Randy Dotinga

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.”

[polldaddy:9767626]

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).

SAN DIEGO – A review of existing research found that newer technologies are safer and more effective at skin rejuvenation than older ones, with two types – intense pulsed laser (IPL) and radiofrequency (RF) – at or near the head of the pack on both fronts.

In addition, 10 types of treatments, including multiple laser technologies, scored higher than facial peels on safety, although the peels beat almost all comers in terms of efficacy, the study’s lead author, Caerwyn Ash, PhD, said in an interview after presenting the results at the annual meeting of the American Society for Laser Medicine and Surgery.

SAN DIEGO – A review of existing research found that newer technologies are safer and more effective at skin rejuvenation than older ones, with two types – intense pulsed laser (IPL) and radiofrequency (RF) – at or near the head of the pack on both fronts.

In addition, 10 types of treatments, including multiple laser technologies, scored higher than facial peels on safety, although the peels beat almost all comers in terms of efficacy, the study’s lead author, Caerwyn Ash, PhD, said in an interview after presenting the results at the annual meeting of the American Society for Laser Medicine and Surgery.

SAN DIEGO – A review of existing research found that newer technologies are safer and more effective at skin rejuvenation than older ones, with two types – intense pulsed laser (IPL) and radiofrequency (RF) – at or near the head of the pack on both fronts.

In addition, 10 types of treatments, including multiple laser technologies, scored higher than facial peels on safety, although the peels beat almost all comers in terms of efficacy, the study’s lead author, Caerwyn Ash, PhD, said in an interview after presenting the results at the annual meeting of the American Society for Laser Medicine and Surgery.

BOSTON – A new analysis finds that some of the biggest neurologist prescribers of repository corticotropin gel (Acthar) – the extraordinarily expensive multiple sclerosis (MS) relapse drug – reaped extensive payments from its manufacturer, with one taking in $130,307 in a single year.

Together, 51 neurologists accounted for 980 Medicare claims worth more than $39 million in Acthar spending in 2014, almost half of the entire estimated $83 million in Medicare spending on neurologist-prescribed Acthar that year.

“There is a small group of neurologists – less than 1% – who are prescribing Acthar at considerable cost to Medicare and may do this in part because of financial relationships with the company that sells Acthar,” said study lead author Dennis Bourdette, MD, chair and research professor of neurology at Oregon Health and Science University, Portland.

BOSTON – A new analysis finds that some of the biggest neurologist prescribers of repository corticotropin gel (Acthar) – the extraordinarily expensive multiple sclerosis (MS) relapse drug – reaped extensive payments from its manufacturer, with one taking in $130,307 in a single year.

Together, 51 neurologists accounted for 980 Medicare claims worth more than $39 million in Acthar spending in 2014, almost half of the entire estimated $83 million in Medicare spending on neurologist-prescribed Acthar that year.

“There is a small group of neurologists – less than 1% – who are prescribing Acthar at considerable cost to Medicare and may do this in part because of financial relationships with the company that sells Acthar,” said study lead author Dennis Bourdette, MD, chair and research professor of neurology at Oregon Health and Science University, Portland.

BOSTON – A new analysis finds that some of the biggest neurologist prescribers of repository corticotropin gel (Acthar) – the extraordinarily expensive multiple sclerosis (MS) relapse drug – reaped extensive payments from its manufacturer, with one taking in $130,307 in a single year.

Together, 51 neurologists accounted for 980 Medicare claims worth more than $39 million in Acthar spending in 2014, almost half of the entire estimated $83 million in Medicare spending on neurologist-prescribed Acthar that year.

“There is a small group of neurologists – less than 1% – who are prescribing Acthar at considerable cost to Medicare and may do this in part because of financial relationships with the company that sells Acthar,” said study lead author Dennis Bourdette, MD, chair and research professor of neurology at Oregon Health and Science University, Portland.

SAN DIEGO – Laser treatments may be effective for xanthelasma palpebrarum lesions, based on a systematic review of existing studies, although the research is limited.

“The number of cases we looked at was relatively small, so you can’t come up with any definite conclusions,” said review coauthor Christopher J. Huerter, MD, head of the division of dermatology at Creighton University, Omaha. “But it’s promising since the lasers we examined all work with some efficacy, with the CO₂ and Er:YAG [erbium:YAG] lasers probably having the best results.”

Xanthelasma lesions appear as small yellowish plaques on the eyelids. “About half the people who have it have some blood lipid abnormality,” Dr. Huerter said in an interview. “If a person has it, it’s worthwhile to do a cholesterol screen or a lipid profile.”

Courtesy RegionalDerm.com

dermnews@frontlinemedcom.com

SAN DIEGO – Laser treatments may be effective for xanthelasma palpebrarum lesions, based on a systematic review of existing studies, although the research is limited.

“The number of cases we looked at was relatively small, so you can’t come up with any definite conclusions,” said review coauthor Christopher J. Huerter, MD, head of the division of dermatology at Creighton University, Omaha. “But it’s promising since the lasers we examined all work with some efficacy, with the CO₂ and Er:YAG [erbium:YAG] lasers probably having the best results.”

Xanthelasma lesions appear as small yellowish plaques on the eyelids. “About half the people who have it have some blood lipid abnormality,” Dr. Huerter said in an interview. “If a person has it, it’s worthwhile to do a cholesterol screen or a lipid profile.”

Courtesy RegionalDerm.com

dermnews@frontlinemedcom.com

SAN DIEGO – Laser treatments may be effective for xanthelasma palpebrarum lesions, based on a systematic review of existing studies, although the research is limited.

“The number of cases we looked at was relatively small, so you can’t come up with any definite conclusions,” said review coauthor Christopher J. Huerter, MD, head of the division of dermatology at Creighton University, Omaha. “But it’s promising since the lasers we examined all work with some efficacy, with the CO₂ and Er:YAG [erbium:YAG] lasers probably having the best results.”

Xanthelasma lesions appear as small yellowish plaques on the eyelids. “About half the people who have it have some blood lipid abnormality,” Dr. Huerter said in an interview. “If a person has it, it’s worthwhile to do a cholesterol screen or a lipid profile.”

Courtesy RegionalDerm.com

dermnews@frontlinemedcom.com

BOSTON – A new study estimates that 3.4%-6.7% of amyotrophic lateral sclerosis (ALS) patients in Washington state sought to commit physician-assisted suicide over a 5-year period.

The rate is many times higher than that among cancer patients in the state, researchers found. They also discovered that ALS patients were significantly more likely than were other terminally ill people to use the deadly medication after getting prescriptions for it.

The findings appear to reflect the unique hopelessness facing ALS patients. “They’re not afforded as much denial of decline and death as are patients with other terminal illnesses,” said Linda Ganzini, MD, MPH, a professor of psychiatry and medicine at Oregon Health & Science University, Portland, who has studied end of life in ALS patients.

“Many cancer patients, even in the final days of life, receive treatments that they hope will extend their lives,” she said in an interview after reviewing the study findings. “In contrast, treatments for ALS are minimally effective.”

Physician-assisted suicide is legal in California, Colorado, the District of Columbia, Montana, Oregon, Vermont, and Washington.

A team led by Leo H. Wang, MD, PhD, of the University of Washington, Seattle, examined the medical records of 39 ALS patients who sought medication to end their lives at three hospitals in Seattle from March 2009 to Dec. 31, 2014.

Washington’s Death with Dignity (DWD) law, which went into effect in 2009, allows physicians to prescribe lethal medication if the patient has a terminal illness and a prognosis of less than 6 months to live as judged by two physicians.

The researchers reported their findings, a follow-up to a previous study (Neurology. 2016 Nov 15;87[20]:2117-22), at the annual meeting of the American Academy of Neurology.

The median age of the ALS patients at symptom onset was 64 (range, 42-83), and a median of 712 days passed (range, 207-2,407) from the date of diagnosis to date of prescription for lethal medication.

The median time from prescription to death was 22 days, with at least one patient dying immediately (range, 0-386 days). All 39 patients had limb involvement, and 82%-92% had bulbar involvement, dysarthria, dysphagia, and/or dyspnea.

The researchers estimate that 3.4%-6.7% of 1,146 ALS patients in Washington who died over the time period of the study sought a physician-assisted death. The 3.4% figure assumes that the 39 patients at the three hospitals make up all the ALS patients who received medication prescriptions. The 6.7% figure assumes that all patients with neurodegenerative disease who sought DWD in the state over that period had ALS.

“Similarly, 5% (92 of 1,795) of Oregon ALS patient who died sought medication under DWD between 1998 and 2014,” Dr. Wang said. “This is slightly increased compared to the percentage during the first decade, following enactment of the Oregon law (1998-2007), when 2.7% (26 of 962) of ALS patients died using DWD medication.”

Using Washington state data, researchers also estimated that 0.6% of 73,319 cancer patients and 0.2% of 298,178 people in the state who died of all causes sought DWD over the study period.

A total of 30 (77%) ALS patients who received the deadly prescriptions chose to take them, compared with 67% of all-cause patients who took advantage of the DWD law and 60% of cancer patients.

All 30 patients died. The nine who chose to not take the prescribed medication died after a median of 76 days. The patients who did not take the medication were more likely to be married (88% vs. 69%), to be college educated (100% vs. 74%), and to use a motorized wheelchair (78% vs. 31%).

Those who chose to not take the prescribed medication were also less motivated by loss of dignity (63% vs. 93% among those who took the medication) and by being a burden on others (25% vs. 66%). They were more likely to identify themselves as religious (80% vs. 35%).

Multiple factors may explain why ALS patients made different choices regarding the deadly drugs, lead study author Dr. Wang said in an interview. “We thought that the loss of communication may have played a role based on our finding, as most patients who followed through had more substantial trouble speaking,” he said. “For the patients who ultimately did not choose to take the medication, we found more of them had stronger religious beliefs than those who did not.”

As for pain, he reported that it was not a major issue. “Only about 10% of ALS patients were worried about pain, as opposed to 30% of the general Death with Dignity patients,” he said.

Dr. Ganzini noted that some patients who seek the prescribed drugs “want reassurance that, if their quality of life becomes unbearable, they have the option of physician-assisted death. But, they continue to cope and find reasons to live. As such, they ultimately die of their disease without taking the medications. Others lose the ability to ingest the medications, often because of sudden worsening of their disease.”

cnnews@frontlinemedcom.com

BOSTON – A new study estimates that 3.4%-6.7% of amyotrophic lateral sclerosis (ALS) patients in Washington state sought to commit physician-assisted suicide over a 5-year period.

The rate is many times higher than that among cancer patients in the state, researchers found. They also discovered that ALS patients were significantly more likely than were other terminally ill people to use the deadly medication after getting prescriptions for it.

The findings appear to reflect the unique hopelessness facing ALS patients. “They’re not afforded as much denial of decline and death as are patients with other terminal illnesses,” said Linda Ganzini, MD, MPH, a professor of psychiatry and medicine at Oregon Health & Science University, Portland, who has studied end of life in ALS patients.

“Many cancer patients, even in the final days of life, receive treatments that they hope will extend their lives,” she said in an interview after reviewing the study findings. “In contrast, treatments for ALS are minimally effective.”

Physician-assisted suicide is legal in California, Colorado, the District of Columbia, Montana, Oregon, Vermont, and Washington.

A team led by Leo H. Wang, MD, PhD, of the University of Washington, Seattle, examined the medical records of 39 ALS patients who sought medication to end their lives at three hospitals in Seattle from March 2009 to Dec. 31, 2014.

Washington’s Death with Dignity (DWD) law, which went into effect in 2009, allows physicians to prescribe lethal medication if the patient has a terminal illness and a prognosis of less than 6 months to live as judged by two physicians.

The researchers reported their findings, a follow-up to a previous study (Neurology. 2016 Nov 15;87[20]:2117-22), at the annual meeting of the American Academy of Neurology.

The median age of the ALS patients at symptom onset was 64 (range, 42-83), and a median of 712 days passed (range, 207-2,407) from the date of diagnosis to date of prescription for lethal medication.

The median time from prescription to death was 22 days, with at least one patient dying immediately (range, 0-386 days). All 39 patients had limb involvement, and 82%-92% had bulbar involvement, dysarthria, dysphagia, and/or dyspnea.

The researchers estimate that 3.4%-6.7% of 1,146 ALS patients in Washington who died over the time period of the study sought a physician-assisted death. The 3.4% figure assumes that the 39 patients at the three hospitals make up all the ALS patients who received medication prescriptions. The 6.7% figure assumes that all patients with neurodegenerative disease who sought DWD in the state over that period had ALS.

“Similarly, 5% (92 of 1,795) of Oregon ALS patient who died sought medication under DWD between 1998 and 2014,” Dr. Wang said. “This is slightly increased compared to the percentage during the first decade, following enactment of the Oregon law (1998-2007), when 2.7% (26 of 962) of ALS patients died using DWD medication.”

Using Washington state data, researchers also estimated that 0.6% of 73,319 cancer patients and 0.2% of 298,178 people in the state who died of all causes sought DWD over the study period.

A total of 30 (77%) ALS patients who received the deadly prescriptions chose to take them, compared with 67% of all-cause patients who took advantage of the DWD law and 60% of cancer patients.

All 30 patients died. The nine who chose to not take the prescribed medication died after a median of 76 days. The patients who did not take the medication were more likely to be married (88% vs. 69%), to be college educated (100% vs. 74%), and to use a motorized wheelchair (78% vs. 31%).

Those who chose to not take the prescribed medication were also less motivated by loss of dignity (63% vs. 93% among those who took the medication) and by being a burden on others (25% vs. 66%). They were more likely to identify themselves as religious (80% vs. 35%).

Multiple factors may explain why ALS patients made different choices regarding the deadly drugs, lead study author Dr. Wang said in an interview. “We thought that the loss of communication may have played a role based on our finding, as most patients who followed through had more substantial trouble speaking,” he said. “For the patients who ultimately did not choose to take the medication, we found more of them had stronger religious beliefs than those who did not.”

As for pain, he reported that it was not a major issue. “Only about 10% of ALS patients were worried about pain, as opposed to 30% of the general Death with Dignity patients,” he said.

Dr. Ganzini noted that some patients who seek the prescribed drugs “want reassurance that, if their quality of life becomes unbearable, they have the option of physician-assisted death. But, they continue to cope and find reasons to live. As such, they ultimately die of their disease without taking the medications. Others lose the ability to ingest the medications, often because of sudden worsening of their disease.”

cnnews@frontlinemedcom.com

BOSTON – A new study estimates that 3.4%-6.7% of amyotrophic lateral sclerosis (ALS) patients in Washington state sought to commit physician-assisted suicide over a 5-year period.

The rate is many times higher than that among cancer patients in the state, researchers found. They also discovered that ALS patients were significantly more likely than were other terminally ill people to use the deadly medication after getting prescriptions for it.

The findings appear to reflect the unique hopelessness facing ALS patients. “They’re not afforded as much denial of decline and death as are patients with other terminal illnesses,” said Linda Ganzini, MD, MPH, a professor of psychiatry and medicine at Oregon Health & Science University, Portland, who has studied end of life in ALS patients.

“Many cancer patients, even in the final days of life, receive treatments that they hope will extend their lives,” she said in an interview after reviewing the study findings. “In contrast, treatments for ALS are minimally effective.”

Physician-assisted suicide is legal in California, Colorado, the District of Columbia, Montana, Oregon, Vermont, and Washington.

A team led by Leo H. Wang, MD, PhD, of the University of Washington, Seattle, examined the medical records of 39 ALS patients who sought medication to end their lives at three hospitals in Seattle from March 2009 to Dec. 31, 2014.

Washington’s Death with Dignity (DWD) law, which went into effect in 2009, allows physicians to prescribe lethal medication if the patient has a terminal illness and a prognosis of less than 6 months to live as judged by two physicians.

The researchers reported their findings, a follow-up to a previous study (Neurology. 2016 Nov 15;87[20]:2117-22), at the annual meeting of the American Academy of Neurology.

The median age of the ALS patients at symptom onset was 64 (range, 42-83), and a median of 712 days passed (range, 207-2,407) from the date of diagnosis to date of prescription for lethal medication.

The median time from prescription to death was 22 days, with at least one patient dying immediately (range, 0-386 days). All 39 patients had limb involvement, and 82%-92% had bulbar involvement, dysarthria, dysphagia, and/or dyspnea.

The researchers estimate that 3.4%-6.7% of 1,146 ALS patients in Washington who died over the time period of the study sought a physician-assisted death. The 3.4% figure assumes that the 39 patients at the three hospitals make up all the ALS patients who received medication prescriptions. The 6.7% figure assumes that all patients with neurodegenerative disease who sought DWD in the state over that period had ALS.

“Similarly, 5% (92 of 1,795) of Oregon ALS patient who died sought medication under DWD between 1998 and 2014,” Dr. Wang said. “This is slightly increased compared to the percentage during the first decade, following enactment of the Oregon law (1998-2007), when 2.7% (26 of 962) of ALS patients died using DWD medication.”

Using Washington state data, researchers also estimated that 0.6% of 73,319 cancer patients and 0.2% of 298,178 people in the state who died of all causes sought DWD over the study period.

A total of 30 (77%) ALS patients who received the deadly prescriptions chose to take them, compared with 67% of all-cause patients who took advantage of the DWD law and 60% of cancer patients.

All 30 patients died. The nine who chose to not take the prescribed medication died after a median of 76 days. The patients who did not take the medication were more likely to be married (88% vs. 69%), to be college educated (100% vs. 74%), and to use a motorized wheelchair (78% vs. 31%).

Those who chose to not take the prescribed medication were also less motivated by loss of dignity (63% vs. 93% among those who took the medication) and by being a burden on others (25% vs. 66%). They were more likely to identify themselves as religious (80% vs. 35%).

Multiple factors may explain why ALS patients made different choices regarding the deadly drugs, lead study author Dr. Wang said in an interview. “We thought that the loss of communication may have played a role based on our finding, as most patients who followed through had more substantial trouble speaking,” he said. “For the patients who ultimately did not choose to take the medication, we found more of them had stronger religious beliefs than those who did not.”

As for pain, he reported that it was not a major issue. “Only about 10% of ALS patients were worried about pain, as opposed to 30% of the general Death with Dignity patients,” he said.

Dr. Ganzini noted that some patients who seek the prescribed drugs “want reassurance that, if their quality of life becomes unbearable, they have the option of physician-assisted death. But, they continue to cope and find reasons to live. As such, they ultimately die of their disease without taking the medications. Others lose the ability to ingest the medications, often because of sudden worsening of their disease.”

cnnews@frontlinemedcom.com

SAN DIEGO – A new systematic review and meta-analysis, the first of its kind, suggests that most people with schizophrenia – especially men – do not survive past their 60s.

According to findings released at the 2017 International Congress on Schizophrenia Research, schizophrenia patients appear to die a weighted average of 14.5 years earlier than the rest of the population (95% confidence interval, 11.2-17.8).

The weighted average life expectancy for schizophrenia patients was 64.7 years (95% CI, 61.1-71.3) – 59.9 years for men (95% CI, 55.5-64.3) and 67.6 years for women (95% CI, 63.1-72.1).

“There were no indications that this is improving over time,” lead author Carsten Hjorthøj, PhD, senior researcher at the University of Copenhagen, said in an interview.

The researchers launched their paper in order to provide a wider perspective on lives lost in schizophrenia.

Previous studies had used measures like the standardized mortality ratio, which compared schizophrenia patients with a matched group from the general population, Dr. Hjorthøj said. “Saying that people with schizophrenia are, for instance, 2.5 times more likely to die at any given age may be a little difficult to understand. Identifying the actual number of years they die earlier than the rest of the population is easily understood and will probably also make the issue more obvious to policymakers.”

The researchers, whose findings were previously published in Lancet Psychiatry (2017 Apr;4[4]:295-301), examined 11 studies, mostly from Europe (n = 5) and North America (n = 3) with single studies from Africa, Asia, and Australia. (The lowest life expectancies were reported in Asia and Africa.)

One study was published in 1991, and the rest from 2001-2016. Together, the studies tracked 302,691 patients with schizophrenia.

What explains the gap between the life expectancies in men and women? “We did not investigate the reasons for this,” Dr. Hjorthøj said, “but men typically have worse adherence to treatment than women, and men typically also have poorer health-seeking behavior than women even in the general population. Given that schizophrenia is associated with a multitude of adverse somatic outcomes, this could then be aggravated by this difference in health-seeking behavior.”

In addition, he said, “It could also be the case that use of alcohol, tobacco, and illicit substances is even more skewed in schizophrenia than in the general population. Finally, it could also be attributed in part to the fact that men are more likely than women to die from suicide.”

Dr. Hjorthøj said that the findings emphasize the importance of treating physical symptoms in people with schizophrenia.

“I am aware of several cases where physical complaints were not taken seriously because they were raised by people who were known to suffer from delusions,” he said. “But, I do believe that most psychiatrists are aware of this, and the problem is perhaps more that the system in general is underfunded and that somatic and psychiatric hospitals are not good enough at communicating with each other.”

The researchers report no funding and no disclosures.

cpnews@frontlinemedcome.com

SAN DIEGO – A new systematic review and meta-analysis, the first of its kind, suggests that most people with schizophrenia – especially men – do not survive past their 60s.

According to findings released at the 2017 International Congress on Schizophrenia Research, schizophrenia patients appear to die a weighted average of 14.5 years earlier than the rest of the population (95% confidence interval, 11.2-17.8).

The weighted average life expectancy for schizophrenia patients was 64.7 years (95% CI, 61.1-71.3) – 59.9 years for men (95% CI, 55.5-64.3) and 67.6 years for women (95% CI, 63.1-72.1).

“There were no indications that this is improving over time,” lead author Carsten Hjorthøj, PhD, senior researcher at the University of Copenhagen, said in an interview.

The researchers launched their paper in order to provide a wider perspective on lives lost in schizophrenia.

Previous studies had used measures like the standardized mortality ratio, which compared schizophrenia patients with a matched group from the general population, Dr. Hjorthøj said. “Saying that people with schizophrenia are, for instance, 2.5 times more likely to die at any given age may be a little difficult to understand. Identifying the actual number of years they die earlier than the rest of the population is easily understood and will probably also make the issue more obvious to policymakers.”

The researchers, whose findings were previously published in Lancet Psychiatry (2017 Apr;4[4]:295-301), examined 11 studies, mostly from Europe (n = 5) and North America (n = 3) with single studies from Africa, Asia, and Australia. (The lowest life expectancies were reported in Asia and Africa.)

One study was published in 1991, and the rest from 2001-2016. Together, the studies tracked 302,691 patients with schizophrenia.

What explains the gap between the life expectancies in men and women? “We did not investigate the reasons for this,” Dr. Hjorthøj said, “but men typically have worse adherence to treatment than women, and men typically also have poorer health-seeking behavior than women even in the general population. Given that schizophrenia is associated with a multitude of adverse somatic outcomes, this could then be aggravated by this difference in health-seeking behavior.”

In addition, he said, “It could also be the case that use of alcohol, tobacco, and illicit substances is even more skewed in schizophrenia than in the general population. Finally, it could also be attributed in part to the fact that men are more likely than women to die from suicide.”

Dr. Hjorthøj said that the findings emphasize the importance of treating physical symptoms in people with schizophrenia.

“I am aware of several cases where physical complaints were not taken seriously because they were raised by people who were known to suffer from delusions,” he said. “But, I do believe that most psychiatrists are aware of this, and the problem is perhaps more that the system in general is underfunded and that somatic and psychiatric hospitals are not good enough at communicating with each other.”

The researchers report no funding and no disclosures.

cpnews@frontlinemedcome.com

SAN DIEGO – A new systematic review and meta-analysis, the first of its kind, suggests that most people with schizophrenia – especially men – do not survive past their 60s.

According to findings released at the 2017 International Congress on Schizophrenia Research, schizophrenia patients appear to die a weighted average of 14.5 years earlier than the rest of the population (95% confidence interval, 11.2-17.8).

The weighted average life expectancy for schizophrenia patients was 64.7 years (95% CI, 61.1-71.3) – 59.9 years for men (95% CI, 55.5-64.3) and 67.6 years for women (95% CI, 63.1-72.1).

“There were no indications that this is improving over time,” lead author Carsten Hjorthøj, PhD, senior researcher at the University of Copenhagen, said in an interview.

The researchers launched their paper in order to provide a wider perspective on lives lost in schizophrenia.

Previous studies had used measures like the standardized mortality ratio, which compared schizophrenia patients with a matched group from the general population, Dr. Hjorthøj said. “Saying that people with schizophrenia are, for instance, 2.5 times more likely to die at any given age may be a little difficult to understand. Identifying the actual number of years they die earlier than the rest of the population is easily understood and will probably also make the issue more obvious to policymakers.”

The researchers, whose findings were previously published in Lancet Psychiatry (2017 Apr;4[4]:295-301), examined 11 studies, mostly from Europe (n = 5) and North America (n = 3) with single studies from Africa, Asia, and Australia. (The lowest life expectancies were reported in Asia and Africa.)

One study was published in 1991, and the rest from 2001-2016. Together, the studies tracked 302,691 patients with schizophrenia.

What explains the gap between the life expectancies in men and women? “We did not investigate the reasons for this,” Dr. Hjorthøj said, “but men typically have worse adherence to treatment than women, and men typically also have poorer health-seeking behavior than women even in the general population. Given that schizophrenia is associated with a multitude of adverse somatic outcomes, this could then be aggravated by this difference in health-seeking behavior.”

In addition, he said, “It could also be the case that use of alcohol, tobacco, and illicit substances is even more skewed in schizophrenia than in the general population. Finally, it could also be attributed in part to the fact that men are more likely than women to die from suicide.”

Dr. Hjorthøj said that the findings emphasize the importance of treating physical symptoms in people with schizophrenia.

“I am aware of several cases where physical complaints were not taken seriously because they were raised by people who were known to suffer from delusions,” he said. “But, I do believe that most psychiatrists are aware of this, and the problem is perhaps more that the system in general is underfunded and that somatic and psychiatric hospitals are not good enough at communicating with each other.”

The researchers report no funding and no disclosures.

cpnews@frontlinemedcome.com