The ground trembled, trees shook, and voices echoed throughout the city. I looked around in awe as the dew from my breath settled on the tip of my nose, dampening my face mask. Thousands of people with varying backgrounds, together in recognition that while the arc of the moral universe is long, it cannot bend towards justice without our help. The pain, suffering, and anger of the protestors was palpable, their chants vibrating deep in my chest, all against the backdrop of the historic Los Angeles City Hall, with rows of police officers and National Guard troops on its lawn. The countless recent racially motivated attacks and murders had driven people from all walks of life to protest for an end to systemic racism. I listened to people tell stories and challenge each other to comprehend the depths of the trauma that led us to this moment, and I went home that day curious about the history of racism in medicine.

Medicine’s roots in slavery

The uncomfortable truth is that medicine in America has some of its earliest roots in slavery. In an editorial in the New England Journal of Medicine, Evans et al¹ wrote “Slaves provided economic security for physicians and clinical material that permitted the expansion of medical research, improvement of medical care, and enhancement of medical training.”¹

In the 1830s, medical schools would publicize abundant access to “black clinical subjects” as a recruitment method. The Savannah Medical Journal, for example, proudly stated that Savannah Medical College had a Black patient census that “provided abundant clinical opportunities for studying disease.”² The dehumanization of Black people was pervasive, and while racism in medical education today may be less overt because the Black community is no longer sought after as “clinical material,” discrimination continues. Ebede and Papier³ found that patients of color are extremely underrepresented in images used in medical education.

How were trainees learning to recognize clinical findings in dark-skinned patients? Was this ultimately slowing the identification and treatment of diseases in such populations?

Racism in psychiatry

In a 2020 article in Psychiatric News, American Psychiatric Association (APA) president Jeffrey Geller, MD, MPH, provided shocking insight into the history of racism in American psychiatry.⁴ In 1773, the Public Hospital for Persons of Insane and Disordered Minds in Williamsburg, Virginia, became the first public freestanding psychiatric hospital in British North America.⁴ The hospital would only accept Black patients if their admission did not interfere with the admission of White patients. Some clinicians also believed that insanity could not occur in Black people due to their “primitive nature.”⁴ John Galt, physician head of the hospital from 1841 to 1862 and one of the APA’s founding fathers, believed that Black people were “immune” to insanity because they did not experience the “mental excitement” that the free population experienced daily. Further, Benjamin Rush, considered the father of American psychiatry, was adamant that black skin itself was actually a disease, called negritude, and the only treatment involved turning a Black person white.⁴

The blasphemy is endless. John Calhoun, former vice president of the APA in the 1840s, stated “The African is incapable of self care and sinks into lunacy under the burden of freedom. It is mercy to him to give this guardianship and protection from mental health.”⁴

How could a population that was owned, sold, beaten, chained, raped, and ultimately dehumanized not develop mental illness? Race was weaponized by the powerful in order to deny the inalienable rights of Black people. Dr. Geller summarized these atrocities perfectly: “…during [the APA’s first 40 years] … Association members did not debate segregation by race. A few members said it shall be so, and the rest were silent—silent for a very long time.”⁴

While I train as a resident psychiatrist, I am learning the value of cultural sensitivity and the importance of truly understanding the background of all my patients in order to effectively treat mental illness. George Floyd’s murder is the most recent death that has shed light on systemic racism and the challenges that are largely unique to the Black community and their mental health. I recognize that combating disparities in mental health requires an honest and often uncomfortable reckoning with the role that systemic racism has played in creating these health disparities. While the trauma inflicted by centuries of injustice cannot be corrected overnight, it is our responsibility to confront these biases and barriers in medicine on a daily basis as we strive to create a more equitable society.

The ground trembled, trees shook, and voices echoed throughout the city. I looked around in awe as the dew from my breath settled on the tip of my nose, dampening my face mask. Thousands of people with varying backgrounds, together in recognition that while the arc of the moral universe is long, it cannot bend towards justice without our help. The pain, suffering, and anger of the protestors was palpable, their chants vibrating deep in my chest, all against the backdrop of the historic Los Angeles City Hall, with rows of police officers and National Guard troops on its lawn. The countless recent racially motivated attacks and murders had driven people from all walks of life to protest for an end to systemic racism. I listened to people tell stories and challenge each other to comprehend the depths of the trauma that led us to this moment, and I went home that day curious about the history of racism in medicine.

Medicine’s roots in slavery

The uncomfortable truth is that medicine in America has some of its earliest roots in slavery. In an editorial in the New England Journal of Medicine, Evans et al¹ wrote “Slaves provided economic security for physicians and clinical material that permitted the expansion of medical research, improvement of medical care, and enhancement of medical training.”¹

In the 1830s, medical schools would publicize abundant access to “black clinical subjects” as a recruitment method. The Savannah Medical Journal, for example, proudly stated that Savannah Medical College had a Black patient census that “provided abundant clinical opportunities for studying disease.”² The dehumanization of Black people was pervasive, and while racism in medical education today may be less overt because the Black community is no longer sought after as “clinical material,” discrimination continues. Ebede and Papier³ found that patients of color are extremely underrepresented in images used in medical education.

How were trainees learning to recognize clinical findings in dark-skinned patients? Was this ultimately slowing the identification and treatment of diseases in such populations?

Racism in psychiatry

In a 2020 article in Psychiatric News, American Psychiatric Association (APA) president Jeffrey Geller, MD, MPH, provided shocking insight into the history of racism in American psychiatry.⁴ In 1773, the Public Hospital for Persons of Insane and Disordered Minds in Williamsburg, Virginia, became the first public freestanding psychiatric hospital in British North America.⁴ The hospital would only accept Black patients if their admission did not interfere with the admission of White patients. Some clinicians also believed that insanity could not occur in Black people due to their “primitive nature.”⁴ John Galt, physician head of the hospital from 1841 to 1862 and one of the APA’s founding fathers, believed that Black people were “immune” to insanity because they did not experience the “mental excitement” that the free population experienced daily. Further, Benjamin Rush, considered the father of American psychiatry, was adamant that black skin itself was actually a disease, called negritude, and the only treatment involved turning a Black person white.⁴

The blasphemy is endless. John Calhoun, former vice president of the APA in the 1840s, stated “The African is incapable of self care and sinks into lunacy under the burden of freedom. It is mercy to him to give this guardianship and protection from mental health.”⁴

How could a population that was owned, sold, beaten, chained, raped, and ultimately dehumanized not develop mental illness? Race was weaponized by the powerful in order to deny the inalienable rights of Black people. Dr. Geller summarized these atrocities perfectly: “…during [the APA’s first 40 years] … Association members did not debate segregation by race. A few members said it shall be so, and the rest were silent—silent for a very long time.”⁴

While I train as a resident psychiatrist, I am learning the value of cultural sensitivity and the importance of truly understanding the background of all my patients in order to effectively treat mental illness. George Floyd’s murder is the most recent death that has shed light on systemic racism and the challenges that are largely unique to the Black community and their mental health. I recognize that combating disparities in mental health requires an honest and often uncomfortable reckoning with the role that systemic racism has played in creating these health disparities. While the trauma inflicted by centuries of injustice cannot be corrected overnight, it is our responsibility to confront these biases and barriers in medicine on a daily basis as we strive to create a more equitable society.

The ground trembled, trees shook, and voices echoed throughout the city. I looked around in awe as the dew from my breath settled on the tip of my nose, dampening my face mask. Thousands of people with varying backgrounds, together in recognition that while the arc of the moral universe is long, it cannot bend towards justice without our help. The pain, suffering, and anger of the protestors was palpable, their chants vibrating deep in my chest, all against the backdrop of the historic Los Angeles City Hall, with rows of police officers and National Guard troops on its lawn. The countless recent racially motivated attacks and murders had driven people from all walks of life to protest for an end to systemic racism. I listened to people tell stories and challenge each other to comprehend the depths of the trauma that led us to this moment, and I went home that day curious about the history of racism in medicine.

Medicine’s roots in slavery

The uncomfortable truth is that medicine in America has some of its earliest roots in slavery. In an editorial in the New England Journal of Medicine, Evans et al¹ wrote “Slaves provided economic security for physicians and clinical material that permitted the expansion of medical research, improvement of medical care, and enhancement of medical training.”¹

In the 1830s, medical schools would publicize abundant access to “black clinical subjects” as a recruitment method. The Savannah Medical Journal, for example, proudly stated that Savannah Medical College had a Black patient census that “provided abundant clinical opportunities for studying disease.”² The dehumanization of Black people was pervasive, and while racism in medical education today may be less overt because the Black community is no longer sought after as “clinical material,” discrimination continues. Ebede and Papier³ found that patients of color are extremely underrepresented in images used in medical education.

How were trainees learning to recognize clinical findings in dark-skinned patients? Was this ultimately slowing the identification and treatment of diseases in such populations?

Racism in psychiatry

In a 2020 article in Psychiatric News, American Psychiatric Association (APA) president Jeffrey Geller, MD, MPH, provided shocking insight into the history of racism in American psychiatry.⁴ In 1773, the Public Hospital for Persons of Insane and Disordered Minds in Williamsburg, Virginia, became the first public freestanding psychiatric hospital in British North America.⁴ The hospital would only accept Black patients if their admission did not interfere with the admission of White patients. Some clinicians also believed that insanity could not occur in Black people due to their “primitive nature.”⁴ John Galt, physician head of the hospital from 1841 to 1862 and one of the APA’s founding fathers, believed that Black people were “immune” to insanity because they did not experience the “mental excitement” that the free population experienced daily. Further, Benjamin Rush, considered the father of American psychiatry, was adamant that black skin itself was actually a disease, called negritude, and the only treatment involved turning a Black person white.⁴

The blasphemy is endless. John Calhoun, former vice president of the APA in the 1840s, stated “The African is incapable of self care and sinks into lunacy under the burden of freedom. It is mercy to him to give this guardianship and protection from mental health.”⁴

How could a population that was owned, sold, beaten, chained, raped, and ultimately dehumanized not develop mental illness? Race was weaponized by the powerful in order to deny the inalienable rights of Black people. Dr. Geller summarized these atrocities perfectly: “…during [the APA’s first 40 years] … Association members did not debate segregation by race. A few members said it shall be so, and the rest were silent—silent for a very long time.”⁴

While I train as a resident psychiatrist, I am learning the value of cultural sensitivity and the importance of truly understanding the background of all my patients in order to effectively treat mental illness. George Floyd’s murder is the most recent death that has shed light on systemic racism and the challenges that are largely unique to the Black community and their mental health. I recognize that combating disparities in mental health requires an honest and often uncomfortable reckoning with the role that systemic racism has played in creating these health disparities. While the trauma inflicted by centuries of injustice cannot be corrected overnight, it is our responsibility to confront these biases and barriers in medicine on a daily basis as we strive to create a more equitable society.

The coronavirus disease 2019 pandemic, which as of mid-February 2021 had caused more than 486,000 deaths in the United States, has changed our lives forever. Elders and Black, Indigenous, and People of Color (BIPOC) have been overrepresented among those lost. That, when juxtaposed with the civil unrest that followed the brutal killing of George Floyd, an unarmed Black man, by a White law enforcement officer on May 25, 2020, have compelled us to talk about US race relations in unprecedented ways. These and other traumas disproportionately affect the quality of life and health of minority and underserved individuals. The international outcry about racism, serial trauma, and health disparities left the medical profession well positioned to promulgate changes that are conducive to achieving health equity.

Race is a social construct

In November 2020, the American Medical Association (AMA) Board of Trustees made several public acknowledgments about race.¹ First, race is a social, nonbiological classification that is different from biology, ethnicity, or genetic ancestry.¹ Next, race contributes to health disparities and poor health outcomes for minorities and members of underserved communities.¹ Also, racism, which includes disproportionate police brutality against Black and Indigenous people, is a driver of health inequity for them and people in marginalized communities.¹

The AMA also commented on how serial trauma and racism can affect one’s health. The AMA acknowledged that exposure to serial trauma throughout one’s life can have a cumulative effect that is “associated with chronic stress, higher rates of comorbidities and lower life expectancy” and results in increased health care costs and decreased quality of life for those who are affected.¹ Also, the AMA proclaimed that racism is a threat to public health and pledged to dismantle discriminatory practices and policies in health care, including medical education and research.²

Diversity and inclusion in psychiatry

While the AMA has been striving to reduce bias in health care systems, psychiatry has been forging its path. In March 2015, the American Psychiatric Association’s (APA) Board of Trustees approved the APA’s Strategic Initiative, which has 4 goals: 1) advancing the integration of psychiatry in health care; 2) supporting research; 3) supporting education; and 4) promoting diversity and inclusion in psychiatry.³ The latter goal includes advocating for antiracist policies that promote cultural competence and health equity in education, research and psychiatric care; increased recruitment and retention of psychiatrists from groups that historically have been underrepresented in medicine and medical leadership; and ensuring representation of these groups in APA governance at all levels.³

The APA’s antiracism agenda

In March 2020, outgoing APA President Bruce Schwartz concurred with Board members that diversity and inclusion in the APA warranted a closer review. On May 5, 2020, APA President Jeff Geller committed to authorizing a systematic study of diversity and inclusion in various branches of the APA, including councils and governance. By the end of May, with civil unrest in full swing in the United States, President Geller decided to expand the APA’s diversity agenda.

President Geller appointed the APA Presidential Task Force to Address Structural Racism Throughout Psychiatry (SR Task Force), which had its virtual inaugural meeting on June 27, 2020.⁴ The SR Task Force exists to focus on structural racism (aka institutional racism) in organized psychiatry, psychiatric patients, and those who provide psychiatric services to patients. The charge, which is subject to revision, if warranted, is clear: provide resources and education on the history of structural racism in the APA and psychiatry, explain how structural racism impacts psychiatric patients and the profession, craft actionable recommendations to dismantle structural racism in the APA and psychiatry, report those findings to the APA’s Board of Trustees, and implement a quality assurance protocol to ensure that the Task Force’s work is consistent with its charge. President Geller decided to have the Task Force focus on anti-Black racism in its inaugural year and believes that the outcome will benefit all psychiatrists, other mental health professionals, and patients who identify as members of minority and underserved groups in the United States and the profession of psychiatry.⁵

Presidential Task Forces in APA

Presidential Task Forces report directly to the Board of Trustees, which expedites the review of progress reports and deliberation on and, when favorable, implementation of recommendations. Also, Presidential Task Forces are afforded additional APA resources. For example, the SR Task Force has 16 APA staff members who have been appointed or volunteered to assist the Task Force in some way. Many APA staff have graduate degrees in law, education, and other subjects. The skill sets, networks, institutional memory, and commitment that they bring to the project are conducive to advancing the SR Task Force’s agenda at a brisk pace.

Continue to: The APA President...

The APA President decides whom to appoint to each Task Force. President Geller propitiously appointed subject matter experts and members of the Board of Trustees to serve on the SR Task Force. Subject matter experts contribute historical and contemporary content about racism, including anti-Black racism, to the discussion. The data are used to craft research questions that may yield pertinent data. (Note that not all subject matter experts are Black, nor are all Board members White.) APA staff support the Task Force by sharing their expertise, compiling data, coordinating meetings, collaborating on program development, disseminating the work product to APA members and the media, and other important tasks.

The SR Task Force’s work

The SR Task Force strives for transparency in a process that is informed by APA members. The group immediately set up a web hub that is used to communicate with APA members.⁵ Individual members also use social media to alert members to SR Task Force activities and events. Member input has been solicited by posting several brief surveys on the SR Task Force web hub. Topics have included the effect of structural racism on patient care, psychiatric practice, and organized psychiatry, including the APA. The responses, which collectively totaled >1,600, were reviewed and used to inform Task Force priorities while working within the scope of the charge.⁵

Based on member feedback, the first large project of the SR Task Force has been to examine structural racism in the APA. The SR Task Force formed workgroups to study data pertaining to diversity and inclusion in the APA Assembly, governance (the Board of Trustees), Councils and Committees, and Scientific Program Committee. As APA Publishing and the DSM Steering Committee have internal processes to address structural racism, the SR Task Force did not convene workgroups to study this. However, the SR Task Force will be meeting with leaders of those groups to learn about their protocols and will request that information be made available to APA members.

The SR Task Force reviews and interprets data that are compiled by each workgroup, deliberates on its significance, and when appropriate, drafts achievable recommendations to improve diversity and inclusion in the APA. This is where Trustee involvement is invaluable to the SR Task Force, because the report and recommendations will be presented to the Board of Trustees.

There is no guarantee that the recommendations contained in a report that is accepted by the Board of Trustees will be implemented unless they are approved. It is imperative, therefore, that SR Task Force recommendations to the Board take into consideration Board structure, processes, goals, efficiency, history, and other matters. The learning curve can be steep, especially when the first major report was due 3 months after the SR Task Force was appointed. Clarity and efficiency are key in report preparation. For example, during the Winter 2020 Board of Trustees meeting, the SR Task Force presented its report, answered questions, and offered 7 action items to the Board for deliberation and voting. The endeavor, which was completed in 20 minutes, resulted in the Board supporting 6 of the recommendations and deferring the deliberation of the seventh recommendation to the spring Board meeting, due to logistical concerns.

Continue to: Thus far, the SR Task Force Workgroups...

Thus far, the SR Task Force Workgroups on the Assembly and Governance have presented their reports. ⁵ The SR Task Force reports on the Scientific Program Committee and Councils and Committees are scheduled to be presented to the Board during the Spring 2021 meeting.

The SR Task Force has been fulfilling the commitment to provide relevant educational materials to members in several ways. There have been 4 virtual Structural Racism Town Hall meetings that featured subject matter experts. The first Town Hall session addressed the initial steps towards dismantling structural racism and included President Geller’s announcement about appointing a SR Task Force. The next Town Hall meeting addressed structural racism in medicine and psychiatry, its effect on children and individuals who identify as transgender, and its intersectionality (the cumulative effect of discrimination on a person who belongs to 2 non-dominant groups.) The panel in the third Town Hall meeting reviewed the impact of structural racism, including intersectionality, on transgenerational trauma in several minority groups. The meeting ended with an update of Task Force activities. The February 2021 Town Hall meeting focused on how structural racism affects recruitment and retention of minority psychiatry residents, and how this can undermine efforts to grow a diverse workforce. Recordings of these and other events can be accessed on the SR Task Force web hub.⁵ The SR Task Force members plan to present a review of the year’s work during the next Town Hall meeting, which is scheduled to occur on Saturday, May 1, 2021, during the APA’s Annual Meeting.

The SR Task Force web hub contains other resources, including APA position statements, press releases, and news articles, and a glossary of relevant terms. It also includes internet links to President Geller’s 9-part series on the history of Structural Racism in the APA. There are CME and other webinars, a curated list of references, videos, podcasts, and other media.⁴

The SR Task Force believes that much of the antiracism work needs to occur beyond APA headquarters. Consequently, President Geller challenged all APA Councils to work on an antiracism project to support the APA’s antiracism agenda. APA committees and caucuses have been encouraged to do the same. The SR Task Force has asked APA District Branches and Allied Organizations to share information about what they are doing to educate members about structural racism and what they are doing for input regarding their antiracist activities. Additionally, Task Force members have been speaking with these and other groups to inform them about the APA’s antiracism work.

APA’s Board of Trustees actions

It would be inappropriate for the APA to task groups with focusing on antiracism unless the organization was doing its part. In July 2020, the Board of Trustees had a 2-hour round table discussion during which each member spoke about the problem and how the APA should address it. Next, President Geller appointed a Board Workgroup to clarify the definitions of “minority” and “underrepresented.” Although the APA Assembly has defined the terms, the APA has not. Additionally, the APA Board of Trustees retained a consultant to assess all aspects of how it functions as a Board. The Board’s management of matters pertaining to diversity and inclusion was part of the examination. The recommendations are being reviewed and the Board will undergo diversity training.

Continue to: President Geller's study...

President Geller’s study of racism in the APA, which involved a review of past APA presidential addresses, brought to light a long-term pattern of racism in the organization.⁵ On January 18, 2021, Martin Luther King, Jr. Day, the APA acknowledged and apologized to psychiatrists, patients, and the public for its history of engaging in and passively condoning racist behavior.⁶ The APA has committed to being better informed about diversity and inclusion at every level. Lastly, hired consultants with expertise in diversity and inclusion are working with APA staff at every level so that the environment can be a welcoming and comfortable workspace for recruiting and retaining a diverse workforce.

Although it may seem that the APA has engaged in many antiracist activities in a brief period, there is much more to accomplish. The Task Force hopes that the work will speak for itself and will be sustained over time. It’s long overdue.

The coronavirus disease 2019 pandemic, which as of mid-February 2021 had caused more than 486,000 deaths in the United States, has changed our lives forever. Elders and Black, Indigenous, and People of Color (BIPOC) have been overrepresented among those lost. That, when juxtaposed with the civil unrest that followed the brutal killing of George Floyd, an unarmed Black man, by a White law enforcement officer on May 25, 2020, have compelled us to talk about US race relations in unprecedented ways. These and other traumas disproportionately affect the quality of life and health of minority and underserved individuals. The international outcry about racism, serial trauma, and health disparities left the medical profession well positioned to promulgate changes that are conducive to achieving health equity.

Race is a social construct

In November 2020, the American Medical Association (AMA) Board of Trustees made several public acknowledgments about race.¹ First, race is a social, nonbiological classification that is different from biology, ethnicity, or genetic ancestry.¹ Next, race contributes to health disparities and poor health outcomes for minorities and members of underserved communities.¹ Also, racism, which includes disproportionate police brutality against Black and Indigenous people, is a driver of health inequity for them and people in marginalized communities.¹

The AMA also commented on how serial trauma and racism can affect one’s health. The AMA acknowledged that exposure to serial trauma throughout one’s life can have a cumulative effect that is “associated with chronic stress, higher rates of comorbidities and lower life expectancy” and results in increased health care costs and decreased quality of life for those who are affected.¹ Also, the AMA proclaimed that racism is a threat to public health and pledged to dismantle discriminatory practices and policies in health care, including medical education and research.²

Diversity and inclusion in psychiatry

While the AMA has been striving to reduce bias in health care systems, psychiatry has been forging its path. In March 2015, the American Psychiatric Association’s (APA) Board of Trustees approved the APA’s Strategic Initiative, which has 4 goals: 1) advancing the integration of psychiatry in health care; 2) supporting research; 3) supporting education; and 4) promoting diversity and inclusion in psychiatry.³ The latter goal includes advocating for antiracist policies that promote cultural competence and health equity in education, research and psychiatric care; increased recruitment and retention of psychiatrists from groups that historically have been underrepresented in medicine and medical leadership; and ensuring representation of these groups in APA governance at all levels.³

The APA’s antiracism agenda

In March 2020, outgoing APA President Bruce Schwartz concurred with Board members that diversity and inclusion in the APA warranted a closer review. On May 5, 2020, APA President Jeff Geller committed to authorizing a systematic study of diversity and inclusion in various branches of the APA, including councils and governance. By the end of May, with civil unrest in full swing in the United States, President Geller decided to expand the APA’s diversity agenda.

President Geller appointed the APA Presidential Task Force to Address Structural Racism Throughout Psychiatry (SR Task Force), which had its virtual inaugural meeting on June 27, 2020.⁴ The SR Task Force exists to focus on structural racism (aka institutional racism) in organized psychiatry, psychiatric patients, and those who provide psychiatric services to patients. The charge, which is subject to revision, if warranted, is clear: provide resources and education on the history of structural racism in the APA and psychiatry, explain how structural racism impacts psychiatric patients and the profession, craft actionable recommendations to dismantle structural racism in the APA and psychiatry, report those findings to the APA’s Board of Trustees, and implement a quality assurance protocol to ensure that the Task Force’s work is consistent with its charge. President Geller decided to have the Task Force focus on anti-Black racism in its inaugural year and believes that the outcome will benefit all psychiatrists, other mental health professionals, and patients who identify as members of minority and underserved groups in the United States and the profession of psychiatry.⁵

Presidential Task Forces in APA

Presidential Task Forces report directly to the Board of Trustees, which expedites the review of progress reports and deliberation on and, when favorable, implementation of recommendations. Also, Presidential Task Forces are afforded additional APA resources. For example, the SR Task Force has 16 APA staff members who have been appointed or volunteered to assist the Task Force in some way. Many APA staff have graduate degrees in law, education, and other subjects. The skill sets, networks, institutional memory, and commitment that they bring to the project are conducive to advancing the SR Task Force’s agenda at a brisk pace.

Continue to: The APA President...

The APA President decides whom to appoint to each Task Force. President Geller propitiously appointed subject matter experts and members of the Board of Trustees to serve on the SR Task Force. Subject matter experts contribute historical and contemporary content about racism, including anti-Black racism, to the discussion. The data are used to craft research questions that may yield pertinent data. (Note that not all subject matter experts are Black, nor are all Board members White.) APA staff support the Task Force by sharing their expertise, compiling data, coordinating meetings, collaborating on program development, disseminating the work product to APA members and the media, and other important tasks.

The SR Task Force’s work

The SR Task Force strives for transparency in a process that is informed by APA members. The group immediately set up a web hub that is used to communicate with APA members.⁵ Individual members also use social media to alert members to SR Task Force activities and events. Member input has been solicited by posting several brief surveys on the SR Task Force web hub. Topics have included the effect of structural racism on patient care, psychiatric practice, and organized psychiatry, including the APA. The responses, which collectively totaled >1,600, were reviewed and used to inform Task Force priorities while working within the scope of the charge.⁵

Based on member feedback, the first large project of the SR Task Force has been to examine structural racism in the APA. The SR Task Force formed workgroups to study data pertaining to diversity and inclusion in the APA Assembly, governance (the Board of Trustees), Councils and Committees, and Scientific Program Committee. As APA Publishing and the DSM Steering Committee have internal processes to address structural racism, the SR Task Force did not convene workgroups to study this. However, the SR Task Force will be meeting with leaders of those groups to learn about their protocols and will request that information be made available to APA members.

The SR Task Force reviews and interprets data that are compiled by each workgroup, deliberates on its significance, and when appropriate, drafts achievable recommendations to improve diversity and inclusion in the APA. This is where Trustee involvement is invaluable to the SR Task Force, because the report and recommendations will be presented to the Board of Trustees.

There is no guarantee that the recommendations contained in a report that is accepted by the Board of Trustees will be implemented unless they are approved. It is imperative, therefore, that SR Task Force recommendations to the Board take into consideration Board structure, processes, goals, efficiency, history, and other matters. The learning curve can be steep, especially when the first major report was due 3 months after the SR Task Force was appointed. Clarity and efficiency are key in report preparation. For example, during the Winter 2020 Board of Trustees meeting, the SR Task Force presented its report, answered questions, and offered 7 action items to the Board for deliberation and voting. The endeavor, which was completed in 20 minutes, resulted in the Board supporting 6 of the recommendations and deferring the deliberation of the seventh recommendation to the spring Board meeting, due to logistical concerns.

Continue to: Thus far, the SR Task Force Workgroups...

Thus far, the SR Task Force Workgroups on the Assembly and Governance have presented their reports. ⁵ The SR Task Force reports on the Scientific Program Committee and Councils and Committees are scheduled to be presented to the Board during the Spring 2021 meeting.

The SR Task Force has been fulfilling the commitment to provide relevant educational materials to members in several ways. There have been 4 virtual Structural Racism Town Hall meetings that featured subject matter experts. The first Town Hall session addressed the initial steps towards dismantling structural racism and included President Geller’s announcement about appointing a SR Task Force. The next Town Hall meeting addressed structural racism in medicine and psychiatry, its effect on children and individuals who identify as transgender, and its intersectionality (the cumulative effect of discrimination on a person who belongs to 2 non-dominant groups.) The panel in the third Town Hall meeting reviewed the impact of structural racism, including intersectionality, on transgenerational trauma in several minority groups. The meeting ended with an update of Task Force activities. The February 2021 Town Hall meeting focused on how structural racism affects recruitment and retention of minority psychiatry residents, and how this can undermine efforts to grow a diverse workforce. Recordings of these and other events can be accessed on the SR Task Force web hub.⁵ The SR Task Force members plan to present a review of the year’s work during the next Town Hall meeting, which is scheduled to occur on Saturday, May 1, 2021, during the APA’s Annual Meeting.

The SR Task Force web hub contains other resources, including APA position statements, press releases, and news articles, and a glossary of relevant terms. It also includes internet links to President Geller’s 9-part series on the history of Structural Racism in the APA. There are CME and other webinars, a curated list of references, videos, podcasts, and other media.⁴

The SR Task Force believes that much of the antiracism work needs to occur beyond APA headquarters. Consequently, President Geller challenged all APA Councils to work on an antiracism project to support the APA’s antiracism agenda. APA committees and caucuses have been encouraged to do the same. The SR Task Force has asked APA District Branches and Allied Organizations to share information about what they are doing to educate members about structural racism and what they are doing for input regarding their antiracist activities. Additionally, Task Force members have been speaking with these and other groups to inform them about the APA’s antiracism work.

APA’s Board of Trustees actions

It would be inappropriate for the APA to task groups with focusing on antiracism unless the organization was doing its part. In July 2020, the Board of Trustees had a 2-hour round table discussion during which each member spoke about the problem and how the APA should address it. Next, President Geller appointed a Board Workgroup to clarify the definitions of “minority” and “underrepresented.” Although the APA Assembly has defined the terms, the APA has not. Additionally, the APA Board of Trustees retained a consultant to assess all aspects of how it functions as a Board. The Board’s management of matters pertaining to diversity and inclusion was part of the examination. The recommendations are being reviewed and the Board will undergo diversity training.

Continue to: President Geller's study...

President Geller’s study of racism in the APA, which involved a review of past APA presidential addresses, brought to light a long-term pattern of racism in the organization.⁵ On January 18, 2021, Martin Luther King, Jr. Day, the APA acknowledged and apologized to psychiatrists, patients, and the public for its history of engaging in and passively condoning racist behavior.⁶ The APA has committed to being better informed about diversity and inclusion at every level. Lastly, hired consultants with expertise in diversity and inclusion are working with APA staff at every level so that the environment can be a welcoming and comfortable workspace for recruiting and retaining a diverse workforce.

Although it may seem that the APA has engaged in many antiracist activities in a brief period, there is much more to accomplish. The Task Force hopes that the work will speak for itself and will be sustained over time. It’s long overdue.

The coronavirus disease 2019 pandemic, which as of mid-February 2021 had caused more than 486,000 deaths in the United States, has changed our lives forever. Elders and Black, Indigenous, and People of Color (BIPOC) have been overrepresented among those lost. That, when juxtaposed with the civil unrest that followed the brutal killing of George Floyd, an unarmed Black man, by a White law enforcement officer on May 25, 2020, have compelled us to talk about US race relations in unprecedented ways. These and other traumas disproportionately affect the quality of life and health of minority and underserved individuals. The international outcry about racism, serial trauma, and health disparities left the medical profession well positioned to promulgate changes that are conducive to achieving health equity.

Race is a social construct

In November 2020, the American Medical Association (AMA) Board of Trustees made several public acknowledgments about race.¹ First, race is a social, nonbiological classification that is different from biology, ethnicity, or genetic ancestry.¹ Next, race contributes to health disparities and poor health outcomes for minorities and members of underserved communities.¹ Also, racism, which includes disproportionate police brutality against Black and Indigenous people, is a driver of health inequity for them and people in marginalized communities.¹

The AMA also commented on how serial trauma and racism can affect one’s health. The AMA acknowledged that exposure to serial trauma throughout one’s life can have a cumulative effect that is “associated with chronic stress, higher rates of comorbidities and lower life expectancy” and results in increased health care costs and decreased quality of life for those who are affected.¹ Also, the AMA proclaimed that racism is a threat to public health and pledged to dismantle discriminatory practices and policies in health care, including medical education and research.²

Diversity and inclusion in psychiatry

While the AMA has been striving to reduce bias in health care systems, psychiatry has been forging its path. In March 2015, the American Psychiatric Association’s (APA) Board of Trustees approved the APA’s Strategic Initiative, which has 4 goals: 1) advancing the integration of psychiatry in health care; 2) supporting research; 3) supporting education; and 4) promoting diversity and inclusion in psychiatry.³ The latter goal includes advocating for antiracist policies that promote cultural competence and health equity in education, research and psychiatric care; increased recruitment and retention of psychiatrists from groups that historically have been underrepresented in medicine and medical leadership; and ensuring representation of these groups in APA governance at all levels.³

The APA’s antiracism agenda

In March 2020, outgoing APA President Bruce Schwartz concurred with Board members that diversity and inclusion in the APA warranted a closer review. On May 5, 2020, APA President Jeff Geller committed to authorizing a systematic study of diversity and inclusion in various branches of the APA, including councils and governance. By the end of May, with civil unrest in full swing in the United States, President Geller decided to expand the APA’s diversity agenda.

President Geller appointed the APA Presidential Task Force to Address Structural Racism Throughout Psychiatry (SR Task Force), which had its virtual inaugural meeting on June 27, 2020.⁴ The SR Task Force exists to focus on structural racism (aka institutional racism) in organized psychiatry, psychiatric patients, and those who provide psychiatric services to patients. The charge, which is subject to revision, if warranted, is clear: provide resources and education on the history of structural racism in the APA and psychiatry, explain how structural racism impacts psychiatric patients and the profession, craft actionable recommendations to dismantle structural racism in the APA and psychiatry, report those findings to the APA’s Board of Trustees, and implement a quality assurance protocol to ensure that the Task Force’s work is consistent with its charge. President Geller decided to have the Task Force focus on anti-Black racism in its inaugural year and believes that the outcome will benefit all psychiatrists, other mental health professionals, and patients who identify as members of minority and underserved groups in the United States and the profession of psychiatry.⁵

Presidential Task Forces in APA

Presidential Task Forces report directly to the Board of Trustees, which expedites the review of progress reports and deliberation on and, when favorable, implementation of recommendations. Also, Presidential Task Forces are afforded additional APA resources. For example, the SR Task Force has 16 APA staff members who have been appointed or volunteered to assist the Task Force in some way. Many APA staff have graduate degrees in law, education, and other subjects. The skill sets, networks, institutional memory, and commitment that they bring to the project are conducive to advancing the SR Task Force’s agenda at a brisk pace.

Continue to: The APA President...

The APA President decides whom to appoint to each Task Force. President Geller propitiously appointed subject matter experts and members of the Board of Trustees to serve on the SR Task Force. Subject matter experts contribute historical and contemporary content about racism, including anti-Black racism, to the discussion. The data are used to craft research questions that may yield pertinent data. (Note that not all subject matter experts are Black, nor are all Board members White.) APA staff support the Task Force by sharing their expertise, compiling data, coordinating meetings, collaborating on program development, disseminating the work product to APA members and the media, and other important tasks.

The SR Task Force’s work

The SR Task Force strives for transparency in a process that is informed by APA members. The group immediately set up a web hub that is used to communicate with APA members.⁵ Individual members also use social media to alert members to SR Task Force activities and events. Member input has been solicited by posting several brief surveys on the SR Task Force web hub. Topics have included the effect of structural racism on patient care, psychiatric practice, and organized psychiatry, including the APA. The responses, which collectively totaled >1,600, were reviewed and used to inform Task Force priorities while working within the scope of the charge.⁵

Based on member feedback, the first large project of the SR Task Force has been to examine structural racism in the APA. The SR Task Force formed workgroups to study data pertaining to diversity and inclusion in the APA Assembly, governance (the Board of Trustees), Councils and Committees, and Scientific Program Committee. As APA Publishing and the DSM Steering Committee have internal processes to address structural racism, the SR Task Force did not convene workgroups to study this. However, the SR Task Force will be meeting with leaders of those groups to learn about their protocols and will request that information be made available to APA members.

The SR Task Force reviews and interprets data that are compiled by each workgroup, deliberates on its significance, and when appropriate, drafts achievable recommendations to improve diversity and inclusion in the APA. This is where Trustee involvement is invaluable to the SR Task Force, because the report and recommendations will be presented to the Board of Trustees.

There is no guarantee that the recommendations contained in a report that is accepted by the Board of Trustees will be implemented unless they are approved. It is imperative, therefore, that SR Task Force recommendations to the Board take into consideration Board structure, processes, goals, efficiency, history, and other matters. The learning curve can be steep, especially when the first major report was due 3 months after the SR Task Force was appointed. Clarity and efficiency are key in report preparation. For example, during the Winter 2020 Board of Trustees meeting, the SR Task Force presented its report, answered questions, and offered 7 action items to the Board for deliberation and voting. The endeavor, which was completed in 20 minutes, resulted in the Board supporting 6 of the recommendations and deferring the deliberation of the seventh recommendation to the spring Board meeting, due to logistical concerns.

Continue to: Thus far, the SR Task Force Workgroups...

Thus far, the SR Task Force Workgroups on the Assembly and Governance have presented their reports. ⁵ The SR Task Force reports on the Scientific Program Committee and Councils and Committees are scheduled to be presented to the Board during the Spring 2021 meeting.

The SR Task Force has been fulfilling the commitment to provide relevant educational materials to members in several ways. There have been 4 virtual Structural Racism Town Hall meetings that featured subject matter experts. The first Town Hall session addressed the initial steps towards dismantling structural racism and included President Geller’s announcement about appointing a SR Task Force. The next Town Hall meeting addressed structural racism in medicine and psychiatry, its effect on children and individuals who identify as transgender, and its intersectionality (the cumulative effect of discrimination on a person who belongs to 2 non-dominant groups.) The panel in the third Town Hall meeting reviewed the impact of structural racism, including intersectionality, on transgenerational trauma in several minority groups. The meeting ended with an update of Task Force activities. The February 2021 Town Hall meeting focused on how structural racism affects recruitment and retention of minority psychiatry residents, and how this can undermine efforts to grow a diverse workforce. Recordings of these and other events can be accessed on the SR Task Force web hub.⁵ The SR Task Force members plan to present a review of the year’s work during the next Town Hall meeting, which is scheduled to occur on Saturday, May 1, 2021, during the APA’s Annual Meeting.

The SR Task Force web hub contains other resources, including APA position statements, press releases, and news articles, and a glossary of relevant terms. It also includes internet links to President Geller’s 9-part series on the history of Structural Racism in the APA. There are CME and other webinars, a curated list of references, videos, podcasts, and other media.⁴

The SR Task Force believes that much of the antiracism work needs to occur beyond APA headquarters. Consequently, President Geller challenged all APA Councils to work on an antiracism project to support the APA’s antiracism agenda. APA committees and caucuses have been encouraged to do the same. The SR Task Force has asked APA District Branches and Allied Organizations to share information about what they are doing to educate members about structural racism and what they are doing for input regarding their antiracist activities. Additionally, Task Force members have been speaking with these and other groups to inform them about the APA’s antiracism work.

APA’s Board of Trustees actions

It would be inappropriate for the APA to task groups with focusing on antiracism unless the organization was doing its part. In July 2020, the Board of Trustees had a 2-hour round table discussion during which each member spoke about the problem and how the APA should address it. Next, President Geller appointed a Board Workgroup to clarify the definitions of “minority” and “underrepresented.” Although the APA Assembly has defined the terms, the APA has not. Additionally, the APA Board of Trustees retained a consultant to assess all aspects of how it functions as a Board. The Board’s management of matters pertaining to diversity and inclusion was part of the examination. The recommendations are being reviewed and the Board will undergo diversity training.

Continue to: President Geller's study...

President Geller’s study of racism in the APA, which involved a review of past APA presidential addresses, brought to light a long-term pattern of racism in the organization.⁵ On January 18, 2021, Martin Luther King, Jr. Day, the APA acknowledged and apologized to psychiatrists, patients, and the public for its history of engaging in and passively condoning racist behavior.⁶ The APA has committed to being better informed about diversity and inclusion at every level. Lastly, hired consultants with expertise in diversity and inclusion are working with APA staff at every level so that the environment can be a welcoming and comfortable workspace for recruiting and retaining a diverse workforce.

Although it may seem that the APA has engaged in many antiracist activities in a brief period, there is much more to accomplish. The Task Force hopes that the work will speak for itself and will be sustained over time. It’s long overdue.

For millennia, serious psychiatric brain disorders (aka mental illnesses, melancholia, madness, insanity) were written off as incurable, permanent afflictions. It’s no wonder that they were engulfed with the stigma of hopelessness.

But then came the era of serendipitous discoveries in the mid-20th century, with the felicitous arrival of antipsychotics, antidepressants, and lithium. The dogma of untreatability was shattered, but in its wake, the notion of treatment resistance emerged, and promptly became the bane of psychiatric clinicians and the practice of psychopharmacology.

Many patients with mood and psychotic disorders responded to the medications that were introduced in the 1950s and 1960s, but some either derived partial benefit or did not improve at all. These partial or poor responders were labeled “treatment-resistant,” and caring for them became a major challenge for psychiatric physicians that continues to this day. However, rapid advances in understanding the many etiologies and subtypes of the heterogeneous mood and psychotic disorders are invalidating the notion of treatment resistance, showing it is a fallacy and a misnomer. Let’s examine why.

Treatment-resistant depression (TRD)

Psychiatric clinics and hospitals are clogged with patients who do not respond to ≥2 evidence-based antidepressants and carry the disparaging label of “TRD.” But a patient manifesting what appears to be major depressive disorder (MDD) may actually have one of several types of depression that are unlikely to respond to an antidepressant, including:

• iatrogenic depression due to a prescription medication
• depression secondary to recreational drug use
• depressive symptoms secondary to a general medical condition
• bipolar depression.

Thus, a significant proportion of patients diagnosed with MDD are labeled TRD because they do not respond to standard antidepressants, when in fact they have been misdiagnosed and need a different treatment.

Even when the diagnosis of MDD is accurate, psychiatric neuroscience advances have informed us that MDD is a heterogeneous syndrome with multiple “biotypes” that share a similar phenotype.^1,2 In the past, TRD has been defined as a failure to respond to ≥2 adequate trials (8 to 12 weeks at a maximum tolerated dose) of antidepressants from different classes (such as tricyclic or heterocyclic antidepressants, selective serotonin reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors). For decades, patients with TRD have been referred to electroconvulsive therapy (ECT), and have experienced an excellent response rate. So TRD is in fact an artificial concept and term, applied to a subtype of MDD that does not respond to standard antidepressants, but often responds very well to neurostimulation (ECT and transcranial magnetic stimulation [TMS]).

When an antidepressant is approved by the FDA based on “successful” placebo-controlled double-blind trials, there is always a subset of patients who do not respond. However, the success of a controlled clinical trial is based on a decline in overall mean depression rating scale score in the antidepressant group compared with the placebo group. Not a single antidepressant has ever exerted full efficacy in 100% of patients who received it in an FDA trial because the sample is always a heterogeneous mix of patients with various depression biotypes who meet the DSM clinical diagnosis of MDD. Most often, only approximately 50% do, which is enough to be statistically significantly better than the roughly 30% response rate in the placebo group. It is impossible for a heterogeneous syndrome comprised of biologically different “diseases” to respond to any single medication! Patients who do not respond to an antidepressant medication that works in other patients represent a different subtype of depression that is not TRD. Biotypes of the depression syndrome have different neurochemical underpinnings and may respond to different mechanisms of therapeutic action, yet to be discovered.

Continue to: A very common...

A very common clinical mistake occurs when patients with bipolar depression are misdiagnosed as having MDD because most of them experience depression as their initial mood episode. These patients often end up being classified as having TRD because bipolar depression very frequently fails to respond to several of the antidepressants that are FDA-approved for MDD. When these patients are correctly diagnosed, many will respond to one of the medications specifically approved for bipolar depression that were launched over the past 15 years (quetiapine, lurasidone, and cariprazine). However, bipolar disorder is also a heterogeneous spectrum, and some patients with bipolar depression may fail to respond to any of these 3 medications and are promptly regarded as TRD. Such patients often respond to neuromodulation (TMS, ECT, or vagus nerve stimulation [VNS]), indicating that they may have a different type of bipolar depression, such as bipolar type II.

A more recent example of the falsehood of TRD as a spurious diagnosis is the dramatic and rapid response of patients who are chronically depressed (both those with MDD and those with bipolar depression) to ketamine infusions.^3,4 Responders to ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, prove that nonresponders to monoamine reuptake inhibitors must not be falsely labeled as having TRD. They have a different subtype within the depression syndrome that is mediated by glutamatergic pathways, instead of monoamines such as serotonin, norepinephrine, or dopamine. In addition, unlike monoaminergic antidepressants, NMDA antagonists rapidly reverse suicidal urges, above and beyond rapidly reversing chronic, so-called TRD.

In the same vein, numerous reports have shown that buprenorphine has significant efficacy in TRD (and suicide urges, as does ketamine), which implicates opioid pathways as mediating some subtypes of TRD.⁵ The monoamine model of depression, which dominated the field and dragged on for half a century, has distracted psychiatric researchers from exploring and recognizing the multiple neurochemical and neuroplastic pathways of the depression syndrome, thus falsely assuming that depression is a monolithic disorder that responds to elevating the activity of brain monoamines. This major blind spot led to the ersatz concept of TRD.

Treatment-resistant schizophrenia (TRS)

Since the discovery of chlorpromazine and other antipsychotics in the 1950s, it became apparent that a subset of patients with schizophrenia do not respond to medications that block dopamine D2 receptors. Partial responders were labeled as having TRS, and complete nonresponse was called refractory schizophrenia. Many patients with severe and persistent delusions and hallucinations were permanently hospitalized, and unable to live in the community like those who responded to dopamine antagonism.

In the late 1980s, the discovery that clozapine has significant efficacy in TRS and refractory schizophrenia provided the first insight that TRS and refractory schizophrenia represent different neuro­biologic subtypes of schizophrenia.^6,7 The extensive heterogeneity of schizophrenia (with hundreds of genetic and nongenetic etiologies) is now widely accepted.⁸ Patients with schizophrenia who do not respond to dopamine receptor antagonism should not be labeled TRS, because they can respond to a different antipsychotic agent, such as clozapine, which is believed to exert its efficacy via glutamate pathways.

Continue to: But what about the 50%...

But what about the 50% of patients with TRS or refractory schizophrenia who do not respond to clozapine?⁹ They do not have TRS, either, but represent different schizophrenia biotypes that may respond to other medications with different mechanisms of action, such as lamotrigine,¹⁰ which is a glutamate modulator; pimavanserin,¹¹ which is an inverse agonist of the serotonin 5HT-2A receptor; allopurinol,^12,13 an adenosine modulator; or estrogen,¹⁴ a neurosteroid. Future research will continue to unravel the many biotypes of the highly heterogeneous schizophrenia syndrome that are “nondopaminergic” and do not respond to the standard class of dopamine antagonists (previously called neuroleptics and now known as antipsychotics).¹⁵ Future treatments for schizophrenia may depart from modulating various neurotransmitter receptors to targeting entirely different neurobiologic processes, such as correcting mitochondria pathology, inhibiting microglia activation, repairing white matter, reversing apoptosis pathways, inducing neuroplasticity, arresting oxidative stress and inflammation, and other neuroprotective mechanisms.

The rapid growth of biomarkers in psychiatry¹⁶ will usher in an era of precision psychiatry¹⁷ that will eliminate the term “treatment resistance.” Our psychiatric practice will then benefit from “canceling” this demoralizing and clinically unjustified term that has needlessly fostered therapeutic nihilism among psychiatric physicians.

For millennia, serious psychiatric brain disorders (aka mental illnesses, melancholia, madness, insanity) were written off as incurable, permanent afflictions. It’s no wonder that they were engulfed with the stigma of hopelessness.

But then came the era of serendipitous discoveries in the mid-20th century, with the felicitous arrival of antipsychotics, antidepressants, and lithium. The dogma of untreatability was shattered, but in its wake, the notion of treatment resistance emerged, and promptly became the bane of psychiatric clinicians and the practice of psychopharmacology.

Many patients with mood and psychotic disorders responded to the medications that were introduced in the 1950s and 1960s, but some either derived partial benefit or did not improve at all. These partial or poor responders were labeled “treatment-resistant,” and caring for them became a major challenge for psychiatric physicians that continues to this day. However, rapid advances in understanding the many etiologies and subtypes of the heterogeneous mood and psychotic disorders are invalidating the notion of treatment resistance, showing it is a fallacy and a misnomer. Let’s examine why.

Treatment-resistant depression (TRD)

Psychiatric clinics and hospitals are clogged with patients who do not respond to ≥2 evidence-based antidepressants and carry the disparaging label of “TRD.” But a patient manifesting what appears to be major depressive disorder (MDD) may actually have one of several types of depression that are unlikely to respond to an antidepressant, including:

• iatrogenic depression due to a prescription medication
• depression secondary to recreational drug use
• depressive symptoms secondary to a general medical condition
• bipolar depression.

Thus, a significant proportion of patients diagnosed with MDD are labeled TRD because they do not respond to standard antidepressants, when in fact they have been misdiagnosed and need a different treatment.

Even when the diagnosis of MDD is accurate, psychiatric neuroscience advances have informed us that MDD is a heterogeneous syndrome with multiple “biotypes” that share a similar phenotype.^1,2 In the past, TRD has been defined as a failure to respond to ≥2 adequate trials (8 to 12 weeks at a maximum tolerated dose) of antidepressants from different classes (such as tricyclic or heterocyclic antidepressants, selective serotonin reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors). For decades, patients with TRD have been referred to electroconvulsive therapy (ECT), and have experienced an excellent response rate. So TRD is in fact an artificial concept and term, applied to a subtype of MDD that does not respond to standard antidepressants, but often responds very well to neurostimulation (ECT and transcranial magnetic stimulation [TMS]).

When an antidepressant is approved by the FDA based on “successful” placebo-controlled double-blind trials, there is always a subset of patients who do not respond. However, the success of a controlled clinical trial is based on a decline in overall mean depression rating scale score in the antidepressant group compared with the placebo group. Not a single antidepressant has ever exerted full efficacy in 100% of patients who received it in an FDA trial because the sample is always a heterogeneous mix of patients with various depression biotypes who meet the DSM clinical diagnosis of MDD. Most often, only approximately 50% do, which is enough to be statistically significantly better than the roughly 30% response rate in the placebo group. It is impossible for a heterogeneous syndrome comprised of biologically different “diseases” to respond to any single medication! Patients who do not respond to an antidepressant medication that works in other patients represent a different subtype of depression that is not TRD. Biotypes of the depression syndrome have different neurochemical underpinnings and may respond to different mechanisms of therapeutic action, yet to be discovered.

Continue to: A very common...

A very common clinical mistake occurs when patients with bipolar depression are misdiagnosed as having MDD because most of them experience depression as their initial mood episode. These patients often end up being classified as having TRD because bipolar depression very frequently fails to respond to several of the antidepressants that are FDA-approved for MDD. When these patients are correctly diagnosed, many will respond to one of the medications specifically approved for bipolar depression that were launched over the past 15 years (quetiapine, lurasidone, and cariprazine). However, bipolar disorder is also a heterogeneous spectrum, and some patients with bipolar depression may fail to respond to any of these 3 medications and are promptly regarded as TRD. Such patients often respond to neuromodulation (TMS, ECT, or vagus nerve stimulation [VNS]), indicating that they may have a different type of bipolar depression, such as bipolar type II.

A more recent example of the falsehood of TRD as a spurious diagnosis is the dramatic and rapid response of patients who are chronically depressed (both those with MDD and those with bipolar depression) to ketamine infusions.^3,4 Responders to ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, prove that nonresponders to monoamine reuptake inhibitors must not be falsely labeled as having TRD. They have a different subtype within the depression syndrome that is mediated by glutamatergic pathways, instead of monoamines such as serotonin, norepinephrine, or dopamine. In addition, unlike monoaminergic antidepressants, NMDA antagonists rapidly reverse suicidal urges, above and beyond rapidly reversing chronic, so-called TRD.

In the same vein, numerous reports have shown that buprenorphine has significant efficacy in TRD (and suicide urges, as does ketamine), which implicates opioid pathways as mediating some subtypes of TRD.⁵ The monoamine model of depression, which dominated the field and dragged on for half a century, has distracted psychiatric researchers from exploring and recognizing the multiple neurochemical and neuroplastic pathways of the depression syndrome, thus falsely assuming that depression is a monolithic disorder that responds to elevating the activity of brain monoamines. This major blind spot led to the ersatz concept of TRD.

Treatment-resistant schizophrenia (TRS)

Since the discovery of chlorpromazine and other antipsychotics in the 1950s, it became apparent that a subset of patients with schizophrenia do not respond to medications that block dopamine D2 receptors. Partial responders were labeled as having TRS, and complete nonresponse was called refractory schizophrenia. Many patients with severe and persistent delusions and hallucinations were permanently hospitalized, and unable to live in the community like those who responded to dopamine antagonism.

In the late 1980s, the discovery that clozapine has significant efficacy in TRS and refractory schizophrenia provided the first insight that TRS and refractory schizophrenia represent different neuro­biologic subtypes of schizophrenia.^6,7 The extensive heterogeneity of schizophrenia (with hundreds of genetic and nongenetic etiologies) is now widely accepted.⁸ Patients with schizophrenia who do not respond to dopamine receptor antagonism should not be labeled TRS, because they can respond to a different antipsychotic agent, such as clozapine, which is believed to exert its efficacy via glutamate pathways.

Continue to: But what about the 50%...

But what about the 50% of patients with TRS or refractory schizophrenia who do not respond to clozapine?⁹ They do not have TRS, either, but represent different schizophrenia biotypes that may respond to other medications with different mechanisms of action, such as lamotrigine,¹⁰ which is a glutamate modulator; pimavanserin,¹¹ which is an inverse agonist of the serotonin 5HT-2A receptor; allopurinol,^12,13 an adenosine modulator; or estrogen,¹⁴ a neurosteroid. Future research will continue to unravel the many biotypes of the highly heterogeneous schizophrenia syndrome that are “nondopaminergic” and do not respond to the standard class of dopamine antagonists (previously called neuroleptics and now known as antipsychotics).¹⁵ Future treatments for schizophrenia may depart from modulating various neurotransmitter receptors to targeting entirely different neurobiologic processes, such as correcting mitochondria pathology, inhibiting microglia activation, repairing white matter, reversing apoptosis pathways, inducing neuroplasticity, arresting oxidative stress and inflammation, and other neuroprotective mechanisms.

The rapid growth of biomarkers in psychiatry¹⁶ will usher in an era of precision psychiatry¹⁷ that will eliminate the term “treatment resistance.” Our psychiatric practice will then benefit from “canceling” this demoralizing and clinically unjustified term that has needlessly fostered therapeutic nihilism among psychiatric physicians.

For millennia, serious psychiatric brain disorders (aka mental illnesses, melancholia, madness, insanity) were written off as incurable, permanent afflictions. It’s no wonder that they were engulfed with the stigma of hopelessness.

But then came the era of serendipitous discoveries in the mid-20th century, with the felicitous arrival of antipsychotics, antidepressants, and lithium. The dogma of untreatability was shattered, but in its wake, the notion of treatment resistance emerged, and promptly became the bane of psychiatric clinicians and the practice of psychopharmacology.

Many patients with mood and psychotic disorders responded to the medications that were introduced in the 1950s and 1960s, but some either derived partial benefit or did not improve at all. These partial or poor responders were labeled “treatment-resistant,” and caring for them became a major challenge for psychiatric physicians that continues to this day. However, rapid advances in understanding the many etiologies and subtypes of the heterogeneous mood and psychotic disorders are invalidating the notion of treatment resistance, showing it is a fallacy and a misnomer. Let’s examine why.

Treatment-resistant depression (TRD)

Psychiatric clinics and hospitals are clogged with patients who do not respond to ≥2 evidence-based antidepressants and carry the disparaging label of “TRD.” But a patient manifesting what appears to be major depressive disorder (MDD) may actually have one of several types of depression that are unlikely to respond to an antidepressant, including:

• iatrogenic depression due to a prescription medication
• depression secondary to recreational drug use
• depressive symptoms secondary to a general medical condition
• bipolar depression.

Thus, a significant proportion of patients diagnosed with MDD are labeled TRD because they do not respond to standard antidepressants, when in fact they have been misdiagnosed and need a different treatment.

Even when the diagnosis of MDD is accurate, psychiatric neuroscience advances have informed us that MDD is a heterogeneous syndrome with multiple “biotypes” that share a similar phenotype.^1,2 In the past, TRD has been defined as a failure to respond to ≥2 adequate trials (8 to 12 weeks at a maximum tolerated dose) of antidepressants from different classes (such as tricyclic or heterocyclic antidepressants, selective serotonin reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors). For decades, patients with TRD have been referred to electroconvulsive therapy (ECT), and have experienced an excellent response rate. So TRD is in fact an artificial concept and term, applied to a subtype of MDD that does not respond to standard antidepressants, but often responds very well to neurostimulation (ECT and transcranial magnetic stimulation [TMS]).

When an antidepressant is approved by the FDA based on “successful” placebo-controlled double-blind trials, there is always a subset of patients who do not respond. However, the success of a controlled clinical trial is based on a decline in overall mean depression rating scale score in the antidepressant group compared with the placebo group. Not a single antidepressant has ever exerted full efficacy in 100% of patients who received it in an FDA trial because the sample is always a heterogeneous mix of patients with various depression biotypes who meet the DSM clinical diagnosis of MDD. Most often, only approximately 50% do, which is enough to be statistically significantly better than the roughly 30% response rate in the placebo group. It is impossible for a heterogeneous syndrome comprised of biologically different “diseases” to respond to any single medication! Patients who do not respond to an antidepressant medication that works in other patients represent a different subtype of depression that is not TRD. Biotypes of the depression syndrome have different neurochemical underpinnings and may respond to different mechanisms of therapeutic action, yet to be discovered.

Continue to: A very common...

A very common clinical mistake occurs when patients with bipolar depression are misdiagnosed as having MDD because most of them experience depression as their initial mood episode. These patients often end up being classified as having TRD because bipolar depression very frequently fails to respond to several of the antidepressants that are FDA-approved for MDD. When these patients are correctly diagnosed, many will respond to one of the medications specifically approved for bipolar depression that were launched over the past 15 years (quetiapine, lurasidone, and cariprazine). However, bipolar disorder is also a heterogeneous spectrum, and some patients with bipolar depression may fail to respond to any of these 3 medications and are promptly regarded as TRD. Such patients often respond to neuromodulation (TMS, ECT, or vagus nerve stimulation [VNS]), indicating that they may have a different type of bipolar depression, such as bipolar type II.

A more recent example of the falsehood of TRD as a spurious diagnosis is the dramatic and rapid response of patients who are chronically depressed (both those with MDD and those with bipolar depression) to ketamine infusions.^3,4 Responders to ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, prove that nonresponders to monoamine reuptake inhibitors must not be falsely labeled as having TRD. They have a different subtype within the depression syndrome that is mediated by glutamatergic pathways, instead of monoamines such as serotonin, norepinephrine, or dopamine. In addition, unlike monoaminergic antidepressants, NMDA antagonists rapidly reverse suicidal urges, above and beyond rapidly reversing chronic, so-called TRD.

In the same vein, numerous reports have shown that buprenorphine has significant efficacy in TRD (and suicide urges, as does ketamine), which implicates opioid pathways as mediating some subtypes of TRD.⁵ The monoamine model of depression, which dominated the field and dragged on for half a century, has distracted psychiatric researchers from exploring and recognizing the multiple neurochemical and neuroplastic pathways of the depression syndrome, thus falsely assuming that depression is a monolithic disorder that responds to elevating the activity of brain monoamines. This major blind spot led to the ersatz concept of TRD.

Treatment-resistant schizophrenia (TRS)

Since the discovery of chlorpromazine and other antipsychotics in the 1950s, it became apparent that a subset of patients with schizophrenia do not respond to medications that block dopamine D2 receptors. Partial responders were labeled as having TRS, and complete nonresponse was called refractory schizophrenia. Many patients with severe and persistent delusions and hallucinations were permanently hospitalized, and unable to live in the community like those who responded to dopamine antagonism.

In the late 1980s, the discovery that clozapine has significant efficacy in TRS and refractory schizophrenia provided the first insight that TRS and refractory schizophrenia represent different neuro­biologic subtypes of schizophrenia.^6,7 The extensive heterogeneity of schizophrenia (with hundreds of genetic and nongenetic etiologies) is now widely accepted.⁸ Patients with schizophrenia who do not respond to dopamine receptor antagonism should not be labeled TRS, because they can respond to a different antipsychotic agent, such as clozapine, which is believed to exert its efficacy via glutamate pathways.

Continue to: But what about the 50%...

But what about the 50% of patients with TRS or refractory schizophrenia who do not respond to clozapine?⁹ They do not have TRS, either, but represent different schizophrenia biotypes that may respond to other medications with different mechanisms of action, such as lamotrigine,¹⁰ which is a glutamate modulator; pimavanserin,¹¹ which is an inverse agonist of the serotonin 5HT-2A receptor; allopurinol,^12,13 an adenosine modulator; or estrogen,¹⁴ a neurosteroid. Future research will continue to unravel the many biotypes of the highly heterogeneous schizophrenia syndrome that are “nondopaminergic” and do not respond to the standard class of dopamine antagonists (previously called neuroleptics and now known as antipsychotics).¹⁵ Future treatments for schizophrenia may depart from modulating various neurotransmitter receptors to targeting entirely different neurobiologic processes, such as correcting mitochondria pathology, inhibiting microglia activation, repairing white matter, reversing apoptosis pathways, inducing neuroplasticity, arresting oxidative stress and inflammation, and other neuroprotective mechanisms.

The rapid growth of biomarkers in psychiatry¹⁶ will usher in an era of precision psychiatry¹⁷ that will eliminate the term “treatment resistance.” Our psychiatric practice will then benefit from “canceling” this demoralizing and clinically unjustified term that has needlessly fostered therapeutic nihilism among psychiatric physicians.

Mr. E, age 39, presents to the mental health (MH) intake clinic, reporting he has had depressed mood almost every day, lack of interests, poor appetite, difficulty sleeping, inability to concentrate on daily activities, low energy and motivation, and feelings of guilt. He is diagnosed with major depressive disorder and agrees to a trial of sertraline, which is titrated up to 100 mg/d. He is also referred to the MH pharmacy clinic for interim visits.

Four weeks later during a follow-up visit, Mr. E reports tolerating sertraline, 100 mg/d, with a slight improvement in his mood. He reports that he has started working on his previous hobbies again and tries to consistently eat 2 meals a day. He feels that his sleep remains unchanged. He would like to enroll in school again, but is concerned about his poor concentration. He asks whether a further increase in his sertraline dose would improve his symptoms. What would you advise?

Escalating antidepressant doses up to, or even above, the FDA-approved maximum dose is a strategy for clinicians to consider for patients who are nonresponders or partial responders to treatment. This practice assumes that the effectiveness of an antidepressant is dependent on the dosage. However, based on our review of available literature, this recommendation is equivocally supported for general practice.

Selective serotonin reuptake inhibitors

The Table^1-3 summarizes the results of 3 studies of high-dose selective serotonin reuptake inhibitors (SSRIs).

Adli et al¹ evaluated 3 types of studies—studies of patients with treatment-resistant depression receiving high-dose treatment, comparative dose studies, and studies of therapeutic drug-monitoring (TDM) of antidepressants—to assess the effectiveness of high-dose antidepressants after a treatment failure with a medium dose. They concluded that SSRIs exhibit a flat dose-dependency pattern, where increasing a dose above the minimum effective dose (MED) does not increase efficacy but results in more adverse effects. Because treatment at the MED inhibits 70% of serotonin reuptake and is only marginally less effective than medium therapeutic doses, the authors recommended reserving treatment at higher doses for patients who have failed other standard treatment options, such as augmentation.

Ruhe et al² evaluated 8 randomized controlled trials and 3 systematic analyses that investigated dose escalation of SSRIs, including paroxetine, fluoxetine, and sertraline. The authors noted that all included studies had methodological limitations and discussed 1 study that showed potential benefit from dose escalation when dropouts due to adverse effects were excluded from analysis. They determined that the evidence for increased efficacy with dose escalation was inconclusive; however, dose escalation un-­doubtedly resulted in more adverse effects.

Hieronymus et al³ found a dose-dependency pattern with selected SSRIs—citalopram, paroxetine, and sertraline—in a mega-analysis of studies of adult patients with depression. All company-funded, acute-phase, placebo-controlled fixed-dose trials of these agents were included in this analysis. It included a total of 2,859 patients: 600 patients received citalopram (10 to 60 mg/d); 1,043 patients received paroxetine (10 to 40 mg/d); 481 patients received sertraline (50 to 400 mg/d); and 735 patients received placebo. They further divided the SSRIs into “low” vs “optimal” doses based on the dose curves of these agents. For citalopram, 10 to 20 mg/d was considered low vs 40 to 60 mg/d, which was considered optimal. For paroxetine, 10 mg/d was considered low vs other doses as optimal (20, 30, and 40 mg/d). For sertraline, 50 mg was considered low vs other doses as optimal (100, 200, and 400 mg/d). The authors concluded that at low doses, these antidepressants were superior to placebo but inferior to higher doses. Interestingly, they suggested that the dose-response relationship plateaued at 20 mg/d for paroxetine, 40 mg/d for citalopram, and 100 mg/d for sertraline. One of the limitations of the study was a lack of information on the tolerability of higher vs lower doses.

Continue to: Other antidepressants

Other antidepressants

Adli et al¹ found a high-dose study and several comparative studies that supported a dose-response relationship with a reasonable degree of tolerability for venlafaxine, but there were no pertinent studies that evaluated mirtazapine. The only fixed-dose study found for bupropion did not support a dose-response relationship.¹

The authors also concluded that there may be evidence supporting high-dose prescribing of tricyclic and tetracyclic antidepressants (TCAs and TeCAs, respectively). Despite the lack of clinical data that directly addressed the dose-dependency of TCAs and TeCAs, the authors supported dose escalation with amitriptyline, clomipramine, imipramine, desipramine, nortriptyline, and maprotiline, based on the data from comparative dose and TDM studies.¹ The authors urged caution in interpreting and applying the results of TDM studies because the pharmacodynamic of each medication—such as being linear, curvilinear, or uncorrelated— may vary, which suggests there is a targeted therapeutic dose range.¹

Important considerations

Differences in the pharmacokinetic and pharmacogenetic properties of individual medications may account for the mixed outcomes found when evaluating antidepressant dose-response relationships. Genetic polymorphisms of cytochrome (CYP) P450 enzymes, mainly CYP2D6 and CYP2D19, have been shown to directly affect antidepressants’ serum levels. Depending on the patient’s phenotype expression, such as poor, intermediate, extensive (ie, normal), or ultra-metabolizers, use of a specific antidepressant at a similar dose may result in therapeutic effectiveness, ineffectiveness, or toxicity. For antidepressants such as TCAs, which have a narrow therapeutic index compared with SSRIs, the differences in pharmacokinetic and pharmacogenetic properties becomes more impactful.^1,4

Escalation within approved dose ranges

Few quality studies have conclusively found a relationship between antidepressant dose escalation within the FDA-approved dose ranges and efficacy, and there are few to no recommendations for prescribing doses above FDA-approved ranges. However, in clinical practice, clinicians may consider a dose escalation within the allowable dose ranges based on anecdotal evidence from previous patient cases. Consideration of relevant pharmacokinetic parameters and the patient’s individual pharmacogenetic factors may further guide clinicians and patients in making an informed decision on dose escalation to and beyond the FDA-approved doses.

CASE CONTINUED

After reviewing the evidence of antidepressant dose escalation and Mr. E’s progress, the MH pharmacist recommends that the psychiatrist increase Mr. E’s sertraline to 150 mg/d with close monitoring.

Related Resources

• Berney P. Dose-response relationship of recent antidepressants in the short-term treatment of depression. Dialogues Clin Neurosci. 2005;7:249.
• Jakubovski E, Varigonda AL, Freemantle N, et al. Systematic review and meta-analysis: dose-response relationship of selective serotonin reuptake inhibitors in major depressive disorder. Am J Psychiatry. 2016;173:174-183.

Drug Brand Names

Amitriptyline • Elavil
Bupropion • Wellbutrin
Citalopram • Celexa
Clomipramine • Anafranil
Desipramine • Norpramin
Fluoxetine • Prozac
Imipramine • Tofranil
Maprotiline • Ludiomil
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor

Mr. E, age 39, presents to the mental health (MH) intake clinic, reporting he has had depressed mood almost every day, lack of interests, poor appetite, difficulty sleeping, inability to concentrate on daily activities, low energy and motivation, and feelings of guilt. He is diagnosed with major depressive disorder and agrees to a trial of sertraline, which is titrated up to 100 mg/d. He is also referred to the MH pharmacy clinic for interim visits.

Four weeks later during a follow-up visit, Mr. E reports tolerating sertraline, 100 mg/d, with a slight improvement in his mood. He reports that he has started working on his previous hobbies again and tries to consistently eat 2 meals a day. He feels that his sleep remains unchanged. He would like to enroll in school again, but is concerned about his poor concentration. He asks whether a further increase in his sertraline dose would improve his symptoms. What would you advise?

Escalating antidepressant doses up to, or even above, the FDA-approved maximum dose is a strategy for clinicians to consider for patients who are nonresponders or partial responders to treatment. This practice assumes that the effectiveness of an antidepressant is dependent on the dosage. However, based on our review of available literature, this recommendation is equivocally supported for general practice.

Selective serotonin reuptake inhibitors

The Table^1-3 summarizes the results of 3 studies of high-dose selective serotonin reuptake inhibitors (SSRIs).

Adli et al¹ evaluated 3 types of studies—studies of patients with treatment-resistant depression receiving high-dose treatment, comparative dose studies, and studies of therapeutic drug-monitoring (TDM) of antidepressants—to assess the effectiveness of high-dose antidepressants after a treatment failure with a medium dose. They concluded that SSRIs exhibit a flat dose-dependency pattern, where increasing a dose above the minimum effective dose (MED) does not increase efficacy but results in more adverse effects. Because treatment at the MED inhibits 70% of serotonin reuptake and is only marginally less effective than medium therapeutic doses, the authors recommended reserving treatment at higher doses for patients who have failed other standard treatment options, such as augmentation.

Ruhe et al² evaluated 8 randomized controlled trials and 3 systematic analyses that investigated dose escalation of SSRIs, including paroxetine, fluoxetine, and sertraline. The authors noted that all included studies had methodological limitations and discussed 1 study that showed potential benefit from dose escalation when dropouts due to adverse effects were excluded from analysis. They determined that the evidence for increased efficacy with dose escalation was inconclusive; however, dose escalation un-­doubtedly resulted in more adverse effects.

Hieronymus et al³ found a dose-dependency pattern with selected SSRIs—citalopram, paroxetine, and sertraline—in a mega-analysis of studies of adult patients with depression. All company-funded, acute-phase, placebo-controlled fixed-dose trials of these agents were included in this analysis. It included a total of 2,859 patients: 600 patients received citalopram (10 to 60 mg/d); 1,043 patients received paroxetine (10 to 40 mg/d); 481 patients received sertraline (50 to 400 mg/d); and 735 patients received placebo. They further divided the SSRIs into “low” vs “optimal” doses based on the dose curves of these agents. For citalopram, 10 to 20 mg/d was considered low vs 40 to 60 mg/d, which was considered optimal. For paroxetine, 10 mg/d was considered low vs other doses as optimal (20, 30, and 40 mg/d). For sertraline, 50 mg was considered low vs other doses as optimal (100, 200, and 400 mg/d). The authors concluded that at low doses, these antidepressants were superior to placebo but inferior to higher doses. Interestingly, they suggested that the dose-response relationship plateaued at 20 mg/d for paroxetine, 40 mg/d for citalopram, and 100 mg/d for sertraline. One of the limitations of the study was a lack of information on the tolerability of higher vs lower doses.

Continue to: Other antidepressants

Other antidepressants

Adli et al¹ found a high-dose study and several comparative studies that supported a dose-response relationship with a reasonable degree of tolerability for venlafaxine, but there were no pertinent studies that evaluated mirtazapine. The only fixed-dose study found for bupropion did not support a dose-response relationship.¹

The authors also concluded that there may be evidence supporting high-dose prescribing of tricyclic and tetracyclic antidepressants (TCAs and TeCAs, respectively). Despite the lack of clinical data that directly addressed the dose-dependency of TCAs and TeCAs, the authors supported dose escalation with amitriptyline, clomipramine, imipramine, desipramine, nortriptyline, and maprotiline, based on the data from comparative dose and TDM studies.¹ The authors urged caution in interpreting and applying the results of TDM studies because the pharmacodynamic of each medication—such as being linear, curvilinear, or uncorrelated— may vary, which suggests there is a targeted therapeutic dose range.¹

Important considerations

Differences in the pharmacokinetic and pharmacogenetic properties of individual medications may account for the mixed outcomes found when evaluating antidepressant dose-response relationships. Genetic polymorphisms of cytochrome (CYP) P450 enzymes, mainly CYP2D6 and CYP2D19, have been shown to directly affect antidepressants’ serum levels. Depending on the patient’s phenotype expression, such as poor, intermediate, extensive (ie, normal), or ultra-metabolizers, use of a specific antidepressant at a similar dose may result in therapeutic effectiveness, ineffectiveness, or toxicity. For antidepressants such as TCAs, which have a narrow therapeutic index compared with SSRIs, the differences in pharmacokinetic and pharmacogenetic properties becomes more impactful.^1,4

Escalation within approved dose ranges

Few quality studies have conclusively found a relationship between antidepressant dose escalation within the FDA-approved dose ranges and efficacy, and there are few to no recommendations for prescribing doses above FDA-approved ranges. However, in clinical practice, clinicians may consider a dose escalation within the allowable dose ranges based on anecdotal evidence from previous patient cases. Consideration of relevant pharmacokinetic parameters and the patient’s individual pharmacogenetic factors may further guide clinicians and patients in making an informed decision on dose escalation to and beyond the FDA-approved doses.

CASE CONTINUED

After reviewing the evidence of antidepressant dose escalation and Mr. E’s progress, the MH pharmacist recommends that the psychiatrist increase Mr. E’s sertraline to 150 mg/d with close monitoring.

Related Resources

• Berney P. Dose-response relationship of recent antidepressants in the short-term treatment of depression. Dialogues Clin Neurosci. 2005;7:249.
• Jakubovski E, Varigonda AL, Freemantle N, et al. Systematic review and meta-analysis: dose-response relationship of selective serotonin reuptake inhibitors in major depressive disorder. Am J Psychiatry. 2016;173:174-183.

Drug Brand Names

Amitriptyline • Elavil
Bupropion • Wellbutrin
Citalopram • Celexa
Clomipramine • Anafranil
Desipramine • Norpramin
Fluoxetine • Prozac
Imipramine • Tofranil
Maprotiline • Ludiomil
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor

Mr. E, age 39, presents to the mental health (MH) intake clinic, reporting he has had depressed mood almost every day, lack of interests, poor appetite, difficulty sleeping, inability to concentrate on daily activities, low energy and motivation, and feelings of guilt. He is diagnosed with major depressive disorder and agrees to a trial of sertraline, which is titrated up to 100 mg/d. He is also referred to the MH pharmacy clinic for interim visits.

Four weeks later during a follow-up visit, Mr. E reports tolerating sertraline, 100 mg/d, with a slight improvement in his mood. He reports that he has started working on his previous hobbies again and tries to consistently eat 2 meals a day. He feels that his sleep remains unchanged. He would like to enroll in school again, but is concerned about his poor concentration. He asks whether a further increase in his sertraline dose would improve his symptoms. What would you advise?

Escalating antidepressant doses up to, or even above, the FDA-approved maximum dose is a strategy for clinicians to consider for patients who are nonresponders or partial responders to treatment. This practice assumes that the effectiveness of an antidepressant is dependent on the dosage. However, based on our review of available literature, this recommendation is equivocally supported for general practice.

Selective serotonin reuptake inhibitors

The Table^1-3 summarizes the results of 3 studies of high-dose selective serotonin reuptake inhibitors (SSRIs).

Adli et al¹ evaluated 3 types of studies—studies of patients with treatment-resistant depression receiving high-dose treatment, comparative dose studies, and studies of therapeutic drug-monitoring (TDM) of antidepressants—to assess the effectiveness of high-dose antidepressants after a treatment failure with a medium dose. They concluded that SSRIs exhibit a flat dose-dependency pattern, where increasing a dose above the minimum effective dose (MED) does not increase efficacy but results in more adverse effects. Because treatment at the MED inhibits 70% of serotonin reuptake and is only marginally less effective than medium therapeutic doses, the authors recommended reserving treatment at higher doses for patients who have failed other standard treatment options, such as augmentation.

Ruhe et al² evaluated 8 randomized controlled trials and 3 systematic analyses that investigated dose escalation of SSRIs, including paroxetine, fluoxetine, and sertraline. The authors noted that all included studies had methodological limitations and discussed 1 study that showed potential benefit from dose escalation when dropouts due to adverse effects were excluded from analysis. They determined that the evidence for increased efficacy with dose escalation was inconclusive; however, dose escalation un-­doubtedly resulted in more adverse effects.

Hieronymus et al³ found a dose-dependency pattern with selected SSRIs—citalopram, paroxetine, and sertraline—in a mega-analysis of studies of adult patients with depression. All company-funded, acute-phase, placebo-controlled fixed-dose trials of these agents were included in this analysis. It included a total of 2,859 patients: 600 patients received citalopram (10 to 60 mg/d); 1,043 patients received paroxetine (10 to 40 mg/d); 481 patients received sertraline (50 to 400 mg/d); and 735 patients received placebo. They further divided the SSRIs into “low” vs “optimal” doses based on the dose curves of these agents. For citalopram, 10 to 20 mg/d was considered low vs 40 to 60 mg/d, which was considered optimal. For paroxetine, 10 mg/d was considered low vs other doses as optimal (20, 30, and 40 mg/d). For sertraline, 50 mg was considered low vs other doses as optimal (100, 200, and 400 mg/d). The authors concluded that at low doses, these antidepressants were superior to placebo but inferior to higher doses. Interestingly, they suggested that the dose-response relationship plateaued at 20 mg/d for paroxetine, 40 mg/d for citalopram, and 100 mg/d for sertraline. One of the limitations of the study was a lack of information on the tolerability of higher vs lower doses.

Continue to: Other antidepressants

Other antidepressants

Adli et al¹ found a high-dose study and several comparative studies that supported a dose-response relationship with a reasonable degree of tolerability for venlafaxine, but there were no pertinent studies that evaluated mirtazapine. The only fixed-dose study found for bupropion did not support a dose-response relationship.¹

The authors also concluded that there may be evidence supporting high-dose prescribing of tricyclic and tetracyclic antidepressants (TCAs and TeCAs, respectively). Despite the lack of clinical data that directly addressed the dose-dependency of TCAs and TeCAs, the authors supported dose escalation with amitriptyline, clomipramine, imipramine, desipramine, nortriptyline, and maprotiline, based on the data from comparative dose and TDM studies.¹ The authors urged caution in interpreting and applying the results of TDM studies because the pharmacodynamic of each medication—such as being linear, curvilinear, or uncorrelated— may vary, which suggests there is a targeted therapeutic dose range.¹

Important considerations

Differences in the pharmacokinetic and pharmacogenetic properties of individual medications may account for the mixed outcomes found when evaluating antidepressant dose-response relationships. Genetic polymorphisms of cytochrome (CYP) P450 enzymes, mainly CYP2D6 and CYP2D19, have been shown to directly affect antidepressants’ serum levels. Depending on the patient’s phenotype expression, such as poor, intermediate, extensive (ie, normal), or ultra-metabolizers, use of a specific antidepressant at a similar dose may result in therapeutic effectiveness, ineffectiveness, or toxicity. For antidepressants such as TCAs, which have a narrow therapeutic index compared with SSRIs, the differences in pharmacokinetic and pharmacogenetic properties becomes more impactful.^1,4

Escalation within approved dose ranges

Few quality studies have conclusively found a relationship between antidepressant dose escalation within the FDA-approved dose ranges and efficacy, and there are few to no recommendations for prescribing doses above FDA-approved ranges. However, in clinical practice, clinicians may consider a dose escalation within the allowable dose ranges based on anecdotal evidence from previous patient cases. Consideration of relevant pharmacokinetic parameters and the patient’s individual pharmacogenetic factors may further guide clinicians and patients in making an informed decision on dose escalation to and beyond the FDA-approved doses.

CASE CONTINUED

After reviewing the evidence of antidepressant dose escalation and Mr. E’s progress, the MH pharmacist recommends that the psychiatrist increase Mr. E’s sertraline to 150 mg/d with close monitoring.

Related Resources

• Berney P. Dose-response relationship of recent antidepressants in the short-term treatment of depression. Dialogues Clin Neurosci. 2005;7:249.
• Jakubovski E, Varigonda AL, Freemantle N, et al. Systematic review and meta-analysis: dose-response relationship of selective serotonin reuptake inhibitors in major depressive disorder. Am J Psychiatry. 2016;173:174-183.

Drug Brand Names

Amitriptyline • Elavil
Bupropion • Wellbutrin
Citalopram • Celexa
Clomipramine • Anafranil
Desipramine • Norpramin
Fluoxetine • Prozac
Imipramine • Tofranil
Maprotiline • Ludiomil
Mirtazapine • Remeron
Nortriptyline • Pamelor
Paroxetine • Paxil
Sertraline • Zoloft
Venlafaxine • Effexor

While the implementation of mass vaccinations is a public health task, individual clinicians are critical for the success of any vaccination campaign. Psychiatrists may be well positioned to help increase vaccine uptake among psychiatric patients. They see their patients more frequently than primary care physicians do, which allows for patient engagement over time regarding vaccinations. Also, as physicians, psychiatrists are a trusted source of medical information, and they are well-versed in using the tools of nudging and motivational interviewing to manage ambivalence about receiving a vaccine (vaccine hesitancy).¹

The “ABCs of successful vaccinations” (Figure) provide a framework that psychiatrists can use when speaking with their patients about vaccinations. The ABCs assess psychological factors that hinder acceptance of vaccination (A = Attitudes toward vaccination), practical challenges in vaccine access for patients who are willing to get vaccinated (B = Barriers to vaccination), and the actual outcome of “shot in the arm” (C = Completed vaccination series). The Figure provides examples of each area of focus.

How to talk to patients about vaccines

“Attitudes toward vaccination” is an area in which psychiatrists can potentially move patients from hesitancy to vaccine confidence and acceptance. First, express confidence in the vaccine (ie, make a clear statement: “You are an excellent candidate for this vaccine.”). Then, begin a discussion using presumptive language: “You must be ready to receive the vaccine.” In individuals who hesitate, elicit their concern: “What would make vaccination more acceptable?” In those who agree in principle about the benefits of vaccinations, ask about any impediments: “What would get in the way of getting vaccinated?” While some patients may require more information about the vaccine, others may need more time or mostly concrete help, such as assistance with scheduling a vaccine appointment. Do not to forget to follow up to see if a planned and complete vaccination series has taken place. The CDC offers an excellent online toolkit to help clinicians discuss vaccinations with their patients.²

Psychiatric patients, particularly those from disadvantaged and marginalized populations, have much to gain if psychiatrists are involved in preventive health care, including the coronavirus vaccination drive or the annual flu vaccination campaign.

While the implementation of mass vaccinations is a public health task, individual clinicians are critical for the success of any vaccination campaign. Psychiatrists may be well positioned to help increase vaccine uptake among psychiatric patients. They see their patients more frequently than primary care physicians do, which allows for patient engagement over time regarding vaccinations. Also, as physicians, psychiatrists are a trusted source of medical information, and they are well-versed in using the tools of nudging and motivational interviewing to manage ambivalence about receiving a vaccine (vaccine hesitancy).¹

The “ABCs of successful vaccinations” (Figure) provide a framework that psychiatrists can use when speaking with their patients about vaccinations. The ABCs assess psychological factors that hinder acceptance of vaccination (A = Attitudes toward vaccination), practical challenges in vaccine access for patients who are willing to get vaccinated (B = Barriers to vaccination), and the actual outcome of “shot in the arm” (C = Completed vaccination series). The Figure provides examples of each area of focus.

How to talk to patients about vaccines

“Attitudes toward vaccination” is an area in which psychiatrists can potentially move patients from hesitancy to vaccine confidence and acceptance. First, express confidence in the vaccine (ie, make a clear statement: “You are an excellent candidate for this vaccine.”). Then, begin a discussion using presumptive language: “You must be ready to receive the vaccine.” In individuals who hesitate, elicit their concern: “What would make vaccination more acceptable?” In those who agree in principle about the benefits of vaccinations, ask about any impediments: “What would get in the way of getting vaccinated?” While some patients may require more information about the vaccine, others may need more time or mostly concrete help, such as assistance with scheduling a vaccine appointment. Do not to forget to follow up to see if a planned and complete vaccination series has taken place. The CDC offers an excellent online toolkit to help clinicians discuss vaccinations with their patients.²

Psychiatric patients, particularly those from disadvantaged and marginalized populations, have much to gain if psychiatrists are involved in preventive health care, including the coronavirus vaccination drive or the annual flu vaccination campaign.

While the implementation of mass vaccinations is a public health task, individual clinicians are critical for the success of any vaccination campaign. Psychiatrists may be well positioned to help increase vaccine uptake among psychiatric patients. They see their patients more frequently than primary care physicians do, which allows for patient engagement over time regarding vaccinations. Also, as physicians, psychiatrists are a trusted source of medical information, and they are well-versed in using the tools of nudging and motivational interviewing to manage ambivalence about receiving a vaccine (vaccine hesitancy).¹

The “ABCs of successful vaccinations” (Figure) provide a framework that psychiatrists can use when speaking with their patients about vaccinations. The ABCs assess psychological factors that hinder acceptance of vaccination (A = Attitudes toward vaccination), practical challenges in vaccine access for patients who are willing to get vaccinated (B = Barriers to vaccination), and the actual outcome of “shot in the arm” (C = Completed vaccination series). The Figure provides examples of each area of focus.

How to talk to patients about vaccines

“Attitudes toward vaccination” is an area in which psychiatrists can potentially move patients from hesitancy to vaccine confidence and acceptance. First, express confidence in the vaccine (ie, make a clear statement: “You are an excellent candidate for this vaccine.”). Then, begin a discussion using presumptive language: “You must be ready to receive the vaccine.” In individuals who hesitate, elicit their concern: “What would make vaccination more acceptable?” In those who agree in principle about the benefits of vaccinations, ask about any impediments: “What would get in the way of getting vaccinated?” While some patients may require more information about the vaccine, others may need more time or mostly concrete help, such as assistance with scheduling a vaccine appointment. Do not to forget to follow up to see if a planned and complete vaccination series has taken place. The CDC offers an excellent online toolkit to help clinicians discuss vaccinations with their patients.²

Psychiatric patients, particularly those from disadvantaged and marginalized populations, have much to gain if psychiatrists are involved in preventive health care, including the coronavirus vaccination drive or the annual flu vaccination campaign.

I am hopeful that we are beginning to see a sustained decline in COVID-19 cases and hospitalizations. Although, total COVID-19 cases and deaths continue to rise (more than 460,000 deaths in the United States), vaccinations and treatment options have reduced the prevalence of severe disease, hospitalizations, and mortality rates. Worries about variants continue, but we now will enter a prolonged phase before we finally subdue COVID-19 and fully open our economies.

Health systems and practices are looking ahead and beginning to focus on how practice will look after COVID-19. From a business standpoint, we are seeing an accelerating consolidation of community practices. We anticipate the first resale of a private equity (PE)–acquired GI practice: Gastro Health was the first practice to join with a PE firm in 2016. Published rumors suggest a sale of the (now larger, multistate) practice at 15-times-plus EBITDA (earnings before interest, taxes, depreciation, and amortization) could begin as early as this quarter. It would not be a surprise to see 40% of independent gastroenterologists employed in a PE-backed model within a few years. Health systems and payers (especially United Health Group) continue to scoop up practices as well.

Clinical care has been changed forever. I expect fully 30% of visits will remain virtual, and innovative health systems will capitalize on that fact to right-size their brick-and-mortar facilities. Start-up companies will virtualize care and develop new models that allow board-certified gastroenterologist to focus on care they only can provide, resulting in substantial cost savings and (hopefully) similar or better outcomes. Remote patient monitoring (both reactive and predictive) is now firmly entrenched in our care armamentarium.

As you will see in this issue, we must create more effective interventions for NAFLD. Obesity will play an increasingly important role in the development of digestive and liver disease, so gastroenterologists must develop better tools and processes to combat root causes.

Begin thinking about DDW. While it again will be a virtual meeting, the content will be rich. Virtual meetings open up additional possibilities to gain new knowledge, although those personal connections over cocktails will be sorely missed.

John I. Allen, MD, MBA, AGAF
Editor in Chief

I am hopeful that we are beginning to see a sustained decline in COVID-19 cases and hospitalizations. Although, total COVID-19 cases and deaths continue to rise (more than 460,000 deaths in the United States), vaccinations and treatment options have reduced the prevalence of severe disease, hospitalizations, and mortality rates. Worries about variants continue, but we now will enter a prolonged phase before we finally subdue COVID-19 and fully open our economies.

Health systems and practices are looking ahead and beginning to focus on how practice will look after COVID-19. From a business standpoint, we are seeing an accelerating consolidation of community practices. We anticipate the first resale of a private equity (PE)–acquired GI practice: Gastro Health was the first practice to join with a PE firm in 2016. Published rumors suggest a sale of the (now larger, multistate) practice at 15-times-plus EBITDA (earnings before interest, taxes, depreciation, and amortization) could begin as early as this quarter. It would not be a surprise to see 40% of independent gastroenterologists employed in a PE-backed model within a few years. Health systems and payers (especially United Health Group) continue to scoop up practices as well.

Clinical care has been changed forever. I expect fully 30% of visits will remain virtual, and innovative health systems will capitalize on that fact to right-size their brick-and-mortar facilities. Start-up companies will virtualize care and develop new models that allow board-certified gastroenterologist to focus on care they only can provide, resulting in substantial cost savings and (hopefully) similar or better outcomes. Remote patient monitoring (both reactive and predictive) is now firmly entrenched in our care armamentarium.

As you will see in this issue, we must create more effective interventions for NAFLD. Obesity will play an increasingly important role in the development of digestive and liver disease, so gastroenterologists must develop better tools and processes to combat root causes.

Begin thinking about DDW. While it again will be a virtual meeting, the content will be rich. Virtual meetings open up additional possibilities to gain new knowledge, although those personal connections over cocktails will be sorely missed.

John I. Allen, MD, MBA, AGAF
Editor in Chief

I am hopeful that we are beginning to see a sustained decline in COVID-19 cases and hospitalizations. Although, total COVID-19 cases and deaths continue to rise (more than 460,000 deaths in the United States), vaccinations and treatment options have reduced the prevalence of severe disease, hospitalizations, and mortality rates. Worries about variants continue, but we now will enter a prolonged phase before we finally subdue COVID-19 and fully open our economies.

Health systems and practices are looking ahead and beginning to focus on how practice will look after COVID-19. From a business standpoint, we are seeing an accelerating consolidation of community practices. We anticipate the first resale of a private equity (PE)–acquired GI practice: Gastro Health was the first practice to join with a PE firm in 2016. Published rumors suggest a sale of the (now larger, multistate) practice at 15-times-plus EBITDA (earnings before interest, taxes, depreciation, and amortization) could begin as early as this quarter. It would not be a surprise to see 40% of independent gastroenterologists employed in a PE-backed model within a few years. Health systems and payers (especially United Health Group) continue to scoop up practices as well.

Clinical care has been changed forever. I expect fully 30% of visits will remain virtual, and innovative health systems will capitalize on that fact to right-size their brick-and-mortar facilities. Start-up companies will virtualize care and develop new models that allow board-certified gastroenterologist to focus on care they only can provide, resulting in substantial cost savings and (hopefully) similar or better outcomes. Remote patient monitoring (both reactive and predictive) is now firmly entrenched in our care armamentarium.

As you will see in this issue, we must create more effective interventions for NAFLD. Obesity will play an increasingly important role in the development of digestive and liver disease, so gastroenterologists must develop better tools and processes to combat root causes.

Begin thinking about DDW. While it again will be a virtual meeting, the content will be rich. Virtual meetings open up additional possibilities to gain new knowledge, although those personal connections over cocktails will be sorely missed.

John I. Allen, MD, MBA, AGAF
Editor in Chief

Until recently, atopic dermatitis was considered a childhood disease that was self-limited over a few years. Emerging studies have shown that the burden of atopic dermatitis includes potential cardiac disease in adulthood, comorbidities including allergy and psychological disorders, and possible superinfection complications. 

Dr Lawrence F. Eichenfield, chief of the department of pediatric and adolescent dermatology at Rady Children's Hospital, reports on biological, systemic, and topical treatments either currently in use or being studied for children suffering from atopic dermatitis. These studies include both steroid and steroid-sparing topical agents, a novel AhR modulating agent, as well as JAK inhibitors that are under active investigation.

--

Lawrence F. Eichenfield, MD, Distinguished Professor; Vice Chair, Department of Dermatology and Pediatrics, University of California, San Diego; Chief, Department of Pediatric and Adolescent Dermatology, Rady Children's Hospital, San Diego, California.

Lawrence F. Eichenfield, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AbbVie; Dermavant; Dermira; Forte Biosciences; Galderma Laboratories; Incyte; Leo Pharma; Eli Lilly and Company; Otsuka; Novartis; Pfizer. Serve(d) as a speaker or a member of a speakers bureau for: Regeneron; Sanofi-Genzyme; Pfizer. Received research grant from: AbbVie; Regeneron; Sanofi Genzyme; Ortho Dermatology. Serve(d) on the data safety monitoring board for: Asana; Glenmark/Ichnos.

Until recently, atopic dermatitis was considered a childhood disease that was self-limited over a few years. Emerging studies have shown that the burden of atopic dermatitis includes potential cardiac disease in adulthood, comorbidities including allergy and psychological disorders, and possible superinfection complications. 

Dr Lawrence F. Eichenfield, chief of the department of pediatric and adolescent dermatology at Rady Children's Hospital, reports on biological, systemic, and topical treatments either currently in use or being studied for children suffering from atopic dermatitis. These studies include both steroid and steroid-sparing topical agents, a novel AhR modulating agent, as well as JAK inhibitors that are under active investigation.

--

Lawrence F. Eichenfield, MD, Distinguished Professor; Vice Chair, Department of Dermatology and Pediatrics, University of California, San Diego; Chief, Department of Pediatric and Adolescent Dermatology, Rady Children's Hospital, San Diego, California.

Lawrence F. Eichenfield, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AbbVie; Dermavant; Dermira; Forte Biosciences; Galderma Laboratories; Incyte; Leo Pharma; Eli Lilly and Company; Otsuka; Novartis; Pfizer. Serve(d) as a speaker or a member of a speakers bureau for: Regeneron; Sanofi-Genzyme; Pfizer. Received research grant from: AbbVie; Regeneron; Sanofi Genzyme; Ortho Dermatology. Serve(d) on the data safety monitoring board for: Asana; Glenmark/Ichnos.

Until recently, atopic dermatitis was considered a childhood disease that was self-limited over a few years. Emerging studies have shown that the burden of atopic dermatitis includes potential cardiac disease in adulthood, comorbidities including allergy and psychological disorders, and possible superinfection complications. 

Dr Lawrence F. Eichenfield, chief of the department of pediatric and adolescent dermatology at Rady Children's Hospital, reports on biological, systemic, and topical treatments either currently in use or being studied for children suffering from atopic dermatitis. These studies include both steroid and steroid-sparing topical agents, a novel AhR modulating agent, as well as JAK inhibitors that are under active investigation.

--

Lawrence F. Eichenfield, MD, Distinguished Professor; Vice Chair, Department of Dermatology and Pediatrics, University of California, San Diego; Chief, Department of Pediatric and Adolescent Dermatology, Rady Children's Hospital, San Diego, California.

Lawrence F. Eichenfield, MD, has disclosed the following relevant financial relationships:
Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AbbVie; Dermavant; Dermira; Forte Biosciences; Galderma Laboratories; Incyte; Leo Pharma; Eli Lilly and Company; Otsuka; Novartis; Pfizer. Serve(d) as a speaker or a member of a speakers bureau for: Regeneron; Sanofi-Genzyme; Pfizer. Received research grant from: AbbVie; Regeneron; Sanofi Genzyme; Ortho Dermatology. Serve(d) on the data safety monitoring board for: Asana; Glenmark/Ichnos.

Systemic sclerosis, also known as scleroderma, is a rare autoimmune disease characterized by thickening of the skin, which often causes significant disability or physical distress. Early on in the disease course, it is commonly misdiagnosed as other diseases such as lupus or rheumatoid arthritis.  

Patients are classified as having either limited or diffuse cutaneous disease depending on where it presents on the body. All patients with systemic sclerosis are susceptible to internal organ involvement regardless of whether they have limited or diffuse disease. 

Dr. Elizabeth Volkmann, Director of the UCLA Scleroderma Program, discusses key defining symptoms that can signal early presentation of systemic sclerosis. She also reviews how to properly screen patients with a high resolution chest CT scan, as interstitial lung disease is the leading cause of death among these patients. 
 

Elizabeth Volkmann, MD, MS, Assistant Professor of Medicine, Director, UCLA Scleroderma Program, Co-Director, CTD-ILD Program, Division of Rheumatology, Department of Medicine, University of California, Los Angeles

Dr. Volkmann has disclosed the following financial relationships: 
Grants: Corbus, Forbius. Consulting: Boehringer Ingelheim.

Systemic sclerosis, also known as scleroderma, is a rare autoimmune disease characterized by thickening of the skin, which often causes significant disability or physical distress. Early on in the disease course, it is commonly misdiagnosed as other diseases such as lupus or rheumatoid arthritis.  

Patients are classified as having either limited or diffuse cutaneous disease depending on where it presents on the body. All patients with systemic sclerosis are susceptible to internal organ involvement regardless of whether they have limited or diffuse disease. 

Dr. Elizabeth Volkmann, Director of the UCLA Scleroderma Program, discusses key defining symptoms that can signal early presentation of systemic sclerosis. She also reviews how to properly screen patients with a high resolution chest CT scan, as interstitial lung disease is the leading cause of death among these patients. 
 

Elizabeth Volkmann, MD, MS, Assistant Professor of Medicine, Director, UCLA Scleroderma Program, Co-Director, CTD-ILD Program, Division of Rheumatology, Department of Medicine, University of California, Los Angeles

Dr. Volkmann has disclosed the following financial relationships: 
Grants: Corbus, Forbius. Consulting: Boehringer Ingelheim.

Systemic sclerosis, also known as scleroderma, is a rare autoimmune disease characterized by thickening of the skin, which often causes significant disability or physical distress. Early on in the disease course, it is commonly misdiagnosed as other diseases such as lupus or rheumatoid arthritis.  

Patients are classified as having either limited or diffuse cutaneous disease depending on where it presents on the body. All patients with systemic sclerosis are susceptible to internal organ involvement regardless of whether they have limited or diffuse disease. 

Dr. Elizabeth Volkmann, Director of the UCLA Scleroderma Program, discusses key defining symptoms that can signal early presentation of systemic sclerosis. She also reviews how to properly screen patients with a high resolution chest CT scan, as interstitial lung disease is the leading cause of death among these patients. 
 

Elizabeth Volkmann, MD, MS, Assistant Professor of Medicine, Director, UCLA Scleroderma Program, Co-Director, CTD-ILD Program, Division of Rheumatology, Department of Medicine, University of California, Los Angeles

Dr. Volkmann has disclosed the following financial relationships: 
Grants: Corbus, Forbius. Consulting: Boehringer Ingelheim.

Hormone-positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) breast cancer is not curable, but it can have an indolent course that can be controlled for many years with effective treatment.

For postmenopausal women with HR+ breast cancers, the standard of care is endocrine therapy such as exemestane, anastrozole, tamoxifen, or fulvestrant.

In the first-line setting, endocrine therapy may be given alone. In advanced or metastatic disease, endocrine therapy may be combined with one of several newer treatment options, most notably CDK4/6 inhibitors.

Dr Peter Kaufman, of the University of Vermont Cancer Center, takes us through the latest evidence underlining the benefit of CDK4/6 inhibitors in terms of both progression-free and overall survival.

He also outlines the key research questions relating to the use of these drugs, including whether biomarkers can be identified to allow better patient selection.

Finally, Dr Kaufman discusses other therapeutic options for HR+/HER2- advanced breast cancer, such as CDK4/6 inhibitors combined with alpelisib or everolimus, and the emerging use of selective estrogen receptor degraders.

--

Professor, Department of Medicine, Division of Hematology and Oncology, The Robert Larner, M.D. College of Medicine, University of Vermont

Attending Physician, Department of Medicine, Division of Hematology and Oncology, University of Vermont Cancer Center, Burlington, Vermont.

Peter A. Kaufman, MD, has disclosed the following relevant financial relationships:

Serve(d) as a speaker or a member of a speakers bureau for: Eli Lilly and Company

Received research grant from: Eli Lilly and Company; Eisai; Pfizer; Macrogenics; Polyphor; Sanofi

Received income in an amount equal to or greater than $250 from: Eli Lilly and Company; Eisai; Pfizer; Macrogenics; Polyphor; Sanofi; Amgen; Puma

Hormone-positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) breast cancer is not curable, but it can have an indolent course that can be controlled for many years with effective treatment.

For postmenopausal women with HR+ breast cancers, the standard of care is endocrine therapy such as exemestane, anastrozole, tamoxifen, or fulvestrant.

In the first-line setting, endocrine therapy may be given alone. In advanced or metastatic disease, endocrine therapy may be combined with one of several newer treatment options, most notably CDK4/6 inhibitors.

Dr Peter Kaufman, of the University of Vermont Cancer Center, takes us through the latest evidence underlining the benefit of CDK4/6 inhibitors in terms of both progression-free and overall survival.

He also outlines the key research questions relating to the use of these drugs, including whether biomarkers can be identified to allow better patient selection.

Finally, Dr Kaufman discusses other therapeutic options for HR+/HER2- advanced breast cancer, such as CDK4/6 inhibitors combined with alpelisib or everolimus, and the emerging use of selective estrogen receptor degraders.

--

Professor, Department of Medicine, Division of Hematology and Oncology, The Robert Larner, M.D. College of Medicine, University of Vermont

Attending Physician, Department of Medicine, Division of Hematology and Oncology, University of Vermont Cancer Center, Burlington, Vermont.

Peter A. Kaufman, MD, has disclosed the following relevant financial relationships:

Serve(d) as a speaker or a member of a speakers bureau for: Eli Lilly and Company

Received research grant from: Eli Lilly and Company; Eisai; Pfizer; Macrogenics; Polyphor; Sanofi

Received income in an amount equal to or greater than $250 from: Eli Lilly and Company; Eisai; Pfizer; Macrogenics; Polyphor; Sanofi; Amgen; Puma

Hormone-positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) breast cancer is not curable, but it can have an indolent course that can be controlled for many years with effective treatment.

For postmenopausal women with HR+ breast cancers, the standard of care is endocrine therapy such as exemestane, anastrozole, tamoxifen, or fulvestrant.

In the first-line setting, endocrine therapy may be given alone. In advanced or metastatic disease, endocrine therapy may be combined with one of several newer treatment options, most notably CDK4/6 inhibitors.

Dr Peter Kaufman, of the University of Vermont Cancer Center, takes us through the latest evidence underlining the benefit of CDK4/6 inhibitors in terms of both progression-free and overall survival.

He also outlines the key research questions relating to the use of these drugs, including whether biomarkers can be identified to allow better patient selection.

Finally, Dr Kaufman discusses other therapeutic options for HR+/HER2- advanced breast cancer, such as CDK4/6 inhibitors combined with alpelisib or everolimus, and the emerging use of selective estrogen receptor degraders.

--

Professor, Department of Medicine, Division of Hematology and Oncology, The Robert Larner, M.D. College of Medicine, University of Vermont

Attending Physician, Department of Medicine, Division of Hematology and Oncology, University of Vermont Cancer Center, Burlington, Vermont.

Peter A. Kaufman, MD, has disclosed the following relevant financial relationships:

Serve(d) as a speaker or a member of a speakers bureau for: Eli Lilly and Company

Received research grant from: Eli Lilly and Company; Eisai; Pfizer; Macrogenics; Polyphor; Sanofi

Received income in an amount equal to or greater than $250 from: Eli Lilly and Company; Eisai; Pfizer; Macrogenics; Polyphor; Sanofi; Amgen; Puma

Asthma is not an independent risk factor for more severe disease or hospitalization due to COVID-19, according to recent research presented at the annual meeting of the American Academy of Allergy, Asthma, and Immunology, held virtually this year.

“In our cohort of patients tested for SARS-CoV-2 at Stanford between March and September, asthma was not an independent risk factor in and of itself for hospitalization or more severe disease from COVID,” Lauren E. Eggert, MD, of the Sean N. Parker Center for Allergy and Asthma Research at Stanford (Calif.) University, said in a poster presentation at the meeting. “What’s more, allergic asthma actually decreased the risk of hospitalization by nearly half.”

Dr. Eggert noted that there have been conflicting data on whether comorbid asthma is or is not a risk factor for more severe COVID-19. “The general thought at the beginning of the pandemic was that because COVID-19 is predominantly a viral respiratory illness, and viral illnesses are known to cause asthma exacerbations, that patients with asthma may be at higher risk if they got COVID infection,” she explained. “But some of the data also showed that Th2 inflammation downregulates ACE2 receptor [expression], which has been shown to be the port of entry for the SARS-CoV-2 virus, so maybe allergy might have a protective effect.”

The researchers at Stanford University identified 168,190 patients at Stanford Health Care who had a positive real-time reverse transcriptase polymerase chain reaction (RT-PCR) test for SARS-CoV-2 between March and September 2020 and collected data from their electronic medical records on their history of asthma, if they were hospitalized, comorbid conditions, and laboratory values. Patients who had no other data available except for a positive SARS-CoV-2 result, or were younger than 28 days, were excluded from the study. Dr. Eggert and colleagues used COVID-19 treatment guidelines from the National Institutes of Health to assess disease severity, which grades COVID-19 severity as asymptomatic or presymptomatic infection, mild illness, moderate illness, severe illness, and critical illness.

In total, the researchers analyzed 5,596 patients who were SARS-CoV-2 positive, with 605 patients (10.8%) hospitalized within 14 days of receiving a positive test. Of these, 100 patients (16.5%) were patients with asthma. There were no significant differences between groups hospitalized and not hospitalized due to COVID-19 in patients with asthma and with no asthma.

Among patients with asthma and COVID-19, 28.0% had asymptomatic illness, 19.0% had moderate disease, 33.0% had severe disease, and 20.0% had critical COVID-19, compared with 36.0% of patients without asthma who had asymptomatic illness, 12.0% with moderate disease, 30.0% with severe disease, and 21.0% with critical COVID-19. Dr. Eggert and colleagues performed a univariate analysis, which showed a significant association between asthma and COVID-19 related hospitalization (odds ratio, 1.53; 95% confidence interval, 1.2-1.93; P < .001), but when adjusting for factors such as diabetes, obesity coronary heart disease, and hypertension, they found there was not a significant association between asthma and hospitalization due to COVID-19 (OR, 1.12; 95% CI, 0.86-1.45; P < .40).

In a univariate analysis, asthma was associated with more severe disease in patients hospitalized for COVID-19, but the results were not significant (OR, 1.21; 95% CI, 0.8-1.85; P = .37). When analyzing allergic asthma alone in a univariate analysis, the researchers found a significant association between allergic asthma and lower hospitalization risk, compared with patients who had nonallergic asthma (OR, 0.55; 95% CI, 0.31-0.92; P = .029), and this association remained after they performed a multivariate analysis as well.

“When we stratified by allergic asthma versus nonallergic asthma, we found that having a diagnosis of allergic asthma actually conferred a protective effect, and there was almost half the risk of hospitalization in asthmatics with allergic asthma as compared to others, which we thought was very interesting,” Dr. Eggert said.

“Eosinophil levels during hospitalization, even when adjusted for systemic steroid use – and we followed patients out through September, when dexamethasone was standard of care – also correlated with better outcomes,” she explained. “This is independent of asthmatic status.”

Asthma is not an independent risk factor for more severe disease or hospitalization due to COVID-19, according to recent research presented at the annual meeting of the American Academy of Allergy, Asthma, and Immunology, held virtually this year.

“In our cohort of patients tested for SARS-CoV-2 at Stanford between March and September, asthma was not an independent risk factor in and of itself for hospitalization or more severe disease from COVID,” Lauren E. Eggert, MD, of the Sean N. Parker Center for Allergy and Asthma Research at Stanford (Calif.) University, said in a poster presentation at the meeting. “What’s more, allergic asthma actually decreased the risk of hospitalization by nearly half.”

Dr. Eggert noted that there have been conflicting data on whether comorbid asthma is or is not a risk factor for more severe COVID-19. “The general thought at the beginning of the pandemic was that because COVID-19 is predominantly a viral respiratory illness, and viral illnesses are known to cause asthma exacerbations, that patients with asthma may be at higher risk if they got COVID infection,” she explained. “But some of the data also showed that Th2 inflammation downregulates ACE2 receptor [expression], which has been shown to be the port of entry for the SARS-CoV-2 virus, so maybe allergy might have a protective effect.”

The researchers at Stanford University identified 168,190 patients at Stanford Health Care who had a positive real-time reverse transcriptase polymerase chain reaction (RT-PCR) test for SARS-CoV-2 between March and September 2020 and collected data from their electronic medical records on their history of asthma, if they were hospitalized, comorbid conditions, and laboratory values. Patients who had no other data available except for a positive SARS-CoV-2 result, or were younger than 28 days, were excluded from the study. Dr. Eggert and colleagues used COVID-19 treatment guidelines from the National Institutes of Health to assess disease severity, which grades COVID-19 severity as asymptomatic or presymptomatic infection, mild illness, moderate illness, severe illness, and critical illness.

In total, the researchers analyzed 5,596 patients who were SARS-CoV-2 positive, with 605 patients (10.8%) hospitalized within 14 days of receiving a positive test. Of these, 100 patients (16.5%) were patients with asthma. There were no significant differences between groups hospitalized and not hospitalized due to COVID-19 in patients with asthma and with no asthma.

Among patients with asthma and COVID-19, 28.0% had asymptomatic illness, 19.0% had moderate disease, 33.0% had severe disease, and 20.0% had critical COVID-19, compared with 36.0% of patients without asthma who had asymptomatic illness, 12.0% with moderate disease, 30.0% with severe disease, and 21.0% with critical COVID-19. Dr. Eggert and colleagues performed a univariate analysis, which showed a significant association between asthma and COVID-19 related hospitalization (odds ratio, 1.53; 95% confidence interval, 1.2-1.93; P < .001), but when adjusting for factors such as diabetes, obesity coronary heart disease, and hypertension, they found there was not a significant association between asthma and hospitalization due to COVID-19 (OR, 1.12; 95% CI, 0.86-1.45; P < .40).

In a univariate analysis, asthma was associated with more severe disease in patients hospitalized for COVID-19, but the results were not significant (OR, 1.21; 95% CI, 0.8-1.85; P = .37). When analyzing allergic asthma alone in a univariate analysis, the researchers found a significant association between allergic asthma and lower hospitalization risk, compared with patients who had nonallergic asthma (OR, 0.55; 95% CI, 0.31-0.92; P = .029), and this association remained after they performed a multivariate analysis as well.

“When we stratified by allergic asthma versus nonallergic asthma, we found that having a diagnosis of allergic asthma actually conferred a protective effect, and there was almost half the risk of hospitalization in asthmatics with allergic asthma as compared to others, which we thought was very interesting,” Dr. Eggert said.

“Eosinophil levels during hospitalization, even when adjusted for systemic steroid use – and we followed patients out through September, when dexamethasone was standard of care – also correlated with better outcomes,” she explained. “This is independent of asthmatic status.”

Asthma is not an independent risk factor for more severe disease or hospitalization due to COVID-19, according to recent research presented at the annual meeting of the American Academy of Allergy, Asthma, and Immunology, held virtually this year.

“In our cohort of patients tested for SARS-CoV-2 at Stanford between March and September, asthma was not an independent risk factor in and of itself for hospitalization or more severe disease from COVID,” Lauren E. Eggert, MD, of the Sean N. Parker Center for Allergy and Asthma Research at Stanford (Calif.) University, said in a poster presentation at the meeting. “What’s more, allergic asthma actually decreased the risk of hospitalization by nearly half.”

Dr. Eggert noted that there have been conflicting data on whether comorbid asthma is or is not a risk factor for more severe COVID-19. “The general thought at the beginning of the pandemic was that because COVID-19 is predominantly a viral respiratory illness, and viral illnesses are known to cause asthma exacerbations, that patients with asthma may be at higher risk if they got COVID infection,” she explained. “But some of the data also showed that Th2 inflammation downregulates ACE2 receptor [expression], which has been shown to be the port of entry for the SARS-CoV-2 virus, so maybe allergy might have a protective effect.”

The researchers at Stanford University identified 168,190 patients at Stanford Health Care who had a positive real-time reverse transcriptase polymerase chain reaction (RT-PCR) test for SARS-CoV-2 between March and September 2020 and collected data from their electronic medical records on their history of asthma, if they were hospitalized, comorbid conditions, and laboratory values. Patients who had no other data available except for a positive SARS-CoV-2 result, or were younger than 28 days, were excluded from the study. Dr. Eggert and colleagues used COVID-19 treatment guidelines from the National Institutes of Health to assess disease severity, which grades COVID-19 severity as asymptomatic or presymptomatic infection, mild illness, moderate illness, severe illness, and critical illness.

In total, the researchers analyzed 5,596 patients who were SARS-CoV-2 positive, with 605 patients (10.8%) hospitalized within 14 days of receiving a positive test. Of these, 100 patients (16.5%) were patients with asthma. There were no significant differences between groups hospitalized and not hospitalized due to COVID-19 in patients with asthma and with no asthma.

Among patients with asthma and COVID-19, 28.0% had asymptomatic illness, 19.0% had moderate disease, 33.0% had severe disease, and 20.0% had critical COVID-19, compared with 36.0% of patients without asthma who had asymptomatic illness, 12.0% with moderate disease, 30.0% with severe disease, and 21.0% with critical COVID-19. Dr. Eggert and colleagues performed a univariate analysis, which showed a significant association between asthma and COVID-19 related hospitalization (odds ratio, 1.53; 95% confidence interval, 1.2-1.93; P < .001), but when adjusting for factors such as diabetes, obesity coronary heart disease, and hypertension, they found there was not a significant association between asthma and hospitalization due to COVID-19 (OR, 1.12; 95% CI, 0.86-1.45; P < .40).

In a univariate analysis, asthma was associated with more severe disease in patients hospitalized for COVID-19, but the results were not significant (OR, 1.21; 95% CI, 0.8-1.85; P = .37). When analyzing allergic asthma alone in a univariate analysis, the researchers found a significant association between allergic asthma and lower hospitalization risk, compared with patients who had nonallergic asthma (OR, 0.55; 95% CI, 0.31-0.92; P = .029), and this association remained after they performed a multivariate analysis as well.

“When we stratified by allergic asthma versus nonallergic asthma, we found that having a diagnosis of allergic asthma actually conferred a protective effect, and there was almost half the risk of hospitalization in asthmatics with allergic asthma as compared to others, which we thought was very interesting,” Dr. Eggert said.

“Eosinophil levels during hospitalization, even when adjusted for systemic steroid use – and we followed patients out through September, when dexamethasone was standard of care – also correlated with better outcomes,” she explained. “This is independent of asthmatic status.”