Researchers say they have discovered how Ras proteins find their proper place in cells, a finding that may aid the development of novel approaches to treat cancers.

The team noted that cancers develop if Ras proteins start to trigger misregulation, and Ras misregulates if it misses its correct location on the cell wall—the membrane.

What the researchers discovered is that Ras cannot reach its designated location if the membrane has the wrong shape.

“If the curvature of the cell is right, Ras goes to the right place,” said Dimitrios Stamou, PhD, of the University of Copenhagen in Denmark.

“If the membrane is too straight or too bent, it does not. And Ras is very much like any other worker. If it never finds the way to its workplace, it is not likely to get any work done.”

Dr Stamou and his colleagues described this discovery in Nature Chemical Biology.

Ras proteins are thought to be misregulated in upwards of 30% of all cancers. For 3 decades, researchers have been searching for ways to quell the killer protein.

Their lack of success has given Ras a reputation as the “undruggable cancer target,” but Dr Stamou believes we can change by moving in a new direction.

“If Ras goes off the rails because of changes in the curvature of the cell, perhaps we should target whatever changes the shape of the cell membrane,” he said.

Looking for a correlation between cell shape and Ras misregulation was unusual, even bordering on controversial, said study author Jannik Bruun Larsen, PhD, of the University of Copenhagen.

The researchers were investigating how Ras proteins attach themselves to the cell wall, and Dr Larsen tried to attach Ras to a variety of simulated cell membranes formed into small spheres or vesicles of varying sizes.

He found that Ras would attach more readily to smaller spheres, which were more curved than the large ones, and Dr Larsen started to see a pattern.

“For more than a decade, people thought that the constituents of the cell wall was the thing that controlled where Ras was localized,” Dr Larson said. “We have shown that at least one other aspect—namely, membrane curvature—governs where Ras ends up in the cell and is therefore likely to be a factor in cancer development.”

All of the research so far has been conducted in vitro. Dr Stamou said the next big challenge is to uncover how these effects play out in living systems.

“It will be 10 times more difficult to uncover these effects in living systems, but it needs to happen,” he said. “We have started, and we really hope others will follow. It may prove complicated to develop a drug that changes the shape of cells, but I am certain that the discovery of the shape/misregulation-correlation will at least lead to new ways to diagnose cancers.”

Researchers say they have discovered how Ras proteins find their proper place in cells, a finding that may aid the development of novel approaches to treat cancers.

The team noted that cancers develop if Ras proteins start to trigger misregulation, and Ras misregulates if it misses its correct location on the cell wall—the membrane.

What the researchers discovered is that Ras cannot reach its designated location if the membrane has the wrong shape.

“If the curvature of the cell is right, Ras goes to the right place,” said Dimitrios Stamou, PhD, of the University of Copenhagen in Denmark.

“If the membrane is too straight or too bent, it does not. And Ras is very much like any other worker. If it never finds the way to its workplace, it is not likely to get any work done.”

Dr Stamou and his colleagues described this discovery in Nature Chemical Biology.

Ras proteins are thought to be misregulated in upwards of 30% of all cancers. For 3 decades, researchers have been searching for ways to quell the killer protein.

Their lack of success has given Ras a reputation as the “undruggable cancer target,” but Dr Stamou believes we can change by moving in a new direction.

“If Ras goes off the rails because of changes in the curvature of the cell, perhaps we should target whatever changes the shape of the cell membrane,” he said.

Looking for a correlation between cell shape and Ras misregulation was unusual, even bordering on controversial, said study author Jannik Bruun Larsen, PhD, of the University of Copenhagen.

The researchers were investigating how Ras proteins attach themselves to the cell wall, and Dr Larsen tried to attach Ras to a variety of simulated cell membranes formed into small spheres or vesicles of varying sizes.

He found that Ras would attach more readily to smaller spheres, which were more curved than the large ones, and Dr Larsen started to see a pattern.

“For more than a decade, people thought that the constituents of the cell wall was the thing that controlled where Ras was localized,” Dr Larson said. “We have shown that at least one other aspect—namely, membrane curvature—governs where Ras ends up in the cell and is therefore likely to be a factor in cancer development.”

All of the research so far has been conducted in vitro. Dr Stamou said the next big challenge is to uncover how these effects play out in living systems.

“It will be 10 times more difficult to uncover these effects in living systems, but it needs to happen,” he said. “We have started, and we really hope others will follow. It may prove complicated to develop a drug that changes the shape of cells, but I am certain that the discovery of the shape/misregulation-correlation will at least lead to new ways to diagnose cancers.”

Researchers say they have discovered how Ras proteins find their proper place in cells, a finding that may aid the development of novel approaches to treat cancers.

The team noted that cancers develop if Ras proteins start to trigger misregulation, and Ras misregulates if it misses its correct location on the cell wall—the membrane.

What the researchers discovered is that Ras cannot reach its designated location if the membrane has the wrong shape.

“If the curvature of the cell is right, Ras goes to the right place,” said Dimitrios Stamou, PhD, of the University of Copenhagen in Denmark.

“If the membrane is too straight or too bent, it does not. And Ras is very much like any other worker. If it never finds the way to its workplace, it is not likely to get any work done.”

Dr Stamou and his colleagues described this discovery in Nature Chemical Biology.

Ras proteins are thought to be misregulated in upwards of 30% of all cancers. For 3 decades, researchers have been searching for ways to quell the killer protein.

Their lack of success has given Ras a reputation as the “undruggable cancer target,” but Dr Stamou believes we can change by moving in a new direction.

“If Ras goes off the rails because of changes in the curvature of the cell, perhaps we should target whatever changes the shape of the cell membrane,” he said.

Looking for a correlation between cell shape and Ras misregulation was unusual, even bordering on controversial, said study author Jannik Bruun Larsen, PhD, of the University of Copenhagen.

The researchers were investigating how Ras proteins attach themselves to the cell wall, and Dr Larsen tried to attach Ras to a variety of simulated cell membranes formed into small spheres or vesicles of varying sizes.

He found that Ras would attach more readily to smaller spheres, which were more curved than the large ones, and Dr Larsen started to see a pattern.

“For more than a decade, people thought that the constituents of the cell wall was the thing that controlled where Ras was localized,” Dr Larson said. “We have shown that at least one other aspect—namely, membrane curvature—governs where Ras ends up in the cell and is therefore likely to be a factor in cancer development.”

All of the research so far has been conducted in vitro. Dr Stamou said the next big challenge is to uncover how these effects play out in living systems.

“It will be 10 times more difficult to uncover these effects in living systems, but it needs to happen,” he said. “We have started, and we really hope others will follow. It may prove complicated to develop a drug that changes the shape of cells, but I am certain that the discovery of the shape/misregulation-correlation will at least lead to new ways to diagnose cancers.”

The detection and imaging of protein-protein interactions in live cells just got a lot more colorful, researchers have reported in Nature Methods.

The team created a  technique that converts biochemical processes into color changes that are easily visualized.

The group said this provides a new tool scientists can use to answer questions about fundamental mechanisms in cell biology, aid the discovery of novel therapeutics, and more.

Robert E. Campbell, PhD, of the University of Alberta in Edmonton, Alberta, Canada, and his colleagues conducted this research.

They developed the technique, dubbed FPX, that employs genetically encoded fluorescent proteins to image dynamic biochemical events in live cells and tissues. The FPX method converts a change in protein-protein interactions into a dramatic green to red (or vice versa) color change that is immediately visible.

“Strategies for converting fluorescent proteins into active biosensors of intracellular biochemistry are few in number and technically challenging,” Dr Campbell said. “With this development, we can immediately image activity happening at the cellular level, offering an alternative to existing methods for detecting and imaging of protein-protein interactions in live cells.”

The FPX method is based on green and red dimerization-dependent fluorescent proteins (ddFPs) that Dr Campbell and his colleagues first reported in 2012.

Yidan Ding, PhD, a research assistant at the University of Alberta and the primary contributor to this work, found she could combine the use of both green and red ddFPs in single cells, such that the proteins could be green or red, but not both, at the same time.

By introducing modified versions of the proteins into live cells, and taking advantage of the fact that green and red fluorescence are mutually exclusive, Dr Ding was able to construct a wide variety of biosensors that underwent dramatic changes in fluorescence in response to biochemical processes of interest.

By adding this new dimension to fluorescent proteins and engineering them to be biosensors that change their color in response to specific biological events, Drs Ding and Campbell and their colleagues have provided a tool for researchers to immediately pinpoint a major change at the cellular level.

This minimizes the need for extensive biosensor optimization and provides a versatile new approach to building the next generation of biosensors.

“This allows for a wide scope of applications,” Dr Campbell said. “It will be immediately relevant to many areas of fundamental cell biology research and practical applications such as drug discovery. Ultimately, it will help researchers achieve breakthroughs in a wide variety of areas in the life sciences, such as neuroscience, diabetes, and cancer.”

Dr Campbell has a patent pending on the technology.

The detection and imaging of protein-protein interactions in live cells just got a lot more colorful, researchers have reported in Nature Methods.

The team created a  technique that converts biochemical processes into color changes that are easily visualized.

The group said this provides a new tool scientists can use to answer questions about fundamental mechanisms in cell biology, aid the discovery of novel therapeutics, and more.

Robert E. Campbell, PhD, of the University of Alberta in Edmonton, Alberta, Canada, and his colleagues conducted this research.

They developed the technique, dubbed FPX, that employs genetically encoded fluorescent proteins to image dynamic biochemical events in live cells and tissues. The FPX method converts a change in protein-protein interactions into a dramatic green to red (or vice versa) color change that is immediately visible.

“Strategies for converting fluorescent proteins into active biosensors of intracellular biochemistry are few in number and technically challenging,” Dr Campbell said. “With this development, we can immediately image activity happening at the cellular level, offering an alternative to existing methods for detecting and imaging of protein-protein interactions in live cells.”

The FPX method is based on green and red dimerization-dependent fluorescent proteins (ddFPs) that Dr Campbell and his colleagues first reported in 2012.

Yidan Ding, PhD, a research assistant at the University of Alberta and the primary contributor to this work, found she could combine the use of both green and red ddFPs in single cells, such that the proteins could be green or red, but not both, at the same time.

By introducing modified versions of the proteins into live cells, and taking advantage of the fact that green and red fluorescence are mutually exclusive, Dr Ding was able to construct a wide variety of biosensors that underwent dramatic changes in fluorescence in response to biochemical processes of interest.

By adding this new dimension to fluorescent proteins and engineering them to be biosensors that change their color in response to specific biological events, Drs Ding and Campbell and their colleagues have provided a tool for researchers to immediately pinpoint a major change at the cellular level.

This minimizes the need for extensive biosensor optimization and provides a versatile new approach to building the next generation of biosensors.

“This allows for a wide scope of applications,” Dr Campbell said. “It will be immediately relevant to many areas of fundamental cell biology research and practical applications such as drug discovery. Ultimately, it will help researchers achieve breakthroughs in a wide variety of areas in the life sciences, such as neuroscience, diabetes, and cancer.”

Dr Campbell has a patent pending on the technology.

The detection and imaging of protein-protein interactions in live cells just got a lot more colorful, researchers have reported in Nature Methods.

The team created a  technique that converts biochemical processes into color changes that are easily visualized.

The group said this provides a new tool scientists can use to answer questions about fundamental mechanisms in cell biology, aid the discovery of novel therapeutics, and more.

Robert E. Campbell, PhD, of the University of Alberta in Edmonton, Alberta, Canada, and his colleagues conducted this research.

They developed the technique, dubbed FPX, that employs genetically encoded fluorescent proteins to image dynamic biochemical events in live cells and tissues. The FPX method converts a change in protein-protein interactions into a dramatic green to red (or vice versa) color change that is immediately visible.

“Strategies for converting fluorescent proteins into active biosensors of intracellular biochemistry are few in number and technically challenging,” Dr Campbell said. “With this development, we can immediately image activity happening at the cellular level, offering an alternative to existing methods for detecting and imaging of protein-protein interactions in live cells.”

The FPX method is based on green and red dimerization-dependent fluorescent proteins (ddFPs) that Dr Campbell and his colleagues first reported in 2012.

Yidan Ding, PhD, a research assistant at the University of Alberta and the primary contributor to this work, found she could combine the use of both green and red ddFPs in single cells, such that the proteins could be green or red, but not both, at the same time.

By introducing modified versions of the proteins into live cells, and taking advantage of the fact that green and red fluorescence are mutually exclusive, Dr Ding was able to construct a wide variety of biosensors that underwent dramatic changes in fluorescence in response to biochemical processes of interest.

By adding this new dimension to fluorescent proteins and engineering them to be biosensors that change their color in response to specific biological events, Drs Ding and Campbell and their colleagues have provided a tool for researchers to immediately pinpoint a major change at the cellular level.

This minimizes the need for extensive biosensor optimization and provides a versatile new approach to building the next generation of biosensors.

“This allows for a wide scope of applications,” Dr Campbell said. “It will be immediately relevant to many areas of fundamental cell biology research and practical applications such as drug discovery. Ultimately, it will help researchers achieve breakthroughs in a wide variety of areas in the life sciences, such as neuroscience, diabetes, and cancer.”

Dr Campbell has a patent pending on the technology.

Antihypertensive therapy would prevent about 56,000 cardiovascular events annually and 13,000 deaths from strokes, myocardial infarctions, and other causes if it were used by all U.S. adults who qualify for treatment under 2014 Joint National Committee hypertension guidelines, according to computer modeling published online Jan. 28 in the New England Journal of Medicine.

Even though the new Joint Committee guidelines are a bit less stringent than the committee’s prior 2003 advice, blood pressure remains inadequately controlled in 44% of the 64 million U.S. adults with hypertension, according to the investigators, led by Dr. Andrew Moran of Columbia University Medical Center, New York (N. Engl. J. Med. 2015;372:447-55).

The team used data from the National Health and Nutrition Examination Survey, the Framingham Heart Study, and other sources to estimate costs and benefits of expanding treatment to all U.S. adults aged 35-74 years who meet the 2014 benchmarks. They then calculated cost-effectiveness of expanding use in various subpopulations, using $50,000/quality-adjusted life-year (QALY) gained, or less, as their cut-off.

Overall, the investigators found that fuller implementation of the Joint Committee goals would pay for itself in reduced cardiovascular morbidity and mortality. The results were driven primarily by secondary prevention in patients with cardiovascular disease and primary prevention in patients with stage 2 hypertension, meaning systolic BP of 160 mm Hg or higher or diastolic BP of 100 mm Hg or higher.

“There is an enormous potential for improving population health by expanding treatment and improving control. Our findings clearly show that it would be worthwhile to significantly increase spending on office visits, home blood pressure monitoring, and interventions to improve treatment adherence. In fact, we could double treatment and monitoring spending for some patients – namely those with severe hypertension – and still break even,” Dr. Moran said in a statement announcing the results.

Treatment of patients with existing cardiovascular disease or stage 2 hypertension would save lives and costs in all men 35-74 years old and in women aged 45-74 years. The treatment of more modest hypertension – systolic BP of 140-159 mm Hg or a diastolic BP of 90-99 mm Hg – was cost effective for all men and for women also between the ages of 45 and 74 years, but treating women 35-44 years old with moderate hypertension and diabetes or kidney disease had intermediate cost-effectiveness ($125,000 per QALY), and low cost-effectiveness ($181,000 per QALY) if those comorbidities were not present.

“Some people will be alarmed about our conclusion that it may not be cost effective to treat hypertension in young adults, especially young women. It’s worth noting that our analysis didn’t capture the cumulative, lifetime effects of hypertension. It may well turn out to be cost effective to treat this group if we look at data on costs and benefits over several decades,” Dr. Moran said.

The team assumed a medication adherence rate of 75%. The costs of treatment included medications, monitoring, and drug side effects.

They did not analyze the effect of diet and lifestyle interventions for lowering blood pressure, or compare the cost-effectiveness of specific antihypertensive medication classes or combinations.

The work was funded by the National Heart, Lung, and Blood Institute, among others. The authors reported no relevant financial disclosures.

aotto@frontlinemedcom.com

Antihypertensive therapy would prevent about 56,000 cardiovascular events annually and 13,000 deaths from strokes, myocardial infarctions, and other causes if it were used by all U.S. adults who qualify for treatment under 2014 Joint National Committee hypertension guidelines, according to computer modeling published online Jan. 28 in the New England Journal of Medicine.

Even though the new Joint Committee guidelines are a bit less stringent than the committee’s prior 2003 advice, blood pressure remains inadequately controlled in 44% of the 64 million U.S. adults with hypertension, according to the investigators, led by Dr. Andrew Moran of Columbia University Medical Center, New York (N. Engl. J. Med. 2015;372:447-55).

The team used data from the National Health and Nutrition Examination Survey, the Framingham Heart Study, and other sources to estimate costs and benefits of expanding treatment to all U.S. adults aged 35-74 years who meet the 2014 benchmarks. They then calculated cost-effectiveness of expanding use in various subpopulations, using $50,000/quality-adjusted life-year (QALY) gained, or less, as their cut-off.

Overall, the investigators found that fuller implementation of the Joint Committee goals would pay for itself in reduced cardiovascular morbidity and mortality. The results were driven primarily by secondary prevention in patients with cardiovascular disease and primary prevention in patients with stage 2 hypertension, meaning systolic BP of 160 mm Hg or higher or diastolic BP of 100 mm Hg or higher.

“There is an enormous potential for improving population health by expanding treatment and improving control. Our findings clearly show that it would be worthwhile to significantly increase spending on office visits, home blood pressure monitoring, and interventions to improve treatment adherence. In fact, we could double treatment and monitoring spending for some patients – namely those with severe hypertension – and still break even,” Dr. Moran said in a statement announcing the results.

Treatment of patients with existing cardiovascular disease or stage 2 hypertension would save lives and costs in all men 35-74 years old and in women aged 45-74 years. The treatment of more modest hypertension – systolic BP of 140-159 mm Hg or a diastolic BP of 90-99 mm Hg – was cost effective for all men and for women also between the ages of 45 and 74 years, but treating women 35-44 years old with moderate hypertension and diabetes or kidney disease had intermediate cost-effectiveness ($125,000 per QALY), and low cost-effectiveness ($181,000 per QALY) if those comorbidities were not present.

“Some people will be alarmed about our conclusion that it may not be cost effective to treat hypertension in young adults, especially young women. It’s worth noting that our analysis didn’t capture the cumulative, lifetime effects of hypertension. It may well turn out to be cost effective to treat this group if we look at data on costs and benefits over several decades,” Dr. Moran said.

The team assumed a medication adherence rate of 75%. The costs of treatment included medications, monitoring, and drug side effects.

They did not analyze the effect of diet and lifestyle interventions for lowering blood pressure, or compare the cost-effectiveness of specific antihypertensive medication classes or combinations.

The work was funded by the National Heart, Lung, and Blood Institute, among others. The authors reported no relevant financial disclosures.

aotto@frontlinemedcom.com

Antihypertensive therapy would prevent about 56,000 cardiovascular events annually and 13,000 deaths from strokes, myocardial infarctions, and other causes if it were used by all U.S. adults who qualify for treatment under 2014 Joint National Committee hypertension guidelines, according to computer modeling published online Jan. 28 in the New England Journal of Medicine.

Even though the new Joint Committee guidelines are a bit less stringent than the committee’s prior 2003 advice, blood pressure remains inadequately controlled in 44% of the 64 million U.S. adults with hypertension, according to the investigators, led by Dr. Andrew Moran of Columbia University Medical Center, New York (N. Engl. J. Med. 2015;372:447-55).

The team used data from the National Health and Nutrition Examination Survey, the Framingham Heart Study, and other sources to estimate costs and benefits of expanding treatment to all U.S. adults aged 35-74 years who meet the 2014 benchmarks. They then calculated cost-effectiveness of expanding use in various subpopulations, using $50,000/quality-adjusted life-year (QALY) gained, or less, as their cut-off.

Overall, the investigators found that fuller implementation of the Joint Committee goals would pay for itself in reduced cardiovascular morbidity and mortality. The results were driven primarily by secondary prevention in patients with cardiovascular disease and primary prevention in patients with stage 2 hypertension, meaning systolic BP of 160 mm Hg or higher or diastolic BP of 100 mm Hg or higher.

“There is an enormous potential for improving population health by expanding treatment and improving control. Our findings clearly show that it would be worthwhile to significantly increase spending on office visits, home blood pressure monitoring, and interventions to improve treatment adherence. In fact, we could double treatment and monitoring spending for some patients – namely those with severe hypertension – and still break even,” Dr. Moran said in a statement announcing the results.

Treatment of patients with existing cardiovascular disease or stage 2 hypertension would save lives and costs in all men 35-74 years old and in women aged 45-74 years. The treatment of more modest hypertension – systolic BP of 140-159 mm Hg or a diastolic BP of 90-99 mm Hg – was cost effective for all men and for women also between the ages of 45 and 74 years, but treating women 35-44 years old with moderate hypertension and diabetes or kidney disease had intermediate cost-effectiveness ($125,000 per QALY), and low cost-effectiveness ($181,000 per QALY) if those comorbidities were not present.

“Some people will be alarmed about our conclusion that it may not be cost effective to treat hypertension in young adults, especially young women. It’s worth noting that our analysis didn’t capture the cumulative, lifetime effects of hypertension. It may well turn out to be cost effective to treat this group if we look at data on costs and benefits over several decades,” Dr. Moran said.

The team assumed a medication adherence rate of 75%. The costs of treatment included medications, monitoring, and drug side effects.

They did not analyze the effect of diet and lifestyle interventions for lowering blood pressure, or compare the cost-effectiveness of specific antihypertensive medication classes or combinations.

The work was funded by the National Heart, Lung, and Blood Institute, among others. The authors reported no relevant financial disclosures.

aotto@frontlinemedcom.com

Angioedema caused by ACE inhibitors resolved 70% more rapidly with icatibant than did standard therapy in a multicenter phase II study in Germany, which was reported online Jan. 29 in the New England Journal of Medicine.

Because of the increasing use of ACE inhibitors, approximately one-third of all cases of angioedema treated in emergency departments now are attributed to these agents. The current standard ED treatment of ACE inhibitor–induced angioedema is glucocorticoids plus antihistamines. However, patients generally don’t respond to this therapy, likely because this form of angioedema isn’t a histamine-mediated reaction. Instead, it is thought by some to be a bradykinin-mediated reaction, said Dr. Murat Bas of the department of otorhinolaryngology, Technische Universität München (Germany), and his associates.

Icatibant injections (Firazyr) are approved by the Food and Drug Administration for the treatment of acute attacks of hereditary angioedema in adults 18 years of age and older. The drug also is being studied in the United States for the treatment of ACE-inhibitor–induced angioedema.

Since ACE inhibitors interfere with the breakdown of bradykinin, and bradykinin-mediated hereditary angioedema is usually treated with bradykinin-receptor antagonists such as icatibant, the investigators performed a double-blind randomized trial comparing subcutaneous icatibant against standard treatment in 27 adults who presented to four German EDs during a 1.5-year period.

The primary endpoint – the time to complete resolution of ACE inhibitor–induced angioedema – was 8 hours with icatibant and 27 hours with standard therapy. Angioedema resolved within 4 hours in five patients (38%) given icatibant; none of the patients given standard therapy responded that quickly. The onset of symptom relief was 2 hours with icatibant and 12 hours with standard glucocorticoids plus antihistamines, a significant difference as judged by the study participants and the researchers. Also, the physician-assessed severity of angioedema began to abate within 1 hour of icatibant administration and within 8 hours for standard treatment (N. Engl. J. Med. 2015 Jan. 29 [doi:10.1056/NEJMoa1312524]).

“Although the sample size in this trial was too small to allow for a robust evaluation of safety, no patient discontinued participation in the study owing to adverse events,” Dr. Bas and his associates added.

Dr. Bas reported receiving grants and personal fees from Shire, the maker of icatibant, as did some of his associates.

Angioedema caused by ACE inhibitors resolved 70% more rapidly with icatibant than did standard therapy in a multicenter phase II study in Germany, which was reported online Jan. 29 in the New England Journal of Medicine.

Because of the increasing use of ACE inhibitors, approximately one-third of all cases of angioedema treated in emergency departments now are attributed to these agents. The current standard ED treatment of ACE inhibitor–induced angioedema is glucocorticoids plus antihistamines. However, patients generally don’t respond to this therapy, likely because this form of angioedema isn’t a histamine-mediated reaction. Instead, it is thought by some to be a bradykinin-mediated reaction, said Dr. Murat Bas of the department of otorhinolaryngology, Technische Universität München (Germany), and his associates.

Icatibant injections (Firazyr) are approved by the Food and Drug Administration for the treatment of acute attacks of hereditary angioedema in adults 18 years of age and older. The drug also is being studied in the United States for the treatment of ACE-inhibitor–induced angioedema.

Since ACE inhibitors interfere with the breakdown of bradykinin, and bradykinin-mediated hereditary angioedema is usually treated with bradykinin-receptor antagonists such as icatibant, the investigators performed a double-blind randomized trial comparing subcutaneous icatibant against standard treatment in 27 adults who presented to four German EDs during a 1.5-year period.

The primary endpoint – the time to complete resolution of ACE inhibitor–induced angioedema – was 8 hours with icatibant and 27 hours with standard therapy. Angioedema resolved within 4 hours in five patients (38%) given icatibant; none of the patients given standard therapy responded that quickly. The onset of symptom relief was 2 hours with icatibant and 12 hours with standard glucocorticoids plus antihistamines, a significant difference as judged by the study participants and the researchers. Also, the physician-assessed severity of angioedema began to abate within 1 hour of icatibant administration and within 8 hours for standard treatment (N. Engl. J. Med. 2015 Jan. 29 [doi:10.1056/NEJMoa1312524]).

“Although the sample size in this trial was too small to allow for a robust evaluation of safety, no patient discontinued participation in the study owing to adverse events,” Dr. Bas and his associates added.

Dr. Bas reported receiving grants and personal fees from Shire, the maker of icatibant, as did some of his associates.

Angioedema caused by ACE inhibitors resolved 70% more rapidly with icatibant than did standard therapy in a multicenter phase II study in Germany, which was reported online Jan. 29 in the New England Journal of Medicine.

Because of the increasing use of ACE inhibitors, approximately one-third of all cases of angioedema treated in emergency departments now are attributed to these agents. The current standard ED treatment of ACE inhibitor–induced angioedema is glucocorticoids plus antihistamines. However, patients generally don’t respond to this therapy, likely because this form of angioedema isn’t a histamine-mediated reaction. Instead, it is thought by some to be a bradykinin-mediated reaction, said Dr. Murat Bas of the department of otorhinolaryngology, Technische Universität München (Germany), and his associates.

Icatibant injections (Firazyr) are approved by the Food and Drug Administration for the treatment of acute attacks of hereditary angioedema in adults 18 years of age and older. The drug also is being studied in the United States for the treatment of ACE-inhibitor–induced angioedema.

Since ACE inhibitors interfere with the breakdown of bradykinin, and bradykinin-mediated hereditary angioedema is usually treated with bradykinin-receptor antagonists such as icatibant, the investigators performed a double-blind randomized trial comparing subcutaneous icatibant against standard treatment in 27 adults who presented to four German EDs during a 1.5-year period.

The primary endpoint – the time to complete resolution of ACE inhibitor–induced angioedema – was 8 hours with icatibant and 27 hours with standard therapy. Angioedema resolved within 4 hours in five patients (38%) given icatibant; none of the patients given standard therapy responded that quickly. The onset of symptom relief was 2 hours with icatibant and 12 hours with standard glucocorticoids plus antihistamines, a significant difference as judged by the study participants and the researchers. Also, the physician-assessed severity of angioedema began to abate within 1 hour of icatibant administration and within 8 hours for standard treatment (N. Engl. J. Med. 2015 Jan. 29 [doi:10.1056/NEJMoa1312524]).

“Although the sample size in this trial was too small to allow for a robust evaluation of safety, no patient discontinued participation in the study owing to adverse events,” Dr. Bas and his associates added.

Dr. Bas reported receiving grants and personal fees from Shire, the maker of icatibant, as did some of his associates.

Clinical question: Is there any difference between different resuscitative fluids (crystalloids or colloids) on mortality in critically ill sepsis patients?

Background: Fluid resuscitation, in addition to antibiotics and source control, is a cornerstone of initial management of sepsis. Resuscitation with crystalloids compared with colloids for critically ill patients has been evaluated in large randomized controlled trials and meta-analyses; however, whether any of these fluid properties translates into a survival advantage, particularly regarding the optimal fluid for resuscitation in critically ill sepsis patients, remains unclear.

Study design: Systematic review, network meta-analysis (NMA).

Setting: Database search in MEDLINE, Embase, ACP Journal Club, Cumulative Index to Nursing and Allied Health Literature (CINAHL), HealthSTAR, the Allied and Complementary Medicine Database (AMED), and the Cochrane Central Register of Controlled Trials (CENTRAL).

Synopsis: Of 9,875 records that involved adult (age =16 years) critically ill patients with severe sepsis or septic shock who required fluid resuscitation, with no restrictions on language or publication date, 14 randomized controlled trials were considered eligible. Interventions studied included any fluid or fluid strategy used for resuscitation compared with another fluid or fluid strategy. The endpoint was 90-day mortality or, if not available, 30-day intensive care unit or hospital mortality, whichever was longest.

The analysis classified fluids as crystalloids or colloids. The relevant analyses were a four-node NMA (crystalloids versus albumin versus hydroxyethyl starch [HES] versus gelatin) and a six-node NMA (crystalloids versus albumin versus HES versus gelatin, with crystalloids divided into balanced or unbalanced and HES divided into low or high molecular weight), and a conventional fixed-effects meta-analytic comparison of crystalloids versus colloids.

In the four-node analysis, the results suggested higher mortality with starches (versus crystalloids) and lower mortality with albumin (versus crystalloids and starches). In the six-node analysis, the results suggested that albumin is superior to saline and low-molecular-weight starch and that balanced crystalloids are superior to saline and starch (both high and low molecular weight).

These results highlight potentially important differences in mortality among solutions; they suggest an advantage of balanced crystalloids versus saline and low- or high-molecular-weight starch, with similar mortality results for balanced crystalloids and albumin. These differences were not detectable using a standard meta-analytic approach directly comparing “any crystalloids versus any colloids.” Biological rationale is consistent with the findings of lower mortality with balanced crystalloid solutions than with saline as it mimics the homeostatic composition of body fluids to a greater extent than unbalanced fluids. These results raise concerns about using unbalanced crystalloids in the acute resuscitation of patients with sepsis.

Bottom line: Among patients with sepsis, resuscitation with balanced crystalloids or albumin is associated with reduced mortality compared to other fluids.

Citation: Rochwerg B, Alhazzani W, Sindi A, et al; Fluids in Sepsis and Septic Shock Group. Fluid resuscitation in sepsis: a systematic review and network meta-analysis. Ann Intern Med. 2014;161(5):347-355.

Clinical question: Is there any difference between different resuscitative fluids (crystalloids or colloids) on mortality in critically ill sepsis patients?

Background: Fluid resuscitation, in addition to antibiotics and source control, is a cornerstone of initial management of sepsis. Resuscitation with crystalloids compared with colloids for critically ill patients has been evaluated in large randomized controlled trials and meta-analyses; however, whether any of these fluid properties translates into a survival advantage, particularly regarding the optimal fluid for resuscitation in critically ill sepsis patients, remains unclear.

Study design: Systematic review, network meta-analysis (NMA).

Setting: Database search in MEDLINE, Embase, ACP Journal Club, Cumulative Index to Nursing and Allied Health Literature (CINAHL), HealthSTAR, the Allied and Complementary Medicine Database (AMED), and the Cochrane Central Register of Controlled Trials (CENTRAL).

Synopsis: Of 9,875 records that involved adult (age =16 years) critically ill patients with severe sepsis or septic shock who required fluid resuscitation, with no restrictions on language or publication date, 14 randomized controlled trials were considered eligible. Interventions studied included any fluid or fluid strategy used for resuscitation compared with another fluid or fluid strategy. The endpoint was 90-day mortality or, if not available, 30-day intensive care unit or hospital mortality, whichever was longest.

The analysis classified fluids as crystalloids or colloids. The relevant analyses were a four-node NMA (crystalloids versus albumin versus hydroxyethyl starch [HES] versus gelatin) and a six-node NMA (crystalloids versus albumin versus HES versus gelatin, with crystalloids divided into balanced or unbalanced and HES divided into low or high molecular weight), and a conventional fixed-effects meta-analytic comparison of crystalloids versus colloids.

In the four-node analysis, the results suggested higher mortality with starches (versus crystalloids) and lower mortality with albumin (versus crystalloids and starches). In the six-node analysis, the results suggested that albumin is superior to saline and low-molecular-weight starch and that balanced crystalloids are superior to saline and starch (both high and low molecular weight).

These results highlight potentially important differences in mortality among solutions; they suggest an advantage of balanced crystalloids versus saline and low- or high-molecular-weight starch, with similar mortality results for balanced crystalloids and albumin. These differences were not detectable using a standard meta-analytic approach directly comparing “any crystalloids versus any colloids.” Biological rationale is consistent with the findings of lower mortality with balanced crystalloid solutions than with saline as it mimics the homeostatic composition of body fluids to a greater extent than unbalanced fluids. These results raise concerns about using unbalanced crystalloids in the acute resuscitation of patients with sepsis.

Bottom line: Among patients with sepsis, resuscitation with balanced crystalloids or albumin is associated with reduced mortality compared to other fluids.

Citation: Rochwerg B, Alhazzani W, Sindi A, et al; Fluids in Sepsis and Septic Shock Group. Fluid resuscitation in sepsis: a systematic review and network meta-analysis. Ann Intern Med. 2014;161(5):347-355.

Clinical question: Is there any difference between different resuscitative fluids (crystalloids or colloids) on mortality in critically ill sepsis patients?

Background: Fluid resuscitation, in addition to antibiotics and source control, is a cornerstone of initial management of sepsis. Resuscitation with crystalloids compared with colloids for critically ill patients has been evaluated in large randomized controlled trials and meta-analyses; however, whether any of these fluid properties translates into a survival advantage, particularly regarding the optimal fluid for resuscitation in critically ill sepsis patients, remains unclear.

Study design: Systematic review, network meta-analysis (NMA).

Setting: Database search in MEDLINE, Embase, ACP Journal Club, Cumulative Index to Nursing and Allied Health Literature (CINAHL), HealthSTAR, the Allied and Complementary Medicine Database (AMED), and the Cochrane Central Register of Controlled Trials (CENTRAL).

Synopsis: Of 9,875 records that involved adult (age =16 years) critically ill patients with severe sepsis or septic shock who required fluid resuscitation, with no restrictions on language or publication date, 14 randomized controlled trials were considered eligible. Interventions studied included any fluid or fluid strategy used for resuscitation compared with another fluid or fluid strategy. The endpoint was 90-day mortality or, if not available, 30-day intensive care unit or hospital mortality, whichever was longest.

The analysis classified fluids as crystalloids or colloids. The relevant analyses were a four-node NMA (crystalloids versus albumin versus hydroxyethyl starch [HES] versus gelatin) and a six-node NMA (crystalloids versus albumin versus HES versus gelatin, with crystalloids divided into balanced or unbalanced and HES divided into low or high molecular weight), and a conventional fixed-effects meta-analytic comparison of crystalloids versus colloids.

In the four-node analysis, the results suggested higher mortality with starches (versus crystalloids) and lower mortality with albumin (versus crystalloids and starches). In the six-node analysis, the results suggested that albumin is superior to saline and low-molecular-weight starch and that balanced crystalloids are superior to saline and starch (both high and low molecular weight).

These results highlight potentially important differences in mortality among solutions; they suggest an advantage of balanced crystalloids versus saline and low- or high-molecular-weight starch, with similar mortality results for balanced crystalloids and albumin. These differences were not detectable using a standard meta-analytic approach directly comparing “any crystalloids versus any colloids.” Biological rationale is consistent with the findings of lower mortality with balanced crystalloid solutions than with saline as it mimics the homeostatic composition of body fluids to a greater extent than unbalanced fluids. These results raise concerns about using unbalanced crystalloids in the acute resuscitation of patients with sepsis.

Bottom line: Among patients with sepsis, resuscitation with balanced crystalloids or albumin is associated with reduced mortality compared to other fluids.

Citation: Rochwerg B, Alhazzani W, Sindi A, et al; Fluids in Sepsis and Septic Shock Group. Fluid resuscitation in sepsis: a systematic review and network meta-analysis. Ann Intern Med. 2014;161(5):347-355.

The combination of direct feedback from web-based physician dashboards and a pay-for-performance program “significantly improved” hospitalists’ compliance with VTE prophylaxis, according to a recent study in the Journal of Hospital Medicine.

In the report, hospitalist Henry Michtalik, MD, MPH, MHS, and colleagues noted that while physicians’ compliance increased most by using dashboards, the combination of the two methods is recommended to “combine extrinsic and intrinsic motivations.”

“They end up enhancing each other,” says Dr. Michtalik, associate faculty and international consultant at the Armstrong Institute for Patient Safety and Quality at Johns Hopkins Medicine in Baltimore. “I really don’t think you can have one without the other. If you have a pay-for-performance program without a dashboard, that’s the equivalent of driving down an unfamiliar highway without any signs. You’re not really sure where you were, you’re not really sure where you’re going, you think you’re on the right path, but you would sure feel a lot better if you had some markers along the way.”

The study analyzed 3,144 inpatient admissions at a tertiary-care medical center from 2009 to 2012. During the dashboard-only intervention period, providers improved compliance by 4% on average (95% CI, 3–5; P<0.001). With the addition of the pay-for-performance program, providers improved another 4% (95% CI, 3–5; P<0.001). Group compliance improved from 86% (95% CI, 85–88) during the baseline period to 90% (95% CI, 88–93) during the dashboard period (P=0.01) and 94% (95% CI, 93–96) during the pay-for-performance program (P=0.01).

Dr. Michtalik says that in an era of value-based purchasing and broader healthcare reform, most institutions are already collecting data on VTE prophylaxis. The next step, he says, should be bringing data to the provider level and making that an agent for change.

Visit our website for more information on VTE prophylaxis.

The combination of direct feedback from web-based physician dashboards and a pay-for-performance program “significantly improved” hospitalists’ compliance with VTE prophylaxis, according to a recent study in the Journal of Hospital Medicine.

In the report, hospitalist Henry Michtalik, MD, MPH, MHS, and colleagues noted that while physicians’ compliance increased most by using dashboards, the combination of the two methods is recommended to “combine extrinsic and intrinsic motivations.”

“They end up enhancing each other,” says Dr. Michtalik, associate faculty and international consultant at the Armstrong Institute for Patient Safety and Quality at Johns Hopkins Medicine in Baltimore. “I really don’t think you can have one without the other. If you have a pay-for-performance program without a dashboard, that’s the equivalent of driving down an unfamiliar highway without any signs. You’re not really sure where you were, you’re not really sure where you’re going, you think you’re on the right path, but you would sure feel a lot better if you had some markers along the way.”

The study analyzed 3,144 inpatient admissions at a tertiary-care medical center from 2009 to 2012. During the dashboard-only intervention period, providers improved compliance by 4% on average (95% CI, 3–5; P<0.001). With the addition of the pay-for-performance program, providers improved another 4% (95% CI, 3–5; P<0.001). Group compliance improved from 86% (95% CI, 85–88) during the baseline period to 90% (95% CI, 88–93) during the dashboard period (P=0.01) and 94% (95% CI, 93–96) during the pay-for-performance program (P=0.01).

Dr. Michtalik says that in an era of value-based purchasing and broader healthcare reform, most institutions are already collecting data on VTE prophylaxis. The next step, he says, should be bringing data to the provider level and making that an agent for change.

Visit our website for more information on VTE prophylaxis.

The combination of direct feedback from web-based physician dashboards and a pay-for-performance program “significantly improved” hospitalists’ compliance with VTE prophylaxis, according to a recent study in the Journal of Hospital Medicine.

In the report, hospitalist Henry Michtalik, MD, MPH, MHS, and colleagues noted that while physicians’ compliance increased most by using dashboards, the combination of the two methods is recommended to “combine extrinsic and intrinsic motivations.”

“They end up enhancing each other,” says Dr. Michtalik, associate faculty and international consultant at the Armstrong Institute for Patient Safety and Quality at Johns Hopkins Medicine in Baltimore. “I really don’t think you can have one without the other. If you have a pay-for-performance program without a dashboard, that’s the equivalent of driving down an unfamiliar highway without any signs. You’re not really sure where you were, you’re not really sure where you’re going, you think you’re on the right path, but you would sure feel a lot better if you had some markers along the way.”

The study analyzed 3,144 inpatient admissions at a tertiary-care medical center from 2009 to 2012. During the dashboard-only intervention period, providers improved compliance by 4% on average (95% CI, 3–5; P<0.001). With the addition of the pay-for-performance program, providers improved another 4% (95% CI, 3–5; P<0.001). Group compliance improved from 86% (95% CI, 85–88) during the baseline period to 90% (95% CI, 88–93) during the dashboard period (P=0.01) and 94% (95% CI, 93–96) during the pay-for-performance program (P=0.01).

Dr. Michtalik says that in an era of value-based purchasing and broader healthcare reform, most institutions are already collecting data on VTE prophylaxis. The next step, he says, should be bringing data to the provider level and making that an agent for change.

Visit our website for more information on VTE prophylaxis.

Suicide is the tenth leading cause of death among Americans and the third leading cause among those age 15 to 24.¹ As many as 36% of suicide victims leave a sui­cide note.² Researchers have analyzed such notes with the aim of identifying specific content and patterns that might aid in creating more effective strategies for preventing suicide.^3-5

One study found that the presence of a suicide note is an indi­cator of serious intent; that is, when the initial attempt fails, those who had left a suicide note were found to be at increased risk of subsequent completed suicide.4 Researchers also found that 75% of suicide notes contained the theme “apology/shame,” suggesting that many suicide victims might have welcomed an alternative to suicide to solve their personal predicament. Tragically, however, most suicide notes are not discovered until suicide has been attempted or completed.⁴

That’s where social media comes in. As platforms for self-expression, social networking sites such as Facebook, Twitter, and Tumblr are sources of real-time information that could aid in suicide prevention.⁶ With that in mind, we:
   • present 2 cases in which a patient announced her sui­cidal ideation on Facebook
   • consider the opportunities that social media present for early intervention
   • propose high-tech monitoring methods for high-risk patients.

CASE 1 Major depressive disorder (MDD) and nonadherence
Ms. S, age 24, has a 4-year history of MDD and treatment non­adherence. She had no history of suicide attempt or inpatient treatment, but she had briefly engaged in psychotherapy before discontinuing visits. Physically healthy and employed as a security officer, Ms. S recently broke up with her boy­friend who had abused her physically—and against whom she had an order of protection.

On the day in question, Ms. S posted several status updates on Facebook expressing hope­lessness, which, over the course of the day, esca­lated to expression of frank suicidal ideation:
   • “I am ugly, no man would ever want to live with me.”
   • “I have made no effect on the world and I’m just a waste of space.”
   • “It’s sad that I want to die but such is life. We all die one day.”
   • “I’m going to kill myself. It was nice knowing you world. Goodbye everyone.”

CASE 2 Substance abuse and previous suicide attempt
Ms. B, age 21, had a remote (approximately age 16) history of a suicide attempt and was actively abusing 3,4-methylenedioxymeth­amphetamine (MDMA [“Ecstasy,” “Molly”]) and Cannabis. She was not receiving outpatient care. One afternoon, Ms. B walked into the emergency department (ED) and said she had just taken 17 ibuprofen pills with the intent of killing herself.

On initial evaluation, Ms. B was irritable and uncooperative, denying all psychiatric symptoms and refusing to divulge details of her recent behavior. Her mother, who had not accompanied her daughter to the ED, reported that Ms. B had engaged in excessive risk-taking—speeding, driving while intoxi­cated, having multiple sex partners—for the past 5 years, resulting in several arrests for minor offenses, and she had been depressed and was sleeping and eating poorly in the 2 weeks leading up to the suicide attempt.

Two days ago, her mother added, Ms. B had posted disturbing notes on Facebook: ”Life is useless,” she declared in one post; “I’d be better off dead,” in another.

Suicidal content online
Worldwide, Facebook has 1.35 billion active users each month.⁷ Thus far, a limited num­ber of posts indicating suicidal intent have been reported in the lay press,⁸ but evidence suggests that the use of social media for this purpose is an emerging trend.⁹

A search of the literature yielded only 3 case reports.^8,10,11 In one case, a delayed response to a suicide note resulted in a fail­ure to prevent the suicide.⁸ In another, a cli­nician’s discovery of a patient’s explicitly suicidal Facebook post led to what the team leader described as a more meaningful thera­peutic relationship.¹⁰ The clinician’s discov­ery might have been pivotal in preventing the patient from committing suicide.

The authors of these case reports explored the idea of using Facebook for suicide pre­vention, raising a number of practical and ethical issues. Among them are the poten­tial for immediate intervention by other Facebook users and the extent to which sui­cidal posts on social media sites induce copy­cat suicides.⁸

Issues associated with clinicians’ use of social media to follow or monitor patients include the ethical concepts of beneficence and nonmaleficence, privacy and confi­dentiality, clinical judgment, and informed consent,8,10 including potential benefit and harm and the difference between actual and perceived privacy violations. Bennett et al11 recommend developing guidelines for the use of social media to enhance medical care and provide appropriate protections to both patients and providers.

Reporting suicidal content. Although the primary purpose of Facebook is to give users the opportunity to share life events and thoughts with friends and family, the com­pany does address the question of suicidal content in its Help Center (Box 1).¹² As our 2 cases illustrate, however, intervention can be significantly delayed.

 

CASE 1 CONTINUED Call to 911
Fortunately for Ms. S, a friend who read her Facebook posts called 911; even then, however, 16 hours passed between the initial postings and the patient’s arrival at the ED. When emer­gency medical services brought Ms. S to the Comprehensive Psychiatry Emergency Program, she acknowledged suicidal ideation with­out an active plan. Other symptoms included depressed mood, a sense of hopelessness, feel­ings of worthlessness lasting >2 months, low self-esteem, dissatisfaction with body image, and a recent verbal altercation with a friend.

Ms. S was admitted to the inpatient unit for further observation and stabilization.

CASE 2 CONTINUED No one answered her calls
Ms. B, who did not arrive at the ED until 2 days after her suicidal posts, corroborated the history given by her mother. She also reported that she had attempted to reach out to her friends for support, but no one had answered her phone calls. She felt hurt because of this, Ms. B said, and impulsively ingested the pills.

Ms. B said she regretted the suicide attempt. Nevertheless, in light of her recent attempt and persistent distress, she was admitted to the inpa­tient unit for observation and stabilization.

Can artificial intelligence help?
There is no effective means of tracking high-risk patients after their first contact with the mental health system, despite the fact that (1) those who attempt suicide are at high risk of subsequent suicide attempts³ and (2) we have the potential to prevent future attempts based on self-expressed online cues. We pro­pose machine learning algorithms—a branch of artificial intelligence—to capture and process suicide notes on Facebook in real time.

Machine learning can be broadly defined as computational methods using experience to improve performance or make accurate pre­dictions. In this context, “experience” refers to past information, typically in the form of electronic data collected and analyzed to design accurate and efficient predictive algorithms. Machine learning, which incor­porates fundamental concepts in computer science, as well as statistics, probability, and optimization, already has been established in a variety of applications, such as detecting e-mail spam, natural language processing, and computational biology.¹³

Affective computing, known as emotion-oriented computing, is a branch of artifi­cial intelligence that involves the design of systems and devices that can recognize, interpret, and process human moods and emotions (Box 2).¹⁴

Prediction models, developed by Poulin et al¹⁵ to estimate the risk of suicide (based on keywords and multiword phrases from unstructured clinical notes from a national sample of U.S. Veterans Administration medical records), resulted in an inference accuracy of ≥65%. Pestian et al¹⁶ created and annotated a collection of suicide notes—a vital resource for scientists to use for machine learning and data mining. Machine learning algorithms based on such notes and clini­cal data might be used to capture alarming social media posts by high-risk patients and activate crisis management, with potentially life-saving results.

But limitations remain
It is not easy to identify or analyze people’s emotions based on social media posts; emo­tions can be implicit, based on specific events or situations. To distinguish among different emotions purely on the basis of keywords is to deal in great subtlety. Framing algorithms to include multiple parameters—the dura­tion of suicidal content and the number of suicidal posts, for example—would help mitigate the risk of false alarms.

Another problem is that not all Facebook profiles are public. In fact, only 28% of users share all or most of their posts with anyone other than their friends.¹⁷ This limitation could be addressed by urging patients iden­tified as being at high risk of suicide during an initial clinical encounter with a mental health provider to “friend” a generic Web page created by the hospital or clinic to pro­tect patients’ privacy.

As Levahot et al¹⁰ wrote in their report of the patient whose clinician discovered a patient’s explicitly suicidal Facebook post, the incident “did not hinder the therapeu­tic alliance.” Instead, the team leader said, the discovery deepened the therapeutic relationship and helped the patient “better understand his mental illness and need for increased support.”

Bottom Line
Machine learning algorithms offer the possibility of analyzing status updates from patients who express suicidal ideation on social media and alerting clinicians to the need for early intervention. There are steps clinicians can take now, however, to take advantage of Facebook, in particular, to monitor and potentially prevent suicide attempts by those at high risk.

Related Resource
• Ahuja AK, Biesaga K, Sudak DM, et al. Suicide on Facebook. J Psychiatr Pract. 2014;20(2):141-146.

Acknowledgement
Zafar Sharif MD, Associate Clinical Professor of Psychiatry, Columbia University College of Physicians and Surgeons, and Director of Psychiatry, Harlem Hospital Center, New York, New York, and Michael Yogman MD, Assistant Clinical Professor of Pediatrics, Harvard Medical School, Boston Children’s Hospital, Boston, Massachusetts, provided insight into the topic and useful feedback on the manuscript of this article.

 

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Suicide is the tenth leading cause of death among Americans and the third leading cause among those age 15 to 24.¹ As many as 36% of suicide victims leave a sui­cide note.² Researchers have analyzed such notes with the aim of identifying specific content and patterns that might aid in creating more effective strategies for preventing suicide.^3-5

One study found that the presence of a suicide note is an indi­cator of serious intent; that is, when the initial attempt fails, those who had left a suicide note were found to be at increased risk of subsequent completed suicide.4 Researchers also found that 75% of suicide notes contained the theme “apology/shame,” suggesting that many suicide victims might have welcomed an alternative to suicide to solve their personal predicament. Tragically, however, most suicide notes are not discovered until suicide has been attempted or completed.⁴

That’s where social media comes in. As platforms for self-expression, social networking sites such as Facebook, Twitter, and Tumblr are sources of real-time information that could aid in suicide prevention.⁶ With that in mind, we:
   • present 2 cases in which a patient announced her sui­cidal ideation on Facebook
   • consider the opportunities that social media present for early intervention
   • propose high-tech monitoring methods for high-risk patients.

CASE 1 Major depressive disorder (MDD) and nonadherence
Ms. S, age 24, has a 4-year history of MDD and treatment non­adherence. She had no history of suicide attempt or inpatient treatment, but she had briefly engaged in psychotherapy before discontinuing visits. Physically healthy and employed as a security officer, Ms. S recently broke up with her boy­friend who had abused her physically—and against whom she had an order of protection.

On the day in question, Ms. S posted several status updates on Facebook expressing hope­lessness, which, over the course of the day, esca­lated to expression of frank suicidal ideation:
   • “I am ugly, no man would ever want to live with me.”
   • “I have made no effect on the world and I’m just a waste of space.”
   • “It’s sad that I want to die but such is life. We all die one day.”
   • “I’m going to kill myself. It was nice knowing you world. Goodbye everyone.”

CASE 2 Substance abuse and previous suicide attempt
Ms. B, age 21, had a remote (approximately age 16) history of a suicide attempt and was actively abusing 3,4-methylenedioxymeth­amphetamine (MDMA [“Ecstasy,” “Molly”]) and Cannabis. She was not receiving outpatient care. One afternoon, Ms. B walked into the emergency department (ED) and said she had just taken 17 ibuprofen pills with the intent of killing herself.

On initial evaluation, Ms. B was irritable and uncooperative, denying all psychiatric symptoms and refusing to divulge details of her recent behavior. Her mother, who had not accompanied her daughter to the ED, reported that Ms. B had engaged in excessive risk-taking—speeding, driving while intoxi­cated, having multiple sex partners—for the past 5 years, resulting in several arrests for minor offenses, and she had been depressed and was sleeping and eating poorly in the 2 weeks leading up to the suicide attempt.

Two days ago, her mother added, Ms. B had posted disturbing notes on Facebook: ”Life is useless,” she declared in one post; “I’d be better off dead,” in another.

Suicidal content online
Worldwide, Facebook has 1.35 billion active users each month.⁷ Thus far, a limited num­ber of posts indicating suicidal intent have been reported in the lay press,⁸ but evidence suggests that the use of social media for this purpose is an emerging trend.⁹

A search of the literature yielded only 3 case reports.^8,10,11 In one case, a delayed response to a suicide note resulted in a fail­ure to prevent the suicide.⁸ In another, a cli­nician’s discovery of a patient’s explicitly suicidal Facebook post led to what the team leader described as a more meaningful thera­peutic relationship.¹⁰ The clinician’s discov­ery might have been pivotal in preventing the patient from committing suicide.

The authors of these case reports explored the idea of using Facebook for suicide pre­vention, raising a number of practical and ethical issues. Among them are the poten­tial for immediate intervention by other Facebook users and the extent to which sui­cidal posts on social media sites induce copy­cat suicides.⁸

Issues associated with clinicians’ use of social media to follow or monitor patients include the ethical concepts of beneficence and nonmaleficence, privacy and confi­dentiality, clinical judgment, and informed consent,8,10 including potential benefit and harm and the difference between actual and perceived privacy violations. Bennett et al11 recommend developing guidelines for the use of social media to enhance medical care and provide appropriate protections to both patients and providers.

Reporting suicidal content. Although the primary purpose of Facebook is to give users the opportunity to share life events and thoughts with friends and family, the com­pany does address the question of suicidal content in its Help Center (Box 1).¹² As our 2 cases illustrate, however, intervention can be significantly delayed.

 

CASE 1 CONTINUED Call to 911
Fortunately for Ms. S, a friend who read her Facebook posts called 911; even then, however, 16 hours passed between the initial postings and the patient’s arrival at the ED. When emer­gency medical services brought Ms. S to the Comprehensive Psychiatry Emergency Program, she acknowledged suicidal ideation with­out an active plan. Other symptoms included depressed mood, a sense of hopelessness, feel­ings of worthlessness lasting >2 months, low self-esteem, dissatisfaction with body image, and a recent verbal altercation with a friend.

Ms. S was admitted to the inpatient unit for further observation and stabilization.

CASE 2 CONTINUED No one answered her calls
Ms. B, who did not arrive at the ED until 2 days after her suicidal posts, corroborated the history given by her mother. She also reported that she had attempted to reach out to her friends for support, but no one had answered her phone calls. She felt hurt because of this, Ms. B said, and impulsively ingested the pills.

Ms. B said she regretted the suicide attempt. Nevertheless, in light of her recent attempt and persistent distress, she was admitted to the inpa­tient unit for observation and stabilization.

Can artificial intelligence help?
There is no effective means of tracking high-risk patients after their first contact with the mental health system, despite the fact that (1) those who attempt suicide are at high risk of subsequent suicide attempts³ and (2) we have the potential to prevent future attempts based on self-expressed online cues. We pro­pose machine learning algorithms—a branch of artificial intelligence—to capture and process suicide notes on Facebook in real time.

Machine learning can be broadly defined as computational methods using experience to improve performance or make accurate pre­dictions. In this context, “experience” refers to past information, typically in the form of electronic data collected and analyzed to design accurate and efficient predictive algorithms. Machine learning, which incor­porates fundamental concepts in computer science, as well as statistics, probability, and optimization, already has been established in a variety of applications, such as detecting e-mail spam, natural language processing, and computational biology.¹³

Affective computing, known as emotion-oriented computing, is a branch of artifi­cial intelligence that involves the design of systems and devices that can recognize, interpret, and process human moods and emotions (Box 2).¹⁴

Prediction models, developed by Poulin et al¹⁵ to estimate the risk of suicide (based on keywords and multiword phrases from unstructured clinical notes from a national sample of U.S. Veterans Administration medical records), resulted in an inference accuracy of ≥65%. Pestian et al¹⁶ created and annotated a collection of suicide notes—a vital resource for scientists to use for machine learning and data mining. Machine learning algorithms based on such notes and clini­cal data might be used to capture alarming social media posts by high-risk patients and activate crisis management, with potentially life-saving results.

But limitations remain
It is not easy to identify or analyze people’s emotions based on social media posts; emo­tions can be implicit, based on specific events or situations. To distinguish among different emotions purely on the basis of keywords is to deal in great subtlety. Framing algorithms to include multiple parameters—the dura­tion of suicidal content and the number of suicidal posts, for example—would help mitigate the risk of false alarms.

Another problem is that not all Facebook profiles are public. In fact, only 28% of users share all or most of their posts with anyone other than their friends.¹⁷ This limitation could be addressed by urging patients iden­tified as being at high risk of suicide during an initial clinical encounter with a mental health provider to “friend” a generic Web page created by the hospital or clinic to pro­tect patients’ privacy.

As Levahot et al¹⁰ wrote in their report of the patient whose clinician discovered a patient’s explicitly suicidal Facebook post, the incident “did not hinder the therapeu­tic alliance.” Instead, the team leader said, the discovery deepened the therapeutic relationship and helped the patient “better understand his mental illness and need for increased support.”

Bottom Line
Machine learning algorithms offer the possibility of analyzing status updates from patients who express suicidal ideation on social media and alerting clinicians to the need for early intervention. There are steps clinicians can take now, however, to take advantage of Facebook, in particular, to monitor and potentially prevent suicide attempts by those at high risk.

Related Resource
• Ahuja AK, Biesaga K, Sudak DM, et al. Suicide on Facebook. J Psychiatr Pract. 2014;20(2):141-146.

Acknowledgement
Zafar Sharif MD, Associate Clinical Professor of Psychiatry, Columbia University College of Physicians and Surgeons, and Director of Psychiatry, Harlem Hospital Center, New York, New York, and Michael Yogman MD, Assistant Clinical Professor of Pediatrics, Harvard Medical School, Boston Children’s Hospital, Boston, Massachusetts, provided insight into the topic and useful feedback on the manuscript of this article.

 

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Suicide is the tenth leading cause of death among Americans and the third leading cause among those age 15 to 24.¹ As many as 36% of suicide victims leave a sui­cide note.² Researchers have analyzed such notes with the aim of identifying specific content and patterns that might aid in creating more effective strategies for preventing suicide.^3-5

One study found that the presence of a suicide note is an indi­cator of serious intent; that is, when the initial attempt fails, those who had left a suicide note were found to be at increased risk of subsequent completed suicide.4 Researchers also found that 75% of suicide notes contained the theme “apology/shame,” suggesting that many suicide victims might have welcomed an alternative to suicide to solve their personal predicament. Tragically, however, most suicide notes are not discovered until suicide has been attempted or completed.⁴

That’s where social media comes in. As platforms for self-expression, social networking sites such as Facebook, Twitter, and Tumblr are sources of real-time information that could aid in suicide prevention.⁶ With that in mind, we:
   • present 2 cases in which a patient announced her sui­cidal ideation on Facebook
   • consider the opportunities that social media present for early intervention
   • propose high-tech monitoring methods for high-risk patients.

CASE 1 Major depressive disorder (MDD) and nonadherence
Ms. S, age 24, has a 4-year history of MDD and treatment non­adherence. She had no history of suicide attempt or inpatient treatment, but she had briefly engaged in psychotherapy before discontinuing visits. Physically healthy and employed as a security officer, Ms. S recently broke up with her boy­friend who had abused her physically—and against whom she had an order of protection.

On the day in question, Ms. S posted several status updates on Facebook expressing hope­lessness, which, over the course of the day, esca­lated to expression of frank suicidal ideation:
   • “I am ugly, no man would ever want to live with me.”
   • “I have made no effect on the world and I’m just a waste of space.”
   • “It’s sad that I want to die but such is life. We all die one day.”
   • “I’m going to kill myself. It was nice knowing you world. Goodbye everyone.”

CASE 2 Substance abuse and previous suicide attempt
Ms. B, age 21, had a remote (approximately age 16) history of a suicide attempt and was actively abusing 3,4-methylenedioxymeth­amphetamine (MDMA [“Ecstasy,” “Molly”]) and Cannabis. She was not receiving outpatient care. One afternoon, Ms. B walked into the emergency department (ED) and said she had just taken 17 ibuprofen pills with the intent of killing herself.

On initial evaluation, Ms. B was irritable and uncooperative, denying all psychiatric symptoms and refusing to divulge details of her recent behavior. Her mother, who had not accompanied her daughter to the ED, reported that Ms. B had engaged in excessive risk-taking—speeding, driving while intoxi­cated, having multiple sex partners—for the past 5 years, resulting in several arrests for minor offenses, and she had been depressed and was sleeping and eating poorly in the 2 weeks leading up to the suicide attempt.

Two days ago, her mother added, Ms. B had posted disturbing notes on Facebook: ”Life is useless,” she declared in one post; “I’d be better off dead,” in another.

Suicidal content online
Worldwide, Facebook has 1.35 billion active users each month.⁷ Thus far, a limited num­ber of posts indicating suicidal intent have been reported in the lay press,⁸ but evidence suggests that the use of social media for this purpose is an emerging trend.⁹

A search of the literature yielded only 3 case reports.^8,10,11 In one case, a delayed response to a suicide note resulted in a fail­ure to prevent the suicide.⁸ In another, a cli­nician’s discovery of a patient’s explicitly suicidal Facebook post led to what the team leader described as a more meaningful thera­peutic relationship.¹⁰ The clinician’s discov­ery might have been pivotal in preventing the patient from committing suicide.

The authors of these case reports explored the idea of using Facebook for suicide pre­vention, raising a number of practical and ethical issues. Among them are the poten­tial for immediate intervention by other Facebook users and the extent to which sui­cidal posts on social media sites induce copy­cat suicides.⁸

Issues associated with clinicians’ use of social media to follow or monitor patients include the ethical concepts of beneficence and nonmaleficence, privacy and confi­dentiality, clinical judgment, and informed consent,8,10 including potential benefit and harm and the difference between actual and perceived privacy violations. Bennett et al11 recommend developing guidelines for the use of social media to enhance medical care and provide appropriate protections to both patients and providers.

Reporting suicidal content. Although the primary purpose of Facebook is to give users the opportunity to share life events and thoughts with friends and family, the com­pany does address the question of suicidal content in its Help Center (Box 1).¹² As our 2 cases illustrate, however, intervention can be significantly delayed.

 

CASE 1 CONTINUED Call to 911
Fortunately for Ms. S, a friend who read her Facebook posts called 911; even then, however, 16 hours passed between the initial postings and the patient’s arrival at the ED. When emer­gency medical services brought Ms. S to the Comprehensive Psychiatry Emergency Program, she acknowledged suicidal ideation with­out an active plan. Other symptoms included depressed mood, a sense of hopelessness, feel­ings of worthlessness lasting >2 months, low self-esteem, dissatisfaction with body image, and a recent verbal altercation with a friend.

Ms. S was admitted to the inpatient unit for further observation and stabilization.

CASE 2 CONTINUED No one answered her calls
Ms. B, who did not arrive at the ED until 2 days after her suicidal posts, corroborated the history given by her mother. She also reported that she had attempted to reach out to her friends for support, but no one had answered her phone calls. She felt hurt because of this, Ms. B said, and impulsively ingested the pills.

Ms. B said she regretted the suicide attempt. Nevertheless, in light of her recent attempt and persistent distress, she was admitted to the inpa­tient unit for observation and stabilization.

Can artificial intelligence help?
There is no effective means of tracking high-risk patients after their first contact with the mental health system, despite the fact that (1) those who attempt suicide are at high risk of subsequent suicide attempts³ and (2) we have the potential to prevent future attempts based on self-expressed online cues. We pro­pose machine learning algorithms—a branch of artificial intelligence—to capture and process suicide notes on Facebook in real time.

Machine learning can be broadly defined as computational methods using experience to improve performance or make accurate pre­dictions. In this context, “experience” refers to past information, typically in the form of electronic data collected and analyzed to design accurate and efficient predictive algorithms. Machine learning, which incor­porates fundamental concepts in computer science, as well as statistics, probability, and optimization, already has been established in a variety of applications, such as detecting e-mail spam, natural language processing, and computational biology.¹³

Affective computing, known as emotion-oriented computing, is a branch of artifi­cial intelligence that involves the design of systems and devices that can recognize, interpret, and process human moods and emotions (Box 2).¹⁴

Prediction models, developed by Poulin et al¹⁵ to estimate the risk of suicide (based on keywords and multiword phrases from unstructured clinical notes from a national sample of U.S. Veterans Administration medical records), resulted in an inference accuracy of ≥65%. Pestian et al¹⁶ created and annotated a collection of suicide notes—a vital resource for scientists to use for machine learning and data mining. Machine learning algorithms based on such notes and clini­cal data might be used to capture alarming social media posts by high-risk patients and activate crisis management, with potentially life-saving results.

But limitations remain
It is not easy to identify or analyze people’s emotions based on social media posts; emo­tions can be implicit, based on specific events or situations. To distinguish among different emotions purely on the basis of keywords is to deal in great subtlety. Framing algorithms to include multiple parameters—the dura­tion of suicidal content and the number of suicidal posts, for example—would help mitigate the risk of false alarms.

Another problem is that not all Facebook profiles are public. In fact, only 28% of users share all or most of their posts with anyone other than their friends.¹⁷ This limitation could be addressed by urging patients iden­tified as being at high risk of suicide during an initial clinical encounter with a mental health provider to “friend” a generic Web page created by the hospital or clinic to pro­tect patients’ privacy.

As Levahot et al¹⁰ wrote in their report of the patient whose clinician discovered a patient’s explicitly suicidal Facebook post, the incident “did not hinder the therapeu­tic alliance.” Instead, the team leader said, the discovery deepened the therapeutic relationship and helped the patient “better understand his mental illness and need for increased support.”

Bottom Line
Machine learning algorithms offer the possibility of analyzing status updates from patients who express suicidal ideation on social media and alerting clinicians to the need for early intervention. There are steps clinicians can take now, however, to take advantage of Facebook, in particular, to monitor and potentially prevent suicide attempts by those at high risk.

Related Resource
• Ahuja AK, Biesaga K, Sudak DM, et al. Suicide on Facebook. J Psychiatr Pract. 2014;20(2):141-146.

Acknowledgement
Zafar Sharif MD, Associate Clinical Professor of Psychiatry, Columbia University College of Physicians and Surgeons, and Director of Psychiatry, Harlem Hospital Center, New York, New York, and Michael Yogman MD, Assistant Clinical Professor of Pediatrics, Harvard Medical School, Boston Children’s Hospital, Boston, Massachusetts, provided insight into the topic and useful feedback on the manuscript of this article.

 

Disclosures
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

With a prevalence >17%, depression is one of the most common mental disorders in the United States and the second leading cause of disability worldwide.^1,2 For decades, primary care and mental health providers have used selective serotonin reuptake inhibitors (SSRIs) as first-line treatment for depression—yet the remission rate after the first trial of an antidepressant is <30%, and continues to decline after a first antidepressant failure.³

That is why clinicians continue to seek effective treatments for depres­sion—ones that will provide quick and sustainable remission—and why scientists and pharmaceutical manufacturers have been competing to develop more effective antidepressant medications.

In the past 4 years, the FDA has approved 3 antidepressants—vilazodone, levomilnacipran, and vortioxetine—with the hope of increasing options for patients who suffer from major depression. These 3 antidepressants differ in their mechanisms of action from other available antidepressants, and all have been shown to have acceptable safety and tolerability profiles.

In this article, we review these novel antidepressants and present some clinical pearls for their use. We also present our observations that each agent appears to show particular advantage in a certain subpopulation of depressed patients who often do not respond, or who do not adequately respond, to other antidepressants.

Vilazodone
Vilazodone was approved by the FDA in 2011 (Table 1). The drug increases serotonin bioavailability in synapses through a strong dual action:
   • blocking serotonin reuptake through the serotonin transporter
   • partial agonism of the 5-HT1A presyn­aptic receptor.

Vilazodone also has a moderate effect on the 5-HT4 receptor and on dopamine and norepinephrine uptake inhibition.

The unique presynaptic 5-HT1A partial agonism of vilazodone is similar to that of buspirone, in which both drugs initially inhibit serotonin synthesis and neuronal firing.⁴ Researchers therefore expected that vilazodone would be more suitable for patients who have depression and a comor­bid anxiety disorder; current FDA approval, however, is for depression only.

Adverse effects. The 5-HT4 receptor on which vilazodone acts is present in the gas­trointestinal (GI) tract, and contributes to regulating symptoms in patients with irri­table bowel syndrome (IBS)⁵; not surpris­ingly, the most frequent adverse effects of vilazodone are GI in nature (diarrhea, nau­sea, vomiting).

Headache is the most common non- GI side effect of vilazodone. Depressed patients who took vilazodone had no sig­nificant weight gain and did not report adverse sexual effects, compared with sub­jects given placebo.⁶

The following case—a patient with depression, significant anxiety, and IBS— exemplifies the type of patient for whom we find vilazodone most useful.

CASE Ms. A, age 19, is a college student with a history of major depressive disorder, social anxiety, and panic attacks for 2 years and IBS for 3 years. She was taking lubiprostone for IBS, with incomplete relief of GI symptoms. Because the family history included depres­sion in Ms. A’s mother and sister, and both were doing well on escitalopram, we began a trial of that drug, 10 mg/d, that was quickly titrated to 20 mg/d.

Ms. A did not respond to 20 mg of escitalo­pram combined with psychotherapy.

We then started vilazodone, 10 mg/d after breakfast, for the first week, and reduced escital­opram to 10 mg/d. During Week 2, escitalopram was discontinued and vilazodone was increased to 20 mg/d. During Week 3, vilazodone was titrated to 40 mg/d.

Ms. A tolerated vilazodone well. Her depressive symptoms improved at the end of Week 2.

Unlike her experience with escitalopram, Ms. A’s anxiety symptoms—tenseness, racing thoughts, and panic attacks—all diminished when she switched to vilazodone. Notably, her IBS symptoms also were relieved, and she dis­continued lubiprostone.

Ms. A’s depression remained in remission for 2 years, except for a brief period one sum­mer, when she thought she “could do without any medication.” She tapered the vilazodone, week by week, to 10 mg/d, but her anxiety and bowel symptoms resurfaced to a degree that she resumed the 40-mg/d dosage.

Levomilnacipran
This drug is a 2013 addition to the small serotonin–norepinephrine reuptake inhibi­tor (SNRI) family of venlafaxine, des­venlafaxine, and duloxetine⁷ (Table 2). Levomilnacipran is the enantiomer of mil­nacipran, approved in Europe for depres­sion but only for fibromyalgia pain and peripheral neuropathy in the United States.⁸ (Levomilnacipran is not FDA-approved for treating fibromyalgia pain.)

Levomilnacipran is unique because it is more of an NSRI, so to speak, than an SNRI: That is, the drug’s uptake inhibition of norepinephrine is more potent than its serotonin inhibition. Theoretically, levomilnacipran should help improve cognitive functions linked to the action of norepinephrine, such as concentration and motivation, and in turn, improve social function. The FDA also has approved levomilnacipran for treating functional impairment in depression.⁹

Adverse effects. The norepinephrine uptake inhibition of levomilnacipran might be responsible for observed increases in heart rate and blood pressure in some patients, and dose-dependent urinary hesitancy and erectile dysfunction in others. The drug has no significant effect on weight in depressed patients, compared with placebo.

Continue to: The benefits of levomilnacipran

 

The following case illustrates the benefits of levomilnacipran in a depressed patient who suffers from chronic pain and impaired social function.

CASE Mrs. C, age 44, was referred by her outpatient psychologist and her primary care provider for management of refractory depression. She did not respond to an SSRI, an SNRI, or augmentation with bupropion and aripiprazole.

Mrs. C was on disability leave from work because of depression and cervical spine pain that might have been related to repeti­tive movement as a telephone customer service representative. She complained of loss of motivation, fatigue, and high anxiety about returning to work because of the many unhappy customers she felt she had to soothe.

Levomilnacipran was started at 20 mg/d for 2 days, then titrated to 40 mg/d for 5 days, 80 mg/d for 1 week, and 120 mg/d thereafter. Her previous antidepressants, fluoxetine and bupropion, were discontinued while levomil­nacipran was titrated.

Mrs. C continued to receive weekly psy­chotherapy and physical therapy and to take tizanidine, a muscle relaxant, and over-the-counter medications for pain. Her Patient Health Questionnaire (PHQ-9) score declined from 13 when levomilnacipran was started to 5 at the next visit, 6 weeks later.

Within 4 months of initiating levomilnacipran, Mrs. C returned to work with a series of cue cards to use when speaking with irate or unhappy customers. At that point, her cervical spine pain was barely noticeable and no longer interfered with function.

Vortioxetine
This agent has a novel multimodal mecha­nism of action (Table 3). It is an SSRI as well as a 5-HT1A full agonist and 5-HT3 receptor antagonist. Vortioxetine also has an inhibitory effect on 5-HT7 and 5-HT1D receptors and partial agonism of 5-HT1B receptors.

The downstream effect of this multi­modal action is an increase in dopamine, norepinephrine, and acetylcholine activ­ity in the prefrontal cortex.¹⁰ These down­stream effects are thought to help restore some cognitive deficits associated with depression.¹¹

Vortioxetine is the only antidepressant among the 3 discussed in this article that was studied over a long period to ensure that short-term benefits continue beyond the 6- to 8-week acute Phase-III studies. A high remission rate (61%) was observed in patients who were treated on an open-label basis with vortioxetine, 10 mg/d, then ran­domized to maintenance with vortioxetine or placebo.¹²

Older patients. Vortioxetine is unique among these 3 antidepressants in that it is the only one studied separately in geri­atric patients: In an 8-week Phase-III trial, 452 geriatric patients age 64 to 88 were ran­domized to 5 mg/d of vortioxetine or pla­cebo.¹³ Vortioxetine was significantly more effective than placebo at Week 6.

Vortioxetine also is the only antidepres­sant investigated for an effect on cognitive deficits: In a Phase-III double-blind, placebo-controlled study of 602 patients with major depressive disorder, using duloxetine as active reference, vortioxetine was found to have a significant effect on Digit Symbol Substitution Test scores, compared with pla­cebo, independent of its antidepressant effect (ie, patients who did not show any anti­depressant benefit still showed an improve­ment in attention, speed processing, memory, and executive function).¹⁴

We have found, therefore, that vortiox­etine is helpful for depressed patients who have cognitive deficits, especially geriatric patients.

CASE Mrs. B, age 84, married, has a 4-year history of depression. She has taken several antidepressants with little consistent relief.

A brief psychiatric hospitalization 2 years ago temporarily reduced the severity of Mrs. B’s depression; gradually, she relapsed. She felt hopeless and resisted another psychiatric evalu­ation. Mrs. B’s family includes several clinicians, who wondered if she was developing cognitive deficits that were interfering with her recovery.

At initial evaluation, Mrs. B failed to recall 2 of 3 objects but performed the clock drawing test perfectly—qualifying her for a diagnosis of mild cognitive impairment in addition to major depression. Her PHQ-9 score at baseline was 22.

On the assumption that the severity of her depression was contributing to cognitive defi­cits, vortioxetine, 5 mg/d, was initiated for 2 weeks and then titrated to 10 mg/d.

At 4 weeks’ follow-up, Mrs. B passed the Mini-Cog test; her PHQ-9 score fell to 8. She has remained asymptomatic for 6 months at the 10-mg/d dosage; her lowest PHQ-9 score was 5.

Adverse effects. The most common adverse effects are mild or moderate GI in nature. Weight gain and adverse sexual effects were not significantly different among patients receiving vortioxetine than among patients given placebo.

A note about the safety of these agents
All 3 of these antidepressants carry the stan­dard black-box warning about the elevated risk of suicide in patients taking an antide­pressant. None of them are approved for patients age <18.

Continue to: Suicidal ideation was reported

 

Suicidal ideation was reported in 11.2% of patients taking vortioxetine, compared with 12.5% of those given placebo15; 24% of patients taking levomilnacipran reported suicidal ideation, compared with 22% of those who took placebo.¹⁶ In a long-term study of 599 patients taking vilazodone, 4 given placebo exhibited suicidal behavior, compared with 2 who took vilazodone.¹⁷

Drug-drug interactions are an important consideration when vilazodone, levomil­nacipran, and vortioxetine are prescribed in combination with other medications. See the following discussion.

Vilazodone should be taken with food because it has 72% bioavailability after a meal.¹⁸ The drug is metabolized primarily by cytochrome P (CYP) 3A4 and CYP3A5; it does not affect CYP substrates or, it’s likely, produce significant changes to other medica­tions metabolized by the CYP pathway.

Conversely, the dosage of vilazodone should be reduced to 20 mg/d if it is co- administered with a strong CYP3A4 inhibi­tor (eg, ketoconazole). The dosage should be increased as much as 2-fold when vilazo­done is used concomitantly used with a strong CYP3A4 inducer (eg, carbamazepine) for >14 days. The maximum daily dosage should not exceed 80 mg/d.

Levomilnacipran. Unlike vilazodone and vortioxetine, levomilnacipran is affected by renal function.¹⁹ Concomitant medications, however, including those that influence CYP renal transporters (particularly CYP3A4, which metabolizes levomilnacipran), do not show an impact on the blood level of levomilnacipran.

No dosage adjustment is needed for patients who have mild renal impairment, but the maintenance dosage of levomil­nacipran for patients who have moderate or severe renal impairment should not exceed 80 mg/d in 1 dose, and 60 mg/d in 1 dose, respectively.²⁰

Vortioxetine. Seventy percent of a dose of vortioxetine is absorbed independent of food; the drug has a half-life of 66 hours. Vortioxetine is metabolized primarily by the CYP450 enzyme system, including 2D6, and, to a lesser extent, by CYP3A4, CYP3A5, CYP2C9, and CYP2C19.²¹

Vortioxetine has minimal effect on P450 substrates in in vitro studies, which was confirmed in 4 other in vivo studies.^21-23 In studies of hormonal contraception, bupro­pion, and omeprazole, vortioxetine did not produce significant changes in the blood level of the other medications. The blood level of vortioxetine increased by 128% when taken with the CYP2D6 inhibitor bupropion,²⁴ but the blood level did not markedly change with other inhibitors because the drug utilizes uses several CYP pathways. Use caution, therefore, when adding bupropion to vortioxetine because the combination elevates the risk of nausea, diarrhea, and headache.

With each agent, specific benefit
Vilazodone, levomilnacipran, and vor­tioxetine each add distinct benefit to the clinician’s toolbox of treatments for major depressive disorder. Although all antidepres­sants to some extent alleviate anxiety and pain and reverse cognitive decline associated with depression, our experience suggests using vilazodone for anxious depressed patients; levomilnacipran for depressed patients who experience pain; and vortiox­etine for depressed patients who suffer cog­nitive decline and for geriatric patients.

Bottom Line
The FDA has approved 3 antidepressants in the past 4 years: vilazodone, levomilnacipran, and vortioxetine. The hope is that these agents will bolster treatment options for major depression—perhaps especially so, as we have seen, in the anxious depressed (vilazodone), the depressed in pain (levomilnacipran), and the depressed with cognitive decline, or geriatric patients (vortioxetine).

 

Related Resources
• Kalia R, Mittal M, Preskorn S. Vilazodone for major depres­sive disorder. Current Psychiatry. 2011;10(4):84-86,88.
• Lincoln J, Wehler C. Vortioxetine for major depressive disor­der. Current Psychiatry. 2014;13(2):67-70.
• Macaluso M, Kazanchi H, Malhotra V. Levomilnacipran for the treatment of major depressive disorder. Current Psychiatry. 2013;12(12):50-52,54,55.
• McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014;17(10):1557-1567.
• Thase ME, Chen D, Edwards J, et al. Efficacy of vilazodone on anxiety symptoms in patients with major depressive disor­der. Int Clin Psychopharmacol. 2014;29(6):351-356.

Drug Brand Names
Aripiprazole • Abilify                                    Levomilnacipran • Fetzima
Bupropion • Wellbutrin, Zyban                      Lubiprostone • Amitiza
Buspirone • BuSpar                                     Milnacipran • Savella
Carbamazepine • Tegretol, Equetro               Omeprazole • Prilosec
Desvenlafaxine • Pristiq                               Tizanidine • Zanaflex
Duloxetine • Cymbalta                                 Venlafaxine • Effexor
Escitalopram • Lexapro                                Vilazodone • Viibryd
Fluoxetine • Prozac                                     Vortioxetine • Brintellix
Ketoconazole • Nizoral

With a prevalence >17%, depression is one of the most common mental disorders in the United States and the second leading cause of disability worldwide.^1,2 For decades, primary care and mental health providers have used selective serotonin reuptake inhibitors (SSRIs) as first-line treatment for depression—yet the remission rate after the first trial of an antidepressant is <30%, and continues to decline after a first antidepressant failure.³

That is why clinicians continue to seek effective treatments for depres­sion—ones that will provide quick and sustainable remission—and why scientists and pharmaceutical manufacturers have been competing to develop more effective antidepressant medications.

In the past 4 years, the FDA has approved 3 antidepressants—vilazodone, levomilnacipran, and vortioxetine—with the hope of increasing options for patients who suffer from major depression. These 3 antidepressants differ in their mechanisms of action from other available antidepressants, and all have been shown to have acceptable safety and tolerability profiles.

In this article, we review these novel antidepressants and present some clinical pearls for their use. We also present our observations that each agent appears to show particular advantage in a certain subpopulation of depressed patients who often do not respond, or who do not adequately respond, to other antidepressants.

Vilazodone
Vilazodone was approved by the FDA in 2011 (Table 1). The drug increases serotonin bioavailability in synapses through a strong dual action:
   • blocking serotonin reuptake through the serotonin transporter
   • partial agonism of the 5-HT1A presyn­aptic receptor.

Vilazodone also has a moderate effect on the 5-HT4 receptor and on dopamine and norepinephrine uptake inhibition.

The unique presynaptic 5-HT1A partial agonism of vilazodone is similar to that of buspirone, in which both drugs initially inhibit serotonin synthesis and neuronal firing.⁴ Researchers therefore expected that vilazodone would be more suitable for patients who have depression and a comor­bid anxiety disorder; current FDA approval, however, is for depression only.

Adverse effects. The 5-HT4 receptor on which vilazodone acts is present in the gas­trointestinal (GI) tract, and contributes to regulating symptoms in patients with irri­table bowel syndrome (IBS)⁵; not surpris­ingly, the most frequent adverse effects of vilazodone are GI in nature (diarrhea, nau­sea, vomiting).

Headache is the most common non- GI side effect of vilazodone. Depressed patients who took vilazodone had no sig­nificant weight gain and did not report adverse sexual effects, compared with sub­jects given placebo.⁶

The following case—a patient with depression, significant anxiety, and IBS— exemplifies the type of patient for whom we find vilazodone most useful.

CASE Ms. A, age 19, is a college student with a history of major depressive disorder, social anxiety, and panic attacks for 2 years and IBS for 3 years. She was taking lubiprostone for IBS, with incomplete relief of GI symptoms. Because the family history included depres­sion in Ms. A’s mother and sister, and both were doing well on escitalopram, we began a trial of that drug, 10 mg/d, that was quickly titrated to 20 mg/d.

Ms. A did not respond to 20 mg of escitalo­pram combined with psychotherapy.

We then started vilazodone, 10 mg/d after breakfast, for the first week, and reduced escital­opram to 10 mg/d. During Week 2, escitalopram was discontinued and vilazodone was increased to 20 mg/d. During Week 3, vilazodone was titrated to 40 mg/d.

Ms. A tolerated vilazodone well. Her depressive symptoms improved at the end of Week 2.

Unlike her experience with escitalopram, Ms. A’s anxiety symptoms—tenseness, racing thoughts, and panic attacks—all diminished when she switched to vilazodone. Notably, her IBS symptoms also were relieved, and she dis­continued lubiprostone.

Ms. A’s depression remained in remission for 2 years, except for a brief period one sum­mer, when she thought she “could do without any medication.” She tapered the vilazodone, week by week, to 10 mg/d, but her anxiety and bowel symptoms resurfaced to a degree that she resumed the 40-mg/d dosage.

Levomilnacipran
This drug is a 2013 addition to the small serotonin–norepinephrine reuptake inhibi­tor (SNRI) family of venlafaxine, des­venlafaxine, and duloxetine⁷ (Table 2). Levomilnacipran is the enantiomer of mil­nacipran, approved in Europe for depres­sion but only for fibromyalgia pain and peripheral neuropathy in the United States.⁸ (Levomilnacipran is not FDA-approved for treating fibromyalgia pain.)

Levomilnacipran is unique because it is more of an NSRI, so to speak, than an SNRI: That is, the drug’s uptake inhibition of norepinephrine is more potent than its serotonin inhibition. Theoretically, levomilnacipran should help improve cognitive functions linked to the action of norepinephrine, such as concentration and motivation, and in turn, improve social function. The FDA also has approved levomilnacipran for treating functional impairment in depression.⁹

Adverse effects. The norepinephrine uptake inhibition of levomilnacipran might be responsible for observed increases in heart rate and blood pressure in some patients, and dose-dependent urinary hesitancy and erectile dysfunction in others. The drug has no significant effect on weight in depressed patients, compared with placebo.

Continue to: The benefits of levomilnacipran

 

The following case illustrates the benefits of levomilnacipran in a depressed patient who suffers from chronic pain and impaired social function.

CASE Mrs. C, age 44, was referred by her outpatient psychologist and her primary care provider for management of refractory depression. She did not respond to an SSRI, an SNRI, or augmentation with bupropion and aripiprazole.

Mrs. C was on disability leave from work because of depression and cervical spine pain that might have been related to repeti­tive movement as a telephone customer service representative. She complained of loss of motivation, fatigue, and high anxiety about returning to work because of the many unhappy customers she felt she had to soothe.

Levomilnacipran was started at 20 mg/d for 2 days, then titrated to 40 mg/d for 5 days, 80 mg/d for 1 week, and 120 mg/d thereafter. Her previous antidepressants, fluoxetine and bupropion, were discontinued while levomil­nacipran was titrated.

Mrs. C continued to receive weekly psy­chotherapy and physical therapy and to take tizanidine, a muscle relaxant, and over-the-counter medications for pain. Her Patient Health Questionnaire (PHQ-9) score declined from 13 when levomilnacipran was started to 5 at the next visit, 6 weeks later.

Within 4 months of initiating levomilnacipran, Mrs. C returned to work with a series of cue cards to use when speaking with irate or unhappy customers. At that point, her cervical spine pain was barely noticeable and no longer interfered with function.

Vortioxetine
This agent has a novel multimodal mecha­nism of action (Table 3). It is an SSRI as well as a 5-HT1A full agonist and 5-HT3 receptor antagonist. Vortioxetine also has an inhibitory effect on 5-HT7 and 5-HT1D receptors and partial agonism of 5-HT1B receptors.

The downstream effect of this multi­modal action is an increase in dopamine, norepinephrine, and acetylcholine activ­ity in the prefrontal cortex.¹⁰ These down­stream effects are thought to help restore some cognitive deficits associated with depression.¹¹

Vortioxetine is the only antidepressant among the 3 discussed in this article that was studied over a long period to ensure that short-term benefits continue beyond the 6- to 8-week acute Phase-III studies. A high remission rate (61%) was observed in patients who were treated on an open-label basis with vortioxetine, 10 mg/d, then ran­domized to maintenance with vortioxetine or placebo.¹²

Older patients. Vortioxetine is unique among these 3 antidepressants in that it is the only one studied separately in geri­atric patients: In an 8-week Phase-III trial, 452 geriatric patients age 64 to 88 were ran­domized to 5 mg/d of vortioxetine or pla­cebo.¹³ Vortioxetine was significantly more effective than placebo at Week 6.

Vortioxetine also is the only antidepres­sant investigated for an effect on cognitive deficits: In a Phase-III double-blind, placebo-controlled study of 602 patients with major depressive disorder, using duloxetine as active reference, vortioxetine was found to have a significant effect on Digit Symbol Substitution Test scores, compared with pla­cebo, independent of its antidepressant effect (ie, patients who did not show any anti­depressant benefit still showed an improve­ment in attention, speed processing, memory, and executive function).¹⁴

We have found, therefore, that vortiox­etine is helpful for depressed patients who have cognitive deficits, especially geriatric patients.

CASE Mrs. B, age 84, married, has a 4-year history of depression. She has taken several antidepressants with little consistent relief.

A brief psychiatric hospitalization 2 years ago temporarily reduced the severity of Mrs. B’s depression; gradually, she relapsed. She felt hopeless and resisted another psychiatric evalu­ation. Mrs. B’s family includes several clinicians, who wondered if she was developing cognitive deficits that were interfering with her recovery.

At initial evaluation, Mrs. B failed to recall 2 of 3 objects but performed the clock drawing test perfectly—qualifying her for a diagnosis of mild cognitive impairment in addition to major depression. Her PHQ-9 score at baseline was 22.

On the assumption that the severity of her depression was contributing to cognitive defi­cits, vortioxetine, 5 mg/d, was initiated for 2 weeks and then titrated to 10 mg/d.

At 4 weeks’ follow-up, Mrs. B passed the Mini-Cog test; her PHQ-9 score fell to 8. She has remained asymptomatic for 6 months at the 10-mg/d dosage; her lowest PHQ-9 score was 5.

Adverse effects. The most common adverse effects are mild or moderate GI in nature. Weight gain and adverse sexual effects were not significantly different among patients receiving vortioxetine than among patients given placebo.

A note about the safety of these agents
All 3 of these antidepressants carry the stan­dard black-box warning about the elevated risk of suicide in patients taking an antide­pressant. None of them are approved for patients age <18.

Continue to: Suicidal ideation was reported

 

Suicidal ideation was reported in 11.2% of patients taking vortioxetine, compared with 12.5% of those given placebo15; 24% of patients taking levomilnacipran reported suicidal ideation, compared with 22% of those who took placebo.¹⁶ In a long-term study of 599 patients taking vilazodone, 4 given placebo exhibited suicidal behavior, compared with 2 who took vilazodone.¹⁷

Drug-drug interactions are an important consideration when vilazodone, levomil­nacipran, and vortioxetine are prescribed in combination with other medications. See the following discussion.

Vilazodone should be taken with food because it has 72% bioavailability after a meal.¹⁸ The drug is metabolized primarily by cytochrome P (CYP) 3A4 and CYP3A5; it does not affect CYP substrates or, it’s likely, produce significant changes to other medica­tions metabolized by the CYP pathway.

Conversely, the dosage of vilazodone should be reduced to 20 mg/d if it is co- administered with a strong CYP3A4 inhibi­tor (eg, ketoconazole). The dosage should be increased as much as 2-fold when vilazo­done is used concomitantly used with a strong CYP3A4 inducer (eg, carbamazepine) for >14 days. The maximum daily dosage should not exceed 80 mg/d.

Levomilnacipran. Unlike vilazodone and vortioxetine, levomilnacipran is affected by renal function.¹⁹ Concomitant medications, however, including those that influence CYP renal transporters (particularly CYP3A4, which metabolizes levomilnacipran), do not show an impact on the blood level of levomilnacipran.

No dosage adjustment is needed for patients who have mild renal impairment, but the maintenance dosage of levomil­nacipran for patients who have moderate or severe renal impairment should not exceed 80 mg/d in 1 dose, and 60 mg/d in 1 dose, respectively.²⁰

Vortioxetine. Seventy percent of a dose of vortioxetine is absorbed independent of food; the drug has a half-life of 66 hours. Vortioxetine is metabolized primarily by the CYP450 enzyme system, including 2D6, and, to a lesser extent, by CYP3A4, CYP3A5, CYP2C9, and CYP2C19.²¹

Vortioxetine has minimal effect on P450 substrates in in vitro studies, which was confirmed in 4 other in vivo studies.^21-23 In studies of hormonal contraception, bupro­pion, and omeprazole, vortioxetine did not produce significant changes in the blood level of the other medications. The blood level of vortioxetine increased by 128% when taken with the CYP2D6 inhibitor bupropion,²⁴ but the blood level did not markedly change with other inhibitors because the drug utilizes uses several CYP pathways. Use caution, therefore, when adding bupropion to vortioxetine because the combination elevates the risk of nausea, diarrhea, and headache.

With each agent, specific benefit
Vilazodone, levomilnacipran, and vor­tioxetine each add distinct benefit to the clinician’s toolbox of treatments for major depressive disorder. Although all antidepres­sants to some extent alleviate anxiety and pain and reverse cognitive decline associated with depression, our experience suggests using vilazodone for anxious depressed patients; levomilnacipran for depressed patients who experience pain; and vortiox­etine for depressed patients who suffer cog­nitive decline and for geriatric patients.

Bottom Line
The FDA has approved 3 antidepressants in the past 4 years: vilazodone, levomilnacipran, and vortioxetine. The hope is that these agents will bolster treatment options for major depression—perhaps especially so, as we have seen, in the anxious depressed (vilazodone), the depressed in pain (levomilnacipran), and the depressed with cognitive decline, or geriatric patients (vortioxetine).

 

Related Resources
• Kalia R, Mittal M, Preskorn S. Vilazodone for major depres­sive disorder. Current Psychiatry. 2011;10(4):84-86,88.
• Lincoln J, Wehler C. Vortioxetine for major depressive disor­der. Current Psychiatry. 2014;13(2):67-70.
• Macaluso M, Kazanchi H, Malhotra V. Levomilnacipran for the treatment of major depressive disorder. Current Psychiatry. 2013;12(12):50-52,54,55.
• McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014;17(10):1557-1567.
• Thase ME, Chen D, Edwards J, et al. Efficacy of vilazodone on anxiety symptoms in patients with major depressive disor­der. Int Clin Psychopharmacol. 2014;29(6):351-356.

Drug Brand Names
Aripiprazole • Abilify                                    Levomilnacipran • Fetzima
Bupropion • Wellbutrin, Zyban                      Lubiprostone • Amitiza
Buspirone • BuSpar                                     Milnacipran • Savella
Carbamazepine • Tegretol, Equetro               Omeprazole • Prilosec
Desvenlafaxine • Pristiq                               Tizanidine • Zanaflex
Duloxetine • Cymbalta                                 Venlafaxine • Effexor
Escitalopram • Lexapro                                Vilazodone • Viibryd
Fluoxetine • Prozac                                     Vortioxetine • Brintellix
Ketoconazole • Nizoral

With a prevalence >17%, depression is one of the most common mental disorders in the United States and the second leading cause of disability worldwide.^1,2 For decades, primary care and mental health providers have used selective serotonin reuptake inhibitors (SSRIs) as first-line treatment for depression—yet the remission rate after the first trial of an antidepressant is <30%, and continues to decline after a first antidepressant failure.³

That is why clinicians continue to seek effective treatments for depres­sion—ones that will provide quick and sustainable remission—and why scientists and pharmaceutical manufacturers have been competing to develop more effective antidepressant medications.

In the past 4 years, the FDA has approved 3 antidepressants—vilazodone, levomilnacipran, and vortioxetine—with the hope of increasing options for patients who suffer from major depression. These 3 antidepressants differ in their mechanisms of action from other available antidepressants, and all have been shown to have acceptable safety and tolerability profiles.

In this article, we review these novel antidepressants and present some clinical pearls for their use. We also present our observations that each agent appears to show particular advantage in a certain subpopulation of depressed patients who often do not respond, or who do not adequately respond, to other antidepressants.

Vilazodone
Vilazodone was approved by the FDA in 2011 (Table 1). The drug increases serotonin bioavailability in synapses through a strong dual action:
   • blocking serotonin reuptake through the serotonin transporter
   • partial agonism of the 5-HT1A presyn­aptic receptor.

Vilazodone also has a moderate effect on the 5-HT4 receptor and on dopamine and norepinephrine uptake inhibition.

The unique presynaptic 5-HT1A partial agonism of vilazodone is similar to that of buspirone, in which both drugs initially inhibit serotonin synthesis and neuronal firing.⁴ Researchers therefore expected that vilazodone would be more suitable for patients who have depression and a comor­bid anxiety disorder; current FDA approval, however, is for depression only.

Adverse effects. The 5-HT4 receptor on which vilazodone acts is present in the gas­trointestinal (GI) tract, and contributes to regulating symptoms in patients with irri­table bowel syndrome (IBS)⁵; not surpris­ingly, the most frequent adverse effects of vilazodone are GI in nature (diarrhea, nau­sea, vomiting).

Headache is the most common non- GI side effect of vilazodone. Depressed patients who took vilazodone had no sig­nificant weight gain and did not report adverse sexual effects, compared with sub­jects given placebo.⁶

The following case—a patient with depression, significant anxiety, and IBS— exemplifies the type of patient for whom we find vilazodone most useful.

CASE Ms. A, age 19, is a college student with a history of major depressive disorder, social anxiety, and panic attacks for 2 years and IBS for 3 years. She was taking lubiprostone for IBS, with incomplete relief of GI symptoms. Because the family history included depres­sion in Ms. A’s mother and sister, and both were doing well on escitalopram, we began a trial of that drug, 10 mg/d, that was quickly titrated to 20 mg/d.

Ms. A did not respond to 20 mg of escitalo­pram combined with psychotherapy.

We then started vilazodone, 10 mg/d after breakfast, for the first week, and reduced escital­opram to 10 mg/d. During Week 2, escitalopram was discontinued and vilazodone was increased to 20 mg/d. During Week 3, vilazodone was titrated to 40 mg/d.

Ms. A tolerated vilazodone well. Her depressive symptoms improved at the end of Week 2.

Unlike her experience with escitalopram, Ms. A’s anxiety symptoms—tenseness, racing thoughts, and panic attacks—all diminished when she switched to vilazodone. Notably, her IBS symptoms also were relieved, and she dis­continued lubiprostone.

Ms. A’s depression remained in remission for 2 years, except for a brief period one sum­mer, when she thought she “could do without any medication.” She tapered the vilazodone, week by week, to 10 mg/d, but her anxiety and bowel symptoms resurfaced to a degree that she resumed the 40-mg/d dosage.

Levomilnacipran
This drug is a 2013 addition to the small serotonin–norepinephrine reuptake inhibi­tor (SNRI) family of venlafaxine, des­venlafaxine, and duloxetine⁷ (Table 2). Levomilnacipran is the enantiomer of mil­nacipran, approved in Europe for depres­sion but only for fibromyalgia pain and peripheral neuropathy in the United States.⁸ (Levomilnacipran is not FDA-approved for treating fibromyalgia pain.)

Levomilnacipran is unique because it is more of an NSRI, so to speak, than an SNRI: That is, the drug’s uptake inhibition of norepinephrine is more potent than its serotonin inhibition. Theoretically, levomilnacipran should help improve cognitive functions linked to the action of norepinephrine, such as concentration and motivation, and in turn, improve social function. The FDA also has approved levomilnacipran for treating functional impairment in depression.⁹

Adverse effects. The norepinephrine uptake inhibition of levomilnacipran might be responsible for observed increases in heart rate and blood pressure in some patients, and dose-dependent urinary hesitancy and erectile dysfunction in others. The drug has no significant effect on weight in depressed patients, compared with placebo.

Continue to: The benefits of levomilnacipran

 

The following case illustrates the benefits of levomilnacipran in a depressed patient who suffers from chronic pain and impaired social function.

CASE Mrs. C, age 44, was referred by her outpatient psychologist and her primary care provider for management of refractory depression. She did not respond to an SSRI, an SNRI, or augmentation with bupropion and aripiprazole.

Mrs. C was on disability leave from work because of depression and cervical spine pain that might have been related to repeti­tive movement as a telephone customer service representative. She complained of loss of motivation, fatigue, and high anxiety about returning to work because of the many unhappy customers she felt she had to soothe.

Levomilnacipran was started at 20 mg/d for 2 days, then titrated to 40 mg/d for 5 days, 80 mg/d for 1 week, and 120 mg/d thereafter. Her previous antidepressants, fluoxetine and bupropion, were discontinued while levomil­nacipran was titrated.

Mrs. C continued to receive weekly psy­chotherapy and physical therapy and to take tizanidine, a muscle relaxant, and over-the-counter medications for pain. Her Patient Health Questionnaire (PHQ-9) score declined from 13 when levomilnacipran was started to 5 at the next visit, 6 weeks later.

Within 4 months of initiating levomilnacipran, Mrs. C returned to work with a series of cue cards to use when speaking with irate or unhappy customers. At that point, her cervical spine pain was barely noticeable and no longer interfered with function.

Vortioxetine
This agent has a novel multimodal mecha­nism of action (Table 3). It is an SSRI as well as a 5-HT1A full agonist and 5-HT3 receptor antagonist. Vortioxetine also has an inhibitory effect on 5-HT7 and 5-HT1D receptors and partial agonism of 5-HT1B receptors.

The downstream effect of this multi­modal action is an increase in dopamine, norepinephrine, and acetylcholine activ­ity in the prefrontal cortex.¹⁰ These down­stream effects are thought to help restore some cognitive deficits associated with depression.¹¹

Vortioxetine is the only antidepressant among the 3 discussed in this article that was studied over a long period to ensure that short-term benefits continue beyond the 6- to 8-week acute Phase-III studies. A high remission rate (61%) was observed in patients who were treated on an open-label basis with vortioxetine, 10 mg/d, then ran­domized to maintenance with vortioxetine or placebo.¹²

Older patients. Vortioxetine is unique among these 3 antidepressants in that it is the only one studied separately in geri­atric patients: In an 8-week Phase-III trial, 452 geriatric patients age 64 to 88 were ran­domized to 5 mg/d of vortioxetine or pla­cebo.¹³ Vortioxetine was significantly more effective than placebo at Week 6.

Vortioxetine also is the only antidepres­sant investigated for an effect on cognitive deficits: In a Phase-III double-blind, placebo-controlled study of 602 patients with major depressive disorder, using duloxetine as active reference, vortioxetine was found to have a significant effect on Digit Symbol Substitution Test scores, compared with pla­cebo, independent of its antidepressant effect (ie, patients who did not show any anti­depressant benefit still showed an improve­ment in attention, speed processing, memory, and executive function).¹⁴

We have found, therefore, that vortiox­etine is helpful for depressed patients who have cognitive deficits, especially geriatric patients.

CASE Mrs. B, age 84, married, has a 4-year history of depression. She has taken several antidepressants with little consistent relief.

A brief psychiatric hospitalization 2 years ago temporarily reduced the severity of Mrs. B’s depression; gradually, she relapsed. She felt hopeless and resisted another psychiatric evalu­ation. Mrs. B’s family includes several clinicians, who wondered if she was developing cognitive deficits that were interfering with her recovery.

At initial evaluation, Mrs. B failed to recall 2 of 3 objects but performed the clock drawing test perfectly—qualifying her for a diagnosis of mild cognitive impairment in addition to major depression. Her PHQ-9 score at baseline was 22.

On the assumption that the severity of her depression was contributing to cognitive defi­cits, vortioxetine, 5 mg/d, was initiated for 2 weeks and then titrated to 10 mg/d.

At 4 weeks’ follow-up, Mrs. B passed the Mini-Cog test; her PHQ-9 score fell to 8. She has remained asymptomatic for 6 months at the 10-mg/d dosage; her lowest PHQ-9 score was 5.

Adverse effects. The most common adverse effects are mild or moderate GI in nature. Weight gain and adverse sexual effects were not significantly different among patients receiving vortioxetine than among patients given placebo.

A note about the safety of these agents
All 3 of these antidepressants carry the stan­dard black-box warning about the elevated risk of suicide in patients taking an antide­pressant. None of them are approved for patients age <18.

Continue to: Suicidal ideation was reported

 

Suicidal ideation was reported in 11.2% of patients taking vortioxetine, compared with 12.5% of those given placebo15; 24% of patients taking levomilnacipran reported suicidal ideation, compared with 22% of those who took placebo.¹⁶ In a long-term study of 599 patients taking vilazodone, 4 given placebo exhibited suicidal behavior, compared with 2 who took vilazodone.¹⁷

Drug-drug interactions are an important consideration when vilazodone, levomil­nacipran, and vortioxetine are prescribed in combination with other medications. See the following discussion.

Vilazodone should be taken with food because it has 72% bioavailability after a meal.¹⁸ The drug is metabolized primarily by cytochrome P (CYP) 3A4 and CYP3A5; it does not affect CYP substrates or, it’s likely, produce significant changes to other medica­tions metabolized by the CYP pathway.

Conversely, the dosage of vilazodone should be reduced to 20 mg/d if it is co- administered with a strong CYP3A4 inhibi­tor (eg, ketoconazole). The dosage should be increased as much as 2-fold when vilazo­done is used concomitantly used with a strong CYP3A4 inducer (eg, carbamazepine) for >14 days. The maximum daily dosage should not exceed 80 mg/d.

Levomilnacipran. Unlike vilazodone and vortioxetine, levomilnacipran is affected by renal function.¹⁹ Concomitant medications, however, including those that influence CYP renal transporters (particularly CYP3A4, which metabolizes levomilnacipran), do not show an impact on the blood level of levomilnacipran.

No dosage adjustment is needed for patients who have mild renal impairment, but the maintenance dosage of levomil­nacipran for patients who have moderate or severe renal impairment should not exceed 80 mg/d in 1 dose, and 60 mg/d in 1 dose, respectively.²⁰

Vortioxetine. Seventy percent of a dose of vortioxetine is absorbed independent of food; the drug has a half-life of 66 hours. Vortioxetine is metabolized primarily by the CYP450 enzyme system, including 2D6, and, to a lesser extent, by CYP3A4, CYP3A5, CYP2C9, and CYP2C19.²¹

Vortioxetine has minimal effect on P450 substrates in in vitro studies, which was confirmed in 4 other in vivo studies.^21-23 In studies of hormonal contraception, bupro­pion, and omeprazole, vortioxetine did not produce significant changes in the blood level of the other medications. The blood level of vortioxetine increased by 128% when taken with the CYP2D6 inhibitor bupropion,²⁴ but the blood level did not markedly change with other inhibitors because the drug utilizes uses several CYP pathways. Use caution, therefore, when adding bupropion to vortioxetine because the combination elevates the risk of nausea, diarrhea, and headache.

With each agent, specific benefit
Vilazodone, levomilnacipran, and vor­tioxetine each add distinct benefit to the clinician’s toolbox of treatments for major depressive disorder. Although all antidepres­sants to some extent alleviate anxiety and pain and reverse cognitive decline associated with depression, our experience suggests using vilazodone for anxious depressed patients; levomilnacipran for depressed patients who experience pain; and vortiox­etine for depressed patients who suffer cog­nitive decline and for geriatric patients.

Bottom Line
The FDA has approved 3 antidepressants in the past 4 years: vilazodone, levomilnacipran, and vortioxetine. The hope is that these agents will bolster treatment options for major depression—perhaps especially so, as we have seen, in the anxious depressed (vilazodone), the depressed in pain (levomilnacipran), and the depressed with cognitive decline, or geriatric patients (vortioxetine).

 

Related Resources
• Kalia R, Mittal M, Preskorn S. Vilazodone for major depres­sive disorder. Current Psychiatry. 2011;10(4):84-86,88.
• Lincoln J, Wehler C. Vortioxetine for major depressive disor­der. Current Psychiatry. 2014;13(2):67-70.
• Macaluso M, Kazanchi H, Malhotra V. Levomilnacipran for the treatment of major depressive disorder. Current Psychiatry. 2013;12(12):50-52,54,55.
• McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014;17(10):1557-1567.
• Thase ME, Chen D, Edwards J, et al. Efficacy of vilazodone on anxiety symptoms in patients with major depressive disor­der. Int Clin Psychopharmacol. 2014;29(6):351-356.

Drug Brand Names
Aripiprazole • Abilify                                    Levomilnacipran • Fetzima
Bupropion • Wellbutrin, Zyban                      Lubiprostone • Amitiza
Buspirone • BuSpar                                     Milnacipran • Savella
Carbamazepine • Tegretol, Equetro               Omeprazole • Prilosec
Desvenlafaxine • Pristiq                               Tizanidine • Zanaflex
Duloxetine • Cymbalta                                 Venlafaxine • Effexor
Escitalopram • Lexapro                                Vilazodone • Viibryd
Fluoxetine • Prozac                                     Vortioxetine • Brintellix
Ketoconazole • Nizoral

After a 5-year monopoly on the sale of colchicine put the gout medication out of reach for many patients, a federal judge in January denied an injunction request by Takeda Pharmaceuticals U.S.A. to halt the distribution of colchicine products by Hikma Pharmaceuticals PLC.

The availability of a generic colchicine will introduce competition into the marketplace and drive down costs, said Dr. E. William St.Clair, president of the American College of Rheumatology and chief of the division of rheumatology and immunology at Duke University, Durham, N.C. The ACR issued a friend-of-the-court brief to the federal district court in support of a generic colchicine product entering the market.

“With the steep price increase in colchicine, many patients with gout were now unable to afford chronic colchicine therapy,” Dr. St.Clair said in an interview. “Improving access to colchicine by making it more affordable will increase patient compliance and reduce the suffering and disability associated with repeated gout flares.”

The debate over colchicine and the right to market the medication has a lengthy history. The drug has been prescribed to treat gout for decades, predating the law that requires drugs to be approved by the Food and Drug Administration. In 2009, the FDA approved a brand name colchicine product (Colcrys) by Mutual Pharmaceutical Company/URL Pharmacy Inc. – now Takeda Pharmaceuticals U.S.A. – after the company conducted clinical trials on dosing regimens and performed drug interaction studies. The FDA’s approval of Colcrys came with exclusive marketing rights for gout for 3 years and for familial Mediterranean fever for 7 years.

Mutual Pharmaceutical Company then sued other manufacturers of colchicine, claiming the drug makers were falsely implying that their products were FDA approved. Shortly later, the FDA ordered companies marketing single-ingredient oral colchicine to remove their unapproved products from the market. Physicians and patients meanwhile saw the price of colchicine increase from about 10 cents per tablet to $5 per tablet.

In September 2014, the FDA granted approval for Hikma to market and sell Mitigare, a colchicine capsule for the prophylactic treatment of gout. Hikma had also planned to launch an authorized generic of Mitigare. Before Mitigare could fully launch, Takeda obtained a temporary restraining order against the sale of colchicine products by Hikma, citing Takeda’s patents for acute gout treatment. Takeda simultaneously sued the FDA in a separate proceeding. Takeda said the FDA’s approval of Hikma’s colchicine product was legally impermissible.

In its brief to the federal court, the ACR argued the public interest would be severely disserved by the barring of Hikma’s colchicine product.

“The unfortunate reality is that nearly 30% of patients in the United States take risky and potentially dangerous steps to save money on prescription medicines, with many choosing to skip doses, or not fill their prescriptions altogether,” the ACR said in its brief. “Takeda’s monopoly and the associated price increase for colchicine has resulted in precisely the sorts of risky behavior described.”

A lower court denied Takeda’s preliminary injunction request and the decision was upheld by the U.S. Court of Appeals for the Federal Circuit on Jan. 9. Pending the outcome of further litigation, the federal court ruled that both Takeda and Hikma are free to immediately offer colchicine products for prophylactic use. Also on Jan. 9, the U.S. District Court for the District of Columbia denied Takeda’s request to overturn the FDA’s approval of Mitigare.

In an interview, a Takeda spokeswoman said the company will continue its patent infringement litigation against Hikma and its U.S. subsidiary, West-Ward Pharmaceuticals, along with its lawsuit against the FDA. The company offered no comment on the judge’s decision to deny the injunction.

West-Ward, meanwhile, launched its authorized generic to Mitigare following the judge’s Jan. 9 decision, and Mitigare’s entry to the market was resumed.

“We immediately sought to launch a generic of Mitigare to ensure that adult patients in need of treatment for the prophylaxis of gout flares had access to a lower-cost, alternative colchicine capsule product,” said Spiro Gavaris, vice president of sales and marketing for West-Ward Pharmaceuticals. “We understood that in recent years, some patients may have lost access to, or became frustrated with, colchicine when there was one brand product at a significantly higher price point. With our launch of the authorized generic of Mitigare capsules, doctors can now choose to prescribe Mitigare for the prophylaxis of gout flares in adults, thereby providing these patients with a lower cost generic medication.”

Days after the decision, Takeda announced that it also would be offering access to a generic colchicine. In a statement, the company said it would partner with Prasco Laboratories to distribute Colchicine Tablets, USP, an authorized generic version of Colcrys. The product is being marketed under the Prasco label and became available in U.S. pharmacies in mid-January.

 

“At Takeda, we remain committed to providing patients with therapies that are safe, efficacious and meet high quality standards,” Douglas Cole, Takeda Pharmaceuticals President, said in a statement. “This new partnership will help enhance patient access to an important gout medicine by supplying Prasco with Colchicine Tablets, USP, manufactured under the same rigorous standards and processes as Colcrys.”

Prices for the Mitigare authorized generic and the Colcrys authorized generic have not been publicly announced. In an interview, West-Ward said it could not comment on exact savings to patients as savings will vary between insurance plans and pharmacy distribution channels.

“Our goal is to provide the most aggressive discounts on generic colchicine in the market with the intent for those discounts to be passed on to adult patients in need of treatment for the prophylaxis of gout flares,” Mr. Gavaris said.

At this article’s deadline, Takeda and Prasco had not responded to a question about the price of the generic Colcrys.

While rheumatologists expressed relief that generic colchicine products have finally become available, they also voiced concerns about potential barriers to access.

“I am proud of what the ACR did here and would hope that it serves as a model for future efforts by professional medical organizations to get into the (often legal) trenches and truly help their patients get affordable care. … [They] put their mouth where the money is and stood up for patients,” said Dr. Christopher M. Burns, a rheumatologist at the Geisel School of Medicine at Dartmouth College, Lebanon, N.H.

“I hope that this will, in fact, reduce the pricing for colchicine, and that it will not allow payers to add an onerous out-of-pocket cost for the drug far in excess of the cost if paid without utilizing pharmacy benefits,” said Dr. Norman B. Gaylis, a rheumatologist in private practice in Aventura, Fla.

Dr. St.Clair added that the future availability and cost of generic colchicine is not certain given common supply-and-demand problems that can arise with generic drugs.

“We have observed critical shortages of several generic medications during the past several years that have drastically affected medical therapy for many common conditions,” he said in an interview. “We will need to keep a close eye on the supply of generic colchicine to ensure it keeps up with the demand. The FDA and the pharmaceutical industry has an obligation to ensure that patients have access to these critical generic drugs.”

agallegos@frontlinemedcom.com

On Twitter @legal_med

After a 5-year monopoly on the sale of colchicine put the gout medication out of reach for many patients, a federal judge in January denied an injunction request by Takeda Pharmaceuticals U.S.A. to halt the distribution of colchicine products by Hikma Pharmaceuticals PLC.

The availability of a generic colchicine will introduce competition into the marketplace and drive down costs, said Dr. E. William St.Clair, president of the American College of Rheumatology and chief of the division of rheumatology and immunology at Duke University, Durham, N.C. The ACR issued a friend-of-the-court brief to the federal district court in support of a generic colchicine product entering the market.

“With the steep price increase in colchicine, many patients with gout were now unable to afford chronic colchicine therapy,” Dr. St.Clair said in an interview. “Improving access to colchicine by making it more affordable will increase patient compliance and reduce the suffering and disability associated with repeated gout flares.”

The debate over colchicine and the right to market the medication has a lengthy history. The drug has been prescribed to treat gout for decades, predating the law that requires drugs to be approved by the Food and Drug Administration. In 2009, the FDA approved a brand name colchicine product (Colcrys) by Mutual Pharmaceutical Company/URL Pharmacy Inc. – now Takeda Pharmaceuticals U.S.A. – after the company conducted clinical trials on dosing regimens and performed drug interaction studies. The FDA’s approval of Colcrys came with exclusive marketing rights for gout for 3 years and for familial Mediterranean fever for 7 years.

Mutual Pharmaceutical Company then sued other manufacturers of colchicine, claiming the drug makers were falsely implying that their products were FDA approved. Shortly later, the FDA ordered companies marketing single-ingredient oral colchicine to remove their unapproved products from the market. Physicians and patients meanwhile saw the price of colchicine increase from about 10 cents per tablet to $5 per tablet.

In September 2014, the FDA granted approval for Hikma to market and sell Mitigare, a colchicine capsule for the prophylactic treatment of gout. Hikma had also planned to launch an authorized generic of Mitigare. Before Mitigare could fully launch, Takeda obtained a temporary restraining order against the sale of colchicine products by Hikma, citing Takeda’s patents for acute gout treatment. Takeda simultaneously sued the FDA in a separate proceeding. Takeda said the FDA’s approval of Hikma’s colchicine product was legally impermissible.

In its brief to the federal court, the ACR argued the public interest would be severely disserved by the barring of Hikma’s colchicine product.

“The unfortunate reality is that nearly 30% of patients in the United States take risky and potentially dangerous steps to save money on prescription medicines, with many choosing to skip doses, or not fill their prescriptions altogether,” the ACR said in its brief. “Takeda’s monopoly and the associated price increase for colchicine has resulted in precisely the sorts of risky behavior described.”

A lower court denied Takeda’s preliminary injunction request and the decision was upheld by the U.S. Court of Appeals for the Federal Circuit on Jan. 9. Pending the outcome of further litigation, the federal court ruled that both Takeda and Hikma are free to immediately offer colchicine products for prophylactic use. Also on Jan. 9, the U.S. District Court for the District of Columbia denied Takeda’s request to overturn the FDA’s approval of Mitigare.

In an interview, a Takeda spokeswoman said the company will continue its patent infringement litigation against Hikma and its U.S. subsidiary, West-Ward Pharmaceuticals, along with its lawsuit against the FDA. The company offered no comment on the judge’s decision to deny the injunction.

West-Ward, meanwhile, launched its authorized generic to Mitigare following the judge’s Jan. 9 decision, and Mitigare’s entry to the market was resumed.

“We immediately sought to launch a generic of Mitigare to ensure that adult patients in need of treatment for the prophylaxis of gout flares had access to a lower-cost, alternative colchicine capsule product,” said Spiro Gavaris, vice president of sales and marketing for West-Ward Pharmaceuticals. “We understood that in recent years, some patients may have lost access to, or became frustrated with, colchicine when there was one brand product at a significantly higher price point. With our launch of the authorized generic of Mitigare capsules, doctors can now choose to prescribe Mitigare for the prophylaxis of gout flares in adults, thereby providing these patients with a lower cost generic medication.”

Days after the decision, Takeda announced that it also would be offering access to a generic colchicine. In a statement, the company said it would partner with Prasco Laboratories to distribute Colchicine Tablets, USP, an authorized generic version of Colcrys. The product is being marketed under the Prasco label and became available in U.S. pharmacies in mid-January.

 

“At Takeda, we remain committed to providing patients with therapies that are safe, efficacious and meet high quality standards,” Douglas Cole, Takeda Pharmaceuticals President, said in a statement. “This new partnership will help enhance patient access to an important gout medicine by supplying Prasco with Colchicine Tablets, USP, manufactured under the same rigorous standards and processes as Colcrys.”

Prices for the Mitigare authorized generic and the Colcrys authorized generic have not been publicly announced. In an interview, West-Ward said it could not comment on exact savings to patients as savings will vary between insurance plans and pharmacy distribution channels.

“Our goal is to provide the most aggressive discounts on generic colchicine in the market with the intent for those discounts to be passed on to adult patients in need of treatment for the prophylaxis of gout flares,” Mr. Gavaris said.

At this article’s deadline, Takeda and Prasco had not responded to a question about the price of the generic Colcrys.

While rheumatologists expressed relief that generic colchicine products have finally become available, they also voiced concerns about potential barriers to access.

“I am proud of what the ACR did here and would hope that it serves as a model for future efforts by professional medical organizations to get into the (often legal) trenches and truly help their patients get affordable care. … [They] put their mouth where the money is and stood up for patients,” said Dr. Christopher M. Burns, a rheumatologist at the Geisel School of Medicine at Dartmouth College, Lebanon, N.H.

“I hope that this will, in fact, reduce the pricing for colchicine, and that it will not allow payers to add an onerous out-of-pocket cost for the drug far in excess of the cost if paid without utilizing pharmacy benefits,” said Dr. Norman B. Gaylis, a rheumatologist in private practice in Aventura, Fla.

Dr. St.Clair added that the future availability and cost of generic colchicine is not certain given common supply-and-demand problems that can arise with generic drugs.

“We have observed critical shortages of several generic medications during the past several years that have drastically affected medical therapy for many common conditions,” he said in an interview. “We will need to keep a close eye on the supply of generic colchicine to ensure it keeps up with the demand. The FDA and the pharmaceutical industry has an obligation to ensure that patients have access to these critical generic drugs.”

agallegos@frontlinemedcom.com

On Twitter @legal_med

After a 5-year monopoly on the sale of colchicine put the gout medication out of reach for many patients, a federal judge in January denied an injunction request by Takeda Pharmaceuticals U.S.A. to halt the distribution of colchicine products by Hikma Pharmaceuticals PLC.

The availability of a generic colchicine will introduce competition into the marketplace and drive down costs, said Dr. E. William St.Clair, president of the American College of Rheumatology and chief of the division of rheumatology and immunology at Duke University, Durham, N.C. The ACR issued a friend-of-the-court brief to the federal district court in support of a generic colchicine product entering the market.

“With the steep price increase in colchicine, many patients with gout were now unable to afford chronic colchicine therapy,” Dr. St.Clair said in an interview. “Improving access to colchicine by making it more affordable will increase patient compliance and reduce the suffering and disability associated with repeated gout flares.”

The debate over colchicine and the right to market the medication has a lengthy history. The drug has been prescribed to treat gout for decades, predating the law that requires drugs to be approved by the Food and Drug Administration. In 2009, the FDA approved a brand name colchicine product (Colcrys) by Mutual Pharmaceutical Company/URL Pharmacy Inc. – now Takeda Pharmaceuticals U.S.A. – after the company conducted clinical trials on dosing regimens and performed drug interaction studies. The FDA’s approval of Colcrys came with exclusive marketing rights for gout for 3 years and for familial Mediterranean fever for 7 years.

Mutual Pharmaceutical Company then sued other manufacturers of colchicine, claiming the drug makers were falsely implying that their products were FDA approved. Shortly later, the FDA ordered companies marketing single-ingredient oral colchicine to remove their unapproved products from the market. Physicians and patients meanwhile saw the price of colchicine increase from about 10 cents per tablet to $5 per tablet.

In September 2014, the FDA granted approval for Hikma to market and sell Mitigare, a colchicine capsule for the prophylactic treatment of gout. Hikma had also planned to launch an authorized generic of Mitigare. Before Mitigare could fully launch, Takeda obtained a temporary restraining order against the sale of colchicine products by Hikma, citing Takeda’s patents for acute gout treatment. Takeda simultaneously sued the FDA in a separate proceeding. Takeda said the FDA’s approval of Hikma’s colchicine product was legally impermissible.

In its brief to the federal court, the ACR argued the public interest would be severely disserved by the barring of Hikma’s colchicine product.

“The unfortunate reality is that nearly 30% of patients in the United States take risky and potentially dangerous steps to save money on prescription medicines, with many choosing to skip doses, or not fill their prescriptions altogether,” the ACR said in its brief. “Takeda’s monopoly and the associated price increase for colchicine has resulted in precisely the sorts of risky behavior described.”

A lower court denied Takeda’s preliminary injunction request and the decision was upheld by the U.S. Court of Appeals for the Federal Circuit on Jan. 9. Pending the outcome of further litigation, the federal court ruled that both Takeda and Hikma are free to immediately offer colchicine products for prophylactic use. Also on Jan. 9, the U.S. District Court for the District of Columbia denied Takeda’s request to overturn the FDA’s approval of Mitigare.

In an interview, a Takeda spokeswoman said the company will continue its patent infringement litigation against Hikma and its U.S. subsidiary, West-Ward Pharmaceuticals, along with its lawsuit against the FDA. The company offered no comment on the judge’s decision to deny the injunction.

West-Ward, meanwhile, launched its authorized generic to Mitigare following the judge’s Jan. 9 decision, and Mitigare’s entry to the market was resumed.

“We immediately sought to launch a generic of Mitigare to ensure that adult patients in need of treatment for the prophylaxis of gout flares had access to a lower-cost, alternative colchicine capsule product,” said Spiro Gavaris, vice president of sales and marketing for West-Ward Pharmaceuticals. “We understood that in recent years, some patients may have lost access to, or became frustrated with, colchicine when there was one brand product at a significantly higher price point. With our launch of the authorized generic of Mitigare capsules, doctors can now choose to prescribe Mitigare for the prophylaxis of gout flares in adults, thereby providing these patients with a lower cost generic medication.”

Days after the decision, Takeda announced that it also would be offering access to a generic colchicine. In a statement, the company said it would partner with Prasco Laboratories to distribute Colchicine Tablets, USP, an authorized generic version of Colcrys. The product is being marketed under the Prasco label and became available in U.S. pharmacies in mid-January.

 

“At Takeda, we remain committed to providing patients with therapies that are safe, efficacious and meet high quality standards,” Douglas Cole, Takeda Pharmaceuticals President, said in a statement. “This new partnership will help enhance patient access to an important gout medicine by supplying Prasco with Colchicine Tablets, USP, manufactured under the same rigorous standards and processes as Colcrys.”

Prices for the Mitigare authorized generic and the Colcrys authorized generic have not been publicly announced. In an interview, West-Ward said it could not comment on exact savings to patients as savings will vary between insurance plans and pharmacy distribution channels.

“Our goal is to provide the most aggressive discounts on generic colchicine in the market with the intent for those discounts to be passed on to adult patients in need of treatment for the prophylaxis of gout flares,” Mr. Gavaris said.

At this article’s deadline, Takeda and Prasco had not responded to a question about the price of the generic Colcrys.

While rheumatologists expressed relief that generic colchicine products have finally become available, they also voiced concerns about potential barriers to access.

“I am proud of what the ACR did here and would hope that it serves as a model for future efforts by professional medical organizations to get into the (often legal) trenches and truly help their patients get affordable care. … [They] put their mouth where the money is and stood up for patients,” said Dr. Christopher M. Burns, a rheumatologist at the Geisel School of Medicine at Dartmouth College, Lebanon, N.H.

“I hope that this will, in fact, reduce the pricing for colchicine, and that it will not allow payers to add an onerous out-of-pocket cost for the drug far in excess of the cost if paid without utilizing pharmacy benefits,” said Dr. Norman B. Gaylis, a rheumatologist in private practice in Aventura, Fla.

Dr. St.Clair added that the future availability and cost of generic colchicine is not certain given common supply-and-demand problems that can arise with generic drugs.

“We have observed critical shortages of several generic medications during the past several years that have drastically affected medical therapy for many common conditions,” he said in an interview. “We will need to keep a close eye on the supply of generic colchicine to ensure it keeps up with the demand. The FDA and the pharmaceutical industry has an obligation to ensure that patients have access to these critical generic drugs.”

agallegos@frontlinemedcom.com

On Twitter @legal_med

Patient-administered teledermoscopy using an iPhone-based mobile dermatoscope attachment and app is an effective and feasible method for short-term monitoring of clinically atypical nevi, with the added benefit of improving patient and physician convenience, based on data from a pilot study of 29 patients.

Researchers found a high level of diagnostic concordance (0.87) between dermatoscope images taken and assessed by an office-based dermatologist and those taken by the patient – albeit in the clinic setting – using the mobile dermatoscope and assessed by a teledermatologist.

All but one of the 29 patients with clinically atypical nevi who completed the study were able to acquire evaluable baseline and follow-up images, the researchers noted. In addition, most of the patients reported that the device was easy to use and that it saved them a trip to the doctor’s office. The study findings were published online Jan. 28 in JAMA Dermatology (doi:10.1001/jamadermatol.2014.3837).

“Under our modality of care, patients needing short-term monitoring will have an established relationship with their dermatologists, who will be the ones identifying concerning lesions that need to be monitored and the ones who evaluate the lesions via teledermoscopy and communicate treatment options directly with the patients,” wrote Xinyuan Wu of Memorial Sloan Kettering Cancer Center, New York, and colleagues.

The authors of an accompanying editorial wrote that recommendations for screening and follow-up for melanoma placed considerable burdens on patients, physicians, and the health care system, and that the patient-led mobile teledermoscopy described in the study was one of a number of options being considered to reduce that burden.

“The study by Wu and colleagues in this issue adds significantly to the discussion on whether regular follow-up visits with clinicians could be replaced by patient self-monitoring with remote feedback by a teledermatologist,” wrote Monika Janda, Ph.D., of the Queensland University of Technology in Brisbane, Australia, and colleagues.

One editorial author reported shares and consultancies with e-derm-consult GmbH and MoleMap, but there were no other conflicts of interest declared.

Patient-administered teledermoscopy using an iPhone-based mobile dermatoscope attachment and app is an effective and feasible method for short-term monitoring of clinically atypical nevi, with the added benefit of improving patient and physician convenience, based on data from a pilot study of 29 patients.

Researchers found a high level of diagnostic concordance (0.87) between dermatoscope images taken and assessed by an office-based dermatologist and those taken by the patient – albeit in the clinic setting – using the mobile dermatoscope and assessed by a teledermatologist.

All but one of the 29 patients with clinically atypical nevi who completed the study were able to acquire evaluable baseline and follow-up images, the researchers noted. In addition, most of the patients reported that the device was easy to use and that it saved them a trip to the doctor’s office. The study findings were published online Jan. 28 in JAMA Dermatology (doi:10.1001/jamadermatol.2014.3837).

“Under our modality of care, patients needing short-term monitoring will have an established relationship with their dermatologists, who will be the ones identifying concerning lesions that need to be monitored and the ones who evaluate the lesions via teledermoscopy and communicate treatment options directly with the patients,” wrote Xinyuan Wu of Memorial Sloan Kettering Cancer Center, New York, and colleagues.

The authors of an accompanying editorial wrote that recommendations for screening and follow-up for melanoma placed considerable burdens on patients, physicians, and the health care system, and that the patient-led mobile teledermoscopy described in the study was one of a number of options being considered to reduce that burden.

“The study by Wu and colleagues in this issue adds significantly to the discussion on whether regular follow-up visits with clinicians could be replaced by patient self-monitoring with remote feedback by a teledermatologist,” wrote Monika Janda, Ph.D., of the Queensland University of Technology in Brisbane, Australia, and colleagues.

One editorial author reported shares and consultancies with e-derm-consult GmbH and MoleMap, but there were no other conflicts of interest declared.

Patient-administered teledermoscopy using an iPhone-based mobile dermatoscope attachment and app is an effective and feasible method for short-term monitoring of clinically atypical nevi, with the added benefit of improving patient and physician convenience, based on data from a pilot study of 29 patients.

Researchers found a high level of diagnostic concordance (0.87) between dermatoscope images taken and assessed by an office-based dermatologist and those taken by the patient – albeit in the clinic setting – using the mobile dermatoscope and assessed by a teledermatologist.

All but one of the 29 patients with clinically atypical nevi who completed the study were able to acquire evaluable baseline and follow-up images, the researchers noted. In addition, most of the patients reported that the device was easy to use and that it saved them a trip to the doctor’s office. The study findings were published online Jan. 28 in JAMA Dermatology (doi:10.1001/jamadermatol.2014.3837).

“Under our modality of care, patients needing short-term monitoring will have an established relationship with their dermatologists, who will be the ones identifying concerning lesions that need to be monitored and the ones who evaluate the lesions via teledermoscopy and communicate treatment options directly with the patients,” wrote Xinyuan Wu of Memorial Sloan Kettering Cancer Center, New York, and colleagues.

The authors of an accompanying editorial wrote that recommendations for screening and follow-up for melanoma placed considerable burdens on patients, physicians, and the health care system, and that the patient-led mobile teledermoscopy described in the study was one of a number of options being considered to reduce that burden.

“The study by Wu and colleagues in this issue adds significantly to the discussion on whether regular follow-up visits with clinicians could be replaced by patient self-monitoring with remote feedback by a teledermatologist,” wrote Monika Janda, Ph.D., of the Queensland University of Technology in Brisbane, Australia, and colleagues.

One editorial author reported shares and consultancies with e-derm-consult GmbH and MoleMap, but there were no other conflicts of interest declared.