In this issue of the Journal of Hospital Medicine, the paper by Gottenborg et al. captures the experiences of female academic hospitalists navigating one of the most significant transitions they will face—becoming new mothers.¹ This article gives an accessible voice to impersonal statistics about the barriers women physicians encounter within and across specialties in academia. The challenges and anecdotes shared by the study participants were eminently relatable and captured the all-too-familiar circumstances most of us with children have faced in our careers as physician mothers.

This study uses qualitative research methods to illustrate the hurdles faced by mothers in hospital medicine beyond what is demonstrated by quantitative measures and provides the helpful step of proposing some solutions to the obstacles they have faced. While the sample size was very small, the women interviewed were diverse in their years in practice, geographic distribution, and percent clinical effort, providing evidence that the themes discussed prevail across demographic categories.

The snowball sampling via the Society of Hospital Medicine committees may not have yielded a representative sample of female hospitalists. It seems possible that women who are involved in this type of leadership may be better supported and/or have different work schedules than their peers who are not in leadership positions. We also wish there had been more emphasis on the systemic and structural factors that can improve the quality of life of physician mothers. These policies include paternity leave and other creative ways of acknowledging the useful skills and experience that motherhood brings to bear on clinical practice, such as increased empathy and compassion, as mentioned by one of the study participants.

Even with the aforementioned limitations, this study is important because it combines authentic quotes from practicing academic hospitalists with concrete and tangible suggestions for structural changes. The most striking element is that the majority of the study participants experienced uncertainty and a lack of transparency around parental leave policies. As nearly half of hospitalists are women and 80% are under age 40,² it seems unimaginable that there would not be explicit policies in place for what is a common and largely anticipated life event. Medicine has made great strides toward gender equality, but we are unlikely to ever reach the goal of true parity without openly addressing the disproportionate effect of childbearing and child rearing on women physicians. Standardized, readily available, and equitable parental leave policies (for both birth parents and nonbirth parents) are the first and most critical step.

The absence of standard leave policies naturally puts physician mothers in the position of having to negotiate or “haggle” with various supervisors, the majority of whom are male division chiefs and department chairs,³ which places all parties in an uncomfortable position, further reinforcing inequities and sowing discord and resentment. Having formal policies around leave protects not only those who utilize parental leave but also the other members of a hospital medicine practice who take on the workload of the person on leave.

Uncertainty around how to address the increased clinical load and for how long, also creates anxiety among other group members and may lead to feelings of bitterness toward clinicians on leave, further contributing to the negative impact of new parenthood on female hospitalists. We can think of no other medical circumstance in which there is as much advance notice of the need for significant time away from work. Yet pregnancy, which is subject to complications and emergencies just like other medical conditions, is treated with so little concern that one may be asked to arrange for their own coverage during such an emergency, as one study subject reported.

We also empathize with the study participants’ reports of feeling that supervisors often mentally discounted their ability to participate in projects on return to work. These pernicious assumptions can compound a cycle of lost productivity, disengagement, and attrition from the workforce.

Female hospitalists returning from leave face additional challenges that place an undue burden on their professional activities, most notably related to breastfeeding. This is particularly relevant in the context of the intensity inherent in practicing hospital medicine, which includes long days of being the primary provider for acutely ill inpatients, as well as long stretches of many consecutive days when it may not be possible to return home before children’s bedtime. Even at our own institution, which has been recognized as a “Healthy Mothers Workplace,” breastfeeding accommodations are not set up to allow for ongoing clinical activities while taking time to express breastmilk, and the clinical schedule does not build in adjustments for this time-consuming and psychologically taxing commitment. Breastfeeding for at least one year is the medical recommendation of the American Academy of Pediatrics in line with a substantial body of evidence.⁴ One quote from the article poignantly notes, “Pumping every 3-4 hours: stopping what you’re doing, finding an empty room to pump, finding a place to store your milk, then going back to work, three times per shift, for the next 9 months of your life, was hell.” If we cannot enable our own medical providers to follow evidence-based recommendations, how can we possibly expect this of our patients?

The notion of women “having it all” is an impossible ideal—both work and life outside of work will inevitably require tradeoffs. However, there is an abundance of evidence and recommendations for concrete steps that can be taken to improve the experience of female physicians who have children. These include formal policies for childbearing and child rearing leave (the American Academy of Pediatrics recommends at least six to nine months⁵), convenient space and protected time for pumping milk during the first year, on-site childcare services and back-up child care, and flexible work schedules.⁶ It is time to stop treating childbirth among female physicians like an unexpected inconvenience and acknowledge the undeniable demographics of physicians in hospital medicine and the duty of healthcare systems and hospital medicine leaders to effectively plan for the needs of half of their workforce.

Disclosures

Neither of the authors have any financial conflicts of interest to disclose.

In this issue of the Journal of Hospital Medicine, the paper by Gottenborg et al. captures the experiences of female academic hospitalists navigating one of the most significant transitions they will face—becoming new mothers.¹ This article gives an accessible voice to impersonal statistics about the barriers women physicians encounter within and across specialties in academia. The challenges and anecdotes shared by the study participants were eminently relatable and captured the all-too-familiar circumstances most of us with children have faced in our careers as physician mothers.

This study uses qualitative research methods to illustrate the hurdles faced by mothers in hospital medicine beyond what is demonstrated by quantitative measures and provides the helpful step of proposing some solutions to the obstacles they have faced. While the sample size was very small, the women interviewed were diverse in their years in practice, geographic distribution, and percent clinical effort, providing evidence that the themes discussed prevail across demographic categories.

The snowball sampling via the Society of Hospital Medicine committees may not have yielded a representative sample of female hospitalists. It seems possible that women who are involved in this type of leadership may be better supported and/or have different work schedules than their peers who are not in leadership positions. We also wish there had been more emphasis on the systemic and structural factors that can improve the quality of life of physician mothers. These policies include paternity leave and other creative ways of acknowledging the useful skills and experience that motherhood brings to bear on clinical practice, such as increased empathy and compassion, as mentioned by one of the study participants.

Even with the aforementioned limitations, this study is important because it combines authentic quotes from practicing academic hospitalists with concrete and tangible suggestions for structural changes. The most striking element is that the majority of the study participants experienced uncertainty and a lack of transparency around parental leave policies. As nearly half of hospitalists are women and 80% are under age 40,² it seems unimaginable that there would not be explicit policies in place for what is a common and largely anticipated life event. Medicine has made great strides toward gender equality, but we are unlikely to ever reach the goal of true parity without openly addressing the disproportionate effect of childbearing and child rearing on women physicians. Standardized, readily available, and equitable parental leave policies (for both birth parents and nonbirth parents) are the first and most critical step.

The absence of standard leave policies naturally puts physician mothers in the position of having to negotiate or “haggle” with various supervisors, the majority of whom are male division chiefs and department chairs,³ which places all parties in an uncomfortable position, further reinforcing inequities and sowing discord and resentment. Having formal policies around leave protects not only those who utilize parental leave but also the other members of a hospital medicine practice who take on the workload of the person on leave.

Uncertainty around how to address the increased clinical load and for how long, also creates anxiety among other group members and may lead to feelings of bitterness toward clinicians on leave, further contributing to the negative impact of new parenthood on female hospitalists. We can think of no other medical circumstance in which there is as much advance notice of the need for significant time away from work. Yet pregnancy, which is subject to complications and emergencies just like other medical conditions, is treated with so little concern that one may be asked to arrange for their own coverage during such an emergency, as one study subject reported.

We also empathize with the study participants’ reports of feeling that supervisors often mentally discounted their ability to participate in projects on return to work. These pernicious assumptions can compound a cycle of lost productivity, disengagement, and attrition from the workforce.

Female hospitalists returning from leave face additional challenges that place an undue burden on their professional activities, most notably related to breastfeeding. This is particularly relevant in the context of the intensity inherent in practicing hospital medicine, which includes long days of being the primary provider for acutely ill inpatients, as well as long stretches of many consecutive days when it may not be possible to return home before children’s bedtime. Even at our own institution, which has been recognized as a “Healthy Mothers Workplace,” breastfeeding accommodations are not set up to allow for ongoing clinical activities while taking time to express breastmilk, and the clinical schedule does not build in adjustments for this time-consuming and psychologically taxing commitment. Breastfeeding for at least one year is the medical recommendation of the American Academy of Pediatrics in line with a substantial body of evidence.⁴ One quote from the article poignantly notes, “Pumping every 3-4 hours: stopping what you’re doing, finding an empty room to pump, finding a place to store your milk, then going back to work, three times per shift, for the next 9 months of your life, was hell.” If we cannot enable our own medical providers to follow evidence-based recommendations, how can we possibly expect this of our patients?

The notion of women “having it all” is an impossible ideal—both work and life outside of work will inevitably require tradeoffs. However, there is an abundance of evidence and recommendations for concrete steps that can be taken to improve the experience of female physicians who have children. These include formal policies for childbearing and child rearing leave (the American Academy of Pediatrics recommends at least six to nine months⁵), convenient space and protected time for pumping milk during the first year, on-site childcare services and back-up child care, and flexible work schedules.⁶ It is time to stop treating childbirth among female physicians like an unexpected inconvenience and acknowledge the undeniable demographics of physicians in hospital medicine and the duty of healthcare systems and hospital medicine leaders to effectively plan for the needs of half of their workforce.

Disclosures

Neither of the authors have any financial conflicts of interest to disclose.

In this issue of the Journal of Hospital Medicine, the paper by Gottenborg et al. captures the experiences of female academic hospitalists navigating one of the most significant transitions they will face—becoming new mothers.¹ This article gives an accessible voice to impersonal statistics about the barriers women physicians encounter within and across specialties in academia. The challenges and anecdotes shared by the study participants were eminently relatable and captured the all-too-familiar circumstances most of us with children have faced in our careers as physician mothers.

This study uses qualitative research methods to illustrate the hurdles faced by mothers in hospital medicine beyond what is demonstrated by quantitative measures and provides the helpful step of proposing some solutions to the obstacles they have faced. While the sample size was very small, the women interviewed were diverse in their years in practice, geographic distribution, and percent clinical effort, providing evidence that the themes discussed prevail across demographic categories.

The snowball sampling via the Society of Hospital Medicine committees may not have yielded a representative sample of female hospitalists. It seems possible that women who are involved in this type of leadership may be better supported and/or have different work schedules than their peers who are not in leadership positions. We also wish there had been more emphasis on the systemic and structural factors that can improve the quality of life of physician mothers. These policies include paternity leave and other creative ways of acknowledging the useful skills and experience that motherhood brings to bear on clinical practice, such as increased empathy and compassion, as mentioned by one of the study participants.

Even with the aforementioned limitations, this study is important because it combines authentic quotes from practicing academic hospitalists with concrete and tangible suggestions for structural changes. The most striking element is that the majority of the study participants experienced uncertainty and a lack of transparency around parental leave policies. As nearly half of hospitalists are women and 80% are under age 40,² it seems unimaginable that there would not be explicit policies in place for what is a common and largely anticipated life event. Medicine has made great strides toward gender equality, but we are unlikely to ever reach the goal of true parity without openly addressing the disproportionate effect of childbearing and child rearing on women physicians. Standardized, readily available, and equitable parental leave policies (for both birth parents and nonbirth parents) are the first and most critical step.

The absence of standard leave policies naturally puts physician mothers in the position of having to negotiate or “haggle” with various supervisors, the majority of whom are male division chiefs and department chairs,³ which places all parties in an uncomfortable position, further reinforcing inequities and sowing discord and resentment. Having formal policies around leave protects not only those who utilize parental leave but also the other members of a hospital medicine practice who take on the workload of the person on leave.

Uncertainty around how to address the increased clinical load and for how long, also creates anxiety among other group members and may lead to feelings of bitterness toward clinicians on leave, further contributing to the negative impact of new parenthood on female hospitalists. We can think of no other medical circumstance in which there is as much advance notice of the need for significant time away from work. Yet pregnancy, which is subject to complications and emergencies just like other medical conditions, is treated with so little concern that one may be asked to arrange for their own coverage during such an emergency, as one study subject reported.

We also empathize with the study participants’ reports of feeling that supervisors often mentally discounted their ability to participate in projects on return to work. These pernicious assumptions can compound a cycle of lost productivity, disengagement, and attrition from the workforce.

Female hospitalists returning from leave face additional challenges that place an undue burden on their professional activities, most notably related to breastfeeding. This is particularly relevant in the context of the intensity inherent in practicing hospital medicine, which includes long days of being the primary provider for acutely ill inpatients, as well as long stretches of many consecutive days when it may not be possible to return home before children’s bedtime. Even at our own institution, which has been recognized as a “Healthy Mothers Workplace,” breastfeeding accommodations are not set up to allow for ongoing clinical activities while taking time to express breastmilk, and the clinical schedule does not build in adjustments for this time-consuming and psychologically taxing commitment. Breastfeeding for at least one year is the medical recommendation of the American Academy of Pediatrics in line with a substantial body of evidence.⁴ One quote from the article poignantly notes, “Pumping every 3-4 hours: stopping what you’re doing, finding an empty room to pump, finding a place to store your milk, then going back to work, three times per shift, for the next 9 months of your life, was hell.” If we cannot enable our own medical providers to follow evidence-based recommendations, how can we possibly expect this of our patients?

The notion of women “having it all” is an impossible ideal—both work and life outside of work will inevitably require tradeoffs. However, there is an abundance of evidence and recommendations for concrete steps that can be taken to improve the experience of female physicians who have children. These include formal policies for childbearing and child rearing leave (the American Academy of Pediatrics recommends at least six to nine months⁵), convenient space and protected time for pumping milk during the first year, on-site childcare services and back-up child care, and flexible work schedules.⁶ It is time to stop treating childbirth among female physicians like an unexpected inconvenience and acknowledge the undeniable demographics of physicians in hospital medicine and the duty of healthcare systems and hospital medicine leaders to effectively plan for the needs of half of their workforce.

Disclosures

Neither of the authors have any financial conflicts of interest to disclose.

In this month’s edition of the Journal of Hospital Medicine, Goodwin and colleagues report their findings from their systematic review of models of care for frequently hospitalized patients. The authors reviewed the literature for interventions to reduce hospital admissions in frequently hospitalized patients with the goal of assessing the success of the interventions. This report contributes to the literature base of interventions to reduce healthcare utilization, particularly in the area of inpatient hospitalization.¹

Goodwin et al. report that only nine studies met their criteria for review after a thorough search of the published literature. Of these nine studies, only four were determined to be high-quality studies. Interestingly, the low-quality studies found positive results in reducing hospital utilization, whereas the high-quality studies found decreases that were mirrored by their control groups. Impressive heterogeneity was found in the range of definitions, interventions, and outcome measures in the studies. These studies highlight the issue of “regression to the mean” for sicker individuals; however, they may not address readmission rates of specific medical systems or procedures that are also cost drivers, even if the patients are not considered critically ill. They also show where research partnerships can assist in increasing the number of members included in the studies for robust analyses.

 From the perspective of a health plan, we applaud all efforts to improve patient outcomes and reduce cost. This report states that efforts to reduce chronic hospitalizations have not been unqualified successes. We must reflect upon how reducing utilization and improving outcomes align with our overall goals as a society. Recently, Federal Reserve Chairman Jay Powell summed up our nation’s particular issue, stating, “It is widely understood that the United States is on an unsustainable fiscal path, largely due to the interaction between an aging population and a healthcare system that delivers pretty average healthcare at a cost that is much higher than that of any other advanced economy.”²

A recent Kaiser Family Foundation analysis showed that 1% of patients accounted for 23% of all medical spending in the United States, and 97% of medical spending is attributed to the top 50% of patients.³ Pharmaceutical costs also play a role in this trend. Blue Cross and Blue Shield of Texas (BCBSTX) found that 2.5% of our population accounted for just under 50% of total medical spending. Conversely, when looking at patients with very high costs, only 0.4% had over $100,000 in spending exclusive of pharmacy. When including pharmacy, that number rises to 0.5%. As we consider annual medical and pharmacy trends year over year, we find that pharmacy spending may outpace hospital expenses in the near future.

Our internal data are also consistent with published reports that fewer than half of high-cost patients in one year continue to be high-cost cases the following year. Niall Brennan et al. reported that only 39% of the top 5% of spenders in a given year are also high spenders the following year.⁴ This finding not only coincides with the author’s statement around regression to the mean for the high admission utilizers, but it may be instructive to those looking to a Pareto method of attacking cost. If more than half of targeted patients will move out of the high cost category on their own, then demonstrating the effectiveness of interventions becomes challenging. Moreover, this regression finding speaks to the need to create effective programs to manage population health on a broad basis, which can address quality to all members and streamline costs for a large group that covers well more than 50% of medical spending.

BCBSTX emphasizes the creation of systems that let providers become responsible and accountable to outcomes and cost. Accountable Care Organizations (ACOs) and Intensive Medical Homes (IMHs) have played important roles in this journey, but physicians need to continue to invent and prioritize interventions that may achieve both goals. In particular, hospitalists have an important role to play. As ACOs flourish, hospitalists will need to join under the value-based umbrella and continue to intervene in patient care, policies, and procedures to reduce avoidable hospitalizations.

The development of value-based arrangements offers the healthcare system a unique opportunity to bring much-needed change. In our medical partnerships, direct communication with providers regarding their member experience and sharing of vital information about their patients’ health status have helped improve patient outcomes and decrease cost. Our IMH partnerships show a savings of up to $45,000 per member per year driven by decreases in admissions and ER visits, and in some cases, expensive medications. The hard work in these successes lies within the subtleties of fostering the relationship between payers and providers. Each pillar within the ecosystem plays a key role offering strengths, but the upside toward change comes in how we support each other’s weaknesses. This support is manifested in two ways: collaboration through communication and transparency through data sharing.

The road to change is one less traveled but not unpaved; advances in technology allow us to take experiences and build from them. At its core, technology has enhanced our collaboration and data capabilities. The ability to stay in touch with providers allows for almost real-time addressing of issues, promoting efficiency. The connection we have with providers has evolved from being solely paper contracts to a multichannel, multifunctional system. The ability to take claims experience, insert clinical acumen, and perform data analysis brings actionable solutions to be executed by our providers.

Those in the healthcare system will need to come together to continue to create interventions that improve quality while decreasing costs. The second part may require even more work than the first. The Health Care Cost Institute recently published data showing that inpatient utilization over a five-year period fell 12.9% in the commercially insured.⁵ However, over that same period, hospital prices for inpatient care rose 24.3%. The fundamental reason for the excess amount of money spent in US healthcare is that the prices are incredibly high.⁶ Currently, when diligence is exercised in reducing utilization, hospitals simply raise prices as a response to compensate for the lost income. Likewise, although prescription drug utilization only increased 1.8% during that period, the prices increased by 24.9%.

For the United States healthcare system to improve its quality and reduce its cost, we will need inventive partnerships to continue to create new systems to interact with patients in the most efficient and effective way possible. Readmissions and hospital utilization will be a large part of that improvement. Hospitals and hospitalists should ensure that they continue to focus on making healthcare more affordable by improving efficiency and outcomes and by resisting the tendencies of hospitals and pharmaceutical companies to raise prices in reaction to the improved efficiency.

Disclosures

The authors have nothing to disclose.

In this month’s edition of the Journal of Hospital Medicine, Goodwin and colleagues report their findings from their systematic review of models of care for frequently hospitalized patients. The authors reviewed the literature for interventions to reduce hospital admissions in frequently hospitalized patients with the goal of assessing the success of the interventions. This report contributes to the literature base of interventions to reduce healthcare utilization, particularly in the area of inpatient hospitalization.¹

Goodwin et al. report that only nine studies met their criteria for review after a thorough search of the published literature. Of these nine studies, only four were determined to be high-quality studies. Interestingly, the low-quality studies found positive results in reducing hospital utilization, whereas the high-quality studies found decreases that were mirrored by their control groups. Impressive heterogeneity was found in the range of definitions, interventions, and outcome measures in the studies. These studies highlight the issue of “regression to the mean” for sicker individuals; however, they may not address readmission rates of specific medical systems or procedures that are also cost drivers, even if the patients are not considered critically ill. They also show where research partnerships can assist in increasing the number of members included in the studies for robust analyses.

 From the perspective of a health plan, we applaud all efforts to improve patient outcomes and reduce cost. This report states that efforts to reduce chronic hospitalizations have not been unqualified successes. We must reflect upon how reducing utilization and improving outcomes align with our overall goals as a society. Recently, Federal Reserve Chairman Jay Powell summed up our nation’s particular issue, stating, “It is widely understood that the United States is on an unsustainable fiscal path, largely due to the interaction between an aging population and a healthcare system that delivers pretty average healthcare at a cost that is much higher than that of any other advanced economy.”²

A recent Kaiser Family Foundation analysis showed that 1% of patients accounted for 23% of all medical spending in the United States, and 97% of medical spending is attributed to the top 50% of patients.³ Pharmaceutical costs also play a role in this trend. Blue Cross and Blue Shield of Texas (BCBSTX) found that 2.5% of our population accounted for just under 50% of total medical spending. Conversely, when looking at patients with very high costs, only 0.4% had over $100,000 in spending exclusive of pharmacy. When including pharmacy, that number rises to 0.5%. As we consider annual medical and pharmacy trends year over year, we find that pharmacy spending may outpace hospital expenses in the near future.

Our internal data are also consistent with published reports that fewer than half of high-cost patients in one year continue to be high-cost cases the following year. Niall Brennan et al. reported that only 39% of the top 5% of spenders in a given year are also high spenders the following year.⁴ This finding not only coincides with the author’s statement around regression to the mean for the high admission utilizers, but it may be instructive to those looking to a Pareto method of attacking cost. If more than half of targeted patients will move out of the high cost category on their own, then demonstrating the effectiveness of interventions becomes challenging. Moreover, this regression finding speaks to the need to create effective programs to manage population health on a broad basis, which can address quality to all members and streamline costs for a large group that covers well more than 50% of medical spending.

BCBSTX emphasizes the creation of systems that let providers become responsible and accountable to outcomes and cost. Accountable Care Organizations (ACOs) and Intensive Medical Homes (IMHs) have played important roles in this journey, but physicians need to continue to invent and prioritize interventions that may achieve both goals. In particular, hospitalists have an important role to play. As ACOs flourish, hospitalists will need to join under the value-based umbrella and continue to intervene in patient care, policies, and procedures to reduce avoidable hospitalizations.

The development of value-based arrangements offers the healthcare system a unique opportunity to bring much-needed change. In our medical partnerships, direct communication with providers regarding their member experience and sharing of vital information about their patients’ health status have helped improve patient outcomes and decrease cost. Our IMH partnerships show a savings of up to $45,000 per member per year driven by decreases in admissions and ER visits, and in some cases, expensive medications. The hard work in these successes lies within the subtleties of fostering the relationship between payers and providers. Each pillar within the ecosystem plays a key role offering strengths, but the upside toward change comes in how we support each other’s weaknesses. This support is manifested in two ways: collaboration through communication and transparency through data sharing.

The road to change is one less traveled but not unpaved; advances in technology allow us to take experiences and build from them. At its core, technology has enhanced our collaboration and data capabilities. The ability to stay in touch with providers allows for almost real-time addressing of issues, promoting efficiency. The connection we have with providers has evolved from being solely paper contracts to a multichannel, multifunctional system. The ability to take claims experience, insert clinical acumen, and perform data analysis brings actionable solutions to be executed by our providers.

Those in the healthcare system will need to come together to continue to create interventions that improve quality while decreasing costs. The second part may require even more work than the first. The Health Care Cost Institute recently published data showing that inpatient utilization over a five-year period fell 12.9% in the commercially insured.⁵ However, over that same period, hospital prices for inpatient care rose 24.3%. The fundamental reason for the excess amount of money spent in US healthcare is that the prices are incredibly high.⁶ Currently, when diligence is exercised in reducing utilization, hospitals simply raise prices as a response to compensate for the lost income. Likewise, although prescription drug utilization only increased 1.8% during that period, the prices increased by 24.9%.

For the United States healthcare system to improve its quality and reduce its cost, we will need inventive partnerships to continue to create new systems to interact with patients in the most efficient and effective way possible. Readmissions and hospital utilization will be a large part of that improvement. Hospitals and hospitalists should ensure that they continue to focus on making healthcare more affordable by improving efficiency and outcomes and by resisting the tendencies of hospitals and pharmaceutical companies to raise prices in reaction to the improved efficiency.

Disclosures

The authors have nothing to disclose.

In this month’s edition of the Journal of Hospital Medicine, Goodwin and colleagues report their findings from their systematic review of models of care for frequently hospitalized patients. The authors reviewed the literature for interventions to reduce hospital admissions in frequently hospitalized patients with the goal of assessing the success of the interventions. This report contributes to the literature base of interventions to reduce healthcare utilization, particularly in the area of inpatient hospitalization.¹

Goodwin et al. report that only nine studies met their criteria for review after a thorough search of the published literature. Of these nine studies, only four were determined to be high-quality studies. Interestingly, the low-quality studies found positive results in reducing hospital utilization, whereas the high-quality studies found decreases that were mirrored by their control groups. Impressive heterogeneity was found in the range of definitions, interventions, and outcome measures in the studies. These studies highlight the issue of “regression to the mean” for sicker individuals; however, they may not address readmission rates of specific medical systems or procedures that are also cost drivers, even if the patients are not considered critically ill. They also show where research partnerships can assist in increasing the number of members included in the studies for robust analyses.

 From the perspective of a health plan, we applaud all efforts to improve patient outcomes and reduce cost. This report states that efforts to reduce chronic hospitalizations have not been unqualified successes. We must reflect upon how reducing utilization and improving outcomes align with our overall goals as a society. Recently, Federal Reserve Chairman Jay Powell summed up our nation’s particular issue, stating, “It is widely understood that the United States is on an unsustainable fiscal path, largely due to the interaction between an aging population and a healthcare system that delivers pretty average healthcare at a cost that is much higher than that of any other advanced economy.”²

A recent Kaiser Family Foundation analysis showed that 1% of patients accounted for 23% of all medical spending in the United States, and 97% of medical spending is attributed to the top 50% of patients.³ Pharmaceutical costs also play a role in this trend. Blue Cross and Blue Shield of Texas (BCBSTX) found that 2.5% of our population accounted for just under 50% of total medical spending. Conversely, when looking at patients with very high costs, only 0.4% had over $100,000 in spending exclusive of pharmacy. When including pharmacy, that number rises to 0.5%. As we consider annual medical and pharmacy trends year over year, we find that pharmacy spending may outpace hospital expenses in the near future.

Our internal data are also consistent with published reports that fewer than half of high-cost patients in one year continue to be high-cost cases the following year. Niall Brennan et al. reported that only 39% of the top 5% of spenders in a given year are also high spenders the following year.⁴ This finding not only coincides with the author’s statement around regression to the mean for the high admission utilizers, but it may be instructive to those looking to a Pareto method of attacking cost. If more than half of targeted patients will move out of the high cost category on their own, then demonstrating the effectiveness of interventions becomes challenging. Moreover, this regression finding speaks to the need to create effective programs to manage population health on a broad basis, which can address quality to all members and streamline costs for a large group that covers well more than 50% of medical spending.

BCBSTX emphasizes the creation of systems that let providers become responsible and accountable to outcomes and cost. Accountable Care Organizations (ACOs) and Intensive Medical Homes (IMHs) have played important roles in this journey, but physicians need to continue to invent and prioritize interventions that may achieve both goals. In particular, hospitalists have an important role to play. As ACOs flourish, hospitalists will need to join under the value-based umbrella and continue to intervene in patient care, policies, and procedures to reduce avoidable hospitalizations.

The development of value-based arrangements offers the healthcare system a unique opportunity to bring much-needed change. In our medical partnerships, direct communication with providers regarding their member experience and sharing of vital information about their patients’ health status have helped improve patient outcomes and decrease cost. Our IMH partnerships show a savings of up to $45,000 per member per year driven by decreases in admissions and ER visits, and in some cases, expensive medications. The hard work in these successes lies within the subtleties of fostering the relationship between payers and providers. Each pillar within the ecosystem plays a key role offering strengths, but the upside toward change comes in how we support each other’s weaknesses. This support is manifested in two ways: collaboration through communication and transparency through data sharing.

The road to change is one less traveled but not unpaved; advances in technology allow us to take experiences and build from them. At its core, technology has enhanced our collaboration and data capabilities. The ability to stay in touch with providers allows for almost real-time addressing of issues, promoting efficiency. The connection we have with providers has evolved from being solely paper contracts to a multichannel, multifunctional system. The ability to take claims experience, insert clinical acumen, and perform data analysis brings actionable solutions to be executed by our providers.

Those in the healthcare system will need to come together to continue to create interventions that improve quality while decreasing costs. The second part may require even more work than the first. The Health Care Cost Institute recently published data showing that inpatient utilization over a five-year period fell 12.9% in the commercially insured.⁵ However, over that same period, hospital prices for inpatient care rose 24.3%. The fundamental reason for the excess amount of money spent in US healthcare is that the prices are incredibly high.⁶ Currently, when diligence is exercised in reducing utilization, hospitals simply raise prices as a response to compensate for the lost income. Likewise, although prescription drug utilization only increased 1.8% during that period, the prices increased by 24.9%.

For the United States healthcare system to improve its quality and reduce its cost, we will need inventive partnerships to continue to create new systems to interact with patients in the most efficient and effective way possible. Readmissions and hospital utilization will be a large part of that improvement. Hospitals and hospitalists should ensure that they continue to focus on making healthcare more affordable by improving efficiency and outcomes and by resisting the tendencies of hospitals and pharmaceutical companies to raise prices in reaction to the improved efficiency.

Disclosures

The authors have nothing to disclose.

There is growing evidence that supports the ability of specialty palliative care to achieve the Triple Aim in healthcare: (1) improve patient and family experience of care, (2) improve health outcomes, and (3) reduce healthcare costs.^1,2 However, the full realization of this value remains elusive due, in large part, to the increasing demand for specialty palliative care services outpacing the supply of specialists.³ Because expansion of the specialty palliative care workforce will never be sufficient to meet the needs of seriously ill patients, and nonspecialist physicians often fail to recognize palliative care needs in a timely manner,⁴ innovative and systematic solutions are needed to provide high-quality palliative care in a manner that is sustainable.⁵

To close the gap between workforce and patient needs, experts have largely advocated for two care delivery models that aim to improve the organization and allocation of limited palliative care resources: (1) a tier-based approach in which primary palliative care (basic skills for all clinicians) and specialty palliative care (advanced skills requiring additional training) have distinct but supportive roles, and (2) a need-based approach where different types of palliative care clinicians are deployed based on specific needs.^5,6 In this issue, Abedini and Chopra propose a “Palliative Care Redistribution Integrated System Model” (PRISM) that combines these two approaches, with need-based care delivery that escalates through skill tiers to improve hospital-based palliative care.⁷

PRISM is attractive because it leverages the skill sets of clinicians across disciplines and is designed for the hospital, where the vast majority of specialty palliative care is provided in the United States. Moreover, it employs hospitalists who routinely care for a high volume of seriously ill patients, and are therefore well positioned to expand the palliative care workforce. The authors suggest several approaches to implement PRISM, such as designating certain hospitalist teams for palliative care, more interdisciplinary support, automated patient risk stratification or mandatory screening checklists, and strategic use of bedside nurses and social workers to facilitate early basic needs assessments. Although sound in principle, there are several foreseeable barriers to each of these approaches and potential unintended consequences of PRISM in the fields of hospital and palliative medicine.

Applying insights from behavioral economics will be essential for the successful implementation and dissemination of PRISM. Changing clinician behavior is not a challenge unique to palliative care interventions, but it may be particularly difficult due to misperceptions that palliative care is synonymous with end-of-life care and that such conversations are always time-intensive. Indeed, Abedini and Chopra acknowledge that all clinicians need to be well versed in basic palliative care skills for PRISM to succeed, yet most educational initiatives have shown modest results at best. The most promising clinician education programs, such as the Serious Illness Care Program and VitalTalk require intensive training simulations and are most effective when implemented on a system level to promote cultural change.^8.9 Thus, training hospitalists in preparation for PRISM will require considerable upfront investment by hospitals. While policy efforts to improve palliative care training in medical education are progressing (Palliative Care and Hospice Education and Training Act, H.R.1676), any evidence of impact is nearly a generation away.

The authors also advocate for a technology-driven solution for systematic and early identification of palliative care needs. However, ideal clinical decision support would not rely on checklists to be completed by bedside clinicians or “hard stop” alerts in the electronic health record, as both of these approaches rely heavily upon consistent and accurate data entry by busy clinicians. Rather, innovative predictive analytics with machine learning and natural language processing methods hold great promise to support an electronic precision medicine approach for palliative care delivery. Even after such prediction models are developed, rigorous studies are needed to understand how they can change clinician behavior and impact the quality and cost of care.

Shifting palliative care tasks to nonspecialists has implications beyond quality and access. First, there are likely to be reimbursement implications as nonbillable clinicians such as social workers provide palliative care services that were previously provided by physicians and advance practice providers. As value-based payment models grow, healthcare systems may be wise to invest in innovative palliative care delivery models such as PRISM, but obtaining financial support will require rigorous evidence of value. Second, it will be important to monitor the already high rates of burnout and emotional exhaustion among palliative care clinicians¹⁰ when implementing care delivery models that select only the most complex patients for referral to specialty palliative care. Finally, new palliative care delivery models must fit within a larger national strategy to grow palliative care across the care continuum.¹¹ This is of particular importance with hospital-focused solutions such as PRISM due to concerns about the growing split in care coordination between inpatient and outpatient care. Since seriously ill patients spend the majority of time outside the hospital and evidence for the value of palliative care is most robust in home and ambulatory settings,¹ an important role for hospitalists could be to systematically identify and refer high-risk patients to community-based palliative care services after discharge from a sentinel hospitalization.

In conclusion, innovative palliative care delivery models such as PRISM are critical to ensuring that seriously ill patients have access to high-quality palliative care; however, more work is still needed to create the training programs, patient identification tools, scalable implementation, and evaluation processes necessary for success.

Disclosures

Dr. Courtright and Dr. O’Connor have nothing to disclose.

Funding

This work was funded in part by a career development award from the National Palliative Care Research Center (KRC). The views expressed herein solely represent those of the authors.

There is growing evidence that supports the ability of specialty palliative care to achieve the Triple Aim in healthcare: (1) improve patient and family experience of care, (2) improve health outcomes, and (3) reduce healthcare costs.^1,2 However, the full realization of this value remains elusive due, in large part, to the increasing demand for specialty palliative care services outpacing the supply of specialists.³ Because expansion of the specialty palliative care workforce will never be sufficient to meet the needs of seriously ill patients, and nonspecialist physicians often fail to recognize palliative care needs in a timely manner,⁴ innovative and systematic solutions are needed to provide high-quality palliative care in a manner that is sustainable.⁵

To close the gap between workforce and patient needs, experts have largely advocated for two care delivery models that aim to improve the organization and allocation of limited palliative care resources: (1) a tier-based approach in which primary palliative care (basic skills for all clinicians) and specialty palliative care (advanced skills requiring additional training) have distinct but supportive roles, and (2) a need-based approach where different types of palliative care clinicians are deployed based on specific needs.^5,6 In this issue, Abedini and Chopra propose a “Palliative Care Redistribution Integrated System Model” (PRISM) that combines these two approaches, with need-based care delivery that escalates through skill tiers to improve hospital-based palliative care.⁷

PRISM is attractive because it leverages the skill sets of clinicians across disciplines and is designed for the hospital, where the vast majority of specialty palliative care is provided in the United States. Moreover, it employs hospitalists who routinely care for a high volume of seriously ill patients, and are therefore well positioned to expand the palliative care workforce. The authors suggest several approaches to implement PRISM, such as designating certain hospitalist teams for palliative care, more interdisciplinary support, automated patient risk stratification or mandatory screening checklists, and strategic use of bedside nurses and social workers to facilitate early basic needs assessments. Although sound in principle, there are several foreseeable barriers to each of these approaches and potential unintended consequences of PRISM in the fields of hospital and palliative medicine.

Applying insights from behavioral economics will be essential for the successful implementation and dissemination of PRISM. Changing clinician behavior is not a challenge unique to palliative care interventions, but it may be particularly difficult due to misperceptions that palliative care is synonymous with end-of-life care and that such conversations are always time-intensive. Indeed, Abedini and Chopra acknowledge that all clinicians need to be well versed in basic palliative care skills for PRISM to succeed, yet most educational initiatives have shown modest results at best. The most promising clinician education programs, such as the Serious Illness Care Program and VitalTalk require intensive training simulations and are most effective when implemented on a system level to promote cultural change.^8.9 Thus, training hospitalists in preparation for PRISM will require considerable upfront investment by hospitals. While policy efforts to improve palliative care training in medical education are progressing (Palliative Care and Hospice Education and Training Act, H.R.1676), any evidence of impact is nearly a generation away.

The authors also advocate for a technology-driven solution for systematic and early identification of palliative care needs. However, ideal clinical decision support would not rely on checklists to be completed by bedside clinicians or “hard stop” alerts in the electronic health record, as both of these approaches rely heavily upon consistent and accurate data entry by busy clinicians. Rather, innovative predictive analytics with machine learning and natural language processing methods hold great promise to support an electronic precision medicine approach for palliative care delivery. Even after such prediction models are developed, rigorous studies are needed to understand how they can change clinician behavior and impact the quality and cost of care.

Shifting palliative care tasks to nonspecialists has implications beyond quality and access. First, there are likely to be reimbursement implications as nonbillable clinicians such as social workers provide palliative care services that were previously provided by physicians and advance practice providers. As value-based payment models grow, healthcare systems may be wise to invest in innovative palliative care delivery models such as PRISM, but obtaining financial support will require rigorous evidence of value. Second, it will be important to monitor the already high rates of burnout and emotional exhaustion among palliative care clinicians¹⁰ when implementing care delivery models that select only the most complex patients for referral to specialty palliative care. Finally, new palliative care delivery models must fit within a larger national strategy to grow palliative care across the care continuum.¹¹ This is of particular importance with hospital-focused solutions such as PRISM due to concerns about the growing split in care coordination between inpatient and outpatient care. Since seriously ill patients spend the majority of time outside the hospital and evidence for the value of palliative care is most robust in home and ambulatory settings,¹ an important role for hospitalists could be to systematically identify and refer high-risk patients to community-based palliative care services after discharge from a sentinel hospitalization.

In conclusion, innovative palliative care delivery models such as PRISM are critical to ensuring that seriously ill patients have access to high-quality palliative care; however, more work is still needed to create the training programs, patient identification tools, scalable implementation, and evaluation processes necessary for success.

Disclosures

Dr. Courtright and Dr. O’Connor have nothing to disclose.

Funding

This work was funded in part by a career development award from the National Palliative Care Research Center (KRC). The views expressed herein solely represent those of the authors.

There is growing evidence that supports the ability of specialty palliative care to achieve the Triple Aim in healthcare: (1) improve patient and family experience of care, (2) improve health outcomes, and (3) reduce healthcare costs.^1,2 However, the full realization of this value remains elusive due, in large part, to the increasing demand for specialty palliative care services outpacing the supply of specialists.³ Because expansion of the specialty palliative care workforce will never be sufficient to meet the needs of seriously ill patients, and nonspecialist physicians often fail to recognize palliative care needs in a timely manner,⁴ innovative and systematic solutions are needed to provide high-quality palliative care in a manner that is sustainable.⁵

To close the gap between workforce and patient needs, experts have largely advocated for two care delivery models that aim to improve the organization and allocation of limited palliative care resources: (1) a tier-based approach in which primary palliative care (basic skills for all clinicians) and specialty palliative care (advanced skills requiring additional training) have distinct but supportive roles, and (2) a need-based approach where different types of palliative care clinicians are deployed based on specific needs.^5,6 In this issue, Abedini and Chopra propose a “Palliative Care Redistribution Integrated System Model” (PRISM) that combines these two approaches, with need-based care delivery that escalates through skill tiers to improve hospital-based palliative care.⁷

PRISM is attractive because it leverages the skill sets of clinicians across disciplines and is designed for the hospital, where the vast majority of specialty palliative care is provided in the United States. Moreover, it employs hospitalists who routinely care for a high volume of seriously ill patients, and are therefore well positioned to expand the palliative care workforce. The authors suggest several approaches to implement PRISM, such as designating certain hospitalist teams for palliative care, more interdisciplinary support, automated patient risk stratification or mandatory screening checklists, and strategic use of bedside nurses and social workers to facilitate early basic needs assessments. Although sound in principle, there are several foreseeable barriers to each of these approaches and potential unintended consequences of PRISM in the fields of hospital and palliative medicine.

Applying insights from behavioral economics will be essential for the successful implementation and dissemination of PRISM. Changing clinician behavior is not a challenge unique to palliative care interventions, but it may be particularly difficult due to misperceptions that palliative care is synonymous with end-of-life care and that such conversations are always time-intensive. Indeed, Abedini and Chopra acknowledge that all clinicians need to be well versed in basic palliative care skills for PRISM to succeed, yet most educational initiatives have shown modest results at best. The most promising clinician education programs, such as the Serious Illness Care Program and VitalTalk require intensive training simulations and are most effective when implemented on a system level to promote cultural change.^8.9 Thus, training hospitalists in preparation for PRISM will require considerable upfront investment by hospitals. While policy efforts to improve palliative care training in medical education are progressing (Palliative Care and Hospice Education and Training Act, H.R.1676), any evidence of impact is nearly a generation away.

The authors also advocate for a technology-driven solution for systematic and early identification of palliative care needs. However, ideal clinical decision support would not rely on checklists to be completed by bedside clinicians or “hard stop” alerts in the electronic health record, as both of these approaches rely heavily upon consistent and accurate data entry by busy clinicians. Rather, innovative predictive analytics with machine learning and natural language processing methods hold great promise to support an electronic precision medicine approach for palliative care delivery. Even after such prediction models are developed, rigorous studies are needed to understand how they can change clinician behavior and impact the quality and cost of care.

Shifting palliative care tasks to nonspecialists has implications beyond quality and access. First, there are likely to be reimbursement implications as nonbillable clinicians such as social workers provide palliative care services that were previously provided by physicians and advance practice providers. As value-based payment models grow, healthcare systems may be wise to invest in innovative palliative care delivery models such as PRISM, but obtaining financial support will require rigorous evidence of value. Second, it will be important to monitor the already high rates of burnout and emotional exhaustion among palliative care clinicians¹⁰ when implementing care delivery models that select only the most complex patients for referral to specialty palliative care. Finally, new palliative care delivery models must fit within a larger national strategy to grow palliative care across the care continuum.¹¹ This is of particular importance with hospital-focused solutions such as PRISM due to concerns about the growing split in care coordination between inpatient and outpatient care. Since seriously ill patients spend the majority of time outside the hospital and evidence for the value of palliative care is most robust in home and ambulatory settings,¹ an important role for hospitalists could be to systematically identify and refer high-risk patients to community-based palliative care services after discharge from a sentinel hospitalization.

In conclusion, innovative palliative care delivery models such as PRISM are critical to ensuring that seriously ill patients have access to high-quality palliative care; however, more work is still needed to create the training programs, patient identification tools, scalable implementation, and evaluation processes necessary for success.

Disclosures

Dr. Courtright and Dr. O’Connor have nothing to disclose.

Funding

This work was funded in part by a career development award from the National Palliative Care Research Center (KRC). The views expressed herein solely represent those of the authors.

Click here to access the December 2018 Digital Edition.

Table of Contents

• Anesthesia Care Practice Models in the Veterans Health Administration
• Role of Point-of-Care Ultrasonography in the Evaluation and Management of Kidney Disease
• PACT ICU Model: Interprofessional Case Conferences for High-Risk/High-Need Patients
• A Pharmacist-Led Transitional Care Program to Reduce Hospital Readmissions in Older Adults
• The Gift and the Thought Both Count
• Overemphasizing Communities in the National Suicide Strategy Could Undercut VA Successes

Click here to access the December 2018 Digital Edition.

Table of Contents

• Anesthesia Care Practice Models in the Veterans Health Administration
• Role of Point-of-Care Ultrasonography in the Evaluation and Management of Kidney Disease
• PACT ICU Model: Interprofessional Case Conferences for High-Risk/High-Need Patients
• A Pharmacist-Led Transitional Care Program to Reduce Hospital Readmissions in Older Adults
• The Gift and the Thought Both Count
• Overemphasizing Communities in the National Suicide Strategy Could Undercut VA Successes

Click here to access the December 2018 Digital Edition.

Table of Contents

• Anesthesia Care Practice Models in the Veterans Health Administration
• Role of Point-of-Care Ultrasonography in the Evaluation and Management of Kidney Disease
• PACT ICU Model: Interprofessional Case Conferences for High-Risk/High-Need Patients
• A Pharmacist-Led Transitional Care Program to Reduce Hospital Readmissions in Older Adults
• The Gift and the Thought Both Count
• Overemphasizing Communities in the National Suicide Strategy Could Undercut VA Successes

Botulinum toxin, a potent neurotoxic protein produced by the bacterium Clostridium botulinum, has been used as treatment for a variety of medical indications for more than 25 years (Box^1-12). Recently, researchers have been exploring the role of botulinum toxin in psychiatry, primarily as an adjunctive treatment for depression, but also for several other possible indications. Several studies, including randomized controlled trials (RCTs), have provided evidence that glabellar botulinum toxin injections may be a safe and effective treatment for depression. In this article, we provide an update on the latest clinical trials that evaluated botulinum toxin for depression, and also summarize the evidence regarding other potential clinical psychiatric applications of botulinum toxin.

Several RCTs suggest efficacy for depression

The use of botulinum toxin to treat depression is based on the facial feedback hypothesis, which was first proposed by Charles Darwin in 1872¹³ and further elaborated by William James,^14,15 who emphasized the importance of the sensation of bodily changes in emotion. Contrary to the popular belief that emotions trigger physiological changes in the body, James postulated that peripheral bodily changes secondary to stimuli perception would exert a sensory feedback, generating emotions. The manipulation of human facial expression with an expression that is associated with a particular emotion (eg, holding a pen with teeth, leading to risorius/zygomaticus muscles contraction and a smile simulation) was found to influence participants’ affective responses in the presence of emotional stimuli (eg, rating cartoons as funnier), reinforcing the facial-feedback hypothesis.^16,17

From a neurobiologic standpoint, facial botulinum toxin A (BTA) injections in rats were associated with increased serotonin and norepinephrine concentrations in the hypothalamus and striatum, respectively.¹⁸ Moreover, amygdala activity in response to angry vs happy faces, measured via functional magnetic resonance imaging (fMRI), was found to be attenuated after BTA applications to muscles involved in angry facial expressions.^19,20 Both the neurotransmitters as well as the aforementioned brain regions have been implicated in the pathophysiology of depression.^21,22

Box

Continue to: In a second RCT involving 74 patients with depression...

Continue to: Benefits for other psychiatric indications

Borderline personality disorder. In a case series of 6 women, BTA injections in the glabellar region were reported to be particularly effective for the treatment of borderline personality disorder symptoms that were resistant to psychotherapy and pharmacotherapy.³¹ Two to 6 weeks after a 29-unit injection, borderline personality disorder symptoms as measured by the Zanarini Rating Scale for Borderline Personality Disorder and/or the Borderline Symptom List were shown to significantly improve by 49% to 94% from baseline (P ≤ .05). These findings emphasize the promising therapeutic role of BTA on depressive symptoms concomitant with the emotional lability, impulsivity, and negative emotions that usually characterize this personality disorder.^31,32 A small sample size and lack of a placebo comparator are limitations of this research.

Neuroleptic-induced sialorrhea. Botulinum toxin injections in the salivary glands have been investigated for treating clozapine-induced sialorrhea because they are thought to directly inhibit the release of acetylcholine from salivary glands. One small RCT that used botulinum toxin B (BTB)³³ and 1 case report that used BTA³⁴ reported successful reduction in hypersalivation, with doses ranging from 150 to 500 units injected in each of the parotid and/or submandibular glands bilaterally. Although the treatment was well tolerated and lasted up to 16 weeks, larger studies are needed to replicate these findings.^33-35

Orofacial tardive dyskinesia. Several case reports of orofacial tardive dyskinesia, including lingual dyskinesia and lingual protrusion dystonia, have found improvements in hyperkinetic movements following muscular BTA injections, such as in the genioglossus muscle in the case of tongue involvement.^36-39 These cases were, however, described in the literature before the recent FDA approval of the vesicular monoamine transporter 2 inhibitors valbenazine and deutetrabenazine for the treatment of tardive dyskinesia.^40,41

Studies examining botulinum toxin’s application in areas of psychiatry other than depression are summarized in Table 2.^31,33,36-38

Continue to: Promising initial findings but multiple limitations

Although BTA injections have been explored as a potential treatment for several psychiatric conditions, the bulk of recent evidence is derived from studies in patients with depressive disorders. BTA injections in the glabellar regions have been shown in small RCTs to be well-tolerated with overall promising improvement of depressive symptoms, optimally 6 weeks after a single injection. Moreover, BTA has been shown to be safe and long-lasting, which would be convenient for patients and might improve adherence to therapy.^42-44 BTA’s antidepressant effects were shown to be independent of frown line severity or patient satisfaction with cosmetic effects.⁴⁵ The trials by Wollmer et al,²³ Finzi and Rosenthal,²⁵ and Magid et al²⁶ mainly studied BTA as an adjunctive treatment to antidepressants in patients with ongoing unipolar depression. However, Finzi and Rosenthal²⁵ included patients who were not medicated at the time of the study.

Pooled analysis of these 3 RCTs found that patients who received BTA monotherapy improved equally to those who received it as an adjunctive treatment to antidepressants. Overall, on primary endpoint measures, a response rate of 54.2% was obtained in the BTA group compared with 10.7% among patients who received placebo saline injections (odds ratio [OR] 11.1, 95% confidence interval [CI], 4.3 to 28.8, number needed to treat [NNT] = 2.3) and a remission rate of 30.5% with BTA compared with 6.7% with placebo (OR 7.3, 95 % CI, 2.4 to 22.5, NNT = 4.2).⁴⁶ However, remission rates tend to be higher in the augmentation groups, and so further studies are needed to compare both treatment strategies.

Nevertheless, these positive findings have been recently challenged by the results of the largest U.S. multicenter phase II RCT,²⁸ which failed to find a significant antidepressant effect at 6 weeks with the 30-unit BTA injection, and also failed to prove a dose-effect relationship, as the 50-unit injection wasn’t superior to the lower dose and didn’t significantly differ from placebo. One hypothesis to explain this discrepancy may be the difference in injection sites between the treatment and placebo groups.⁴⁷ Future studies need to address the various limitations of earlier clinical trials that mainly yielded promising results with BTA.

A major concern is the high rate of unblinding of participants and researchers in BTA trials, as the cosmetic effects of botulinum toxin injections make them easy to distinguish from saline injections. Ninety percent of participants in the Wollmer et al study²³ were able to correctly guess their group allocation, while 60% of evaluators guessed correctly. Finzi and Rozenthal²⁵ reported 52% of participants in the BTA group, 46% in the placebo group, and 73% of evaluators correctly guessed their allocation. Magid et al²⁶ reported 75% of participants were able to guess the order of intervention they received. The high unblinding rates in these trials remains a significant limitation. There is a concern that this may lead to an underestimation of the placebo effect relative to clinical improvement, thus causing inflation of outcome differences between groups. Although various methods have been tried to minimize evaluator unblinding, such as placing surgical caps on participants’ faces during visits to hide the glabellar region, better methods need to be implemented to prevent unblinding of both raters and participants.

Furthermore, except for the multicenter phase II trial, most studies have been conducted in small samples, which limits their statistical power. Larger controlled trials will be needed to replicate the positive findings obtained in smaller RCTs.

Another limitation is that the majority of the well-designed RCTs were conducted in populations that were predominantly female, which makes it difficult to reliably assess treatment efficacy in men. This may be because cosmetic treatment with botulinum toxin injection is more favorably received by women than by men. A recent comparison⁴⁸ of the studies by Wollmer et al²³ and Finzi and Rosenthal²⁵ discussed an interesting observation. Wollmer et al did not explicitly mention botulinum toxin when recruiting for the study, while Finzi and Rosenthal did. While approximately a quarter of the participants in the Wollmer et al study were male, Finzi and Rosenthal attracted an almost entirely female population. Perhaps there is a potential bias for females to be more attracted to these studies due to the secondary gain of receiving a cosmetic procedure.

In an attempt to understand predictors of positive response to botulinum toxin in patients with depression, Wollmer et al⁴⁹ conducted a follow-up study in which they reassessed the data obtained from their initial RCT using the HAM-D agitation item scores to separate the 15 participants who received BTA into low-agitation (≤1 score on agitation item of the HAM-D scale) and high-agitation (≥2 score on agitation item of the HAM-D scale) groups. They found that the 9 participants who responded to BTA treatment had significantly higher baseline agitation scores than participants who did not respond (1.56 ± 0.88 vs 0.33 ± 0.52, P = .01). All of the participants who presented with higher agitation levels experienced response, compared with 40% of those with lower agitation levels (P = .04), although there was no significant difference in magnitude of improvement (14.2 ± 1.92 vs 8.0 ± 9.37, P = .07). The study added additional support to the facial feedback hypothesis, as it links the improvement of depression to facial muscle activation targeted by the injections. It also introduced a potential predictor of response to botulinum toxin treatment, highlighting potential factors to consider when enrolling patients in future investigations.

The case series of patients with borderline personality disorder³¹ also shed light on the potential positive effect of BTA treatment for a particular subtype of patients with depression—those with comorbid emotional instability—to consider as a therapeutic target for the future. Hence, inclusion criteria for future trials might potentially include patient age, gender, existence/quantification of prominent frown lines at baseline, severity of MDD, duration of depression, and personality characteristics of enrolled participants.

In conclusion, BTA injections appear promising as a treatment for depression as well as for other psychiatric disorders. Future studies should focus on identifying optimal candidates for this innovative treatment modality. Furthermore, BTA dosing and administration strategies (monotherapy vs adjunctive treatment to antidepressants) need to be further explored. As retrograde axonal transport of botulinum toxin has been demonstrated in animal studies, it would be interesting to further examine its effects in the human CNS to enhance our knowledge of the pathophysiology of botulinum and its potential applications in psychiatry.⁵⁰

Bottom Line

Botulinum toxin shows promising antidepressant effects and may have a role in the treatment of several other psychiatric disorders. More research is needed to address limitations of previous studies and to establish an adequate treatment regimen.

Related Resources

• Wollmer MA, Magid M, Kruger TH. Botulinum toxin treatment in depression. In: Bewley A, Taylor RE, Reichenberg JS, et al (eds). Practical psychodermatology. Oxford, UK: Wiley; 2014.
• Wollmer MA, Neumann I, Magid M. et al. Shrink that frown! Botulinum toxin therapy is lifting the face of psychiatry. G Ital Dermatol Venereol. 2018;153(4):540-548.

Drug Brand Names

Alprazolam • Xanax
Aripiprazole • Abilify
Biperiden • Akineton
Botulinum toxin A • Botox
Botulinum toxin B • Myobloc
Clozapine • Clozaril
Deutetrabenazine • Austedo
Flupentixol • Prolixin
Imipramine • Tofranil
Olanzapine • Zyprexa
Reserpine • Serpalan, Serpasil
Tetrabenazine • Xenazine
Valbenazine • Ingrezza
Ziprasidone • Geodon

Botulinum toxin, a potent neurotoxic protein produced by the bacterium Clostridium botulinum, has been used as treatment for a variety of medical indications for more than 25 years (Box^1-12). Recently, researchers have been exploring the role of botulinum toxin in psychiatry, primarily as an adjunctive treatment for depression, but also for several other possible indications. Several studies, including randomized controlled trials (RCTs), have provided evidence that glabellar botulinum toxin injections may be a safe and effective treatment for depression. In this article, we provide an update on the latest clinical trials that evaluated botulinum toxin for depression, and also summarize the evidence regarding other potential clinical psychiatric applications of botulinum toxin.

Several RCTs suggest efficacy for depression

The use of botulinum toxin to treat depression is based on the facial feedback hypothesis, which was first proposed by Charles Darwin in 1872¹³ and further elaborated by William James,^14,15 who emphasized the importance of the sensation of bodily changes in emotion. Contrary to the popular belief that emotions trigger physiological changes in the body, James postulated that peripheral bodily changes secondary to stimuli perception would exert a sensory feedback, generating emotions. The manipulation of human facial expression with an expression that is associated with a particular emotion (eg, holding a pen with teeth, leading to risorius/zygomaticus muscles contraction and a smile simulation) was found to influence participants’ affective responses in the presence of emotional stimuli (eg, rating cartoons as funnier), reinforcing the facial-feedback hypothesis.^16,17

From a neurobiologic standpoint, facial botulinum toxin A (BTA) injections in rats were associated with increased serotonin and norepinephrine concentrations in the hypothalamus and striatum, respectively.¹⁸ Moreover, amygdala activity in response to angry vs happy faces, measured via functional magnetic resonance imaging (fMRI), was found to be attenuated after BTA applications to muscles involved in angry facial expressions.^19,20 Both the neurotransmitters as well as the aforementioned brain regions have been implicated in the pathophysiology of depression.^21,22

Box

Continue to: In a second RCT involving 74 patients with depression...

Continue to: Benefits for other psychiatric indications

Borderline personality disorder. In a case series of 6 women, BTA injections in the glabellar region were reported to be particularly effective for the treatment of borderline personality disorder symptoms that were resistant to psychotherapy and pharmacotherapy.³¹ Two to 6 weeks after a 29-unit injection, borderline personality disorder symptoms as measured by the Zanarini Rating Scale for Borderline Personality Disorder and/or the Borderline Symptom List were shown to significantly improve by 49% to 94% from baseline (P ≤ .05). These findings emphasize the promising therapeutic role of BTA on depressive symptoms concomitant with the emotional lability, impulsivity, and negative emotions that usually characterize this personality disorder.^31,32 A small sample size and lack of a placebo comparator are limitations of this research.

Neuroleptic-induced sialorrhea. Botulinum toxin injections in the salivary glands have been investigated for treating clozapine-induced sialorrhea because they are thought to directly inhibit the release of acetylcholine from salivary glands. One small RCT that used botulinum toxin B (BTB)³³ and 1 case report that used BTA³⁴ reported successful reduction in hypersalivation, with doses ranging from 150 to 500 units injected in each of the parotid and/or submandibular glands bilaterally. Although the treatment was well tolerated and lasted up to 16 weeks, larger studies are needed to replicate these findings.^33-35

Orofacial tardive dyskinesia. Several case reports of orofacial tardive dyskinesia, including lingual dyskinesia and lingual protrusion dystonia, have found improvements in hyperkinetic movements following muscular BTA injections, such as in the genioglossus muscle in the case of tongue involvement.^36-39 These cases were, however, described in the literature before the recent FDA approval of the vesicular monoamine transporter 2 inhibitors valbenazine and deutetrabenazine for the treatment of tardive dyskinesia.^40,41

Studies examining botulinum toxin’s application in areas of psychiatry other than depression are summarized in Table 2.^31,33,36-38

Continue to: Promising initial findings but multiple limitations

Although BTA injections have been explored as a potential treatment for several psychiatric conditions, the bulk of recent evidence is derived from studies in patients with depressive disorders. BTA injections in the glabellar regions have been shown in small RCTs to be well-tolerated with overall promising improvement of depressive symptoms, optimally 6 weeks after a single injection. Moreover, BTA has been shown to be safe and long-lasting, which would be convenient for patients and might improve adherence to therapy.^42-44 BTA’s antidepressant effects were shown to be independent of frown line severity or patient satisfaction with cosmetic effects.⁴⁵ The trials by Wollmer et al,²³ Finzi and Rosenthal,²⁵ and Magid et al²⁶ mainly studied BTA as an adjunctive treatment to antidepressants in patients with ongoing unipolar depression. However, Finzi and Rosenthal²⁵ included patients who were not medicated at the time of the study.

Pooled analysis of these 3 RCTs found that patients who received BTA monotherapy improved equally to those who received it as an adjunctive treatment to antidepressants. Overall, on primary endpoint measures, a response rate of 54.2% was obtained in the BTA group compared with 10.7% among patients who received placebo saline injections (odds ratio [OR] 11.1, 95% confidence interval [CI], 4.3 to 28.8, number needed to treat [NNT] = 2.3) and a remission rate of 30.5% with BTA compared with 6.7% with placebo (OR 7.3, 95 % CI, 2.4 to 22.5, NNT = 4.2).⁴⁶ However, remission rates tend to be higher in the augmentation groups, and so further studies are needed to compare both treatment strategies.

Nevertheless, these positive findings have been recently challenged by the results of the largest U.S. multicenter phase II RCT,²⁸ which failed to find a significant antidepressant effect at 6 weeks with the 30-unit BTA injection, and also failed to prove a dose-effect relationship, as the 50-unit injection wasn’t superior to the lower dose and didn’t significantly differ from placebo. One hypothesis to explain this discrepancy may be the difference in injection sites between the treatment and placebo groups.⁴⁷ Future studies need to address the various limitations of earlier clinical trials that mainly yielded promising results with BTA.

A major concern is the high rate of unblinding of participants and researchers in BTA trials, as the cosmetic effects of botulinum toxin injections make them easy to distinguish from saline injections. Ninety percent of participants in the Wollmer et al study²³ were able to correctly guess their group allocation, while 60% of evaluators guessed correctly. Finzi and Rozenthal²⁵ reported 52% of participants in the BTA group, 46% in the placebo group, and 73% of evaluators correctly guessed their allocation. Magid et al²⁶ reported 75% of participants were able to guess the order of intervention they received. The high unblinding rates in these trials remains a significant limitation. There is a concern that this may lead to an underestimation of the placebo effect relative to clinical improvement, thus causing inflation of outcome differences between groups. Although various methods have been tried to minimize evaluator unblinding, such as placing surgical caps on participants’ faces during visits to hide the glabellar region, better methods need to be implemented to prevent unblinding of both raters and participants.

Furthermore, except for the multicenter phase II trial, most studies have been conducted in small samples, which limits their statistical power. Larger controlled trials will be needed to replicate the positive findings obtained in smaller RCTs.

Another limitation is that the majority of the well-designed RCTs were conducted in populations that were predominantly female, which makes it difficult to reliably assess treatment efficacy in men. This may be because cosmetic treatment with botulinum toxin injection is more favorably received by women than by men. A recent comparison⁴⁸ of the studies by Wollmer et al²³ and Finzi and Rosenthal²⁵ discussed an interesting observation. Wollmer et al did not explicitly mention botulinum toxin when recruiting for the study, while Finzi and Rosenthal did. While approximately a quarter of the participants in the Wollmer et al study were male, Finzi and Rosenthal attracted an almost entirely female population. Perhaps there is a potential bias for females to be more attracted to these studies due to the secondary gain of receiving a cosmetic procedure.

In an attempt to understand predictors of positive response to botulinum toxin in patients with depression, Wollmer et al⁴⁹ conducted a follow-up study in which they reassessed the data obtained from their initial RCT using the HAM-D agitation item scores to separate the 15 participants who received BTA into low-agitation (≤1 score on agitation item of the HAM-D scale) and high-agitation (≥2 score on agitation item of the HAM-D scale) groups. They found that the 9 participants who responded to BTA treatment had significantly higher baseline agitation scores than participants who did not respond (1.56 ± 0.88 vs 0.33 ± 0.52, P = .01). All of the participants who presented with higher agitation levels experienced response, compared with 40% of those with lower agitation levels (P = .04), although there was no significant difference in magnitude of improvement (14.2 ± 1.92 vs 8.0 ± 9.37, P = .07). The study added additional support to the facial feedback hypothesis, as it links the improvement of depression to facial muscle activation targeted by the injections. It also introduced a potential predictor of response to botulinum toxin treatment, highlighting potential factors to consider when enrolling patients in future investigations.

The case series of patients with borderline personality disorder³¹ also shed light on the potential positive effect of BTA treatment for a particular subtype of patients with depression—those with comorbid emotional instability—to consider as a therapeutic target for the future. Hence, inclusion criteria for future trials might potentially include patient age, gender, existence/quantification of prominent frown lines at baseline, severity of MDD, duration of depression, and personality characteristics of enrolled participants.

In conclusion, BTA injections appear promising as a treatment for depression as well as for other psychiatric disorders. Future studies should focus on identifying optimal candidates for this innovative treatment modality. Furthermore, BTA dosing and administration strategies (monotherapy vs adjunctive treatment to antidepressants) need to be further explored. As retrograde axonal transport of botulinum toxin has been demonstrated in animal studies, it would be interesting to further examine its effects in the human CNS to enhance our knowledge of the pathophysiology of botulinum and its potential applications in psychiatry.⁵⁰

Bottom Line

Botulinum toxin shows promising antidepressant effects and may have a role in the treatment of several other psychiatric disorders. More research is needed to address limitations of previous studies and to establish an adequate treatment regimen.

Related Resources

• Wollmer MA, Magid M, Kruger TH. Botulinum toxin treatment in depression. In: Bewley A, Taylor RE, Reichenberg JS, et al (eds). Practical psychodermatology. Oxford, UK: Wiley; 2014.
• Wollmer MA, Neumann I, Magid M. et al. Shrink that frown! Botulinum toxin therapy is lifting the face of psychiatry. G Ital Dermatol Venereol. 2018;153(4):540-548.

Drug Brand Names

Alprazolam • Xanax
Aripiprazole • Abilify
Biperiden • Akineton
Botulinum toxin A • Botox
Botulinum toxin B • Myobloc
Clozapine • Clozaril
Deutetrabenazine • Austedo
Flupentixol • Prolixin
Imipramine • Tofranil
Olanzapine • Zyprexa
Reserpine • Serpalan, Serpasil
Tetrabenazine • Xenazine
Valbenazine • Ingrezza
Ziprasidone • Geodon

Botulinum toxin, a potent neurotoxic protein produced by the bacterium Clostridium botulinum, has been used as treatment for a variety of medical indications for more than 25 years (Box^1-12). Recently, researchers have been exploring the role of botulinum toxin in psychiatry, primarily as an adjunctive treatment for depression, but also for several other possible indications. Several studies, including randomized controlled trials (RCTs), have provided evidence that glabellar botulinum toxin injections may be a safe and effective treatment for depression. In this article, we provide an update on the latest clinical trials that evaluated botulinum toxin for depression, and also summarize the evidence regarding other potential clinical psychiatric applications of botulinum toxin.

Several RCTs suggest efficacy for depression

The use of botulinum toxin to treat depression is based on the facial feedback hypothesis, which was first proposed by Charles Darwin in 1872¹³ and further elaborated by William James,^14,15 who emphasized the importance of the sensation of bodily changes in emotion. Contrary to the popular belief that emotions trigger physiological changes in the body, James postulated that peripheral bodily changes secondary to stimuli perception would exert a sensory feedback, generating emotions. The manipulation of human facial expression with an expression that is associated with a particular emotion (eg, holding a pen with teeth, leading to risorius/zygomaticus muscles contraction and a smile simulation) was found to influence participants’ affective responses in the presence of emotional stimuli (eg, rating cartoons as funnier), reinforcing the facial-feedback hypothesis.^16,17

From a neurobiologic standpoint, facial botulinum toxin A (BTA) injections in rats were associated with increased serotonin and norepinephrine concentrations in the hypothalamus and striatum, respectively.¹⁸ Moreover, amygdala activity in response to angry vs happy faces, measured via functional magnetic resonance imaging (fMRI), was found to be attenuated after BTA applications to muscles involved in angry facial expressions.^19,20 Both the neurotransmitters as well as the aforementioned brain regions have been implicated in the pathophysiology of depression.^21,22

Box

Continue to: In a second RCT involving 74 patients with depression...

Continue to: Benefits for other psychiatric indications

Borderline personality disorder. In a case series of 6 women, BTA injections in the glabellar region were reported to be particularly effective for the treatment of borderline personality disorder symptoms that were resistant to psychotherapy and pharmacotherapy.³¹ Two to 6 weeks after a 29-unit injection, borderline personality disorder symptoms as measured by the Zanarini Rating Scale for Borderline Personality Disorder and/or the Borderline Symptom List were shown to significantly improve by 49% to 94% from baseline (P ≤ .05). These findings emphasize the promising therapeutic role of BTA on depressive symptoms concomitant with the emotional lability, impulsivity, and negative emotions that usually characterize this personality disorder.^31,32 A small sample size and lack of a placebo comparator are limitations of this research.

Neuroleptic-induced sialorrhea. Botulinum toxin injections in the salivary glands have been investigated for treating clozapine-induced sialorrhea because they are thought to directly inhibit the release of acetylcholine from salivary glands. One small RCT that used botulinum toxin B (BTB)³³ and 1 case report that used BTA³⁴ reported successful reduction in hypersalivation, with doses ranging from 150 to 500 units injected in each of the parotid and/or submandibular glands bilaterally. Although the treatment was well tolerated and lasted up to 16 weeks, larger studies are needed to replicate these findings.^33-35

Orofacial tardive dyskinesia. Several case reports of orofacial tardive dyskinesia, including lingual dyskinesia and lingual protrusion dystonia, have found improvements in hyperkinetic movements following muscular BTA injections, such as in the genioglossus muscle in the case of tongue involvement.^36-39 These cases were, however, described in the literature before the recent FDA approval of the vesicular monoamine transporter 2 inhibitors valbenazine and deutetrabenazine for the treatment of tardive dyskinesia.^40,41

Studies examining botulinum toxin’s application in areas of psychiatry other than depression are summarized in Table 2.^31,33,36-38

Continue to: Promising initial findings but multiple limitations

Although BTA injections have been explored as a potential treatment for several psychiatric conditions, the bulk of recent evidence is derived from studies in patients with depressive disorders. BTA injections in the glabellar regions have been shown in small RCTs to be well-tolerated with overall promising improvement of depressive symptoms, optimally 6 weeks after a single injection. Moreover, BTA has been shown to be safe and long-lasting, which would be convenient for patients and might improve adherence to therapy.^42-44 BTA’s antidepressant effects were shown to be independent of frown line severity or patient satisfaction with cosmetic effects.⁴⁵ The trials by Wollmer et al,²³ Finzi and Rosenthal,²⁵ and Magid et al²⁶ mainly studied BTA as an adjunctive treatment to antidepressants in patients with ongoing unipolar depression. However, Finzi and Rosenthal²⁵ included patients who were not medicated at the time of the study.

Pooled analysis of these 3 RCTs found that patients who received BTA monotherapy improved equally to those who received it as an adjunctive treatment to antidepressants. Overall, on primary endpoint measures, a response rate of 54.2% was obtained in the BTA group compared with 10.7% among patients who received placebo saline injections (odds ratio [OR] 11.1, 95% confidence interval [CI], 4.3 to 28.8, number needed to treat [NNT] = 2.3) and a remission rate of 30.5% with BTA compared with 6.7% with placebo (OR 7.3, 95 % CI, 2.4 to 22.5, NNT = 4.2).⁴⁶ However, remission rates tend to be higher in the augmentation groups, and so further studies are needed to compare both treatment strategies.

Nevertheless, these positive findings have been recently challenged by the results of the largest U.S. multicenter phase II RCT,²⁸ which failed to find a significant antidepressant effect at 6 weeks with the 30-unit BTA injection, and also failed to prove a dose-effect relationship, as the 50-unit injection wasn’t superior to the lower dose and didn’t significantly differ from placebo. One hypothesis to explain this discrepancy may be the difference in injection sites between the treatment and placebo groups.⁴⁷ Future studies need to address the various limitations of earlier clinical trials that mainly yielded promising results with BTA.

A major concern is the high rate of unblinding of participants and researchers in BTA trials, as the cosmetic effects of botulinum toxin injections make them easy to distinguish from saline injections. Ninety percent of participants in the Wollmer et al study²³ were able to correctly guess their group allocation, while 60% of evaluators guessed correctly. Finzi and Rozenthal²⁵ reported 52% of participants in the BTA group, 46% in the placebo group, and 73% of evaluators correctly guessed their allocation. Magid et al²⁶ reported 75% of participants were able to guess the order of intervention they received. The high unblinding rates in these trials remains a significant limitation. There is a concern that this may lead to an underestimation of the placebo effect relative to clinical improvement, thus causing inflation of outcome differences between groups. Although various methods have been tried to minimize evaluator unblinding, such as placing surgical caps on participants’ faces during visits to hide the glabellar region, better methods need to be implemented to prevent unblinding of both raters and participants.

Furthermore, except for the multicenter phase II trial, most studies have been conducted in small samples, which limits their statistical power. Larger controlled trials will be needed to replicate the positive findings obtained in smaller RCTs.

Another limitation is that the majority of the well-designed RCTs were conducted in populations that were predominantly female, which makes it difficult to reliably assess treatment efficacy in men. This may be because cosmetic treatment with botulinum toxin injection is more favorably received by women than by men. A recent comparison⁴⁸ of the studies by Wollmer et al²³ and Finzi and Rosenthal²⁵ discussed an interesting observation. Wollmer et al did not explicitly mention botulinum toxin when recruiting for the study, while Finzi and Rosenthal did. While approximately a quarter of the participants in the Wollmer et al study were male, Finzi and Rosenthal attracted an almost entirely female population. Perhaps there is a potential bias for females to be more attracted to these studies due to the secondary gain of receiving a cosmetic procedure.

In an attempt to understand predictors of positive response to botulinum toxin in patients with depression, Wollmer et al⁴⁹ conducted a follow-up study in which they reassessed the data obtained from their initial RCT using the HAM-D agitation item scores to separate the 15 participants who received BTA into low-agitation (≤1 score on agitation item of the HAM-D scale) and high-agitation (≥2 score on agitation item of the HAM-D scale) groups. They found that the 9 participants who responded to BTA treatment had significantly higher baseline agitation scores than participants who did not respond (1.56 ± 0.88 vs 0.33 ± 0.52, P = .01). All of the participants who presented with higher agitation levels experienced response, compared with 40% of those with lower agitation levels (P = .04), although there was no significant difference in magnitude of improvement (14.2 ± 1.92 vs 8.0 ± 9.37, P = .07). The study added additional support to the facial feedback hypothesis, as it links the improvement of depression to facial muscle activation targeted by the injections. It also introduced a potential predictor of response to botulinum toxin treatment, highlighting potential factors to consider when enrolling patients in future investigations.

The case series of patients with borderline personality disorder³¹ also shed light on the potential positive effect of BTA treatment for a particular subtype of patients with depression—those with comorbid emotional instability—to consider as a therapeutic target for the future. Hence, inclusion criteria for future trials might potentially include patient age, gender, existence/quantification of prominent frown lines at baseline, severity of MDD, duration of depression, and personality characteristics of enrolled participants.

In conclusion, BTA injections appear promising as a treatment for depression as well as for other psychiatric disorders. Future studies should focus on identifying optimal candidates for this innovative treatment modality. Furthermore, BTA dosing and administration strategies (monotherapy vs adjunctive treatment to antidepressants) need to be further explored. As retrograde axonal transport of botulinum toxin has been demonstrated in animal studies, it would be interesting to further examine its effects in the human CNS to enhance our knowledge of the pathophysiology of botulinum and its potential applications in psychiatry.⁵⁰

Bottom Line

Botulinum toxin shows promising antidepressant effects and may have a role in the treatment of several other psychiatric disorders. More research is needed to address limitations of previous studies and to establish an adequate treatment regimen.

Related Resources

• Wollmer MA, Magid M, Kruger TH. Botulinum toxin treatment in depression. In: Bewley A, Taylor RE, Reichenberg JS, et al (eds). Practical psychodermatology. Oxford, UK: Wiley; 2014.
• Wollmer MA, Neumann I, Magid M. et al. Shrink that frown! Botulinum toxin therapy is lifting the face of psychiatry. G Ital Dermatol Venereol. 2018;153(4):540-548.

Drug Brand Names

Alprazolam • Xanax
Aripiprazole • Abilify
Biperiden • Akineton
Botulinum toxin A • Botox
Botulinum toxin B • Myobloc
Clozapine • Clozaril
Deutetrabenazine • Austedo
Flupentixol • Prolixin
Imipramine • Tofranil
Olanzapine • Zyprexa
Reserpine • Serpalan, Serpasil
Tetrabenazine • Xenazine
Valbenazine • Ingrezza
Ziprasidone • Geodon

In schizophrenia, negative symptoms such as social withdrawal, avoidance, lack of spontaneity and flow of conversation, reduced initiative, anhedonia, and blunted affect are among the most challenging to treat. These symptoms commonly persist after positive symptoms such as hallucinations, delusions, and paranoia have subsided. In an analysis of 20 pivotal placebo-controlled trials of second-generation antipsychotics (SGAs), almost 45% of patients who completed 6 weeks of treatment still had at least 1 residual negative symptom of at least moderate severity, and approximately 25% had 2 or more.¹ Negative symptoms are viewed as being intrinsic to schizophrenia, and also as the result of extrapyramidal symptoms, depression, and psychosis.

Nearly a decade ago, the Schizophrenia Patient Outcomes Research Team (PORT) published its recommendations for psychopharmacologic and psycho­social treatments of schizophrenia. Unfortunately, due to insufficient evidence, there is still no proven treatment for negative symptoms.^2-4 This is particularly problematic because negative symptoms are a major determinant of the poor social and vocational abilities of patients with schizophrenia.

This review focuses on treatments for negative symptoms of schizophrenia that have been evaluated since the PORT treatment recommendations were published and highlights those approaches that show promise.

_

The limitations of antipsychotics

Antipsychotics can both worsen and alleviate negative symptoms by reducing psychotic symptoms. Double-blind, placebo-controlled trials have found that most, if not all, antipsychotics are superior to placebo for treating negative symptoms in patients with acute psychosis.⁴ However, because these improvements occur in the early stages of treatment, concomitantly with improvement of psychotic symptoms, antipsychotics generally are not viewed as being very effective in the treatment of primary negative symptoms.⁴ Indeed, an examination of patients with prominent negative symptoms without prominent positive symptoms in the NEWMEDS cohort, which was extracted from 20 pivotal placebo-controlled trials of SGAs, revealed no clinically meaningful treatment effect on negative symptoms.¹

There is evidence that antipsychotics can contribute to the development of apathy, flat affect, and other negative symptoms.⁵ Dopamine (D2)-blocking antipsychotics produce secondary negative symptoms that are not always easy to distinguish from primary negative symptoms.⁶ In a double-blind, placebo-controlled trial of single doses of risperidone, haloperidol, or placebo in healthy participants, the antipsychotics increased negative symptoms, particularly avolition/apathy.⁷ Another study found that chronic treatment with antipsychotics did not necessarily affect motivation in patients with schizophrenia.⁸

Adverse effects, such as anhedonia, often produce and enhance negative symptoms and therefore can limit the use of pharmacologic treatment options. Other adverse effects associated with specific antipsycho­tics include extrapyramidal symptoms, sedation, increased prolactin secretion, weight gain, and other metabolic abnormalities.

Continue to: Seeking new pharmacologic options

The years since the PORT review have been filled with initial promise, a series of bitter disappointments, and a renewed spark of hope in the quest to treat negative symptoms in schizophrenia.


Compounds that have been abandoned. Since PORT, researchers have evaluated 5 major compounds that mainly targeted cognition and negative symptoms in patients with schizophrenia (Box^9-17). Unfortunately, 4 of them failed to provide significant superiority over placebo, and 1 was withdrawn due to safety concerns.

Box

Initial favorable results. Registered, robust trials of other compounds have had some initial favorable results that need to be replicated. These agents include:

• MIN-101 is a novel cyclic amide derivative.¹⁸ In a phase IIb 12-week study of MIN-101 monotherapy (32 mg, n = 78; 64 mg, n = 83) vs placebo (n = 83), both dose groups had significantly more improvement on the Positive and Negative Syndrome Scale (PANSS) negative factor score, which was the primary outcome measure, than placebo (32 mg/d; effect size = .45, P < .02, 64 mg/d; effect size = .57, P < .004) as well as on PANSS negative symptom score and other measures of negative symptoms.¹⁸
• Cariprazine is a D2 and D3 receptor partial agonist with high selectivity towards the D3 receptor¹⁹
• Minocycline is a broad-spectrum tetracyclic antibiotic displaying neuroprotective properties^18,20,21
• Raloxifene is a selective estrogen receptor modulator for postmenopausal women^22,23
• Pimavanserin, which was FDA-approved in 2016 for the treatment of Parkinson’s disease psychosis, is being tested in a large trial for adjunctive treatment of patients with negative symptoms of schizophrenia. This medication is a nondopaminergic antipsychotic that acts as a selective serotonin inverse agonist that preferentially targets 5-HT2A receptors while avoiding activity at common targets such as dopamine.²⁴

All of these compounds except MIN-101 are currently available in the U.S. but have not been approved for the treatment of negative symptoms in patients with schizophrenia. MIN-101 is in phase III testing (NCT03397134).

Continue to: Nonpharmacologic treatments

Recent studies of nonpharmacologic treatments for negative symptoms, including psychosocial approaches and noninvasive electromagnetic neurostimulation, have also been performed. The major psychosocial approaches that have been studied include social skills training (SST), cognitive-behavioral therapy (CBT) for psychosis, cognitive remediation, and family intervention. Some positive findings have been reported. A recent review of psychosocial treatments for negative symptoms in schizophrenia concluded that CBT and SST have the most empirical support, with some evidence even suggesting that gains from CBT are maintained as long as 6 months after treatment.²⁵ Another review found that CBT was significantly more efficacious for reducing positive symptoms and SST in reducing negative symptoms.²⁶

It remains unclear if a combined treatment approach provides improvements above and beyond those associated with each individual treatment modality. Motivation and Enhancement therapy (MOVE) is a potentially promising approach that combines environmental support, CBT, skills training, and other components in an attempt to address all domains of negative symptoms.²⁷ Preliminary results from a randomized controlled trial examining 51 patients with clinically meaningful negative symptoms suggested that MOVE improves negative symptoms. However, the group differences were not significant until after 9 months of treatment and not for all negative symptom scales. A follow-up study has been completed, but the results are not yet available.²⁸

Some small studies have suggested improvement of negative symptoms after noninvasive electromagnetic neurostimulation,^29-31 but this has not been replicated in larger studies.³² In the last few years, there were several studies underway that could help clarify if there is a role for noninvasive electromagnetic neurostimulation in the treatment of negative symptoms in schizophrenia; however, results have not been reported at this time.^33-35

_

Social skills training and combined interventions

Taken together, the data suggest that treating negative symptoms in schizophrenia remains a major challenge. Patients with negative symptoms are difficult to engage and motivate for treatment and there are no well-supported treatment options. Given the lack of evidence, it is not possible to synthesize this data into clear treatment recommendations. Because many of the negative symptoms are social in nature, it is perhaps not surprising that some evidence has emerged supporting the role of psycho­social approaches. Studies have pointed to the potential role of SST. It is believed to be beneficial as it targets participants’ social functioning by training verbal and nonverbal communication alongside perception and responses to social cues.³⁶ Some evidence suggests that treatment packages that combine several psychosocial interventions (eg, family psychoeducation and skill training) achieve better outcomes than standalone interventions.³⁷ Thus, psychosocial approaches appear to be potentially effective for the treatment of negative symptoms in patients with schizophrenia. In addition, because some antipsychotics has been shown to be associated with fewer negative symptoms than others, another treatment strategy could be to attempt the use of a different antipsychotic, or to revisit whether continued antipsychotic treatment is needed in the absence of positive symptoms.

Bottom Line

Treating negative symptoms in schizophrenia remains a major challenge. There is a lack of evidence for pharmacologic treatments; psychosocial approaches may be beneficial due to the social nature of many negative symptoms. Further, some evidence suggests that treatment packages that combine several psychosocial interventions may achieve better outcomes than standalone interventions.

Related Resource

Tandon R, Jibson M. Negative symptoms of schizophrenia: How to treat them most effectively. Current Psychiatry. 2002;1(9):36-42.

Drug Brand Names

Cariprazine • Vraylar
Haloperidol • Haldol
Minocycline • Dynacin, Minocin
Pimavanserin • Nuplazid
Raloxifene • Evista
Risperidone • Risperdal

In schizophrenia, negative symptoms such as social withdrawal, avoidance, lack of spontaneity and flow of conversation, reduced initiative, anhedonia, and blunted affect are among the most challenging to treat. These symptoms commonly persist after positive symptoms such as hallucinations, delusions, and paranoia have subsided. In an analysis of 20 pivotal placebo-controlled trials of second-generation antipsychotics (SGAs), almost 45% of patients who completed 6 weeks of treatment still had at least 1 residual negative symptom of at least moderate severity, and approximately 25% had 2 or more.¹ Negative symptoms are viewed as being intrinsic to schizophrenia, and also as the result of extrapyramidal symptoms, depression, and psychosis.

Nearly a decade ago, the Schizophrenia Patient Outcomes Research Team (PORT) published its recommendations for psychopharmacologic and psycho­social treatments of schizophrenia. Unfortunately, due to insufficient evidence, there is still no proven treatment for negative symptoms.^2-4 This is particularly problematic because negative symptoms are a major determinant of the poor social and vocational abilities of patients with schizophrenia.

This review focuses on treatments for negative symptoms of schizophrenia that have been evaluated since the PORT treatment recommendations were published and highlights those approaches that show promise.

_

The limitations of antipsychotics

Antipsychotics can both worsen and alleviate negative symptoms by reducing psychotic symptoms. Double-blind, placebo-controlled trials have found that most, if not all, antipsychotics are superior to placebo for treating negative symptoms in patients with acute psychosis.⁴ However, because these improvements occur in the early stages of treatment, concomitantly with improvement of psychotic symptoms, antipsychotics generally are not viewed as being very effective in the treatment of primary negative symptoms.⁴ Indeed, an examination of patients with prominent negative symptoms without prominent positive symptoms in the NEWMEDS cohort, which was extracted from 20 pivotal placebo-controlled trials of SGAs, revealed no clinically meaningful treatment effect on negative symptoms.¹

There is evidence that antipsychotics can contribute to the development of apathy, flat affect, and other negative symptoms.⁵ Dopamine (D2)-blocking antipsychotics produce secondary negative symptoms that are not always easy to distinguish from primary negative symptoms.⁶ In a double-blind, placebo-controlled trial of single doses of risperidone, haloperidol, or placebo in healthy participants, the antipsychotics increased negative symptoms, particularly avolition/apathy.⁷ Another study found that chronic treatment with antipsychotics did not necessarily affect motivation in patients with schizophrenia.⁸

Adverse effects, such as anhedonia, often produce and enhance negative symptoms and therefore can limit the use of pharmacologic treatment options. Other adverse effects associated with specific antipsycho­tics include extrapyramidal symptoms, sedation, increased prolactin secretion, weight gain, and other metabolic abnormalities.

Continue to: Seeking new pharmacologic options

The years since the PORT review have been filled with initial promise, a series of bitter disappointments, and a renewed spark of hope in the quest to treat negative symptoms in schizophrenia.


Compounds that have been abandoned. Since PORT, researchers have evaluated 5 major compounds that mainly targeted cognition and negative symptoms in patients with schizophrenia (Box^9-17). Unfortunately, 4 of them failed to provide significant superiority over placebo, and 1 was withdrawn due to safety concerns.

Box

Initial favorable results. Registered, robust trials of other compounds have had some initial favorable results that need to be replicated. These agents include:

• MIN-101 is a novel cyclic amide derivative.¹⁸ In a phase IIb 12-week study of MIN-101 monotherapy (32 mg, n = 78; 64 mg, n = 83) vs placebo (n = 83), both dose groups had significantly more improvement on the Positive and Negative Syndrome Scale (PANSS) negative factor score, which was the primary outcome measure, than placebo (32 mg/d; effect size = .45, P < .02, 64 mg/d; effect size = .57, P < .004) as well as on PANSS negative symptom score and other measures of negative symptoms.¹⁸
• Cariprazine is a D2 and D3 receptor partial agonist with high selectivity towards the D3 receptor¹⁹
• Minocycline is a broad-spectrum tetracyclic antibiotic displaying neuroprotective properties^18,20,21
• Raloxifene is a selective estrogen receptor modulator for postmenopausal women^22,23
• Pimavanserin, which was FDA-approved in 2016 for the treatment of Parkinson’s disease psychosis, is being tested in a large trial for adjunctive treatment of patients with negative symptoms of schizophrenia. This medication is a nondopaminergic antipsychotic that acts as a selective serotonin inverse agonist that preferentially targets 5-HT2A receptors while avoiding activity at common targets such as dopamine.²⁴

All of these compounds except MIN-101 are currently available in the U.S. but have not been approved for the treatment of negative symptoms in patients with schizophrenia. MIN-101 is in phase III testing (NCT03397134).

Continue to: Nonpharmacologic treatments

Recent studies of nonpharmacologic treatments for negative symptoms, including psychosocial approaches and noninvasive electromagnetic neurostimulation, have also been performed. The major psychosocial approaches that have been studied include social skills training (SST), cognitive-behavioral therapy (CBT) for psychosis, cognitive remediation, and family intervention. Some positive findings have been reported. A recent review of psychosocial treatments for negative symptoms in schizophrenia concluded that CBT and SST have the most empirical support, with some evidence even suggesting that gains from CBT are maintained as long as 6 months after treatment.²⁵ Another review found that CBT was significantly more efficacious for reducing positive symptoms and SST in reducing negative symptoms.²⁶

It remains unclear if a combined treatment approach provides improvements above and beyond those associated with each individual treatment modality. Motivation and Enhancement therapy (MOVE) is a potentially promising approach that combines environmental support, CBT, skills training, and other components in an attempt to address all domains of negative symptoms.²⁷ Preliminary results from a randomized controlled trial examining 51 patients with clinically meaningful negative symptoms suggested that MOVE improves negative symptoms. However, the group differences were not significant until after 9 months of treatment and not for all negative symptom scales. A follow-up study has been completed, but the results are not yet available.²⁸

Some small studies have suggested improvement of negative symptoms after noninvasive electromagnetic neurostimulation,^29-31 but this has not been replicated in larger studies.³² In the last few years, there were several studies underway that could help clarify if there is a role for noninvasive electromagnetic neurostimulation in the treatment of negative symptoms in schizophrenia; however, results have not been reported at this time.^33-35

_

Social skills training and combined interventions

Taken together, the data suggest that treating negative symptoms in schizophrenia remains a major challenge. Patients with negative symptoms are difficult to engage and motivate for treatment and there are no well-supported treatment options. Given the lack of evidence, it is not possible to synthesize this data into clear treatment recommendations. Because many of the negative symptoms are social in nature, it is perhaps not surprising that some evidence has emerged supporting the role of psycho­social approaches. Studies have pointed to the potential role of SST. It is believed to be beneficial as it targets participants’ social functioning by training verbal and nonverbal communication alongside perception and responses to social cues.³⁶ Some evidence suggests that treatment packages that combine several psychosocial interventions (eg, family psychoeducation and skill training) achieve better outcomes than standalone interventions.³⁷ Thus, psychosocial approaches appear to be potentially effective for the treatment of negative symptoms in patients with schizophrenia. In addition, because some antipsychotics has been shown to be associated with fewer negative symptoms than others, another treatment strategy could be to attempt the use of a different antipsychotic, or to revisit whether continued antipsychotic treatment is needed in the absence of positive symptoms.

Bottom Line

Treating negative symptoms in schizophrenia remains a major challenge. There is a lack of evidence for pharmacologic treatments; psychosocial approaches may be beneficial due to the social nature of many negative symptoms. Further, some evidence suggests that treatment packages that combine several psychosocial interventions may achieve better outcomes than standalone interventions.

Related Resource

Tandon R, Jibson M. Negative symptoms of schizophrenia: How to treat them most effectively. Current Psychiatry. 2002;1(9):36-42.

Drug Brand Names

Cariprazine • Vraylar
Haloperidol • Haldol
Minocycline • Dynacin, Minocin
Pimavanserin • Nuplazid
Raloxifene • Evista
Risperidone • Risperdal

In schizophrenia, negative symptoms such as social withdrawal, avoidance, lack of spontaneity and flow of conversation, reduced initiative, anhedonia, and blunted affect are among the most challenging to treat. These symptoms commonly persist after positive symptoms such as hallucinations, delusions, and paranoia have subsided. In an analysis of 20 pivotal placebo-controlled trials of second-generation antipsychotics (SGAs), almost 45% of patients who completed 6 weeks of treatment still had at least 1 residual negative symptom of at least moderate severity, and approximately 25% had 2 or more.¹ Negative symptoms are viewed as being intrinsic to schizophrenia, and also as the result of extrapyramidal symptoms, depression, and psychosis.

Nearly a decade ago, the Schizophrenia Patient Outcomes Research Team (PORT) published its recommendations for psychopharmacologic and psycho­social treatments of schizophrenia. Unfortunately, due to insufficient evidence, there is still no proven treatment for negative symptoms.^2-4 This is particularly problematic because negative symptoms are a major determinant of the poor social and vocational abilities of patients with schizophrenia.

This review focuses on treatments for negative symptoms of schizophrenia that have been evaluated since the PORT treatment recommendations were published and highlights those approaches that show promise.

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The limitations of antipsychotics

Antipsychotics can both worsen and alleviate negative symptoms by reducing psychotic symptoms. Double-blind, placebo-controlled trials have found that most, if not all, antipsychotics are superior to placebo for treating negative symptoms in patients with acute psychosis.⁴ However, because these improvements occur in the early stages of treatment, concomitantly with improvement of psychotic symptoms, antipsychotics generally are not viewed as being very effective in the treatment of primary negative symptoms.⁴ Indeed, an examination of patients with prominent negative symptoms without prominent positive symptoms in the NEWMEDS cohort, which was extracted from 20 pivotal placebo-controlled trials of SGAs, revealed no clinically meaningful treatment effect on negative symptoms.¹

There is evidence that antipsychotics can contribute to the development of apathy, flat affect, and other negative symptoms.⁵ Dopamine (D2)-blocking antipsychotics produce secondary negative symptoms that are not always easy to distinguish from primary negative symptoms.⁶ In a double-blind, placebo-controlled trial of single doses of risperidone, haloperidol, or placebo in healthy participants, the antipsychotics increased negative symptoms, particularly avolition/apathy.⁷ Another study found that chronic treatment with antipsychotics did not necessarily affect motivation in patients with schizophrenia.⁸

Adverse effects, such as anhedonia, often produce and enhance negative symptoms and therefore can limit the use of pharmacologic treatment options. Other adverse effects associated with specific antipsycho­tics include extrapyramidal symptoms, sedation, increased prolactin secretion, weight gain, and other metabolic abnormalities.

Continue to: Seeking new pharmacologic options

The years since the PORT review have been filled with initial promise, a series of bitter disappointments, and a renewed spark of hope in the quest to treat negative symptoms in schizophrenia.


Compounds that have been abandoned. Since PORT, researchers have evaluated 5 major compounds that mainly targeted cognition and negative symptoms in patients with schizophrenia (Box^9-17). Unfortunately, 4 of them failed to provide significant superiority over placebo, and 1 was withdrawn due to safety concerns.

Box

Initial favorable results. Registered, robust trials of other compounds have had some initial favorable results that need to be replicated. These agents include:

• MIN-101 is a novel cyclic amide derivative.¹⁸ In a phase IIb 12-week study of MIN-101 monotherapy (32 mg, n = 78; 64 mg, n = 83) vs placebo (n = 83), both dose groups had significantly more improvement on the Positive and Negative Syndrome Scale (PANSS) negative factor score, which was the primary outcome measure, than placebo (32 mg/d; effect size = .45, P < .02, 64 mg/d; effect size = .57, P < .004) as well as on PANSS negative symptom score and other measures of negative symptoms.¹⁸
• Cariprazine is a D2 and D3 receptor partial agonist with high selectivity towards the D3 receptor¹⁹
• Minocycline is a broad-spectrum tetracyclic antibiotic displaying neuroprotective properties^18,20,21
• Raloxifene is a selective estrogen receptor modulator for postmenopausal women^22,23
• Pimavanserin, which was FDA-approved in 2016 for the treatment of Parkinson’s disease psychosis, is being tested in a large trial for adjunctive treatment of patients with negative symptoms of schizophrenia. This medication is a nondopaminergic antipsychotic that acts as a selective serotonin inverse agonist that preferentially targets 5-HT2A receptors while avoiding activity at common targets such as dopamine.²⁴

All of these compounds except MIN-101 are currently available in the U.S. but have not been approved for the treatment of negative symptoms in patients with schizophrenia. MIN-101 is in phase III testing (NCT03397134).

Continue to: Nonpharmacologic treatments

Recent studies of nonpharmacologic treatments for negative symptoms, including psychosocial approaches and noninvasive electromagnetic neurostimulation, have also been performed. The major psychosocial approaches that have been studied include social skills training (SST), cognitive-behavioral therapy (CBT) for psychosis, cognitive remediation, and family intervention. Some positive findings have been reported. A recent review of psychosocial treatments for negative symptoms in schizophrenia concluded that CBT and SST have the most empirical support, with some evidence even suggesting that gains from CBT are maintained as long as 6 months after treatment.²⁵ Another review found that CBT was significantly more efficacious for reducing positive symptoms and SST in reducing negative symptoms.²⁶

It remains unclear if a combined treatment approach provides improvements above and beyond those associated with each individual treatment modality. Motivation and Enhancement therapy (MOVE) is a potentially promising approach that combines environmental support, CBT, skills training, and other components in an attempt to address all domains of negative symptoms.²⁷ Preliminary results from a randomized controlled trial examining 51 patients with clinically meaningful negative symptoms suggested that MOVE improves negative symptoms. However, the group differences were not significant until after 9 months of treatment and not for all negative symptom scales. A follow-up study has been completed, but the results are not yet available.²⁸

Some small studies have suggested improvement of negative symptoms after noninvasive electromagnetic neurostimulation,^29-31 but this has not been replicated in larger studies.³² In the last few years, there were several studies underway that could help clarify if there is a role for noninvasive electromagnetic neurostimulation in the treatment of negative symptoms in schizophrenia; however, results have not been reported at this time.^33-35

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Social skills training and combined interventions

Taken together, the data suggest that treating negative symptoms in schizophrenia remains a major challenge. Patients with negative symptoms are difficult to engage and motivate for treatment and there are no well-supported treatment options. Given the lack of evidence, it is not possible to synthesize this data into clear treatment recommendations. Because many of the negative symptoms are social in nature, it is perhaps not surprising that some evidence has emerged supporting the role of psycho­social approaches. Studies have pointed to the potential role of SST. It is believed to be beneficial as it targets participants’ social functioning by training verbal and nonverbal communication alongside perception and responses to social cues.³⁶ Some evidence suggests that treatment packages that combine several psychosocial interventions (eg, family psychoeducation and skill training) achieve better outcomes than standalone interventions.³⁷ Thus, psychosocial approaches appear to be potentially effective for the treatment of negative symptoms in patients with schizophrenia. In addition, because some antipsychotics has been shown to be associated with fewer negative symptoms than others, another treatment strategy could be to attempt the use of a different antipsychotic, or to revisit whether continued antipsychotic treatment is needed in the absence of positive symptoms.

Bottom Line

Treating negative symptoms in schizophrenia remains a major challenge. There is a lack of evidence for pharmacologic treatments; psychosocial approaches may be beneficial due to the social nature of many negative symptoms. Further, some evidence suggests that treatment packages that combine several psychosocial interventions may achieve better outcomes than standalone interventions.

Related Resource

Tandon R, Jibson M. Negative symptoms of schizophrenia: How to treat them most effectively. Current Psychiatry. 2002;1(9):36-42.

Drug Brand Names

Cariprazine • Vraylar
Haloperidol • Haldol
Minocycline • Dynacin, Minocin
Pimavanserin • Nuplazid
Raloxifene • Evista
Risperidone • Risperdal

Islands of knowledge in an ocean of ignorance. That summarizes the advances in unraveling the enigma of schizophrenia, arguably the most complex psychiatric brain disorder. The more breakthroughs are made, the more questions emerge.

Progress is definitely being made and the published literature, replete with new findings, is growing logarithmically. Particularly exciting are the recent advances in the etiology of schizophrenia, both genetic and environmental. Collaboration among geneticists around the world has enabled genome-wide association studies on almost 50,000 DNA samples and has revealed 3 genetic pathways to disrupted brain development, which lead to schizophrenia in early adulthood. Those genetic pathways include:

1. Susceptibility genes—more than 340 of them—are found significantly more often in patients with schizophrenia compared with the general population. These risk genes are scattered across all 23 pairs of chromosomes. They influence neurotransmitter functions, neuroplasticity, and immune regulation. The huge task that lies ahead is identifying what each of the risk genes disrupts in brain structure and/or function.

2. Copy number variants (CNVs), such as deletions (1 allele instead of the normal 2) or duplications (3 alleles), are much more frequent in patients with schizophrenia compared with the general population. That means too little or too much protein is made, which can disrupt the 4 stages of brain development (proliferation, migration, differentiation, and elimination).

3. de novo nonsense mutations, leading to complete absence of protein coding by the affected genes, with adverse ripple effects on brain development.

Approximately 10,000 genes (close to 50% of all 22,000 coding genes in the human genome) are involved in constructing the human brain. The latest estimate is that 79% of the hundreds of biotypes of schizophrenia are genetic in etiology.

In addition, multiple environmental factors can disrupt brain development and lead to schizophrenia. These include older paternal age (>45 years) at the time of conception, pregnancy complications (infections, gestational diabetes, vitamin D deficiency, hypoxia during delivery), childhood maltreatment (sexual or physical abuse or neglect) in the first 5 to 6 years of life, as well as migration and urbanicity (being born and raised in a large metropolitan area).

The bottom line: Schizophrenia is not only very complex, but also an extremely heterogeneous brain syndrome, both biologically and clinically. Psychiatric practitioners are fully cognizant of the extensive clinical variability in patients with schizophrenia, including the presence, absence, or severity of various signs and symptoms, such as insight, delusions, hallucinations, conceptual disorganization, bizarre behaviors, emotional withdrawal, agitation, depression, suicidality, anxiety, substance use, somatic concerns, hostility, idiosyncratic mannerisms, blunted affect, apathy, avolition, self-neglect, poor attention, memory impairment, and problems with decision-making, planning ahead, or organizing one’s life.

In addition, heterogeneity is encountered in such variables as age of onset, minor physical anomalies, soft neurologic signs, naturally occurring movement disorders, premorbid functioning, family history, general medical comorbidities, psychiatry comorbidities, structural brain abnormalities on neuroimaging, neurophysiological deviations (pre-pulse inhibition, p50, p300, N100, mismatch negativity, smooth pursuit eye movements), pituitary volume, rapidity and extent of response to antipsychotics, type and frequency of adverse effects, and functional disability or restoration of vocational functioning.

No wonder, then, given the daunting biologic and clinical heterogeneity of this complex brain syndrome, that myriad hypotheses have been proposed over the past century. The Table lists approximately 50 hypotheses, some discredited but others plausible and still viable. The most absurd hypotheses are the double bind theory of schizophrenia in the 1950s by Gregory Bateson et al, or the latent homosexuality theory of Freud. Some hypotheses may be related to a specific biotype within the schizophrenia syndrome (such as the megavitamin theory) that do not apply to other biotypes. Some of the hypotheses seem to be the product of the rich imagination of an enthusiastic researcher based on limited data.

To comment on this editorial or other topics of interest: [email protected].

Islands of knowledge in an ocean of ignorance. That summarizes the advances in unraveling the enigma of schizophrenia, arguably the most complex psychiatric brain disorder. The more breakthroughs are made, the more questions emerge.

Progress is definitely being made and the published literature, replete with new findings, is growing logarithmically. Particularly exciting are the recent advances in the etiology of schizophrenia, both genetic and environmental. Collaboration among geneticists around the world has enabled genome-wide association studies on almost 50,000 DNA samples and has revealed 3 genetic pathways to disrupted brain development, which lead to schizophrenia in early adulthood. Those genetic pathways include:

1. Susceptibility genes—more than 340 of them—are found significantly more often in patients with schizophrenia compared with the general population. These risk genes are scattered across all 23 pairs of chromosomes. They influence neurotransmitter functions, neuroplasticity, and immune regulation. The huge task that lies ahead is identifying what each of the risk genes disrupts in brain structure and/or function.

2. Copy number variants (CNVs), such as deletions (1 allele instead of the normal 2) or duplications (3 alleles), are much more frequent in patients with schizophrenia compared with the general population. That means too little or too much protein is made, which can disrupt the 4 stages of brain development (proliferation, migration, differentiation, and elimination).

3. de novo nonsense mutations, leading to complete absence of protein coding by the affected genes, with adverse ripple effects on brain development.

Approximately 10,000 genes (close to 50% of all 22,000 coding genes in the human genome) are involved in constructing the human brain. The latest estimate is that 79% of the hundreds of biotypes of schizophrenia are genetic in etiology.

In addition, multiple environmental factors can disrupt brain development and lead to schizophrenia. These include older paternal age (>45 years) at the time of conception, pregnancy complications (infections, gestational diabetes, vitamin D deficiency, hypoxia during delivery), childhood maltreatment (sexual or physical abuse or neglect) in the first 5 to 6 years of life, as well as migration and urbanicity (being born and raised in a large metropolitan area).

The bottom line: Schizophrenia is not only very complex, but also an extremely heterogeneous brain syndrome, both biologically and clinically. Psychiatric practitioners are fully cognizant of the extensive clinical variability in patients with schizophrenia, including the presence, absence, or severity of various signs and symptoms, such as insight, delusions, hallucinations, conceptual disorganization, bizarre behaviors, emotional withdrawal, agitation, depression, suicidality, anxiety, substance use, somatic concerns, hostility, idiosyncratic mannerisms, blunted affect, apathy, avolition, self-neglect, poor attention, memory impairment, and problems with decision-making, planning ahead, or organizing one’s life.

In addition, heterogeneity is encountered in such variables as age of onset, minor physical anomalies, soft neurologic signs, naturally occurring movement disorders, premorbid functioning, family history, general medical comorbidities, psychiatry comorbidities, structural brain abnormalities on neuroimaging, neurophysiological deviations (pre-pulse inhibition, p50, p300, N100, mismatch negativity, smooth pursuit eye movements), pituitary volume, rapidity and extent of response to antipsychotics, type and frequency of adverse effects, and functional disability or restoration of vocational functioning.

No wonder, then, given the daunting biologic and clinical heterogeneity of this complex brain syndrome, that myriad hypotheses have been proposed over the past century. The Table lists approximately 50 hypotheses, some discredited but others plausible and still viable. The most absurd hypotheses are the double bind theory of schizophrenia in the 1950s by Gregory Bateson et al, or the latent homosexuality theory of Freud. Some hypotheses may be related to a specific biotype within the schizophrenia syndrome (such as the megavitamin theory) that do not apply to other biotypes. Some of the hypotheses seem to be the product of the rich imagination of an enthusiastic researcher based on limited data.

To comment on this editorial or other topics of interest: [email protected].

Islands of knowledge in an ocean of ignorance. That summarizes the advances in unraveling the enigma of schizophrenia, arguably the most complex psychiatric brain disorder. The more breakthroughs are made, the more questions emerge.

Progress is definitely being made and the published literature, replete with new findings, is growing logarithmically. Particularly exciting are the recent advances in the etiology of schizophrenia, both genetic and environmental. Collaboration among geneticists around the world has enabled genome-wide association studies on almost 50,000 DNA samples and has revealed 3 genetic pathways to disrupted brain development, which lead to schizophrenia in early adulthood. Those genetic pathways include:

1. Susceptibility genes—more than 340 of them—are found significantly more often in patients with schizophrenia compared with the general population. These risk genes are scattered across all 23 pairs of chromosomes. They influence neurotransmitter functions, neuroplasticity, and immune regulation. The huge task that lies ahead is identifying what each of the risk genes disrupts in brain structure and/or function.

2. Copy number variants (CNVs), such as deletions (1 allele instead of the normal 2) or duplications (3 alleles), are much more frequent in patients with schizophrenia compared with the general population. That means too little or too much protein is made, which can disrupt the 4 stages of brain development (proliferation, migration, differentiation, and elimination).

3. de novo nonsense mutations, leading to complete absence of protein coding by the affected genes, with adverse ripple effects on brain development.

Approximately 10,000 genes (close to 50% of all 22,000 coding genes in the human genome) are involved in constructing the human brain. The latest estimate is that 79% of the hundreds of biotypes of schizophrenia are genetic in etiology.

In addition, multiple environmental factors can disrupt brain development and lead to schizophrenia. These include older paternal age (>45 years) at the time of conception, pregnancy complications (infections, gestational diabetes, vitamin D deficiency, hypoxia during delivery), childhood maltreatment (sexual or physical abuse or neglect) in the first 5 to 6 years of life, as well as migration and urbanicity (being born and raised in a large metropolitan area).

The bottom line: Schizophrenia is not only very complex, but also an extremely heterogeneous brain syndrome, both biologically and clinically. Psychiatric practitioners are fully cognizant of the extensive clinical variability in patients with schizophrenia, including the presence, absence, or severity of various signs and symptoms, such as insight, delusions, hallucinations, conceptual disorganization, bizarre behaviors, emotional withdrawal, agitation, depression, suicidality, anxiety, substance use, somatic concerns, hostility, idiosyncratic mannerisms, blunted affect, apathy, avolition, self-neglect, poor attention, memory impairment, and problems with decision-making, planning ahead, or organizing one’s life.

In addition, heterogeneity is encountered in such variables as age of onset, minor physical anomalies, soft neurologic signs, naturally occurring movement disorders, premorbid functioning, family history, general medical comorbidities, psychiatry comorbidities, structural brain abnormalities on neuroimaging, neurophysiological deviations (pre-pulse inhibition, p50, p300, N100, mismatch negativity, smooth pursuit eye movements), pituitary volume, rapidity and extent of response to antipsychotics, type and frequency of adverse effects, and functional disability or restoration of vocational functioning.

No wonder, then, given the daunting biologic and clinical heterogeneity of this complex brain syndrome, that myriad hypotheses have been proposed over the past century. The Table lists approximately 50 hypotheses, some discredited but others plausible and still viable. The most absurd hypotheses are the double bind theory of schizophrenia in the 1950s by Gregory Bateson et al, or the latent homosexuality theory of Freud. Some hypotheses may be related to a specific biotype within the schizophrenia syndrome (such as the megavitamin theory) that do not apply to other biotypes. Some of the hypotheses seem to be the product of the rich imagination of an enthusiastic researcher based on limited data.

To comment on this editorial or other topics of interest: [email protected].

X, a 17-year-old Mexican-American transgender male (assigned female at birth) experienced a traumatic brain injury (TBI) 4 years ago and subsequently developed posttraumatic stress disorder (PTSD). I came to treat X at a pediatric outpatient psychiatric clinic after he developed physiologic dysregulation of his nervous system and began to experience panic attacks, major depressive disorder, and auditory hallucinations. X also developed chronic widespread pain during the next few years, including migraines, abdominal pain, and back pain, which significantly impaired his ability to function socially and academically. X was treated by a child and adolescent psychiatrist who used an integrative approach of traditional and complementary medical practices in a pediatric chronic pain clinic.

X’s treatment course at the pediatric psychiatric clinic included 2 years of field capable mental health services. During this time, fluoxetine was started and titrated up to 40 mg/d to target anxiety and depressive symptoms such as pervasive sadness, poor self-esteem, poor concentration, physiologic arousal, and sleep disruption. Risperidone, 2 mg/d, was temporarily added to address residual mood symptoms and the auditory hallucinations X experienced at school. Neuropsychological testing did not indicate that X had cognitive impairments from the TBI. In the pain clinic, X was encouraged to continue with psychotherapy and the selective serotonin reuptake inhibitor. Another recommendation was to seek out acupuncture and yoga. Over the course of 1 year, X’s pain symptoms began to resolve, and his functioning improved significantly. It was during this year that X came out as transgender, first to his friends, and then to his family and his physicians.

The link between PTSD and chronic pain

X’s PTSD presented as nightmares, hypervigilance, and anxiety, especially when he was in school. He would often describe how his chronic pain symptoms prevented him from functioning academically and socially. I wondered if X’s presentation of PTSD indicated a predisposition for chronic widespread pain symptoms or pain syndromes. This theory could be approximated by an association, but research suggests there is a significant temporal relationship between PTSD and widespread pain symptoms, such as in fibromyalgia.

One multicenter study of patients with fibromyalgia found that the prevalence of comorbid PTSD was 45%.¹ In two-thirds of patients with fibromyalgia, traumatic life events and PTSD symptoms preceded the onset of chronic widespread pain, while in roughly one-third, traumatic life events and PTSD symptoms followed the onset of chronic widespread pain.¹ This study suggests that PTSD could be viewed as a marker of stress vulnerability in which individuals susceptible to stress are more likely to develop chronic widespread pain and other health problems, including fibromyalgia, when a traumatic event occurs.

Benefits of transgender-specific care

During the course of X’s psychiatric treatment, he eventually revealed that he had been experiencing gender dysphoria for many years. His gender transition was occurring during adolescence; during this time, identity formation is a central developmental task.² X was not comfortable asking others to use his preferred pronouns until he had physiologically transitioned. Any further delay to accessing transgender-specific services would increase the likelihood of a poor prognosis, both behaviorally and medically, because sexual minority adolescents are 3 to 4 times more likely to meet criteria for an internalizing disorder and 2 to 5 times more likely to meet criteria for externalizing disorders.³ My understanding of the minority stress model raised concerns that if X did not get appropriate treatment, the interdependence of stressors of being a sexual minority as well as an ethnic minority would further burden his mental health.

Now that X had access to transgender-specific care, how would management affect his pain symptoms or response to treatment? While some of his pain symptoms began to remit before he came out as transgender, I considered whether hormone therapy might improve his subjective pain. Little research has been conducted in transgender patients to determine whether sex-steroid administration might alter nociception. One study that examined daily fluctuations of sex hormones in 8 women with fibromyalgia found trends suggesting progesterone and testosterone are inversely associated with pain, with peaks of those hormones occurring on days with lower reported pain.⁴ A small study of female-to-male transgender patients found that administration of sex steroids was associated with relief from chronic painful conditions (headaches, musculoskeletal pain) in 6 of 16 patients who received testosterone injections.⁵ What little evidence I found in regards to an association between gender-affirming hormone therapy and chronic pain left me feeling optimistic that hormone therapy would not negatively affect the prognosis of X’s chronic pain.

Another consideration in treating X was the practice of chest binding, the compression of chest tissue for masculine gender expression among people who were assigned female sex at birth. One study found that chest binding can improve mood; decrease suicidality, anxiety, and dysphoria; and increase self-esteem.⁶ However, 97.2% of participants reported at least one negative outcome they attributed to binding. The most common was back pain (53.8%), which X had been experiencing before he began chest binding. I found it notable that X’s primary doctors in the transgender clinic kept this adverse effect in mind when they recommended that he take breaks and limit daily hours of chest binding to minimize the risk of increased chronic back pain.

This particular case spanned several specialized services and required coordination and careful consideration to address X’s developmental and gender-related needs. X experienced significant symptoms incited by a TBI; however, the manifestation of his chronic pain symptoms were more than likely influenced by several overlapping stressors, including belonging to an ethnic minority, transitioning into adulthood, transitioning publicly as a male, and mood symptoms. While it pleased me to see how X responded positively to the integrative and holistic treatment he received, I remain concerned that simply not enough research exists that addresses how transgender individuals are affected, physically and affectively, by chronic levels of stress attributable to their minority status.

X, a 17-year-old Mexican-American transgender male (assigned female at birth) experienced a traumatic brain injury (TBI) 4 years ago and subsequently developed posttraumatic stress disorder (PTSD). I came to treat X at a pediatric outpatient psychiatric clinic after he developed physiologic dysregulation of his nervous system and began to experience panic attacks, major depressive disorder, and auditory hallucinations. X also developed chronic widespread pain during the next few years, including migraines, abdominal pain, and back pain, which significantly impaired his ability to function socially and academically. X was treated by a child and adolescent psychiatrist who used an integrative approach of traditional and complementary medical practices in a pediatric chronic pain clinic.

X’s treatment course at the pediatric psychiatric clinic included 2 years of field capable mental health services. During this time, fluoxetine was started and titrated up to 40 mg/d to target anxiety and depressive symptoms such as pervasive sadness, poor self-esteem, poor concentration, physiologic arousal, and sleep disruption. Risperidone, 2 mg/d, was temporarily added to address residual mood symptoms and the auditory hallucinations X experienced at school. Neuropsychological testing did not indicate that X had cognitive impairments from the TBI. In the pain clinic, X was encouraged to continue with psychotherapy and the selective serotonin reuptake inhibitor. Another recommendation was to seek out acupuncture and yoga. Over the course of 1 year, X’s pain symptoms began to resolve, and his functioning improved significantly. It was during this year that X came out as transgender, first to his friends, and then to his family and his physicians.

The link between PTSD and chronic pain

X’s PTSD presented as nightmares, hypervigilance, and anxiety, especially when he was in school. He would often describe how his chronic pain symptoms prevented him from functioning academically and socially. I wondered if X’s presentation of PTSD indicated a predisposition for chronic widespread pain symptoms or pain syndromes. This theory could be approximated by an association, but research suggests there is a significant temporal relationship between PTSD and widespread pain symptoms, such as in fibromyalgia.

One multicenter study of patients with fibromyalgia found that the prevalence of comorbid PTSD was 45%.¹ In two-thirds of patients with fibromyalgia, traumatic life events and PTSD symptoms preceded the onset of chronic widespread pain, while in roughly one-third, traumatic life events and PTSD symptoms followed the onset of chronic widespread pain.¹ This study suggests that PTSD could be viewed as a marker of stress vulnerability in which individuals susceptible to stress are more likely to develop chronic widespread pain and other health problems, including fibromyalgia, when a traumatic event occurs.

Benefits of transgender-specific care

During the course of X’s psychiatric treatment, he eventually revealed that he had been experiencing gender dysphoria for many years. His gender transition was occurring during adolescence; during this time, identity formation is a central developmental task.² X was not comfortable asking others to use his preferred pronouns until he had physiologically transitioned. Any further delay to accessing transgender-specific services would increase the likelihood of a poor prognosis, both behaviorally and medically, because sexual minority adolescents are 3 to 4 times more likely to meet criteria for an internalizing disorder and 2 to 5 times more likely to meet criteria for externalizing disorders.³ My understanding of the minority stress model raised concerns that if X did not get appropriate treatment, the interdependence of stressors of being a sexual minority as well as an ethnic minority would further burden his mental health.

Now that X had access to transgender-specific care, how would management affect his pain symptoms or response to treatment? While some of his pain symptoms began to remit before he came out as transgender, I considered whether hormone therapy might improve his subjective pain. Little research has been conducted in transgender patients to determine whether sex-steroid administration might alter nociception. One study that examined daily fluctuations of sex hormones in 8 women with fibromyalgia found trends suggesting progesterone and testosterone are inversely associated with pain, with peaks of those hormones occurring on days with lower reported pain.⁴ A small study of female-to-male transgender patients found that administration of sex steroids was associated with relief from chronic painful conditions (headaches, musculoskeletal pain) in 6 of 16 patients who received testosterone injections.⁵ What little evidence I found in regards to an association between gender-affirming hormone therapy and chronic pain left me feeling optimistic that hormone therapy would not negatively affect the prognosis of X’s chronic pain.

Another consideration in treating X was the practice of chest binding, the compression of chest tissue for masculine gender expression among people who were assigned female sex at birth. One study found that chest binding can improve mood; decrease suicidality, anxiety, and dysphoria; and increase self-esteem.⁶ However, 97.2% of participants reported at least one negative outcome they attributed to binding. The most common was back pain (53.8%), which X had been experiencing before he began chest binding. I found it notable that X’s primary doctors in the transgender clinic kept this adverse effect in mind when they recommended that he take breaks and limit daily hours of chest binding to minimize the risk of increased chronic back pain.

This particular case spanned several specialized services and required coordination and careful consideration to address X’s developmental and gender-related needs. X experienced significant symptoms incited by a TBI; however, the manifestation of his chronic pain symptoms were more than likely influenced by several overlapping stressors, including belonging to an ethnic minority, transitioning into adulthood, transitioning publicly as a male, and mood symptoms. While it pleased me to see how X responded positively to the integrative and holistic treatment he received, I remain concerned that simply not enough research exists that addresses how transgender individuals are affected, physically and affectively, by chronic levels of stress attributable to their minority status.

X, a 17-year-old Mexican-American transgender male (assigned female at birth) experienced a traumatic brain injury (TBI) 4 years ago and subsequently developed posttraumatic stress disorder (PTSD). I came to treat X at a pediatric outpatient psychiatric clinic after he developed physiologic dysregulation of his nervous system and began to experience panic attacks, major depressive disorder, and auditory hallucinations. X also developed chronic widespread pain during the next few years, including migraines, abdominal pain, and back pain, which significantly impaired his ability to function socially and academically. X was treated by a child and adolescent psychiatrist who used an integrative approach of traditional and complementary medical practices in a pediatric chronic pain clinic.

X’s treatment course at the pediatric psychiatric clinic included 2 years of field capable mental health services. During this time, fluoxetine was started and titrated up to 40 mg/d to target anxiety and depressive symptoms such as pervasive sadness, poor self-esteem, poor concentration, physiologic arousal, and sleep disruption. Risperidone, 2 mg/d, was temporarily added to address residual mood symptoms and the auditory hallucinations X experienced at school. Neuropsychological testing did not indicate that X had cognitive impairments from the TBI. In the pain clinic, X was encouraged to continue with psychotherapy and the selective serotonin reuptake inhibitor. Another recommendation was to seek out acupuncture and yoga. Over the course of 1 year, X’s pain symptoms began to resolve, and his functioning improved significantly. It was during this year that X came out as transgender, first to his friends, and then to his family and his physicians.

The link between PTSD and chronic pain

X’s PTSD presented as nightmares, hypervigilance, and anxiety, especially when he was in school. He would often describe how his chronic pain symptoms prevented him from functioning academically and socially. I wondered if X’s presentation of PTSD indicated a predisposition for chronic widespread pain symptoms or pain syndromes. This theory could be approximated by an association, but research suggests there is a significant temporal relationship between PTSD and widespread pain symptoms, such as in fibromyalgia.

One multicenter study of patients with fibromyalgia found that the prevalence of comorbid PTSD was 45%.¹ In two-thirds of patients with fibromyalgia, traumatic life events and PTSD symptoms preceded the onset of chronic widespread pain, while in roughly one-third, traumatic life events and PTSD symptoms followed the onset of chronic widespread pain.¹ This study suggests that PTSD could be viewed as a marker of stress vulnerability in which individuals susceptible to stress are more likely to develop chronic widespread pain and other health problems, including fibromyalgia, when a traumatic event occurs.

Benefits of transgender-specific care

During the course of X’s psychiatric treatment, he eventually revealed that he had been experiencing gender dysphoria for many years. His gender transition was occurring during adolescence; during this time, identity formation is a central developmental task.² X was not comfortable asking others to use his preferred pronouns until he had physiologically transitioned. Any further delay to accessing transgender-specific services would increase the likelihood of a poor prognosis, both behaviorally and medically, because sexual minority adolescents are 3 to 4 times more likely to meet criteria for an internalizing disorder and 2 to 5 times more likely to meet criteria for externalizing disorders.³ My understanding of the minority stress model raised concerns that if X did not get appropriate treatment, the interdependence of stressors of being a sexual minority as well as an ethnic minority would further burden his mental health.

Now that X had access to transgender-specific care, how would management affect his pain symptoms or response to treatment? While some of his pain symptoms began to remit before he came out as transgender, I considered whether hormone therapy might improve his subjective pain. Little research has been conducted in transgender patients to determine whether sex-steroid administration might alter nociception. One study that examined daily fluctuations of sex hormones in 8 women with fibromyalgia found trends suggesting progesterone and testosterone are inversely associated with pain, with peaks of those hormones occurring on days with lower reported pain.⁴ A small study of female-to-male transgender patients found that administration of sex steroids was associated with relief from chronic painful conditions (headaches, musculoskeletal pain) in 6 of 16 patients who received testosterone injections.⁵ What little evidence I found in regards to an association between gender-affirming hormone therapy and chronic pain left me feeling optimistic that hormone therapy would not negatively affect the prognosis of X’s chronic pain.

Another consideration in treating X was the practice of chest binding, the compression of chest tissue for masculine gender expression among people who were assigned female sex at birth. One study found that chest binding can improve mood; decrease suicidality, anxiety, and dysphoria; and increase self-esteem.⁶ However, 97.2% of participants reported at least one negative outcome they attributed to binding. The most common was back pain (53.8%), which X had been experiencing before he began chest binding. I found it notable that X’s primary doctors in the transgender clinic kept this adverse effect in mind when they recommended that he take breaks and limit daily hours of chest binding to minimize the risk of increased chronic back pain.

This particular case spanned several specialized services and required coordination and careful consideration to address X’s developmental and gender-related needs. X experienced significant symptoms incited by a TBI; however, the manifestation of his chronic pain symptoms were more than likely influenced by several overlapping stressors, including belonging to an ethnic minority, transitioning into adulthood, transitioning publicly as a male, and mood symptoms. While it pleased me to see how X responded positively to the integrative and holistic treatment he received, I remain concerned that simply not enough research exists that addresses how transgender individuals are affected, physically and affectively, by chronic levels of stress attributable to their minority status.

Resilience is like patience; we all wish we had more of it, but we hope to avoid getting it the hard way. This wasn’t really an area of interest for me, until it needed to be. When one academic year brings the suicide of one colleague and the murder of another, resilience becomes the only alternative to despair.

I realize that even though the particular pain or trauma we endured may be unique, it’s becoming increasingly common. The alarming studies of resident depression and suicide are too difficult for us to ignore. Now we must look in that evidence-based mirror and decide where we will go from here, as a profession and as trainees. The 2018 American Psychiatric Association annual meeting gave us a rude awakening that we may not have it figured out. Even during a year-long theme on wellness, and several sessions at the meeting focusing on the same, we all found ourselves mourning the loss of 2 colleagues to suicide that very weekend only a few miles away from the gathering of the world’s experts.

It brought an eerie element to the conversation.

The wellness “window dressing” will not get the job done. I recently had a candid discussion with a mentor in administrative leadership, and his words surprised as well as challenged me. He told me that the “system” will not save you. You must save yourself. I have decided to respectfully reject that. I think everyone should be involved, including the “system” that is entrusted with my training, and the least that it ought to ensure is that I get out alive.

Has that really become too much to ask of our profession?

We must hold our system to a higher standard. More mindfulness and better breathing will surely be helpful—but I hope we can begin to admit that this is not the answer. Unfortunately, the culture of “pay your dues” and “you know how much harder it was when I was a resident?” is still the norm. We now receive our training in an environment where the pressure is extraordinarily high, the margin for error very low, and the possibility of support is almost a fantasy. “Sure, you can get the help you need ... but don’t take time off or you will be off cycle and create extra work for all your colleagues, who are also equally stressed and will hate you. In the meantime … enjoy this free ice cream and breathing exercise to mindfully cope with the madness around you.”

The perfectly resilient resident may very well be a mythical figure, a clinical unicorn, that we continue chasing. This is the resident who remarkably discovers posttraumatic growth in every stressor. The vicarious trauma they experience from their patients only bolsters their deep compassion, and they thrive under pressure, so we can continue to pile it on. In our search for this “super resident,” we seem to continue to lose a few ordinary residents along the way.

Are we brave enough as a health care culture to take a closer look at the way we are training the next generation of healers? As I get to the end of this article, I wish I had more answers. I’m just a trainee. What do I know? My fear is that we’ve been avoiding this question altogether and have had our eyes closed to the real problem while pacifying ourselves with one “wellness” activity after another. My sincere hope is that this article will make you angry enough to be driven by a conviction that this is not OK anymore, and that we will do something about it.

Resilience is like patience; we all wish we had more of it, but we hope to avoid getting it the hard way. This wasn’t really an area of interest for me, until it needed to be. When one academic year brings the suicide of one colleague and the murder of another, resilience becomes the only alternative to despair.

I realize that even though the particular pain or trauma we endured may be unique, it’s becoming increasingly common. The alarming studies of resident depression and suicide are too difficult for us to ignore. Now we must look in that evidence-based mirror and decide where we will go from here, as a profession and as trainees. The 2018 American Psychiatric Association annual meeting gave us a rude awakening that we may not have it figured out. Even during a year-long theme on wellness, and several sessions at the meeting focusing on the same, we all found ourselves mourning the loss of 2 colleagues to suicide that very weekend only a few miles away from the gathering of the world’s experts.

It brought an eerie element to the conversation.

The wellness “window dressing” will not get the job done. I recently had a candid discussion with a mentor in administrative leadership, and his words surprised as well as challenged me. He told me that the “system” will not save you. You must save yourself. I have decided to respectfully reject that. I think everyone should be involved, including the “system” that is entrusted with my training, and the least that it ought to ensure is that I get out alive.

Has that really become too much to ask of our profession?

We must hold our system to a higher standard. More mindfulness and better breathing will surely be helpful—but I hope we can begin to admit that this is not the answer. Unfortunately, the culture of “pay your dues” and “you know how much harder it was when I was a resident?” is still the norm. We now receive our training in an environment where the pressure is extraordinarily high, the margin for error very low, and the possibility of support is almost a fantasy. “Sure, you can get the help you need ... but don’t take time off or you will be off cycle and create extra work for all your colleagues, who are also equally stressed and will hate you. In the meantime … enjoy this free ice cream and breathing exercise to mindfully cope with the madness around you.”

The perfectly resilient resident may very well be a mythical figure, a clinical unicorn, that we continue chasing. This is the resident who remarkably discovers posttraumatic growth in every stressor. The vicarious trauma they experience from their patients only bolsters their deep compassion, and they thrive under pressure, so we can continue to pile it on. In our search for this “super resident,” we seem to continue to lose a few ordinary residents along the way.

Are we brave enough as a health care culture to take a closer look at the way we are training the next generation of healers? As I get to the end of this article, I wish I had more answers. I’m just a trainee. What do I know? My fear is that we’ve been avoiding this question altogether and have had our eyes closed to the real problem while pacifying ourselves with one “wellness” activity after another. My sincere hope is that this article will make you angry enough to be driven by a conviction that this is not OK anymore, and that we will do something about it.

Resilience is like patience; we all wish we had more of it, but we hope to avoid getting it the hard way. This wasn’t really an area of interest for me, until it needed to be. When one academic year brings the suicide of one colleague and the murder of another, resilience becomes the only alternative to despair.

I realize that even though the particular pain or trauma we endured may be unique, it’s becoming increasingly common. The alarming studies of resident depression and suicide are too difficult for us to ignore. Now we must look in that evidence-based mirror and decide where we will go from here, as a profession and as trainees. The 2018 American Psychiatric Association annual meeting gave us a rude awakening that we may not have it figured out. Even during a year-long theme on wellness, and several sessions at the meeting focusing on the same, we all found ourselves mourning the loss of 2 colleagues to suicide that very weekend only a few miles away from the gathering of the world’s experts.

It brought an eerie element to the conversation.

The wellness “window dressing” will not get the job done. I recently had a candid discussion with a mentor in administrative leadership, and his words surprised as well as challenged me. He told me that the “system” will not save you. You must save yourself. I have decided to respectfully reject that. I think everyone should be involved, including the “system” that is entrusted with my training, and the least that it ought to ensure is that I get out alive.

Has that really become too much to ask of our profession?

We must hold our system to a higher standard. More mindfulness and better breathing will surely be helpful—but I hope we can begin to admit that this is not the answer. Unfortunately, the culture of “pay your dues” and “you know how much harder it was when I was a resident?” is still the norm. We now receive our training in an environment where the pressure is extraordinarily high, the margin for error very low, and the possibility of support is almost a fantasy. “Sure, you can get the help you need ... but don’t take time off or you will be off cycle and create extra work for all your colleagues, who are also equally stressed and will hate you. In the meantime … enjoy this free ice cream and breathing exercise to mindfully cope with the madness around you.”

The perfectly resilient resident may very well be a mythical figure, a clinical unicorn, that we continue chasing. This is the resident who remarkably discovers posttraumatic growth in every stressor. The vicarious trauma they experience from their patients only bolsters their deep compassion, and they thrive under pressure, so we can continue to pile it on. In our search for this “super resident,” we seem to continue to lose a few ordinary residents along the way.

Are we brave enough as a health care culture to take a closer look at the way we are training the next generation of healers? As I get to the end of this article, I wish I had more answers. I’m just a trainee. What do I know? My fear is that we’ve been avoiding this question altogether and have had our eyes closed to the real problem while pacifying ourselves with one “wellness” activity after another. My sincere hope is that this article will make you angry enough to be driven by a conviction that this is not OK anymore, and that we will do something about it.

Oral antipsychotic nonadherence is a significant contributor to relapse in patients with schizophrenia spectrum disorders. Long-acting injectable (LAI) antipsychotics have been developed to provide sustained antipsychotic exposure, with evidence that use of LAIs significantly reduces hospitalization rates.¹ One limiting factor in transitioning patients to certain LAIs is the need for prolonged oral coverage at the onset of treatment for agents that cannot be loaded. Nonadherence with this bridging oral therapy places the patient at risk for symptom exacerbation until effective antipsychotic plasma levels are achieved from the LAI.² Although risperidone is one of the more widely used antipsychotics for treating schizophrenia, until recently the only available LAI preparation, risperidone microspheres (Risperdal Consta), required 3 weeks of oral coverage upon initiation.³

Clinical implications

Oral medication nonadherence remains a significant public health issue for patients with schizophrenia, with an estimated 50% of patients failing to achieve 80% adherence even when enrolled in clinical trials specifically designed to track adherence.⁵ Although LAI atypical antipsychotics have been available since the approval of Risperdal Consta, the LAI form of risperidone, and both LAI forms of aripiprazole, were not designed to be loaded. A 1-day initiation regimen for aripiprazole lauroxil has been developed to avoid the need for 3 weeks of oral medication coverage,^6,7 but aripiprazole monohydrate and risperidone microspheres mandate oral bridging of 2 and 3 weeks, respectively.² Because one of the primary indications for LAI antipsychotic therapy is oral medication nonadherence, this prolonged period of oral coverage creates a risk for symptom exacerbation when the bridging period occurs outside of a controlled setting, as is common when patients are discharged from inpatient hospitalization.

One solution to this problem has its antecedents in the development of the Atrigel biodegradable injectable polymer, which was designed to deliver prolonged medication exposure after subcutaneous injection.⁸ This biodegradable polymer drug delivery system suspends and dissolves the medication of interest (in this case, risperidone) in a poly DL-lactide-coglycolide gel and its biocompatible carrier.⁹ The viscous liquid undergoes a phase transition upon contact with tissue fluids after subcutaneous injection, resulting in an implant that releases risperidone in a controlled manner as it is resorbed. Importantly, the kinetic parameters of RBP-7000 are such that effective drug levels are seen within the first week without the need for oral coverage.¹⁰

Use in adults with schizophrenia. After establishing tolerability with oral risperidone, the recommended doses are 90 mg or 120 mg monthly, which correspond to oral daily risperidone doses of 3 mg or 4 mg. RBP-7000 must be administered as a subcutaneous abdominal injection by a health care professional. It is recommended that the patient be in the supine position for the injection and that the injection sites be rotated monthly among 4 quadrants in the abdominal region. The injection volumes for the 90 mg and 120 mg doses are 0.6 mL and 0.8 mL, respectively.¹⁰ As the gel implant becomes firmer, the patient will notice a lump for several weeks that will decrease in size over time. Patients should be advised not to rub or massage the injection site, and to be aware of the placement of any belts or clothing with waistbands.¹⁰

Pharmacologic profile, adverse reactions

Risperidone is an atypical antipsychotic that has been commercially available in the U.S. since December 29, 1993, and its adverse effect profile is well characterized. The most common adverse effects associated with risperidone include those related to dopamine D2 antagonism, metabolic adverse effects, and an increase in serum prolactin. In the 12-month long-term safety study of RBP-7000, 1-minute post-dose injection site pain scores (on a 100-point scale) were highest on Day 1 (mean of 25) and decreased over time with subsequent injections (14 to 16 following the last injection).¹⁰

Continue to: How the Atrigel system works

The kinetics for RBP-7000 are markedly different than those for oral risperidone (Figure 2¹⁵). After a single subcutaneous injection, RBP-7000 shows 2 absorption peaks for risperidone. The first lower peak occurs with a T_max of 4 to 6 hours due to initial release of risperidone during the implant formation process; a second risperidone peak occurs after 10 to 14 days and is associated with slow release from the subcutaneous depot.^9,16,17 For both 9-OH risperidone levels and the total active moiety (risperidone plus 9-OH risperidone levels), the median T_max of the first peak ranges from 4 to 48 hours and the second peak ranges from 7 to 11 days. Following a single subcutaneous injection of RBP-7000, the apparent terminal half-life of risperidone ranges from 9 to 11 days, on average. The mean apparent terminal half-life of the active moiety ranges from 8 to 9 days.^9,16,17 Based on population pharmacokinetic modeling, the 90 mg and 120 mg doses of RBP-7000 are estimated to provide drug exposure equivalent to 3 mg/d and 4 mg/d of oral risperidone, respectively.^9,16,17

Continue to: Efficacy of RBP-7000

Efficacy of RBP-7000 was established in an 8-week, double-blind, placebo-controlled trial of adult patients experiencing an acute exacerbation of schizo­phrenia (age 18 to 55).⁴ Eligible participants had:

• An acute exacerbation of schizophrenia that occurred ≤8 weeks before the screening visit and would have benefited from psychiatric hospitalization or continued hospitalization
• Positive and Negative Syndrome Scale (PANSS) total score between 80 and 120 at visit 1 and a score of >4 on at least 2 of the following 4 items: hallucinatory behavior, delusions, conceptual disorganization, or suspiciousness/persecution
• The diagnosis of acute exacerbation of schizophrenia and PANSS total score were confirmed through an independent video-conference interview conducted by an experienced rater.

Participants were excluded if they:

• Experienced a ≥20% improvement in PANSS total score between the initial screening visit and the first injection
• had been treated at any time with clozapine for treatment-resistant schizophrenia
• had met DSM-IV-TR criteria for substance dependence (with the exception of nicotine or caffeine) before screening.

During the initial screening visit, participants received a 0.25-mg tablet of oral risperidone on 2 consecutive days to assess the tolerability of risperidone.

Outcome. Participants were randomized in a 1:1:1 manner to placebo (n = 112) or 1 of 2 monthly doses of RBP-7000: 90 mg (n = 111) or 120 mg (n = 114). Using the least squares means of repeated-measures changes from baseline in PANSS total scores, there was a significant improvement in the difference in PANSS total scores from baseline to the end of the study compared with placebo: 90-mg RBP-7000, -6.148 points (95% confidence interval [CI], -9.982 to -2.314, P = .0004); 120-mg RBP-7000, -7.237 points (95% CI, -11.045 to -3.429, P < .0001). The absolute change from baseline in PANSS total score was -15.367 points for the 90-mg dose and -16.456 points for the 120-mg dose.⁴ Completion rates across all 3 arms were comparable: placebo 70.6%, RBP-7000 90 mg 77.6%, and RBP-7000 120 mg 71.4%.

Tolerability. In the 8-week phase III efficacy trial of RBP-7000, adverse effects occurring with an incidence ≥5% and at least twice the rate of placebo were weight gain (placebo 3.4%, 90 mg 13.0%, 120 mg 12.8%) and sedation (placebo 0%, 90 mg 7.0%, 120 mg 7.7%).¹⁰ Compared with baseline, participants had a mean weight gain at the end of the study of 2.83 kg in the placebo group, 5.15 kg in the 90-mg RBP-7000 group, and 4.69 kg in the 120-mg RBP-7000 group. There were no clinically significant differences at study endpoint in glucose and lipid parameters. Consistent with the known effects of risperidone, there were increases in mean prolactin levels during the 8-week study, the effects of which were greater for women. For men, mean prolactin levels from baseline to study end were: placebo: 9.8 ± 7.9 vs 9.9 ± 8.0 ng/mL; 90 mg: 8.9 ± 6.9 vs 22.4 ± 11.2 ng/mL; and 120 mg: 8.2 ± 5.2 vs 31.3 ± 14.8 ng/mL. For women, mean prolactin levels from baseline to study end were: placebo: 12.8 ± 11.7 vs 10.4 ± 8.0 ng/mL; 90 mg: 7.7 ± 5.3 vs 60.3 ± 46.9 ng/mL; and 120 mg: 10.9 ± 8.6 vs 85.5 ± 55.1 ng/mL. In the pivotal study, discontinuations due to adverse events were low across all treatment groups: 2.5% for placebo vs 0% for 90 mg and 1.7% for 120 mg.⁴ There was no single adverse reaction leading to discontinuation that occurred at a rate of ≥2% and greater than placebo in patients treated with RBP-7000.¹⁰ There were no clinically relevant differences in mean changes from baseline in corrected QT, QRS, and PR intervals, and in heart rate. Similarly, in the 12-month, long-term safety study, there were no clinically relevant changes in mean electrocardiography interval values from baseline to post-dose assessments.¹⁰

Using a 100-point visual analog scale (VAS), injection site pain scores 1 minute after the first dose decreased from a mean of 27 to the range of 3 to 7 for scores obtained 30 to 60 minutes post-dose. In the 12-month long-term safety study, 1-minute post-dose injection site pain VAS scores were highest on Day 1 (mean of 25) and decreased over time with subsequent injections (14 to 16 following last injection).¹⁰

Clinical considerations

Unique properties. RBP-7000 uses the established Atrigel system to provide effective antipsychotic levels in the first week of treatment, without the need for bridging oral coverage or a second loading injection. The abdominal subcutaneous injection volume is relatively small (0.6 mL or 0.8 mL).

Why Rx? The reasons to prescribe RBP-7000 for adult patients with schizophrenia include:

• no oral coverage required at the initiation of treatment
• effective plasma active moiety levels are seen within the first week without the need for a second loading injection
• monthly injection schedule.

Dosing. The recommended dosage of RBP-7000 is 90 mg or 120 mg once monthly, equivalent to 3 mg/d or 4 mg/d of oral risperidone, respectively. Oral risperidone tolerability should be established before the first injection. No oral risperidone coverage is required. RBP-7000 has not been studied in patients with renal or hepatic impairment and should be used with caution in these patients. Prior to initiating treatment in these patients, it is advised to carefully titrate up to at least 3 mg/d of oral risperidone. If a patient can tolerate 3 mg/d of oral risperidone and is psychiatrically stable, then the 90-mg dose of RBP-7000 can be considered.¹⁰ 

Contraindications. The only contraindications for RBP-7000 are known hypersensitivity to risperidone, paliperidone (9-OH risperidone), or other components of the injection.

Bottom Line

RBP-7000 (Perseris) is the second long-acting injectable (LAI) form of risperidone approved in the U.S. Unlike risperidone microspheres (Consta), RBP-7000 does not require any oral risperidone coverage at the beginning of therapy, provides effective drug levels within the first week of treatment with a single injection, and uses a monthly dosing interval. RBP-7000 does not require loading upon initiation. The monthly injection is <1 mL, is administered in abdominal subcutaneous tissue, and uses the Atrigel system.

Related Resource

• Carpenter J, Wong KK. Long-acting injectable antipsychotics: What to do about missed doses. Current Psychiatry. 2018;17(7):10-12,14-19,56.
   

Drug Brand Names
Aripiprazole • Abilify
Carbamazepine • Carbatrol, Tegretol
Doxycycline • Atridox
Leuprolide acetate injectable suspension • Eligard
Paliperidone palmitate • Invega Sustenna
Risperidone • Risperdal
Risperidone extended-release injectable suspension • Perseris
Risperidone long-acting injection • Risperdal Consta

Oral antipsychotic nonadherence is a significant contributor to relapse in patients with schizophrenia spectrum disorders. Long-acting injectable (LAI) antipsychotics have been developed to provide sustained antipsychotic exposure, with evidence that use of LAIs significantly reduces hospitalization rates.¹ One limiting factor in transitioning patients to certain LAIs is the need for prolonged oral coverage at the onset of treatment for agents that cannot be loaded. Nonadherence with this bridging oral therapy places the patient at risk for symptom exacerbation until effective antipsychotic plasma levels are achieved from the LAI.² Although risperidone is one of the more widely used antipsychotics for treating schizophrenia, until recently the only available LAI preparation, risperidone microspheres (Risperdal Consta), required 3 weeks of oral coverage upon initiation.³

Clinical implications

Oral medication nonadherence remains a significant public health issue for patients with schizophrenia, with an estimated 50% of patients failing to achieve 80% adherence even when enrolled in clinical trials specifically designed to track adherence.⁵ Although LAI atypical antipsychotics have been available since the approval of Risperdal Consta, the LAI form of risperidone, and both LAI forms of aripiprazole, were not designed to be loaded. A 1-day initiation regimen for aripiprazole lauroxil has been developed to avoid the need for 3 weeks of oral medication coverage,^6,7 but aripiprazole monohydrate and risperidone microspheres mandate oral bridging of 2 and 3 weeks, respectively.² Because one of the primary indications for LAI antipsychotic therapy is oral medication nonadherence, this prolonged period of oral coverage creates a risk for symptom exacerbation when the bridging period occurs outside of a controlled setting, as is common when patients are discharged from inpatient hospitalization.

One solution to this problem has its antecedents in the development of the Atrigel biodegradable injectable polymer, which was designed to deliver prolonged medication exposure after subcutaneous injection.⁸ This biodegradable polymer drug delivery system suspends and dissolves the medication of interest (in this case, risperidone) in a poly DL-lactide-coglycolide gel and its biocompatible carrier.⁹ The viscous liquid undergoes a phase transition upon contact with tissue fluids after subcutaneous injection, resulting in an implant that releases risperidone in a controlled manner as it is resorbed. Importantly, the kinetic parameters of RBP-7000 are such that effective drug levels are seen within the first week without the need for oral coverage.¹⁰

Use in adults with schizophrenia. After establishing tolerability with oral risperidone, the recommended doses are 90 mg or 120 mg monthly, which correspond to oral daily risperidone doses of 3 mg or 4 mg. RBP-7000 must be administered as a subcutaneous abdominal injection by a health care professional. It is recommended that the patient be in the supine position for the injection and that the injection sites be rotated monthly among 4 quadrants in the abdominal region. The injection volumes for the 90 mg and 120 mg doses are 0.6 mL and 0.8 mL, respectively.¹⁰ As the gel implant becomes firmer, the patient will notice a lump for several weeks that will decrease in size over time. Patients should be advised not to rub or massage the injection site, and to be aware of the placement of any belts or clothing with waistbands.¹⁰

Pharmacologic profile, adverse reactions

Risperidone is an atypical antipsychotic that has been commercially available in the U.S. since December 29, 1993, and its adverse effect profile is well characterized. The most common adverse effects associated with risperidone include those related to dopamine D2 antagonism, metabolic adverse effects, and an increase in serum prolactin. In the 12-month long-term safety study of RBP-7000, 1-minute post-dose injection site pain scores (on a 100-point scale) were highest on Day 1 (mean of 25) and decreased over time with subsequent injections (14 to 16 following the last injection).¹⁰

Continue to: How the Atrigel system works

The kinetics for RBP-7000 are markedly different than those for oral risperidone (Figure 2¹⁵). After a single subcutaneous injection, RBP-7000 shows 2 absorption peaks for risperidone. The first lower peak occurs with a T_max of 4 to 6 hours due to initial release of risperidone during the implant formation process; a second risperidone peak occurs after 10 to 14 days and is associated with slow release from the subcutaneous depot.^9,16,17 For both 9-OH risperidone levels and the total active moiety (risperidone plus 9-OH risperidone levels), the median T_max of the first peak ranges from 4 to 48 hours and the second peak ranges from 7 to 11 days. Following a single subcutaneous injection of RBP-7000, the apparent terminal half-life of risperidone ranges from 9 to 11 days, on average. The mean apparent terminal half-life of the active moiety ranges from 8 to 9 days.^9,16,17 Based on population pharmacokinetic modeling, the 90 mg and 120 mg doses of RBP-7000 are estimated to provide drug exposure equivalent to 3 mg/d and 4 mg/d of oral risperidone, respectively.^9,16,17

Continue to: Efficacy of RBP-7000

Efficacy of RBP-7000 was established in an 8-week, double-blind, placebo-controlled trial of adult patients experiencing an acute exacerbation of schizo­phrenia (age 18 to 55).⁴ Eligible participants had:

• An acute exacerbation of schizophrenia that occurred ≤8 weeks before the screening visit and would have benefited from psychiatric hospitalization or continued hospitalization
• Positive and Negative Syndrome Scale (PANSS) total score between 80 and 120 at visit 1 and a score of >4 on at least 2 of the following 4 items: hallucinatory behavior, delusions, conceptual disorganization, or suspiciousness/persecution
• The diagnosis of acute exacerbation of schizophrenia and PANSS total score were confirmed through an independent video-conference interview conducted by an experienced rater.

Participants were excluded if they:

• Experienced a ≥20% improvement in PANSS total score between the initial screening visit and the first injection
• had been treated at any time with clozapine for treatment-resistant schizophrenia
• had met DSM-IV-TR criteria for substance dependence (with the exception of nicotine or caffeine) before screening.

During the initial screening visit, participants received a 0.25-mg tablet of oral risperidone on 2 consecutive days to assess the tolerability of risperidone.

Outcome. Participants were randomized in a 1:1:1 manner to placebo (n = 112) or 1 of 2 monthly doses of RBP-7000: 90 mg (n = 111) or 120 mg (n = 114). Using the least squares means of repeated-measures changes from baseline in PANSS total scores, there was a significant improvement in the difference in PANSS total scores from baseline to the end of the study compared with placebo: 90-mg RBP-7000, -6.148 points (95% confidence interval [CI], -9.982 to -2.314, P = .0004); 120-mg RBP-7000, -7.237 points (95% CI, -11.045 to -3.429, P < .0001). The absolute change from baseline in PANSS total score was -15.367 points for the 90-mg dose and -16.456 points for the 120-mg dose.⁴ Completion rates across all 3 arms were comparable: placebo 70.6%, RBP-7000 90 mg 77.6%, and RBP-7000 120 mg 71.4%.

Tolerability. In the 8-week phase III efficacy trial of RBP-7000, adverse effects occurring with an incidence ≥5% and at least twice the rate of placebo were weight gain (placebo 3.4%, 90 mg 13.0%, 120 mg 12.8%) and sedation (placebo 0%, 90 mg 7.0%, 120 mg 7.7%).¹⁰ Compared with baseline, participants had a mean weight gain at the end of the study of 2.83 kg in the placebo group, 5.15 kg in the 90-mg RBP-7000 group, and 4.69 kg in the 120-mg RBP-7000 group. There were no clinically significant differences at study endpoint in glucose and lipid parameters. Consistent with the known effects of risperidone, there were increases in mean prolactin levels during the 8-week study, the effects of which were greater for women. For men, mean prolactin levels from baseline to study end were: placebo: 9.8 ± 7.9 vs 9.9 ± 8.0 ng/mL; 90 mg: 8.9 ± 6.9 vs 22.4 ± 11.2 ng/mL; and 120 mg: 8.2 ± 5.2 vs 31.3 ± 14.8 ng/mL. For women, mean prolactin levels from baseline to study end were: placebo: 12.8 ± 11.7 vs 10.4 ± 8.0 ng/mL; 90 mg: 7.7 ± 5.3 vs 60.3 ± 46.9 ng/mL; and 120 mg: 10.9 ± 8.6 vs 85.5 ± 55.1 ng/mL. In the pivotal study, discontinuations due to adverse events were low across all treatment groups: 2.5% for placebo vs 0% for 90 mg and 1.7% for 120 mg.⁴ There was no single adverse reaction leading to discontinuation that occurred at a rate of ≥2% and greater than placebo in patients treated with RBP-7000.¹⁰ There were no clinically relevant differences in mean changes from baseline in corrected QT, QRS, and PR intervals, and in heart rate. Similarly, in the 12-month, long-term safety study, there were no clinically relevant changes in mean electrocardiography interval values from baseline to post-dose assessments.¹⁰

Using a 100-point visual analog scale (VAS), injection site pain scores 1 minute after the first dose decreased from a mean of 27 to the range of 3 to 7 for scores obtained 30 to 60 minutes post-dose. In the 12-month long-term safety study, 1-minute post-dose injection site pain VAS scores were highest on Day 1 (mean of 25) and decreased over time with subsequent injections (14 to 16 following last injection).¹⁰

Clinical considerations

Unique properties. RBP-7000 uses the established Atrigel system to provide effective antipsychotic levels in the first week of treatment, without the need for bridging oral coverage or a second loading injection. The abdominal subcutaneous injection volume is relatively small (0.6 mL or 0.8 mL).

Why Rx? The reasons to prescribe RBP-7000 for adult patients with schizophrenia include:

• no oral coverage required at the initiation of treatment
• effective plasma active moiety levels are seen within the first week without the need for a second loading injection
• monthly injection schedule.

Dosing. The recommended dosage of RBP-7000 is 90 mg or 120 mg once monthly, equivalent to 3 mg/d or 4 mg/d of oral risperidone, respectively. Oral risperidone tolerability should be established before the first injection. No oral risperidone coverage is required. RBP-7000 has not been studied in patients with renal or hepatic impairment and should be used with caution in these patients. Prior to initiating treatment in these patients, it is advised to carefully titrate up to at least 3 mg/d of oral risperidone. If a patient can tolerate 3 mg/d of oral risperidone and is psychiatrically stable, then the 90-mg dose of RBP-7000 can be considered.¹⁰ 

Contraindications. The only contraindications for RBP-7000 are known hypersensitivity to risperidone, paliperidone (9-OH risperidone), or other components of the injection.

Bottom Line

RBP-7000 (Perseris) is the second long-acting injectable (LAI) form of risperidone approved in the U.S. Unlike risperidone microspheres (Consta), RBP-7000 does not require any oral risperidone coverage at the beginning of therapy, provides effective drug levels within the first week of treatment with a single injection, and uses a monthly dosing interval. RBP-7000 does not require loading upon initiation. The monthly injection is <1 mL, is administered in abdominal subcutaneous tissue, and uses the Atrigel system.

Related Resource

• Carpenter J, Wong KK. Long-acting injectable antipsychotics: What to do about missed doses. Current Psychiatry. 2018;17(7):10-12,14-19,56.
   

Drug Brand Names
Aripiprazole • Abilify
Carbamazepine • Carbatrol, Tegretol
Doxycycline • Atridox
Leuprolide acetate injectable suspension • Eligard
Paliperidone palmitate • Invega Sustenna
Risperidone • Risperdal
Risperidone extended-release injectable suspension • Perseris
Risperidone long-acting injection • Risperdal Consta

Oral antipsychotic nonadherence is a significant contributor to relapse in patients with schizophrenia spectrum disorders. Long-acting injectable (LAI) antipsychotics have been developed to provide sustained antipsychotic exposure, with evidence that use of LAIs significantly reduces hospitalization rates.¹ One limiting factor in transitioning patients to certain LAIs is the need for prolonged oral coverage at the onset of treatment for agents that cannot be loaded. Nonadherence with this bridging oral therapy places the patient at risk for symptom exacerbation until effective antipsychotic plasma levels are achieved from the LAI.² Although risperidone is one of the more widely used antipsychotics for treating schizophrenia, until recently the only available LAI preparation, risperidone microspheres (Risperdal Consta), required 3 weeks of oral coverage upon initiation.³

Clinical implications

Oral medication nonadherence remains a significant public health issue for patients with schizophrenia, with an estimated 50% of patients failing to achieve 80% adherence even when enrolled in clinical trials specifically designed to track adherence.⁵ Although LAI atypical antipsychotics have been available since the approval of Risperdal Consta, the LAI form of risperidone, and both LAI forms of aripiprazole, were not designed to be loaded. A 1-day initiation regimen for aripiprazole lauroxil has been developed to avoid the need for 3 weeks of oral medication coverage,^6,7 but aripiprazole monohydrate and risperidone microspheres mandate oral bridging of 2 and 3 weeks, respectively.² Because one of the primary indications for LAI antipsychotic therapy is oral medication nonadherence, this prolonged period of oral coverage creates a risk for symptom exacerbation when the bridging period occurs outside of a controlled setting, as is common when patients are discharged from inpatient hospitalization.

One solution to this problem has its antecedents in the development of the Atrigel biodegradable injectable polymer, which was designed to deliver prolonged medication exposure after subcutaneous injection.⁸ This biodegradable polymer drug delivery system suspends and dissolves the medication of interest (in this case, risperidone) in a poly DL-lactide-coglycolide gel and its biocompatible carrier.⁹ The viscous liquid undergoes a phase transition upon contact with tissue fluids after subcutaneous injection, resulting in an implant that releases risperidone in a controlled manner as it is resorbed. Importantly, the kinetic parameters of RBP-7000 are such that effective drug levels are seen within the first week without the need for oral coverage.¹⁰

Use in adults with schizophrenia. After establishing tolerability with oral risperidone, the recommended doses are 90 mg or 120 mg monthly, which correspond to oral daily risperidone doses of 3 mg or 4 mg. RBP-7000 must be administered as a subcutaneous abdominal injection by a health care professional. It is recommended that the patient be in the supine position for the injection and that the injection sites be rotated monthly among 4 quadrants in the abdominal region. The injection volumes for the 90 mg and 120 mg doses are 0.6 mL and 0.8 mL, respectively.¹⁰ As the gel implant becomes firmer, the patient will notice a lump for several weeks that will decrease in size over time. Patients should be advised not to rub or massage the injection site, and to be aware of the placement of any belts or clothing with waistbands.¹⁰

Pharmacologic profile, adverse reactions

Risperidone is an atypical antipsychotic that has been commercially available in the U.S. since December 29, 1993, and its adverse effect profile is well characterized. The most common adverse effects associated with risperidone include those related to dopamine D2 antagonism, metabolic adverse effects, and an increase in serum prolactin. In the 12-month long-term safety study of RBP-7000, 1-minute post-dose injection site pain scores (on a 100-point scale) were highest on Day 1 (mean of 25) and decreased over time with subsequent injections (14 to 16 following the last injection).¹⁰

Continue to: How the Atrigel system works

The kinetics for RBP-7000 are markedly different than those for oral risperidone (Figure 2¹⁵). After a single subcutaneous injection, RBP-7000 shows 2 absorption peaks for risperidone. The first lower peak occurs with a T_max of 4 to 6 hours due to initial release of risperidone during the implant formation process; a second risperidone peak occurs after 10 to 14 days and is associated with slow release from the subcutaneous depot.^9,16,17 For both 9-OH risperidone levels and the total active moiety (risperidone plus 9-OH risperidone levels), the median T_max of the first peak ranges from 4 to 48 hours and the second peak ranges from 7 to 11 days. Following a single subcutaneous injection of RBP-7000, the apparent terminal half-life of risperidone ranges from 9 to 11 days, on average. The mean apparent terminal half-life of the active moiety ranges from 8 to 9 days.^9,16,17 Based on population pharmacokinetic modeling, the 90 mg and 120 mg doses of RBP-7000 are estimated to provide drug exposure equivalent to 3 mg/d and 4 mg/d of oral risperidone, respectively.^9,16,17

Continue to: Efficacy of RBP-7000

Efficacy of RBP-7000 was established in an 8-week, double-blind, placebo-controlled trial of adult patients experiencing an acute exacerbation of schizo­phrenia (age 18 to 55).⁴ Eligible participants had:

• An acute exacerbation of schizophrenia that occurred ≤8 weeks before the screening visit and would have benefited from psychiatric hospitalization or continued hospitalization
• Positive and Negative Syndrome Scale (PANSS) total score between 80 and 120 at visit 1 and a score of >4 on at least 2 of the following 4 items: hallucinatory behavior, delusions, conceptual disorganization, or suspiciousness/persecution
• The diagnosis of acute exacerbation of schizophrenia and PANSS total score were confirmed through an independent video-conference interview conducted by an experienced rater.

Participants were excluded if they:

• Experienced a ≥20% improvement in PANSS total score between the initial screening visit and the first injection
• had been treated at any time with clozapine for treatment-resistant schizophrenia
• had met DSM-IV-TR criteria for substance dependence (with the exception of nicotine or caffeine) before screening.

During the initial screening visit, participants received a 0.25-mg tablet of oral risperidone on 2 consecutive days to assess the tolerability of risperidone.

Outcome. Participants were randomized in a 1:1:1 manner to placebo (n = 112) or 1 of 2 monthly doses of RBP-7000: 90 mg (n = 111) or 120 mg (n = 114). Using the least squares means of repeated-measures changes from baseline in PANSS total scores, there was a significant improvement in the difference in PANSS total scores from baseline to the end of the study compared with placebo: 90-mg RBP-7000, -6.148 points (95% confidence interval [CI], -9.982 to -2.314, P = .0004); 120-mg RBP-7000, -7.237 points (95% CI, -11.045 to -3.429, P < .0001). The absolute change from baseline in PANSS total score was -15.367 points for the 90-mg dose and -16.456 points for the 120-mg dose.⁴ Completion rates across all 3 arms were comparable: placebo 70.6%, RBP-7000 90 mg 77.6%, and RBP-7000 120 mg 71.4%.

Tolerability. In the 8-week phase III efficacy trial of RBP-7000, adverse effects occurring with an incidence ≥5% and at least twice the rate of placebo were weight gain (placebo 3.4%, 90 mg 13.0%, 120 mg 12.8%) and sedation (placebo 0%, 90 mg 7.0%, 120 mg 7.7%).¹⁰ Compared with baseline, participants had a mean weight gain at the end of the study of 2.83 kg in the placebo group, 5.15 kg in the 90-mg RBP-7000 group, and 4.69 kg in the 120-mg RBP-7000 group. There were no clinically significant differences at study endpoint in glucose and lipid parameters. Consistent with the known effects of risperidone, there were increases in mean prolactin levels during the 8-week study, the effects of which were greater for women. For men, mean prolactin levels from baseline to study end were: placebo: 9.8 ± 7.9 vs 9.9 ± 8.0 ng/mL; 90 mg: 8.9 ± 6.9 vs 22.4 ± 11.2 ng/mL; and 120 mg: 8.2 ± 5.2 vs 31.3 ± 14.8 ng/mL. For women, mean prolactin levels from baseline to study end were: placebo: 12.8 ± 11.7 vs 10.4 ± 8.0 ng/mL; 90 mg: 7.7 ± 5.3 vs 60.3 ± 46.9 ng/mL; and 120 mg: 10.9 ± 8.6 vs 85.5 ± 55.1 ng/mL. In the pivotal study, discontinuations due to adverse events were low across all treatment groups: 2.5% for placebo vs 0% for 90 mg and 1.7% for 120 mg.⁴ There was no single adverse reaction leading to discontinuation that occurred at a rate of ≥2% and greater than placebo in patients treated with RBP-7000.¹⁰ There were no clinically relevant differences in mean changes from baseline in corrected QT, QRS, and PR intervals, and in heart rate. Similarly, in the 12-month, long-term safety study, there were no clinically relevant changes in mean electrocardiography interval values from baseline to post-dose assessments.¹⁰

Using a 100-point visual analog scale (VAS), injection site pain scores 1 minute after the first dose decreased from a mean of 27 to the range of 3 to 7 for scores obtained 30 to 60 minutes post-dose. In the 12-month long-term safety study, 1-minute post-dose injection site pain VAS scores were highest on Day 1 (mean of 25) and decreased over time with subsequent injections (14 to 16 following last injection).¹⁰

Clinical considerations

Unique properties. RBP-7000 uses the established Atrigel system to provide effective antipsychotic levels in the first week of treatment, without the need for bridging oral coverage or a second loading injection. The abdominal subcutaneous injection volume is relatively small (0.6 mL or 0.8 mL).

Why Rx? The reasons to prescribe RBP-7000 for adult patients with schizophrenia include:

• no oral coverage required at the initiation of treatment
• effective plasma active moiety levels are seen within the first week without the need for a second loading injection
• monthly injection schedule.

Dosing. The recommended dosage of RBP-7000 is 90 mg or 120 mg once monthly, equivalent to 3 mg/d or 4 mg/d of oral risperidone, respectively. Oral risperidone tolerability should be established before the first injection. No oral risperidone coverage is required. RBP-7000 has not been studied in patients with renal or hepatic impairment and should be used with caution in these patients. Prior to initiating treatment in these patients, it is advised to carefully titrate up to at least 3 mg/d of oral risperidone. If a patient can tolerate 3 mg/d of oral risperidone and is psychiatrically stable, then the 90-mg dose of RBP-7000 can be considered.¹⁰ 

Contraindications. The only contraindications for RBP-7000 are known hypersensitivity to risperidone, paliperidone (9-OH risperidone), or other components of the injection.

Bottom Line

RBP-7000 (Perseris) is the second long-acting injectable (LAI) form of risperidone approved in the U.S. Unlike risperidone microspheres (Consta), RBP-7000 does not require any oral risperidone coverage at the beginning of therapy, provides effective drug levels within the first week of treatment with a single injection, and uses a monthly dosing interval. RBP-7000 does not require loading upon initiation. The monthly injection is <1 mL, is administered in abdominal subcutaneous tissue, and uses the Atrigel system.

Related Resource

• Carpenter J, Wong KK. Long-acting injectable antipsychotics: What to do about missed doses. Current Psychiatry. 2018;17(7):10-12,14-19,56.
   

Drug Brand Names
Aripiprazole • Abilify
Carbamazepine • Carbatrol, Tegretol
Doxycycline • Atridox
Leuprolide acetate injectable suspension • Eligard
Paliperidone palmitate • Invega Sustenna
Risperidone • Risperdal
Risperidone extended-release injectable suspension • Perseris
Risperidone long-acting injection • Risperdal Consta