That’s when scientists started looking into the connections between these drugs and the psychotic states that they could induce. “These drugs can mimic, in animals and humans, the negative and cognitive symptoms as well as the positive symptoms of schizophrenia,” Dr. Reynolds said. “Combined with postmortem evidence of changes in various indicators of glutamate neurotransmission in the brain, these findings provide the basis for the glutamate hypothesis.”

The hypothesis theorizes that disruptions in the brain’s processing of glutamate are crucial to schizophrenia. Specifically, scientists believe the key lies in the N-methyl-D-aspartate (NMDA) receptor in nerve cells.

“Glutamatergic models are based upon the observation that the psychotomimetic agents such as phencyclidine and ketamine induce psychotic symptoms and neurocognitive disturbances similar to those of schizophrenia by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors,” writes Daniel C. Javitt, MD, professor of psychiatry and director of schizophrenia research at the Nathan Kline Institute for Psychiatric Research at Columbia University. “Because glutamate/NMDA receptors are located throughout the brain, glutamatergic models predict widespread cortical dysfunction with particular involvement of NMDA receptors throughout the brain.

“Further, NMDA receptors are located on brain circuits that regulate dopamine release, suggesting that dopaminergic deficits in schizophrenia may also be secondary to underlying glutamatergic dysfunction.” (Isr J Psychiatry Relat Sci. 2010;47[1]:4-16).

There’s even more to the story, said Dr. Reynolds, who cautions that the term “glutamate hypothesis” is misleading, because it misses the whole picture.

“The original research identifying the importance of the NMDA receptor highlighted how these receptors were actually on GABA neurons, reflecting the close interaction and interdependence of the two transmitter systems,” he said. (GABA receptors respond to the neurotransmitter gamma-aminobutyric acid, or GABA.)

“Subsequently, it has been established that there is a dysfunction, if not a deficit, of a subgroup of GABA neurons in schizophrenia,” Dr. Reynolds said, “and these neurons, which are important in the control of glutamate neuronal activity, are also a focus of current research.”

Challenges on the drug development front

Earlier findings linking glutamate to schizophrenia “have been strengthened by recent large genetic studies identifying that variability in some genes involved in glutamate’s action is a risk factor for schizophrenia,” Dr. Reynolds said, “while in animal models, some drugs influencing glutamate transmission have shown promise as potential treatments.”

But glutamate-based drugs for schizophrenia remain elusive. “It is disappointing that the new antipsychotic drugs becoming available now are still all variations on the dopamine antagonist or partial agonist theme, even if they have some advantages in terms of side effects and evidence that they may have some limited effects on negative or cognitive symptoms,” Dr. Reynolds said. “Several drugs addressing glutamate systems – indirectly modulating the NMDA receptor or synaptic glutamate – have been developed that had good potential but have failed in clinical trials. Nevertheless, this strategy is still being pursued by the pharma industry.”

Dr. Reynolds points to drug development challenges on several fronts. For one, research subjects don’t necessarily represent patients who’d benefit the most from treatment.

“Drug treatments are likely to be most effective, and most important, in the early stages of the disease,” he said. “However, drug trials are almost inevitably undertaken on subjects who may have had many years of treatment prior to the trial without, perhaps, always responding very well.”

Another challenge: The tight interconnectedness of neural systems linked to schizophrenia. Tinkering with something in one part of the brain may lead to something going wrong somewhere else. “Glutamate and GABA neurons are ubiquitous throughout the brain,” Dr. Reynolds said, “and targeting systems particularly affected in schizophrenia is difficult without influencing other neuronal systems, potentially leading to further side effects.”

Targets offer hope for new medications

The challenges are significant, but the latest schizophrenia research also is opening up opportunities for new medications.

The GABA connection, for example, is a fertile field for researchers. “One interesting and novel approach that seems promising is the development of a drug that modulates ion channels in GABA/parvalbumin neurons, thereby potentially restoring their function,” Dr. Reynolds said. “We are still years away from availability of these new treatments, however.”

Lessons from the latest research

One major thrust of research is to understand exactly how the glutamate system works and what goes wrong in schizophrenia patients. Here are some questions and answers from recent research:

Question: If NMDA receptors are crucial to glutamate, would an NMDA receptor channel blocker help improve symptoms in schizophrenia patients? What about memantine (Namenda), an Alzheimer’s disease medication that treats the cognitive problems caused by dementia?

Answer: A 2017 systematic review of 10 studies (including two case reports) found “unclear results”: “memantine therapy in schizophrenic patients seems to improve mainly negative symptoms while positive symptoms and cognitive symptoms did not improve significantly.”

The researchers add that the “use of memantine should be considered in patients with prevalent negative symptoms and cognitive impairment, even if further trials are required. Memantine could be a new opportunity to treat young patients in order to prevent further cognitive decline that will lead to global impairment” (J Amino Acids. 2017;2017:7021071).

The review did not include a 2017 double-blind, placebo-controlled study of 46 adult male patients (average age around 45 years) comparing the antipsychotic risperidone with risperidone plus memantine. The researchers found no difference in positive symptom improvement between the two groups, but the combination treatment group showed significant improvement in cognitive function (at 6 weeks and study completion at 12 weeks) and negative symptoms (at 12 weeks) (Psychiatry Res. 2017 Jan;247:291-5).

Q: We know that the cognitive symptoms of schizophrenia are difficult to treat. What hope does the glutamate system hold in this area?

A: A 2017 systematic review of 44 studies says “memory, working memory and executive functions appear to be most influenced by the glutamatergic pathway.” But there’s some added complexity: “evidence from the literature suggests that presynaptic components synthesis and uptake of glutamate is involved in memory, while postsynaptic signaling appears to be involved in working memory.”

In the big picture, the review says, “the glutamatergic system appears to contribute to the cognitive deficits in schizophrenia, whereby different parts of the pathway are associated with different cognitive domains” (Neurosci Biobehav Rev. 2017 Apr 13;77:369-87).

Q: Could imaging via proton magnetic resonance spectroscopy prove a link between schizophrenia and certain kinds of glutamate activity in the brain, giving mental health professionals a tool to identify at-risk people who are most likely to develop psychosis?

A: A 2016 meta-analysis examined 59 studies and reported that “schizophrenia is associated with elevations in glutamatergic metabolites across several brain regions. This finding supports the hypothesis that schizophrenia is associated with excess glutamatergic neurotransmission in several limbic areas and further indicates that compounds that reduce glutamatergic transmission may have therapeutic potential” (JAMA Psychiatry. 2016 Jul 1;73[7]:665-74).

A review published in 2016 examined 11 proton magnetic resonance spectroscopy studies in search of signs that the state of the glutamate system could predict future psychosis.

Researchers found that six studies reported “significant alterations in glutamate metabolites across different cerebral areas (frontal lobe, thalamus, and the associative striatum)” in at-risk patients. “A longitudinal analysis in two of these trials confirmed an association between these abnormalities and worsening of symptoms and final transition to psychosis.”

But the other five studies analyzed in the review “found no significant differences across these same areas” (Schizophr Res. 2016 Mar;171[1-3]:166-75).

Mental health researchers like to say a half-century has passed since the last major advance in schizophrenia treatment came along. Gavin P. Reynolds, PhD, a schizophrenia researcher, says that’s wrong. In fact, he says, “it’s more like 60-plus!”

Yes, there have been advances in drug treatment since the early 1950s, when chlorpromazine (Thorazine) was introduced. Available are new types of antipsychotics, a whole bunch in fact, and they’ve helped many patients. “But these have been incremental, rather than the much-needed quantum leap,” said Dr. Reynolds in an interview. “We still need improved treatments. About one-third of patients do not respond to standard drug treatment. And of those who do respond, the negative symptoms and cognitive problems caused by schizophrenia may still be very limiting.”

Thorazine: A pioneer with major limits

Like every person, each illness has a history. But schizophrenia’s past is fuzzier than that of many diseases, and this lack of clarity continues into the present as researchers try to understand exactly what it is – a single disorder? a collection of conditions? – and what it isn’t.

“Schizophrenia is a serious mental illness with a remarkably short recorded history. Unlike depression and mania, which are recognizable in ancient texts, schizophrenia-like disorder appeared rather suddenly in the early 19th century,” wrote R. Walter Heinrichs, PhD, a psychologist at Toronto’s York University (J Hist Behav Sci. 2003 Fall;39[4]:349-63). “This could mean that the illness is a recent disease that was largely unknown in earlier times. But perhaps schizophrenia existed, embedded and disguised within more general concepts of madness, and within the arcane languages and cultures of remote times,” he wrote.

As Dr. Heinrichs noted, schizophrenia’s history has spawned at least three theories: It’s a fairly new disease that just popped up in recent centuries. It has been around a long time but just didn’t get identified. It’s not a real disease but a product of modern thought.

Psychiatrists and researchers have rejected the latter possibility and its implications that psychotherapy could be the best treatment. Instead, they have tried to adjust the workings of the schizophrenic brain via medication.

The main breakthrough came in the 1950s through the development of the antipsychotic chlorpromazine. Its success “was instrumental in the reintegration of psychiatry with the other medical disciplines,” wrote Thomas A. Ban, MD, an emeritus professor at Vanderbilt University, Nashville, Tenn. “It turned psychiatrists from caregivers to full-fledged physicians who can help their patients and not only listen to their problems” (Neuropsychiatr Dis Treat. 2007 Aug; 3[4]:495-500).

Since chlorpromazine, however, medical treatment for schizophrenia has barely evolved, said Dr. Reynolds, professor emeritus at Queen’s University Belfast (Northern Ireland) and honorary professor at Sheffield (England) Hallam University. “The two most important developments have been the introduction of clozapine (Clozaril) for patients who don’t respond to other treatments and aripiprazole (Abilify), which has a somewhat different pharmacological action from other antipsychotics and thereby avoids some of the side effects.”

Negative symptoms fail to crumble

But, he said, side effects such as severe weight gain still can hamper the use of antipsychotics. And antipsychotics don’t fare well at treating the negative symptoms of schizophrenia.

As one overview puts it, “negative symptoms, e.g., social withdrawal, reduced initiative, anhedonia, and affective flattening, are notoriously difficult to treat.” Nonmedical treatments have shown some promise, the overview authors write: “Some positive findings have been reported, with the most robust improvements observed for social skills training. Although cognitive-behavior therapy shows significant effects for negative symptoms as a secondary outcome measure, there is a lack of data to allow for definite conclusions of its effectiveness for patients with predominant negative symptoms.”

As for medications, “antipsychotics have been shown to improve negative symptoms, but this seems to be limited to secondary negative symptoms in acute patients. It has also been suggested that antipsychotics may aggravate negative symptoms” (Schizophr Res. 2016 Jun 9. doi: 10.1016/j.schres.2016.05.015).

Looking to dopamine... and beyond

One solution to the vexing schizophrenia treatment gap is to develop a new medication that does a better job of adjusting the brain’s processing of dopamine.

Some researchers have found evidence that dopamine levels rise in the brains of people with schizophrenia, potentially explaining why chlorpromazine – which blocks receptors that process dopamine – is so effective. There also are signs that genes linked to dopamine play a role in schizophrenia.

But chlorpromazine is not effective enough to help many patients. Some gain no benefit, while others only see improvement in positive schizophrenia symptoms, those that are considered to be brought on – added – such as hallucinations and delusions.

And chlorpromazine isn’t believed to improve cognitive symptoms of schizophrenia like disorganized thoughts and concentration difficulties.

Atypical antipsychotics like clozapine (Clozaril) and risperidone (Risperdal), add the blocking of serotonin receptors to their dopamine focus. But they have serious limitations just like chlorpromazine.

The conclusion to take from the failure of dopamine-based drugs to fully combat schizophrenia, Dr. Kantrowitz and a colleague wrote, is that “dopaminergic dysfunction appears to account for only a part of schizophrenia’s symptomatic and neurocognitive profile.” Something else must be going on.

Enter the neurotransmitter known as glutamate.

The angel dust connection

Children who grew up in the 1970s and 1980s were flooded plenty of media messages about the dangers of illegal drugs. But one drug, “angel dust,” also known as phencyclidine or PCP, stood apart from the rest.

Using PCP, television shows and films suggested, led to consequences that could be deadly in ways that were entirely unlike the usual causes of death by drug use – a car accident, say, or a heroin overdose. Taking PCP, it seemed, was tied to crazed misadventure.

Consider a 1982 TV movie, “Desperate Lives,” starring a young actress named Helen Hunt. In a startling scene, she takes the drug and promptly jumps through a second-story window before screeching and cutting herself with jagged glass. The portrayal of PCP users as vividly unhinged – detached from reality and willing to hurt themselves or others – reflected a real phenomenon. As scientists had discovered, angel dust could made people act as if they were psychotic.

In the 1960s, “people started observing that drugs like PCP and ketamine produced schizophrenia-like symptoms,” Dr. Kantrowitz said. “But these observations were mostly ignored until the 1980s and 1990s.”

That’s when scientists started looking into the connections between these drugs and the psychotic states that they could induce. “These drugs can mimic, in animals and humans, the negative and cognitive symptoms as well as the positive symptoms of schizophrenia,” Dr. Reynolds said. “Combined with postmortem evidence of changes in various indicators of glutamate neurotransmission in the brain, these findings provide the basis for the glutamate hypothesis.”

The hypothesis theorizes that disruptions in the brain’s processing of glutamate are crucial to schizophrenia. Specifically, scientists believe the key lies in the N-methyl-D-aspartate (NMDA) receptor in nerve cells.

“Glutamatergic models are based upon the observation that the psychotomimetic agents such as phencyclidine and ketamine induce psychotic symptoms and neurocognitive disturbances similar to those of schizophrenia by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors,” writes Daniel C. Javitt, MD, professor of psychiatry and director of schizophrenia research at the Nathan Kline Institute for Psychiatric Research at Columbia University. “Because glutamate/NMDA receptors are located throughout the brain, glutamatergic models predict widespread cortical dysfunction with particular involvement of NMDA receptors throughout the brain.

“Further, NMDA receptors are located on brain circuits that regulate dopamine release, suggesting that dopaminergic deficits in schizophrenia may also be secondary to underlying glutamatergic dysfunction.” (Isr J Psychiatry Relat Sci. 2010;47[1]:4-16).

There’s even more to the story, said Dr. Reynolds, who cautions that the term “glutamate hypothesis” is misleading, because it misses the whole picture.

“The original research identifying the importance of the NMDA receptor highlighted how these receptors were actually on GABA neurons, reflecting the close interaction and interdependence of the two transmitter systems,” he said. (GABA receptors respond to the neurotransmitter gamma-aminobutyric acid, or GABA.)

“Subsequently, it has been established that there is a dysfunction, if not a deficit, of a subgroup of GABA neurons in schizophrenia,” Dr. Reynolds said, “and these neurons, which are important in the control of glutamate neuronal activity, are also a focus of current research.”

Challenges on the drug development front

Earlier findings linking glutamate to schizophrenia “have been strengthened by recent large genetic studies identifying that variability in some genes involved in glutamate’s action is a risk factor for schizophrenia,” Dr. Reynolds said, “while in animal models, some drugs influencing glutamate transmission have shown promise as potential treatments.”

But glutamate-based drugs for schizophrenia remain elusive. “It is disappointing that the new antipsychotic drugs becoming available now are still all variations on the dopamine antagonist or partial agonist theme, even if they have some advantages in terms of side effects and evidence that they may have some limited effects on negative or cognitive symptoms,” Dr. Reynolds said. “Several drugs addressing glutamate systems – indirectly modulating the NMDA receptor or synaptic glutamate – have been developed that had good potential but have failed in clinical trials. Nevertheless, this strategy is still being pursued by the pharma industry.”

Dr. Reynolds points to drug development challenges on several fronts. For one, research subjects don’t necessarily represent patients who’d benefit the most from treatment.

“Drug treatments are likely to be most effective, and most important, in the early stages of the disease,” he said. “However, drug trials are almost inevitably undertaken on subjects who may have had many years of treatment prior to the trial without, perhaps, always responding very well.”

Another challenge: The tight interconnectedness of neural systems linked to schizophrenia. Tinkering with something in one part of the brain may lead to something going wrong somewhere else. “Glutamate and GABA neurons are ubiquitous throughout the brain,” Dr. Reynolds said, “and targeting systems particularly affected in schizophrenia is difficult without influencing other neuronal systems, potentially leading to further side effects.”

Targets offer hope for new medications

The challenges are significant, but the latest schizophrenia research also is opening up opportunities for new medications.

The GABA connection, for example, is a fertile field for researchers. “One interesting and novel approach that seems promising is the development of a drug that modulates ion channels in GABA/parvalbumin neurons, thereby potentially restoring their function,” Dr. Reynolds said. “We are still years away from availability of these new treatments, however.”

Lessons from the latest research

One major thrust of research is to understand exactly how the glutamate system works and what goes wrong in schizophrenia patients. Here are some questions and answers from recent research:

Question: If NMDA receptors are crucial to glutamate, would an NMDA receptor channel blocker help improve symptoms in schizophrenia patients? What about memantine (Namenda), an Alzheimer’s disease medication that treats the cognitive problems caused by dementia?

Answer: A 2017 systematic review of 10 studies (including two case reports) found “unclear results”: “memantine therapy in schizophrenic patients seems to improve mainly negative symptoms while positive symptoms and cognitive symptoms did not improve significantly.”

The researchers add that the “use of memantine should be considered in patients with prevalent negative symptoms and cognitive impairment, even if further trials are required. Memantine could be a new opportunity to treat young patients in order to prevent further cognitive decline that will lead to global impairment” (J Amino Acids. 2017;2017:7021071).

The review did not include a 2017 double-blind, placebo-controlled study of 46 adult male patients (average age around 45 years) comparing the antipsychotic risperidone with risperidone plus memantine. The researchers found no difference in positive symptom improvement between the two groups, but the combination treatment group showed significant improvement in cognitive function (at 6 weeks and study completion at 12 weeks) and negative symptoms (at 12 weeks) (Psychiatry Res. 2017 Jan;247:291-5).

Q: We know that the cognitive symptoms of schizophrenia are difficult to treat. What hope does the glutamate system hold in this area?

A: A 2017 systematic review of 44 studies says “memory, working memory and executive functions appear to be most influenced by the glutamatergic pathway.” But there’s some added complexity: “evidence from the literature suggests that presynaptic components synthesis and uptake of glutamate is involved in memory, while postsynaptic signaling appears to be involved in working memory.”

In the big picture, the review says, “the glutamatergic system appears to contribute to the cognitive deficits in schizophrenia, whereby different parts of the pathway are associated with different cognitive domains” (Neurosci Biobehav Rev. 2017 Apr 13;77:369-87).

Q: Could imaging via proton magnetic resonance spectroscopy prove a link between schizophrenia and certain kinds of glutamate activity in the brain, giving mental health professionals a tool to identify at-risk people who are most likely to develop psychosis?

A: A 2016 meta-analysis examined 59 studies and reported that “schizophrenia is associated with elevations in glutamatergic metabolites across several brain regions. This finding supports the hypothesis that schizophrenia is associated with excess glutamatergic neurotransmission in several limbic areas and further indicates that compounds that reduce glutamatergic transmission may have therapeutic potential” (JAMA Psychiatry. 2016 Jul 1;73[7]:665-74).

A review published in 2016 examined 11 proton magnetic resonance spectroscopy studies in search of signs that the state of the glutamate system could predict future psychosis.

Researchers found that six studies reported “significant alterations in glutamate metabolites across different cerebral areas (frontal lobe, thalamus, and the associative striatum)” in at-risk patients. “A longitudinal analysis in two of these trials confirmed an association between these abnormalities and worsening of symptoms and final transition to psychosis.”

But the other five studies analyzed in the review “found no significant differences across these same areas” (Schizophr Res. 2016 Mar;171[1-3]:166-75).

Mental health researchers like to say a half-century has passed since the last major advance in schizophrenia treatment came along. Gavin P. Reynolds, PhD, a schizophrenia researcher, says that’s wrong. In fact, he says, “it’s more like 60-plus!”

Yes, there have been advances in drug treatment since the early 1950s, when chlorpromazine (Thorazine) was introduced. Available are new types of antipsychotics, a whole bunch in fact, and they’ve helped many patients. “But these have been incremental, rather than the much-needed quantum leap,” said Dr. Reynolds in an interview. “We still need improved treatments. About one-third of patients do not respond to standard drug treatment. And of those who do respond, the negative symptoms and cognitive problems caused by schizophrenia may still be very limiting.”

Thorazine: A pioneer with major limits

Like every person, each illness has a history. But schizophrenia’s past is fuzzier than that of many diseases, and this lack of clarity continues into the present as researchers try to understand exactly what it is – a single disorder? a collection of conditions? – and what it isn’t.

“Schizophrenia is a serious mental illness with a remarkably short recorded history. Unlike depression and mania, which are recognizable in ancient texts, schizophrenia-like disorder appeared rather suddenly in the early 19th century,” wrote R. Walter Heinrichs, PhD, a psychologist at Toronto’s York University (J Hist Behav Sci. 2003 Fall;39[4]:349-63). “This could mean that the illness is a recent disease that was largely unknown in earlier times. But perhaps schizophrenia existed, embedded and disguised within more general concepts of madness, and within the arcane languages and cultures of remote times,” he wrote.

As Dr. Heinrichs noted, schizophrenia’s history has spawned at least three theories: It’s a fairly new disease that just popped up in recent centuries. It has been around a long time but just didn’t get identified. It’s not a real disease but a product of modern thought.

Psychiatrists and researchers have rejected the latter possibility and its implications that psychotherapy could be the best treatment. Instead, they have tried to adjust the workings of the schizophrenic brain via medication.

The main breakthrough came in the 1950s through the development of the antipsychotic chlorpromazine. Its success “was instrumental in the reintegration of psychiatry with the other medical disciplines,” wrote Thomas A. Ban, MD, an emeritus professor at Vanderbilt University, Nashville, Tenn. “It turned psychiatrists from caregivers to full-fledged physicians who can help their patients and not only listen to their problems” (Neuropsychiatr Dis Treat. 2007 Aug; 3[4]:495-500).

Since chlorpromazine, however, medical treatment for schizophrenia has barely evolved, said Dr. Reynolds, professor emeritus at Queen’s University Belfast (Northern Ireland) and honorary professor at Sheffield (England) Hallam University. “The two most important developments have been the introduction of clozapine (Clozaril) for patients who don’t respond to other treatments and aripiprazole (Abilify), which has a somewhat different pharmacological action from other antipsychotics and thereby avoids some of the side effects.”

Negative symptoms fail to crumble

But, he said, side effects such as severe weight gain still can hamper the use of antipsychotics. And antipsychotics don’t fare well at treating the negative symptoms of schizophrenia.

As one overview puts it, “negative symptoms, e.g., social withdrawal, reduced initiative, anhedonia, and affective flattening, are notoriously difficult to treat.” Nonmedical treatments have shown some promise, the overview authors write: “Some positive findings have been reported, with the most robust improvements observed for social skills training. Although cognitive-behavior therapy shows significant effects for negative symptoms as a secondary outcome measure, there is a lack of data to allow for definite conclusions of its effectiveness for patients with predominant negative symptoms.”

As for medications, “antipsychotics have been shown to improve negative symptoms, but this seems to be limited to secondary negative symptoms in acute patients. It has also been suggested that antipsychotics may aggravate negative symptoms” (Schizophr Res. 2016 Jun 9. doi: 10.1016/j.schres.2016.05.015).

Looking to dopamine... and beyond

One solution to the vexing schizophrenia treatment gap is to develop a new medication that does a better job of adjusting the brain’s processing of dopamine.

Some researchers have found evidence that dopamine levels rise in the brains of people with schizophrenia, potentially explaining why chlorpromazine – which blocks receptors that process dopamine – is so effective. There also are signs that genes linked to dopamine play a role in schizophrenia.

But chlorpromazine is not effective enough to help many patients. Some gain no benefit, while others only see improvement in positive schizophrenia symptoms, those that are considered to be brought on – added – such as hallucinations and delusions.

And chlorpromazine isn’t believed to improve cognitive symptoms of schizophrenia like disorganized thoughts and concentration difficulties.

Atypical antipsychotics like clozapine (Clozaril) and risperidone (Risperdal), add the blocking of serotonin receptors to their dopamine focus. But they have serious limitations just like chlorpromazine.

The conclusion to take from the failure of dopamine-based drugs to fully combat schizophrenia, Dr. Kantrowitz and a colleague wrote, is that “dopaminergic dysfunction appears to account for only a part of schizophrenia’s symptomatic and neurocognitive profile.” Something else must be going on.

Enter the neurotransmitter known as glutamate.

The angel dust connection

Children who grew up in the 1970s and 1980s were flooded plenty of media messages about the dangers of illegal drugs. But one drug, “angel dust,” also known as phencyclidine or PCP, stood apart from the rest.

Using PCP, television shows and films suggested, led to consequences that could be deadly in ways that were entirely unlike the usual causes of death by drug use – a car accident, say, or a heroin overdose. Taking PCP, it seemed, was tied to crazed misadventure.

Consider a 1982 TV movie, “Desperate Lives,” starring a young actress named Helen Hunt. In a startling scene, she takes the drug and promptly jumps through a second-story window before screeching and cutting herself with jagged glass. The portrayal of PCP users as vividly unhinged – detached from reality and willing to hurt themselves or others – reflected a real phenomenon. As scientists had discovered, angel dust could made people act as if they were psychotic.

In the 1960s, “people started observing that drugs like PCP and ketamine produced schizophrenia-like symptoms,” Dr. Kantrowitz said. “But these observations were mostly ignored until the 1980s and 1990s.”

That’s when scientists started looking into the connections between these drugs and the psychotic states that they could induce. “These drugs can mimic, in animals and humans, the negative and cognitive symptoms as well as the positive symptoms of schizophrenia,” Dr. Reynolds said. “Combined with postmortem evidence of changes in various indicators of glutamate neurotransmission in the brain, these findings provide the basis for the glutamate hypothesis.”

The hypothesis theorizes that disruptions in the brain’s processing of glutamate are crucial to schizophrenia. Specifically, scientists believe the key lies in the N-methyl-D-aspartate (NMDA) receptor in nerve cells.

“Glutamatergic models are based upon the observation that the psychotomimetic agents such as phencyclidine and ketamine induce psychotic symptoms and neurocognitive disturbances similar to those of schizophrenia by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors,” writes Daniel C. Javitt, MD, professor of psychiatry and director of schizophrenia research at the Nathan Kline Institute for Psychiatric Research at Columbia University. “Because glutamate/NMDA receptors are located throughout the brain, glutamatergic models predict widespread cortical dysfunction with particular involvement of NMDA receptors throughout the brain.

“Further, NMDA receptors are located on brain circuits that regulate dopamine release, suggesting that dopaminergic deficits in schizophrenia may also be secondary to underlying glutamatergic dysfunction.” (Isr J Psychiatry Relat Sci. 2010;47[1]:4-16).

There’s even more to the story, said Dr. Reynolds, who cautions that the term “glutamate hypothesis” is misleading, because it misses the whole picture.

“The original research identifying the importance of the NMDA receptor highlighted how these receptors were actually on GABA neurons, reflecting the close interaction and interdependence of the two transmitter systems,” he said. (GABA receptors respond to the neurotransmitter gamma-aminobutyric acid, or GABA.)

“Subsequently, it has been established that there is a dysfunction, if not a deficit, of a subgroup of GABA neurons in schizophrenia,” Dr. Reynolds said, “and these neurons, which are important in the control of glutamate neuronal activity, are also a focus of current research.”

Challenges on the drug development front

Earlier findings linking glutamate to schizophrenia “have been strengthened by recent large genetic studies identifying that variability in some genes involved in glutamate’s action is a risk factor for schizophrenia,” Dr. Reynolds said, “while in animal models, some drugs influencing glutamate transmission have shown promise as potential treatments.”

But glutamate-based drugs for schizophrenia remain elusive. “It is disappointing that the new antipsychotic drugs becoming available now are still all variations on the dopamine antagonist or partial agonist theme, even if they have some advantages in terms of side effects and evidence that they may have some limited effects on negative or cognitive symptoms,” Dr. Reynolds said. “Several drugs addressing glutamate systems – indirectly modulating the NMDA receptor or synaptic glutamate – have been developed that had good potential but have failed in clinical trials. Nevertheless, this strategy is still being pursued by the pharma industry.”

Dr. Reynolds points to drug development challenges on several fronts. For one, research subjects don’t necessarily represent patients who’d benefit the most from treatment.

“Drug treatments are likely to be most effective, and most important, in the early stages of the disease,” he said. “However, drug trials are almost inevitably undertaken on subjects who may have had many years of treatment prior to the trial without, perhaps, always responding very well.”

Another challenge: The tight interconnectedness of neural systems linked to schizophrenia. Tinkering with something in one part of the brain may lead to something going wrong somewhere else. “Glutamate and GABA neurons are ubiquitous throughout the brain,” Dr. Reynolds said, “and targeting systems particularly affected in schizophrenia is difficult without influencing other neuronal systems, potentially leading to further side effects.”

Targets offer hope for new medications

The challenges are significant, but the latest schizophrenia research also is opening up opportunities for new medications.

The GABA connection, for example, is a fertile field for researchers. “One interesting and novel approach that seems promising is the development of a drug that modulates ion channels in GABA/parvalbumin neurons, thereby potentially restoring their function,” Dr. Reynolds said. “We are still years away from availability of these new treatments, however.”

Lessons from the latest research

One major thrust of research is to understand exactly how the glutamate system works and what goes wrong in schizophrenia patients. Here are some questions and answers from recent research:

Question: If NMDA receptors are crucial to glutamate, would an NMDA receptor channel blocker help improve symptoms in schizophrenia patients? What about memantine (Namenda), an Alzheimer’s disease medication that treats the cognitive problems caused by dementia?

Answer: A 2017 systematic review of 10 studies (including two case reports) found “unclear results”: “memantine therapy in schizophrenic patients seems to improve mainly negative symptoms while positive symptoms and cognitive symptoms did not improve significantly.”

The researchers add that the “use of memantine should be considered in patients with prevalent negative symptoms and cognitive impairment, even if further trials are required. Memantine could be a new opportunity to treat young patients in order to prevent further cognitive decline that will lead to global impairment” (J Amino Acids. 2017;2017:7021071).

The review did not include a 2017 double-blind, placebo-controlled study of 46 adult male patients (average age around 45 years) comparing the antipsychotic risperidone with risperidone plus memantine. The researchers found no difference in positive symptom improvement between the two groups, but the combination treatment group showed significant improvement in cognitive function (at 6 weeks and study completion at 12 weeks) and negative symptoms (at 12 weeks) (Psychiatry Res. 2017 Jan;247:291-5).

Q: We know that the cognitive symptoms of schizophrenia are difficult to treat. What hope does the glutamate system hold in this area?

A: A 2017 systematic review of 44 studies says “memory, working memory and executive functions appear to be most influenced by the glutamatergic pathway.” But there’s some added complexity: “evidence from the literature suggests that presynaptic components synthesis and uptake of glutamate is involved in memory, while postsynaptic signaling appears to be involved in working memory.”

In the big picture, the review says, “the glutamatergic system appears to contribute to the cognitive deficits in schizophrenia, whereby different parts of the pathway are associated with different cognitive domains” (Neurosci Biobehav Rev. 2017 Apr 13;77:369-87).

Q: Could imaging via proton magnetic resonance spectroscopy prove a link between schizophrenia and certain kinds of glutamate activity in the brain, giving mental health professionals a tool to identify at-risk people who are most likely to develop psychosis?

A: A 2016 meta-analysis examined 59 studies and reported that “schizophrenia is associated with elevations in glutamatergic metabolites across several brain regions. This finding supports the hypothesis that schizophrenia is associated with excess glutamatergic neurotransmission in several limbic areas and further indicates that compounds that reduce glutamatergic transmission may have therapeutic potential” (JAMA Psychiatry. 2016 Jul 1;73[7]:665-74).

A review published in 2016 examined 11 proton magnetic resonance spectroscopy studies in search of signs that the state of the glutamate system could predict future psychosis.

Researchers found that six studies reported “significant alterations in glutamate metabolites across different cerebral areas (frontal lobe, thalamus, and the associative striatum)” in at-risk patients. “A longitudinal analysis in two of these trials confirmed an association between these abnormalities and worsening of symptoms and final transition to psychosis.”

But the other five studies analyzed in the review “found no significant differences across these same areas” (Schizophr Res. 2016 Mar;171[1-3]:166-75).