Perspectives

The past year presented unprecedented challenges for many. In addition, mental health services have also been stretched to capacity. Anecdotally, some hospitals and emergency departments note that more youth have been presenting in mental health crises, and the severity of symptoms has also been higher. Safety planning is important, including working with patients to identify skills they can use in distress. Even those who do not experience suicidal thoughts may struggle with dysregulation or may use coping strategies that may not be the healthiest in the long term.

Within my practice, I see some families who are still waiting for an available therapist, or some may not wish to participate in therapy despite its being recommended. For these families, supporting them in using strategies that they may be willing and able to use in the moment to help them get through the moment of crisis can been helpful:
 

Case example (identifying details have been changed)

Emily is a 17-year-old girl who has a history of generalized anxiety disorder and obsessive-compulsive disorder. She has had multiple medication trials and a course of cognitive behavioral therapy when younger, with significant improvement in symptoms. She returns to clinic because of increased anxiety related to stressors of the pandemic. She wishes to not return to therapy because of feeling that she received maximal benefit and that further sessions would not be fruitful. However, she struggles with identifying what skills she can use, and her anxiety heightens significantly to near-panic and hyperventilating with even cursory exploration of triggers for her symptoms. Medications are also discussed during this appointment, and it is noted that it may take some time to see therapeutic effect. Of note, she reports no acute safety concerns. She has engaged in skin picking. No reported substance use. As she hyperventilates, she was asked to identify items in the room matching the colors of the rainbow in order. She was able to quickly do this, and then was asked to do it again. Afterward, she noted feeling much less anxious because it distracted her from her thoughts.

Distress tolerance skills can be very helpful to navigate getting through a crisis. When under stress, some may be more likely to engage in behaviors that are not helpful in the long term such as using avoidance; procrastinating; consuming tobacco, alcohol, or other substances; spending too much time on screens; or engaging in self-harm behaviors. While some of these activities may be okay in moderation, others are always harmful. At times, when encouraging patients to use skills with which they may be more familiar, e.g., deep breathing, progressive muscle relaxation, the response may be, “these don’t work!” It can be important to distinguish that the function of these skills is not to make someone feel good or to eliminate the stressor, but to “take some of the edge off” so they are less likely to slide into problematic behaviors. It can be beneficial to have multiple tools at one’s disposal because not all skills will always be effective or available.

TIPP skills (temperature, intense exercise, paced breathing, progressive muscle relaxation) are distress tolerance skills from dialectical behavioral therapy (DBT),¹ which was initially developed to treat individuals with borderline personality disorder. More recently, the therapy modality has been applied to individuals who may struggle with emotion regulation for a variety of reasons. TIPP skills work quickly (within seconds to minutes) with the aim to decrease physiological arousal. They do not require a lot of thinking, and many are portable or easy to use. Given the speed of effect, these skills can also be used in lieu of p.r.n. medications or patients can be counseled about trying these instead of turning to substance use. The effect is brief (5-20 minutes), although this may lower the affective temperature sufficiently for someone to get through the intense moment or to be able to then utilize other skills that may require more cognitive reserves.
 

T – Temperature

Holding one’s breath and placing one’s face in cold water (above 50°) for 10-20 seconds to stimulate the diving response and decrease heart rate. Patients can repeat this up to 3 times. Alternatively, cold compresses or gel eye masks can be used.

I – Intense exercise

Aerobic exercise for 10-20 minutes. This can include running, jumping jacks, dancing to loud music in a way that feels intense. The parasympathetic nervous system (PNS) is activated for approximately 20 minutes after cessation of intense exercise.

P – Paced breathing

Decreasing rate of breathing, with each inhalation/exhalation cycle lasting 10-12 seconds and the exhale being longer than the inhale also activates the PNS.

P – Progressive muscle relaxation (PMR)

Sequentially tensing and relaxing muscles from head to toes. Having at least 5-10 minutes to perform this exercise is preferred.² Children’s Hospital of Philadelphia offerssample PMR recordings.

Body scans can also be helpful. This practice differs from PMR in that it is a mindfulness practice noting body sensations without trying to change them. The University of Vermont offers some sample exercises.³

These skills were described to Emily. She noted that dunking her face in cold water was effective and it was reassuring knowing she had a tool to help her anxiety. She started to push herself to go outside to exercise. We additionally incorporated other distraction techniques such as identifying items from colors of the rainbow that were around her. She appreciated that she could even do this discreetly while at school. At times she had to do a couple of rounds, but this could help stop her repetitive thoughts so she could use other skills.

Helping patients identify skills that can help in the moment can help them feel supported and gain traction in other areas.
 

Dr. Strange is an assistant professor in the department of psychiatry at the University of Vermont Medical Center and University of Vermont Robert Larner College of Medicine, both in Burlington. She works with children and adolescents. She has no relevant financial disclosures

References

1. Rathus JH, Miller AL. DBT® Skills manual for adolescents. 2015. Guilford Press.

2. Guided Relaxation Exercises, Children’s Hospital of Philadelphia.

3. Vermont Center for Children, Youth, and Families: Staying Close While Keeping Your Distance.
 

The past year presented unprecedented challenges for many. In addition, mental health services have also been stretched to capacity. Anecdotally, some hospitals and emergency departments note that more youth have been presenting in mental health crises, and the severity of symptoms has also been higher. Safety planning is important, including working with patients to identify skills they can use in distress. Even those who do not experience suicidal thoughts may struggle with dysregulation or may use coping strategies that may not be the healthiest in the long term.

Within my practice, I see some families who are still waiting for an available therapist, or some may not wish to participate in therapy despite its being recommended. For these families, supporting them in using strategies that they may be willing and able to use in the moment to help them get through the moment of crisis can been helpful:
 

Case example (identifying details have been changed)

Emily is a 17-year-old girl who has a history of generalized anxiety disorder and obsessive-compulsive disorder. She has had multiple medication trials and a course of cognitive behavioral therapy when younger, with significant improvement in symptoms. She returns to clinic because of increased anxiety related to stressors of the pandemic. She wishes to not return to therapy because of feeling that she received maximal benefit and that further sessions would not be fruitful. However, she struggles with identifying what skills she can use, and her anxiety heightens significantly to near-panic and hyperventilating with even cursory exploration of triggers for her symptoms. Medications are also discussed during this appointment, and it is noted that it may take some time to see therapeutic effect. Of note, she reports no acute safety concerns. She has engaged in skin picking. No reported substance use. As she hyperventilates, she was asked to identify items in the room matching the colors of the rainbow in order. She was able to quickly do this, and then was asked to do it again. Afterward, she noted feeling much less anxious because it distracted her from her thoughts.

Distress tolerance skills can be very helpful to navigate getting through a crisis. When under stress, some may be more likely to engage in behaviors that are not helpful in the long term such as using avoidance; procrastinating; consuming tobacco, alcohol, or other substances; spending too much time on screens; or engaging in self-harm behaviors. While some of these activities may be okay in moderation, others are always harmful. At times, when encouraging patients to use skills with which they may be more familiar, e.g., deep breathing, progressive muscle relaxation, the response may be, “these don’t work!” It can be important to distinguish that the function of these skills is not to make someone feel good or to eliminate the stressor, but to “take some of the edge off” so they are less likely to slide into problematic behaviors. It can be beneficial to have multiple tools at one’s disposal because not all skills will always be effective or available.

TIPP skills (temperature, intense exercise, paced breathing, progressive muscle relaxation) are distress tolerance skills from dialectical behavioral therapy (DBT),¹ which was initially developed to treat individuals with borderline personality disorder. More recently, the therapy modality has been applied to individuals who may struggle with emotion regulation for a variety of reasons. TIPP skills work quickly (within seconds to minutes) with the aim to decrease physiological arousal. They do not require a lot of thinking, and many are portable or easy to use. Given the speed of effect, these skills can also be used in lieu of p.r.n. medications or patients can be counseled about trying these instead of turning to substance use. The effect is brief (5-20 minutes), although this may lower the affective temperature sufficiently for someone to get through the intense moment or to be able to then utilize other skills that may require more cognitive reserves.
 

T – Temperature

Holding one’s breath and placing one’s face in cold water (above 50°) for 10-20 seconds to stimulate the diving response and decrease heart rate. Patients can repeat this up to 3 times. Alternatively, cold compresses or gel eye masks can be used.

I – Intense exercise

Aerobic exercise for 10-20 minutes. This can include running, jumping jacks, dancing to loud music in a way that feels intense. The parasympathetic nervous system (PNS) is activated for approximately 20 minutes after cessation of intense exercise.

P – Paced breathing

Decreasing rate of breathing, with each inhalation/exhalation cycle lasting 10-12 seconds and the exhale being longer than the inhale also activates the PNS.

P – Progressive muscle relaxation (PMR)

Sequentially tensing and relaxing muscles from head to toes. Having at least 5-10 minutes to perform this exercise is preferred.² Children’s Hospital of Philadelphia offerssample PMR recordings.

Body scans can also be helpful. This practice differs from PMR in that it is a mindfulness practice noting body sensations without trying to change them. The University of Vermont offers some sample exercises.³

These skills were described to Emily. She noted that dunking her face in cold water was effective and it was reassuring knowing she had a tool to help her anxiety. She started to push herself to go outside to exercise. We additionally incorporated other distraction techniques such as identifying items from colors of the rainbow that were around her. She appreciated that she could even do this discreetly while at school. At times she had to do a couple of rounds, but this could help stop her repetitive thoughts so she could use other skills.

Helping patients identify skills that can help in the moment can help them feel supported and gain traction in other areas.
 

Dr. Strange is an assistant professor in the department of psychiatry at the University of Vermont Medical Center and University of Vermont Robert Larner College of Medicine, both in Burlington. She works with children and adolescents. She has no relevant financial disclosures

References

1. Rathus JH, Miller AL. DBT® Skills manual for adolescents. 2015. Guilford Press.

2. Guided Relaxation Exercises, Children’s Hospital of Philadelphia.

3. Vermont Center for Children, Youth, and Families: Staying Close While Keeping Your Distance.
 

The past year presented unprecedented challenges for many. In addition, mental health services have also been stretched to capacity. Anecdotally, some hospitals and emergency departments note that more youth have been presenting in mental health crises, and the severity of symptoms has also been higher. Safety planning is important, including working with patients to identify skills they can use in distress. Even those who do not experience suicidal thoughts may struggle with dysregulation or may use coping strategies that may not be the healthiest in the long term.

Within my practice, I see some families who are still waiting for an available therapist, or some may not wish to participate in therapy despite its being recommended. For these families, supporting them in using strategies that they may be willing and able to use in the moment to help them get through the moment of crisis can been helpful:
 

Case example (identifying details have been changed)

Emily is a 17-year-old girl who has a history of generalized anxiety disorder and obsessive-compulsive disorder. She has had multiple medication trials and a course of cognitive behavioral therapy when younger, with significant improvement in symptoms. She returns to clinic because of increased anxiety related to stressors of the pandemic. She wishes to not return to therapy because of feeling that she received maximal benefit and that further sessions would not be fruitful. However, she struggles with identifying what skills she can use, and her anxiety heightens significantly to near-panic and hyperventilating with even cursory exploration of triggers for her symptoms. Medications are also discussed during this appointment, and it is noted that it may take some time to see therapeutic effect. Of note, she reports no acute safety concerns. She has engaged in skin picking. No reported substance use. As she hyperventilates, she was asked to identify items in the room matching the colors of the rainbow in order. She was able to quickly do this, and then was asked to do it again. Afterward, she noted feeling much less anxious because it distracted her from her thoughts.

Distress tolerance skills can be very helpful to navigate getting through a crisis. When under stress, some may be more likely to engage in behaviors that are not helpful in the long term such as using avoidance; procrastinating; consuming tobacco, alcohol, or other substances; spending too much time on screens; or engaging in self-harm behaviors. While some of these activities may be okay in moderation, others are always harmful. At times, when encouraging patients to use skills with which they may be more familiar, e.g., deep breathing, progressive muscle relaxation, the response may be, “these don’t work!” It can be important to distinguish that the function of these skills is not to make someone feel good or to eliminate the stressor, but to “take some of the edge off” so they are less likely to slide into problematic behaviors. It can be beneficial to have multiple tools at one’s disposal because not all skills will always be effective or available.

TIPP skills (temperature, intense exercise, paced breathing, progressive muscle relaxation) are distress tolerance skills from dialectical behavioral therapy (DBT),¹ which was initially developed to treat individuals with borderline personality disorder. More recently, the therapy modality has been applied to individuals who may struggle with emotion regulation for a variety of reasons. TIPP skills work quickly (within seconds to minutes) with the aim to decrease physiological arousal. They do not require a lot of thinking, and many are portable or easy to use. Given the speed of effect, these skills can also be used in lieu of p.r.n. medications or patients can be counseled about trying these instead of turning to substance use. The effect is brief (5-20 minutes), although this may lower the affective temperature sufficiently for someone to get through the intense moment or to be able to then utilize other skills that may require more cognitive reserves.
 

T – Temperature

Holding one’s breath and placing one’s face in cold water (above 50°) for 10-20 seconds to stimulate the diving response and decrease heart rate. Patients can repeat this up to 3 times. Alternatively, cold compresses or gel eye masks can be used.

I – Intense exercise

Aerobic exercise for 10-20 minutes. This can include running, jumping jacks, dancing to loud music in a way that feels intense. The parasympathetic nervous system (PNS) is activated for approximately 20 minutes after cessation of intense exercise.

P – Paced breathing

Decreasing rate of breathing, with each inhalation/exhalation cycle lasting 10-12 seconds and the exhale being longer than the inhale also activates the PNS.

P – Progressive muscle relaxation (PMR)

Sequentially tensing and relaxing muscles from head to toes. Having at least 5-10 minutes to perform this exercise is preferred.² Children’s Hospital of Philadelphia offerssample PMR recordings.

Body scans can also be helpful. This practice differs from PMR in that it is a mindfulness practice noting body sensations without trying to change them. The University of Vermont offers some sample exercises.³

These skills were described to Emily. She noted that dunking her face in cold water was effective and it was reassuring knowing she had a tool to help her anxiety. She started to push herself to go outside to exercise. We additionally incorporated other distraction techniques such as identifying items from colors of the rainbow that were around her. She appreciated that she could even do this discreetly while at school. At times she had to do a couple of rounds, but this could help stop her repetitive thoughts so she could use other skills.

Helping patients identify skills that can help in the moment can help them feel supported and gain traction in other areas.
 

Dr. Strange is an assistant professor in the department of psychiatry at the University of Vermont Medical Center and University of Vermont Robert Larner College of Medicine, both in Burlington. She works with children and adolescents. She has no relevant financial disclosures

References

1. Rathus JH, Miller AL. DBT® Skills manual for adolescents. 2015. Guilford Press.

2. Guided Relaxation Exercises, Children’s Hospital of Philadelphia.

3. Vermont Center for Children, Youth, and Families: Staying Close While Keeping Your Distance.
 

One of the top stories in the local newspaper recently described an unfortunate incident in which a previously healthy 19-month-old baby was found unresponsive and apneic in a crib at her day-care center. She was successfully resuscitated by the daycare provider but is now blind, has seizures, and no longer walks or talks. According to the day care owner, the child had not settled down during rest time and her talking was preventing the other children from sleeping. This apparently had happened before and the day-care provider had successfully resorted to triple wrapping the child in a blanket and placing her in a crib in a separate room. The day-care provider had checked on the child once and noted she was snoring. When the child failed to wake after the expected interval of time she was found face down with her head partially covered by a pillow.

An investigation of the day-care center is ongoing and no reports or prior violations, warnings, or license suspensions have surfaced at this point. The day-care provider has been charged with aggravated assault and endangering the welfare of a child. The charges could carry a prison sentence of 30 years.

As I reread this very sad story I began wondering how this tragedy is going to unfold in the next months and years. We can assume one young life has already been permanently damaged. Her family will have to deal with the consequences of this event for decades or longer. What about the day-care provider? I hope we can assume that she intended no harm to the child nor had she ignored prior warnings or training about swaddling. Nor does this lapse in judgment fit a previous pattern of behavior. Regardless of what the courts decide she will carry some degree of guilt for the foreseeable future. The day-care center has been closed voluntarily and given that Maine is a small state where word travels fast it is unlikely that it will ever reopen.

Can we imagine any good coming out of this tragedy? It may be that with luck and diligent therapies that the little girl will be able to lead a life she finds rewarding and gives others some pleasure. It is possible that some individuals involved in her life – her parents or therapists – will find the devotion to her care brings new meaning to their lives.

Will the day-care provider find a new career or a cause that can help her restore some of the self worth she may have lost in the wake of the event? Or, will a protracted course through the legal system take its devastating toll on her life and marriage? It is unlikely that she will spend anywhere near 30 years in prison, if any at all. Will the child’s family sue this small family day-care center? It is hard to imagine they will recover anything more than a tiny fraction of the lifetime costs of this child’s care.

It is also unlikely that the message that swaddling children old enough to turn over carries a significant risk will go beyond one or two more stories in the local Maine newspapers. If this child’s father had been a professional football player or her mother had been an actress or U.S. Senator this tragic turn of events could possibly have stirred enough waters to grab national attention, spawn a foundation, or even result in legislation. But, she appears to come from a family with modest means without claims to notoriety. There is no flawed product to ban. She is a victim of ignorance and our failure to educate. As a result, her tragedy and those of thousands of other children will do little more than accumulate as unfortunate statistics.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

One of the top stories in the local newspaper recently described an unfortunate incident in which a previously healthy 19-month-old baby was found unresponsive and apneic in a crib at her day-care center. She was successfully resuscitated by the daycare provider but is now blind, has seizures, and no longer walks or talks. According to the day care owner, the child had not settled down during rest time and her talking was preventing the other children from sleeping. This apparently had happened before and the day-care provider had successfully resorted to triple wrapping the child in a blanket and placing her in a crib in a separate room. The day-care provider had checked on the child once and noted she was snoring. When the child failed to wake after the expected interval of time she was found face down with her head partially covered by a pillow.

An investigation of the day-care center is ongoing and no reports or prior violations, warnings, or license suspensions have surfaced at this point. The day-care provider has been charged with aggravated assault and endangering the welfare of a child. The charges could carry a prison sentence of 30 years.

As I reread this very sad story I began wondering how this tragedy is going to unfold in the next months and years. We can assume one young life has already been permanently damaged. Her family will have to deal with the consequences of this event for decades or longer. What about the day-care provider? I hope we can assume that she intended no harm to the child nor had she ignored prior warnings or training about swaddling. Nor does this lapse in judgment fit a previous pattern of behavior. Regardless of what the courts decide she will carry some degree of guilt for the foreseeable future. The day-care center has been closed voluntarily and given that Maine is a small state where word travels fast it is unlikely that it will ever reopen.

Can we imagine any good coming out of this tragedy? It may be that with luck and diligent therapies that the little girl will be able to lead a life she finds rewarding and gives others some pleasure. It is possible that some individuals involved in her life – her parents or therapists – will find the devotion to her care brings new meaning to their lives.

Will the day-care provider find a new career or a cause that can help her restore some of the self worth she may have lost in the wake of the event? Or, will a protracted course through the legal system take its devastating toll on her life and marriage? It is unlikely that she will spend anywhere near 30 years in prison, if any at all. Will the child’s family sue this small family day-care center? It is hard to imagine they will recover anything more than a tiny fraction of the lifetime costs of this child’s care.

It is also unlikely that the message that swaddling children old enough to turn over carries a significant risk will go beyond one or two more stories in the local Maine newspapers. If this child’s father had been a professional football player or her mother had been an actress or U.S. Senator this tragic turn of events could possibly have stirred enough waters to grab national attention, spawn a foundation, or even result in legislation. But, she appears to come from a family with modest means without claims to notoriety. There is no flawed product to ban. She is a victim of ignorance and our failure to educate. As a result, her tragedy and those of thousands of other children will do little more than accumulate as unfortunate statistics.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

One of the top stories in the local newspaper recently described an unfortunate incident in which a previously healthy 19-month-old baby was found unresponsive and apneic in a crib at her day-care center. She was successfully resuscitated by the daycare provider but is now blind, has seizures, and no longer walks or talks. According to the day care owner, the child had not settled down during rest time and her talking was preventing the other children from sleeping. This apparently had happened before and the day-care provider had successfully resorted to triple wrapping the child in a blanket and placing her in a crib in a separate room. The day-care provider had checked on the child once and noted she was snoring. When the child failed to wake after the expected interval of time she was found face down with her head partially covered by a pillow.

An investigation of the day-care center is ongoing and no reports or prior violations, warnings, or license suspensions have surfaced at this point. The day-care provider has been charged with aggravated assault and endangering the welfare of a child. The charges could carry a prison sentence of 30 years.

As I reread this very sad story I began wondering how this tragedy is going to unfold in the next months and years. We can assume one young life has already been permanently damaged. Her family will have to deal with the consequences of this event for decades or longer. What about the day-care provider? I hope we can assume that she intended no harm to the child nor had she ignored prior warnings or training about swaddling. Nor does this lapse in judgment fit a previous pattern of behavior. Regardless of what the courts decide she will carry some degree of guilt for the foreseeable future. The day-care center has been closed voluntarily and given that Maine is a small state where word travels fast it is unlikely that it will ever reopen.

Can we imagine any good coming out of this tragedy? It may be that with luck and diligent therapies that the little girl will be able to lead a life she finds rewarding and gives others some pleasure. It is possible that some individuals involved in her life – her parents or therapists – will find the devotion to her care brings new meaning to their lives.

Will the day-care provider find a new career or a cause that can help her restore some of the self worth she may have lost in the wake of the event? Or, will a protracted course through the legal system take its devastating toll on her life and marriage? It is unlikely that she will spend anywhere near 30 years in prison, if any at all. Will the child’s family sue this small family day-care center? It is hard to imagine they will recover anything more than a tiny fraction of the lifetime costs of this child’s care.

It is also unlikely that the message that swaddling children old enough to turn over carries a significant risk will go beyond one or two more stories in the local Maine newspapers. If this child’s father had been a professional football player or her mother had been an actress or U.S. Senator this tragic turn of events could possibly have stirred enough waters to grab national attention, spawn a foundation, or even result in legislation. But, she appears to come from a family with modest means without claims to notoriety. There is no flawed product to ban. She is a victim of ignorance and our failure to educate. As a result, her tragedy and those of thousands of other children will do little more than accumulate as unfortunate statistics.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

It’s pretty clear that, at least globally, we have not reached a steady state with the SARS-COV-2 virus. And here in the United States we should remain concerned that if we can’t convince our vaccine-hesitant population to step forward for their shots, this country may slide back into dangerous instability. Despite these uncertainties, it may be time to polish up the old retrospectoscope again and see what the last year and a half has taught us.

Although it took us too long to discover the reality, it is now pretty clear that the virus is spread in the air and by close personal contact, especially indoors. There continues to be some misplaced over-attention to surface cleaning, but for the most part, the bulk of the population seems to have finally gotten the picture. We are of course still plagued by our own impatience and the unfortunate mix of politics and the disagreement about how personal freedom and the common good can coexist.

A year ago, while we were still on the steep part of the learning curve and the specter of the unknown hung over us like a dark cloud, schools and colleges faced a myriad of challenges as they considered how to safely educate their students. Faced with a relative vacuum in leadership from the federal government, school boards and college administrators were left to interpret the trickle of information that filtered down from the media. Many turned for help to hired consultants and a variety of state and local health departments, all of whom were relying on the same information sources that were available to all of us – sources that often were neither peer reviewed nor based on hard facts. In this land that prides itself on free speech, we were all college administrators, local school board members, and parents basing our decision on the same smorgasbord of information that was frequently self-contradictory.

As I look around at the school systems and colleges with which I have some familiarity it has been interesting to observe how their responses to this hodgepodge of opinion and guesstimates have fallen into two basic categories. Some institutions seem to have been primarily motivated by risk avoidance and others appeared to have struggled to maintain their focus on how best to carry out their primary mission of educating their students.

This dichotomy is not surprising. Institutions are composed of people and people naturally self-sort themselves into pessimists and optimists. When a study is published without peer review suggesting that within schools transmission of the virus between children is unusual the optimist may use the scrap of information to support her decision to craft a hybrid system that includes an abundance of in-class experience. The pessimist will probably observe that it was only one study and instead be more concerned about the number of multi-system-inflammatory syndrome cases reported among children in New York City. He will be far less likely to abandon his all-remote learning system.

There is risk inherent in any decision-making process, including incurring a greater risk by failing to make any decision. The person whose primary focus is on avoiding any risk often shuts off the process of creative thinking and problem solving. At the end of the day, the risk avoider may have achieved his goal with a policy that includes aggressive closings but has fallen far short of his primary mission of educating students.

Here in New England there are several examples of small colleges that have managed to create more normal on-campus educational environments. To my knowledge, their experience with case numbers is no worse and may even be better than that of schools of similar size and geographic siting that chose more restrictive policies. You could argue that the less restrictive schools were just lucky. But my hunch is that the institutions that were able to put risk in perspective and remain focused on their mission were able to navigate the uncharted waters more creatively. The bottom line is that we aren’t talking about right or wrong decisions but grouped together they should provide a foundation to build on for the next turmoil.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

It’s pretty clear that, at least globally, we have not reached a steady state with the SARS-COV-2 virus. And here in the United States we should remain concerned that if we can’t convince our vaccine-hesitant population to step forward for their shots, this country may slide back into dangerous instability. Despite these uncertainties, it may be time to polish up the old retrospectoscope again and see what the last year and a half has taught us.

Although it took us too long to discover the reality, it is now pretty clear that the virus is spread in the air and by close personal contact, especially indoors. There continues to be some misplaced over-attention to surface cleaning, but for the most part, the bulk of the population seems to have finally gotten the picture. We are of course still plagued by our own impatience and the unfortunate mix of politics and the disagreement about how personal freedom and the common good can coexist.

A year ago, while we were still on the steep part of the learning curve and the specter of the unknown hung over us like a dark cloud, schools and colleges faced a myriad of challenges as they considered how to safely educate their students. Faced with a relative vacuum in leadership from the federal government, school boards and college administrators were left to interpret the trickle of information that filtered down from the media. Many turned for help to hired consultants and a variety of state and local health departments, all of whom were relying on the same information sources that were available to all of us – sources that often were neither peer reviewed nor based on hard facts. In this land that prides itself on free speech, we were all college administrators, local school board members, and parents basing our decision on the same smorgasbord of information that was frequently self-contradictory.

As I look around at the school systems and colleges with which I have some familiarity it has been interesting to observe how their responses to this hodgepodge of opinion and guesstimates have fallen into two basic categories. Some institutions seem to have been primarily motivated by risk avoidance and others appeared to have struggled to maintain their focus on how best to carry out their primary mission of educating their students.

This dichotomy is not surprising. Institutions are composed of people and people naturally self-sort themselves into pessimists and optimists. When a study is published without peer review suggesting that within schools transmission of the virus between children is unusual the optimist may use the scrap of information to support her decision to craft a hybrid system that includes an abundance of in-class experience. The pessimist will probably observe that it was only one study and instead be more concerned about the number of multi-system-inflammatory syndrome cases reported among children in New York City. He will be far less likely to abandon his all-remote learning system.

There is risk inherent in any decision-making process, including incurring a greater risk by failing to make any decision. The person whose primary focus is on avoiding any risk often shuts off the process of creative thinking and problem solving. At the end of the day, the risk avoider may have achieved his goal with a policy that includes aggressive closings but has fallen far short of his primary mission of educating students.

Here in New England there are several examples of small colleges that have managed to create more normal on-campus educational environments. To my knowledge, their experience with case numbers is no worse and may even be better than that of schools of similar size and geographic siting that chose more restrictive policies. You could argue that the less restrictive schools were just lucky. But my hunch is that the institutions that were able to put risk in perspective and remain focused on their mission were able to navigate the uncharted waters more creatively. The bottom line is that we aren’t talking about right or wrong decisions but grouped together they should provide a foundation to build on for the next turmoil.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

It’s pretty clear that, at least globally, we have not reached a steady state with the SARS-COV-2 virus. And here in the United States we should remain concerned that if we can’t convince our vaccine-hesitant population to step forward for their shots, this country may slide back into dangerous instability. Despite these uncertainties, it may be time to polish up the old retrospectoscope again and see what the last year and a half has taught us.

Although it took us too long to discover the reality, it is now pretty clear that the virus is spread in the air and by close personal contact, especially indoors. There continues to be some misplaced over-attention to surface cleaning, but for the most part, the bulk of the population seems to have finally gotten the picture. We are of course still plagued by our own impatience and the unfortunate mix of politics and the disagreement about how personal freedom and the common good can coexist.

A year ago, while we were still on the steep part of the learning curve and the specter of the unknown hung over us like a dark cloud, schools and colleges faced a myriad of challenges as they considered how to safely educate their students. Faced with a relative vacuum in leadership from the federal government, school boards and college administrators were left to interpret the trickle of information that filtered down from the media. Many turned for help to hired consultants and a variety of state and local health departments, all of whom were relying on the same information sources that were available to all of us – sources that often were neither peer reviewed nor based on hard facts. In this land that prides itself on free speech, we were all college administrators, local school board members, and parents basing our decision on the same smorgasbord of information that was frequently self-contradictory.

As I look around at the school systems and colleges with which I have some familiarity it has been interesting to observe how their responses to this hodgepodge of opinion and guesstimates have fallen into two basic categories. Some institutions seem to have been primarily motivated by risk avoidance and others appeared to have struggled to maintain their focus on how best to carry out their primary mission of educating their students.

This dichotomy is not surprising. Institutions are composed of people and people naturally self-sort themselves into pessimists and optimists. When a study is published without peer review suggesting that within schools transmission of the virus between children is unusual the optimist may use the scrap of information to support her decision to craft a hybrid system that includes an abundance of in-class experience. The pessimist will probably observe that it was only one study and instead be more concerned about the number of multi-system-inflammatory syndrome cases reported among children in New York City. He will be far less likely to abandon his all-remote learning system.

There is risk inherent in any decision-making process, including incurring a greater risk by failing to make any decision. The person whose primary focus is on avoiding any risk often shuts off the process of creative thinking and problem solving. At the end of the day, the risk avoider may have achieved his goal with a policy that includes aggressive closings but has fallen far short of his primary mission of educating students.

Here in New England there are several examples of small colleges that have managed to create more normal on-campus educational environments. To my knowledge, their experience with case numbers is no worse and may even be better than that of schools of similar size and geographic siting that chose more restrictive policies. You could argue that the less restrictive schools were just lucky. But my hunch is that the institutions that were able to put risk in perspective and remain focused on their mission were able to navigate the uncharted waters more creatively. The bottom line is that we aren’t talking about right or wrong decisions but grouped together they should provide a foundation to build on for the next turmoil.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

Being a physician gives me great privilege. However, this privilege did not start the moment I donned the white coat, but when I was born Asian American, to parents who hold advanced education degrees. It grew when our family moved to a White neighborhood and I was accepted into an elite college. For medical school and residency, I chose an academic program embedded in an urban setting that serves underprivileged minority communities. I entered psychiatry to facilitate healing. Yet as I read the headlines about people of color who had died at the hands of law enforcement, I found myself feeling overwhelmingly hopeless and numb.

In these individuals, I saw people who looked and lived just like the patients I chose to serve. But during this time, I did not see myself as the healer, but part of the system that brought pain and distress. As an Asian American, I identified with Tou Thao—the Asian American police officer involved in George Floyd’s death. In the medical community with which I identified, I found that ever-rising cases of COVID-19 were disproportionately affecting lower-income minority communities. In a polarizing world, I felt my Asian American identity prevented me from experiencing the pain and suffering Black communities faced. This was not my fight, and if it was, I was more immersed in the side that brought trauma to my patients. From a purely rational perspective, I had no right to feel sad. Intellectually, I felt unqualified to share in their pain, yet here I was, crying in my room.

An evolving transformation

As much as I wanted to take a break, training did not stop. A transformation occurred from an emerging awareness of the unique environment within which I was training and the intersection of who I knew myself to be. Serving in an urban program, I was given the opportunity for candid conversations with health professionals of color. I was humbled when Black colleagues proactively reached out to educate me about the historical context of these events and help me process them. I asked hard questions of my fellow residents who were Black, and listened to their answers and personal stories, which was difficult.

With my patients, I began to listen more intently and think about the systemic issues I had previously written off. One patient missed their appointment because public transportation was closed due to COVID-19. Another patient who was homeless was helped immensely by assistance with housing when he could no longer sleep at his place of residence. Really listening to him revealed that his street had become a common route for protests. With my therapy patient who experienced panic attacks listening to the news, I simply sat and grieved with them. I chose these interactions not because I was uniquely qualified, intelligent, or had any ability to change the trajectory of our country, but because they grew from me simply working in the context I chose and seeking the relationships I naturally sought.

How I define myself

As doctors, we accept the burden of caring for society’s ailments with the ultimate hope of celebrating triumph over the adversity of psychiatric illness. However, superseding our profession is the social system in which we live. I am part of a system that has historically caused trauma to some while benefitting others. Thus, between the calling of my practice and the country I practice in, I found a divergence. Once I accepted the truth of this system and the very personal way it affects me, my colleagues, and patients I serve, I was able to internally reconcile and rediscover hope. While I cannot change my experiences, advantages, or privilege, these facts do not change the reality that I am a citizen of the globe and human first. This realization is the silver lining of these perilous times; training among people of color who graciously included me in their experiences, and my willingness to listen and self-reflect. I now choose to define myself by what makes me similar to my patients instead of what isolates me from them. The tangible results of this deliberate step toward authenticity are renewed inspiration and joy.

For those of you who may have found yourself with no “ethnic home team” (or a desire for a new one), I leave you with this simple charge: Let your emotional reactions guide you to truth, and challenge yourself to process them with someone who doesn’t look like you. Leave your title at the door and embrace humility. You might be pleasantly surprised at the human you find when you look in the mirror.

Being a physician gives me great privilege. However, this privilege did not start the moment I donned the white coat, but when I was born Asian American, to parents who hold advanced education degrees. It grew when our family moved to a White neighborhood and I was accepted into an elite college. For medical school and residency, I chose an academic program embedded in an urban setting that serves underprivileged minority communities. I entered psychiatry to facilitate healing. Yet as I read the headlines about people of color who had died at the hands of law enforcement, I found myself feeling overwhelmingly hopeless and numb.

In these individuals, I saw people who looked and lived just like the patients I chose to serve. But during this time, I did not see myself as the healer, but part of the system that brought pain and distress. As an Asian American, I identified with Tou Thao—the Asian American police officer involved in George Floyd’s death. In the medical community with which I identified, I found that ever-rising cases of COVID-19 were disproportionately affecting lower-income minority communities. In a polarizing world, I felt my Asian American identity prevented me from experiencing the pain and suffering Black communities faced. This was not my fight, and if it was, I was more immersed in the side that brought trauma to my patients. From a purely rational perspective, I had no right to feel sad. Intellectually, I felt unqualified to share in their pain, yet here I was, crying in my room.

An evolving transformation

As much as I wanted to take a break, training did not stop. A transformation occurred from an emerging awareness of the unique environment within which I was training and the intersection of who I knew myself to be. Serving in an urban program, I was given the opportunity for candid conversations with health professionals of color. I was humbled when Black colleagues proactively reached out to educate me about the historical context of these events and help me process them. I asked hard questions of my fellow residents who were Black, and listened to their answers and personal stories, which was difficult.

With my patients, I began to listen more intently and think about the systemic issues I had previously written off. One patient missed their appointment because public transportation was closed due to COVID-19. Another patient who was homeless was helped immensely by assistance with housing when he could no longer sleep at his place of residence. Really listening to him revealed that his street had become a common route for protests. With my therapy patient who experienced panic attacks listening to the news, I simply sat and grieved with them. I chose these interactions not because I was uniquely qualified, intelligent, or had any ability to change the trajectory of our country, but because they grew from me simply working in the context I chose and seeking the relationships I naturally sought.

How I define myself

As doctors, we accept the burden of caring for society’s ailments with the ultimate hope of celebrating triumph over the adversity of psychiatric illness. However, superseding our profession is the social system in which we live. I am part of a system that has historically caused trauma to some while benefitting others. Thus, between the calling of my practice and the country I practice in, I found a divergence. Once I accepted the truth of this system and the very personal way it affects me, my colleagues, and patients I serve, I was able to internally reconcile and rediscover hope. While I cannot change my experiences, advantages, or privilege, these facts do not change the reality that I am a citizen of the globe and human first. This realization is the silver lining of these perilous times; training among people of color who graciously included me in their experiences, and my willingness to listen and self-reflect. I now choose to define myself by what makes me similar to my patients instead of what isolates me from them. The tangible results of this deliberate step toward authenticity are renewed inspiration and joy.

For those of you who may have found yourself with no “ethnic home team” (or a desire for a new one), I leave you with this simple charge: Let your emotional reactions guide you to truth, and challenge yourself to process them with someone who doesn’t look like you. Leave your title at the door and embrace humility. You might be pleasantly surprised at the human you find when you look in the mirror.

Being a physician gives me great privilege. However, this privilege did not start the moment I donned the white coat, but when I was born Asian American, to parents who hold advanced education degrees. It grew when our family moved to a White neighborhood and I was accepted into an elite college. For medical school and residency, I chose an academic program embedded in an urban setting that serves underprivileged minority communities. I entered psychiatry to facilitate healing. Yet as I read the headlines about people of color who had died at the hands of law enforcement, I found myself feeling overwhelmingly hopeless and numb.

In these individuals, I saw people who looked and lived just like the patients I chose to serve. But during this time, I did not see myself as the healer, but part of the system that brought pain and distress. As an Asian American, I identified with Tou Thao—the Asian American police officer involved in George Floyd’s death. In the medical community with which I identified, I found that ever-rising cases of COVID-19 were disproportionately affecting lower-income minority communities. In a polarizing world, I felt my Asian American identity prevented me from experiencing the pain and suffering Black communities faced. This was not my fight, and if it was, I was more immersed in the side that brought trauma to my patients. From a purely rational perspective, I had no right to feel sad. Intellectually, I felt unqualified to share in their pain, yet here I was, crying in my room.

An evolving transformation

As much as I wanted to take a break, training did not stop. A transformation occurred from an emerging awareness of the unique environment within which I was training and the intersection of who I knew myself to be. Serving in an urban program, I was given the opportunity for candid conversations with health professionals of color. I was humbled when Black colleagues proactively reached out to educate me about the historical context of these events and help me process them. I asked hard questions of my fellow residents who were Black, and listened to their answers and personal stories, which was difficult.

With my patients, I began to listen more intently and think about the systemic issues I had previously written off. One patient missed their appointment because public transportation was closed due to COVID-19. Another patient who was homeless was helped immensely by assistance with housing when he could no longer sleep at his place of residence. Really listening to him revealed that his street had become a common route for protests. With my therapy patient who experienced panic attacks listening to the news, I simply sat and grieved with them. I chose these interactions not because I was uniquely qualified, intelligent, or had any ability to change the trajectory of our country, but because they grew from me simply working in the context I chose and seeking the relationships I naturally sought.

How I define myself

As doctors, we accept the burden of caring for society’s ailments with the ultimate hope of celebrating triumph over the adversity of psychiatric illness. However, superseding our profession is the social system in which we live. I am part of a system that has historically caused trauma to some while benefitting others. Thus, between the calling of my practice and the country I practice in, I found a divergence. Once I accepted the truth of this system and the very personal way it affects me, my colleagues, and patients I serve, I was able to internally reconcile and rediscover hope. While I cannot change my experiences, advantages, or privilege, these facts do not change the reality that I am a citizen of the globe and human first. This realization is the silver lining of these perilous times; training among people of color who graciously included me in their experiences, and my willingness to listen and self-reflect. I now choose to define myself by what makes me similar to my patients instead of what isolates me from them. The tangible results of this deliberate step toward authenticity are renewed inspiration and joy.

For those of you who may have found yourself with no “ethnic home team” (or a desire for a new one), I leave you with this simple charge: Let your emotional reactions guide you to truth, and challenge yourself to process them with someone who doesn’t look like you. Leave your title at the door and embrace humility. You might be pleasantly surprised at the human you find when you look in the mirror.

It breaks my heart every time young patients with functional disability and a history of several psychotic episodes are referred to me. It makes me wonder why they weren’t protected from a lifetime of disability with the use of one of the FDA-approved long-acting injectable (LAI) antipsychotics right after discharge from their initial hospitalization for first-episode psychosis (FEP).

Two decades ago, psychiatric research discovered that psychotic episodes are neurotoxic and neurodegenerative, with grave consequences for the brain if they recur. Although many clinicians are aware of the high rate of nonadherence in patients with schizophrenia—which inevitably leads to a psychotic relapse—the vast majority (>99%, in my estimate) never prescribe an LAI after the FEP to guarantee full adherence and protect the patient’s brain from further atrophy due to relapses. The overall rate of LAI antipsychotic use is astonishingly low (approximately 10%), despite the neurologic malignancy of psychotic episodes. Further, LAIs are most often used after a patient has experienced multiple psychotic episodes, at which point the patient has already lost a significant amount of brain tissue and has already descended into a life of permanent disability.

Oral antipsychotics have the same efficacy as their LAI counterparts, and certainly should be used initially in the hospital during FEP to ascertain the absence of an allergic reaction after initial exposure, and to establish tolerability. Inpatient nurses are experts at making sure a reluctant patient actually swallows the pills and does not cheek them to spit them out later. So patients who have had FEP do improve with oral medications in the hospital, but all bets are off that those patients will regularly ingest tablets every day after discharge. Studies show patients have a high rate of nonadherence within days or weeks after leaving the hospital for FEP.¹ This leads to repetitive psychotic relapses and rehospitalizations, with dire consequences for young patients with schizophrenia—a very serious brain disorder that had been labeled “the worst disease of mankind”² in the era before studies showed LAI second-generation antipsychotics for FEP had remarkable rates of relapse prevention and recovery.^3,4

Psychiatrists should approach FEP the same way oncologists approach cancer when it is diagnosed as Stage 1. Oncologists immediately take action to prevent the recurrence of the patient’s cancer with chemotherapy and/or radiation therapy, and do not wait for the cancer to advance to Stage 4, with widespread metastasis, before administering these potentially life-saving therapies (despite their toxic adverse effects). In schizophrenia, functional disability is the equivalent of Stage 4 cancer and should be aggressively prevented by using LAIs at the time of initial diagnosis, which is Stage 1 schizophrenia. Knowing the grave consequences of psychotic relapses, there is no logical reason whatsoever not to switch patients who have had FEP to an LAI before they are discharged from the hospital. A well-known study by a UCLA research group that compared patients who had FEP and were assigned to oral vs LAI antipsychotics at the time of discharge reported a stunning difference at the end of 1 year: a 650% higher relapse rate among the oral medication group compared with the LAI group!⁵ In light of such a massive difference, wouldn’t psychiatrists want to treat their sons or daughters with an LAI antipsychotic right after FEP? I certainly would, and I have always believed in treating every patient like a family member.

Catastrophic consequences

This lack of early intervention with LAI antipsychotics following FEP is the main reason schizophrenia is associated with poor clinical and functional outcomes. Patients are prescribed pills that they often take erratically or not at all, and end up relapsing repeatedly, with multiple catastrophic consequences, such as:

1. Brain tissue loss. Until recently, psychiatry did not know that psychosis destroys gray and white matter in the brain and causes progressive brain atrophy with every psychotic relapse.^6,7 The neurotoxicity of psychosis is attributed to 2 destructive processes: neuro­inflammation^8,9 and free radicals.¹⁰ Approximately 11 cc of brain tissue is lost during FEP and with every subsequent relapse.⁶ Simple math shows that after 3 to 5 relapses, patients’ brains will shrink by 35 cc to 60 cc. No wonder recurrent psychoses lead to a life of permanent disability. As I have said in a past editorial,¹¹ just as cardiologists do everything they can to prevent a second myocardial infarction (“heart attack”), psychiatrists must do the same to prevent a second psychotic episode (“brain attack”).

2. Treatment resistance. With each psychotic episode, the low antipsychotic dose that worked well in FEP is no longer enough and must be increased. The neurodegenerative effects of psychosis implies that the brain structure changes with each episode. Higher and higher doses become necessary with every psychotic recurrence, and studies show that approximately 1 in 8 patients may stop responding altogether after a psychotic relapse.¹²

Continue to: Disability

3. Disability. Functional disability, both vocational and social, usually begins after the second psychotic episode, which is why it is so important to prevent the second episode.¹³ Patients usually must drop out of high school or college or quit the job they held before FEP. Most patients with multiple psychotic episodes will never be able to work, get married, have children, live independently, or develop a circle of friends. Disability in schizophrenia is essentially a functional death sentence.¹⁴

4. Incarceration and criminalization. So many of our patients with schizophrenia get arrested when they become psychotic and behave erratically due to delusions, hallucinations, or both. They typically are taken to jail instead of a hospital because almost all the state hospitals around the country have been closed. It is outrageous that a medical condition of the brain leads to criminalization of patients with schizophrenia.¹⁵ The only solution for this ongoing crisis of incarceration of our patients with schizophrenia is to prevent them from relapsing into psychosis. The so-called deinstitutionalization movement has mutated into trans-institutionalization, moving patients who are medically ill from state hospitals to more restrictive state prisons. Patients with schizophrenia should be surrounded by a mental health team, not by armed prison guards. The rate of recidivism among these individuals is extremely high because patients who are released often stop taking their medications and get re-arrested when their behavior deteriorates.

5. Suicide. The rate of suicide in the first year after FEP is astronomical. A recent study reported an unimaginably high suicide rate: 17,000% higher than that of the general population.¹⁶ Many patients with FEP commit suicide after they stop taking their antipsychotic medication, and often no antipsychotic medication is detected in their postmortem blood samples.

6. Homelessness. A disproportionate number of patients with schizophrenia become homeless.¹⁷ It started in the 1980s, when the shuttering of state hospitals began and patients with chronic illnesses were released into the community to fend for themselves. Many perished. Others became homeless, living on the streets of urban areas.

7. Early mortality. Schizophrenia has repeatedly been shown to be associated with early mortality, with a loss of approximately 25 potential years of life.¹⁷ This is attributed to lifestyle risk factors (eg, sedentary living, poor diet) and multiple medical comorbidities (eg, obesity, diabetes, hypertension). To make things worse, patients with schizophrenia do not receive basic medical care to protect them from cardiovascular morbidity, an appalling disparity of care.¹⁸ Interestingly, a recent 7-year follow-up study of patients with schizophrenia found that the lowest rate of mortality from all causes was among patients receiving a second-generation LAI.¹⁹ Relapse prevention with LAIs can reduce mortality! According to that study, the worst mortality rate was observed in patients with schizophrenia who were not receiving any antipsychotic medication.

Continue to: Posttraumatic stress disorder

8. Posttraumatic stress disorder (PTSD). Many studies report that psychosis triggers PTSD symptoms²⁰ because delusions and hallucinations can represent a life-threatening experience. The symptoms of PTSD get embedded within the positive and negative symptoms of schizophrenia, and every psychotic relapse serves as a “booster shot” for PTSD, leading to depression, anxiety, personality changes, aggressive behavior, and suicide.

9. Hopelessness, depression, and demoralization. The stigma of a severe psychiatric brain disorder such as schizophrenia, with multiple episodes, disability, incarceration, and homelessness, extends to the patients themselves, who become hopeless and demoralized by a chronic illness that marginalizes them into desperately ill individuals.²¹ The more psychotic episodes, the more intense the demoralization, hopelessness, and depression.

10. Family burden. The repercussions of psychotic relapses after FEP leads to significant financial and emotional stress on patients’ families.²² The heavy burden of caregiving among family members can be highly distressing, leading to depression and medical illness due to compromised immune functions.

Preventing relapse: It is not rocket science

It is obvious that the single most important therapeutic action for patients with schizophrenia is to prevent psychotic relapses. Even partial nonadherence must be prevented, because a drop of 25% in a patient’s serum antipsychotic level has been reported to lead to a psychotic relapse.²³ Preventing relapse after FEP is not rocket science: Switch the patient to an LAI before discharge from the hospital,²⁴ and provide the clinically necessary psychosocial treatments at every monthly follow-up visit (supportive psychotherapy, social skill training, vocational rehabilitation, and cognitive remediation). I have witnessed firsthand how stable and functional a patient who has had FEP can become when started on a second-generation LAI very soon after the onset of the illness.

I will finish with a simple question to my clinician readers: given the many devastating consequences of psychotic relapses, what would you do for your young patient with FEP? I hope you will treat them like a family member, and protect them from brain atrophy, disability, incarceration, homelessness, and suicide by starting them on an LAI antipsychotic before they leave the hospital. We must do no less for this highly vulnerable, young patient population.

It breaks my heart every time young patients with functional disability and a history of several psychotic episodes are referred to me. It makes me wonder why they weren’t protected from a lifetime of disability with the use of one of the FDA-approved long-acting injectable (LAI) antipsychotics right after discharge from their initial hospitalization for first-episode psychosis (FEP).

Two decades ago, psychiatric research discovered that psychotic episodes are neurotoxic and neurodegenerative, with grave consequences for the brain if they recur. Although many clinicians are aware of the high rate of nonadherence in patients with schizophrenia—which inevitably leads to a psychotic relapse—the vast majority (>99%, in my estimate) never prescribe an LAI after the FEP to guarantee full adherence and protect the patient’s brain from further atrophy due to relapses. The overall rate of LAI antipsychotic use is astonishingly low (approximately 10%), despite the neurologic malignancy of psychotic episodes. Further, LAIs are most often used after a patient has experienced multiple psychotic episodes, at which point the patient has already lost a significant amount of brain tissue and has already descended into a life of permanent disability.

Oral antipsychotics have the same efficacy as their LAI counterparts, and certainly should be used initially in the hospital during FEP to ascertain the absence of an allergic reaction after initial exposure, and to establish tolerability. Inpatient nurses are experts at making sure a reluctant patient actually swallows the pills and does not cheek them to spit them out later. So patients who have had FEP do improve with oral medications in the hospital, but all bets are off that those patients will regularly ingest tablets every day after discharge. Studies show patients have a high rate of nonadherence within days or weeks after leaving the hospital for FEP.¹ This leads to repetitive psychotic relapses and rehospitalizations, with dire consequences for young patients with schizophrenia—a very serious brain disorder that had been labeled “the worst disease of mankind”² in the era before studies showed LAI second-generation antipsychotics for FEP had remarkable rates of relapse prevention and recovery.^3,4

Psychiatrists should approach FEP the same way oncologists approach cancer when it is diagnosed as Stage 1. Oncologists immediately take action to prevent the recurrence of the patient’s cancer with chemotherapy and/or radiation therapy, and do not wait for the cancer to advance to Stage 4, with widespread metastasis, before administering these potentially life-saving therapies (despite their toxic adverse effects). In schizophrenia, functional disability is the equivalent of Stage 4 cancer and should be aggressively prevented by using LAIs at the time of initial diagnosis, which is Stage 1 schizophrenia. Knowing the grave consequences of psychotic relapses, there is no logical reason whatsoever not to switch patients who have had FEP to an LAI before they are discharged from the hospital. A well-known study by a UCLA research group that compared patients who had FEP and were assigned to oral vs LAI antipsychotics at the time of discharge reported a stunning difference at the end of 1 year: a 650% higher relapse rate among the oral medication group compared with the LAI group!⁵ In light of such a massive difference, wouldn’t psychiatrists want to treat their sons or daughters with an LAI antipsychotic right after FEP? I certainly would, and I have always believed in treating every patient like a family member.

Catastrophic consequences

This lack of early intervention with LAI antipsychotics following FEP is the main reason schizophrenia is associated with poor clinical and functional outcomes. Patients are prescribed pills that they often take erratically or not at all, and end up relapsing repeatedly, with multiple catastrophic consequences, such as:

1. Brain tissue loss. Until recently, psychiatry did not know that psychosis destroys gray and white matter in the brain and causes progressive brain atrophy with every psychotic relapse.^6,7 The neurotoxicity of psychosis is attributed to 2 destructive processes: neuro­inflammation^8,9 and free radicals.¹⁰ Approximately 11 cc of brain tissue is lost during FEP and with every subsequent relapse.⁶ Simple math shows that after 3 to 5 relapses, patients’ brains will shrink by 35 cc to 60 cc. No wonder recurrent psychoses lead to a life of permanent disability. As I have said in a past editorial,¹¹ just as cardiologists do everything they can to prevent a second myocardial infarction (“heart attack”), psychiatrists must do the same to prevent a second psychotic episode (“brain attack”).

2. Treatment resistance. With each psychotic episode, the low antipsychotic dose that worked well in FEP is no longer enough and must be increased. The neurodegenerative effects of psychosis implies that the brain structure changes with each episode. Higher and higher doses become necessary with every psychotic recurrence, and studies show that approximately 1 in 8 patients may stop responding altogether after a psychotic relapse.¹²

Continue to: Disability

3. Disability. Functional disability, both vocational and social, usually begins after the second psychotic episode, which is why it is so important to prevent the second episode.¹³ Patients usually must drop out of high school or college or quit the job they held before FEP. Most patients with multiple psychotic episodes will never be able to work, get married, have children, live independently, or develop a circle of friends. Disability in schizophrenia is essentially a functional death sentence.¹⁴

4. Incarceration and criminalization. So many of our patients with schizophrenia get arrested when they become psychotic and behave erratically due to delusions, hallucinations, or both. They typically are taken to jail instead of a hospital because almost all the state hospitals around the country have been closed. It is outrageous that a medical condition of the brain leads to criminalization of patients with schizophrenia.¹⁵ The only solution for this ongoing crisis of incarceration of our patients with schizophrenia is to prevent them from relapsing into psychosis. The so-called deinstitutionalization movement has mutated into trans-institutionalization, moving patients who are medically ill from state hospitals to more restrictive state prisons. Patients with schizophrenia should be surrounded by a mental health team, not by armed prison guards. The rate of recidivism among these individuals is extremely high because patients who are released often stop taking their medications and get re-arrested when their behavior deteriorates.

5. Suicide. The rate of suicide in the first year after FEP is astronomical. A recent study reported an unimaginably high suicide rate: 17,000% higher than that of the general population.¹⁶ Many patients with FEP commit suicide after they stop taking their antipsychotic medication, and often no antipsychotic medication is detected in their postmortem blood samples.

6. Homelessness. A disproportionate number of patients with schizophrenia become homeless.¹⁷ It started in the 1980s, when the shuttering of state hospitals began and patients with chronic illnesses were released into the community to fend for themselves. Many perished. Others became homeless, living on the streets of urban areas.

7. Early mortality. Schizophrenia has repeatedly been shown to be associated with early mortality, with a loss of approximately 25 potential years of life.¹⁷ This is attributed to lifestyle risk factors (eg, sedentary living, poor diet) and multiple medical comorbidities (eg, obesity, diabetes, hypertension). To make things worse, patients with schizophrenia do not receive basic medical care to protect them from cardiovascular morbidity, an appalling disparity of care.¹⁸ Interestingly, a recent 7-year follow-up study of patients with schizophrenia found that the lowest rate of mortality from all causes was among patients receiving a second-generation LAI.¹⁹ Relapse prevention with LAIs can reduce mortality! According to that study, the worst mortality rate was observed in patients with schizophrenia who were not receiving any antipsychotic medication.

Continue to: Posttraumatic stress disorder

8. Posttraumatic stress disorder (PTSD). Many studies report that psychosis triggers PTSD symptoms²⁰ because delusions and hallucinations can represent a life-threatening experience. The symptoms of PTSD get embedded within the positive and negative symptoms of schizophrenia, and every psychotic relapse serves as a “booster shot” for PTSD, leading to depression, anxiety, personality changes, aggressive behavior, and suicide.

9. Hopelessness, depression, and demoralization. The stigma of a severe psychiatric brain disorder such as schizophrenia, with multiple episodes, disability, incarceration, and homelessness, extends to the patients themselves, who become hopeless and demoralized by a chronic illness that marginalizes them into desperately ill individuals.²¹ The more psychotic episodes, the more intense the demoralization, hopelessness, and depression.

10. Family burden. The repercussions of psychotic relapses after FEP leads to significant financial and emotional stress on patients’ families.²² The heavy burden of caregiving among family members can be highly distressing, leading to depression and medical illness due to compromised immune functions.

Preventing relapse: It is not rocket science

It is obvious that the single most important therapeutic action for patients with schizophrenia is to prevent psychotic relapses. Even partial nonadherence must be prevented, because a drop of 25% in a patient’s serum antipsychotic level has been reported to lead to a psychotic relapse.²³ Preventing relapse after FEP is not rocket science: Switch the patient to an LAI before discharge from the hospital,²⁴ and provide the clinically necessary psychosocial treatments at every monthly follow-up visit (supportive psychotherapy, social skill training, vocational rehabilitation, and cognitive remediation). I have witnessed firsthand how stable and functional a patient who has had FEP can become when started on a second-generation LAI very soon after the onset of the illness.

I will finish with a simple question to my clinician readers: given the many devastating consequences of psychotic relapses, what would you do for your young patient with FEP? I hope you will treat them like a family member, and protect them from brain atrophy, disability, incarceration, homelessness, and suicide by starting them on an LAI antipsychotic before they leave the hospital. We must do no less for this highly vulnerable, young patient population.

It breaks my heart every time young patients with functional disability and a history of several psychotic episodes are referred to me. It makes me wonder why they weren’t protected from a lifetime of disability with the use of one of the FDA-approved long-acting injectable (LAI) antipsychotics right after discharge from their initial hospitalization for first-episode psychosis (FEP).

Two decades ago, psychiatric research discovered that psychotic episodes are neurotoxic and neurodegenerative, with grave consequences for the brain if they recur. Although many clinicians are aware of the high rate of nonadherence in patients with schizophrenia—which inevitably leads to a psychotic relapse—the vast majority (>99%, in my estimate) never prescribe an LAI after the FEP to guarantee full adherence and protect the patient’s brain from further atrophy due to relapses. The overall rate of LAI antipsychotic use is astonishingly low (approximately 10%), despite the neurologic malignancy of psychotic episodes. Further, LAIs are most often used after a patient has experienced multiple psychotic episodes, at which point the patient has already lost a significant amount of brain tissue and has already descended into a life of permanent disability.

Oral antipsychotics have the same efficacy as their LAI counterparts, and certainly should be used initially in the hospital during FEP to ascertain the absence of an allergic reaction after initial exposure, and to establish tolerability. Inpatient nurses are experts at making sure a reluctant patient actually swallows the pills and does not cheek them to spit them out later. So patients who have had FEP do improve with oral medications in the hospital, but all bets are off that those patients will regularly ingest tablets every day after discharge. Studies show patients have a high rate of nonadherence within days or weeks after leaving the hospital for FEP.¹ This leads to repetitive psychotic relapses and rehospitalizations, with dire consequences for young patients with schizophrenia—a very serious brain disorder that had been labeled “the worst disease of mankind”² in the era before studies showed LAI second-generation antipsychotics for FEP had remarkable rates of relapse prevention and recovery.^3,4

Psychiatrists should approach FEP the same way oncologists approach cancer when it is diagnosed as Stage 1. Oncologists immediately take action to prevent the recurrence of the patient’s cancer with chemotherapy and/or radiation therapy, and do not wait for the cancer to advance to Stage 4, with widespread metastasis, before administering these potentially life-saving therapies (despite their toxic adverse effects). In schizophrenia, functional disability is the equivalent of Stage 4 cancer and should be aggressively prevented by using LAIs at the time of initial diagnosis, which is Stage 1 schizophrenia. Knowing the grave consequences of psychotic relapses, there is no logical reason whatsoever not to switch patients who have had FEP to an LAI before they are discharged from the hospital. A well-known study by a UCLA research group that compared patients who had FEP and were assigned to oral vs LAI antipsychotics at the time of discharge reported a stunning difference at the end of 1 year: a 650% higher relapse rate among the oral medication group compared with the LAI group!⁵ In light of such a massive difference, wouldn’t psychiatrists want to treat their sons or daughters with an LAI antipsychotic right after FEP? I certainly would, and I have always believed in treating every patient like a family member.

Catastrophic consequences

This lack of early intervention with LAI antipsychotics following FEP is the main reason schizophrenia is associated with poor clinical and functional outcomes. Patients are prescribed pills that they often take erratically or not at all, and end up relapsing repeatedly, with multiple catastrophic consequences, such as:

1. Brain tissue loss. Until recently, psychiatry did not know that psychosis destroys gray and white matter in the brain and causes progressive brain atrophy with every psychotic relapse.^6,7 The neurotoxicity of psychosis is attributed to 2 destructive processes: neuro­inflammation^8,9 and free radicals.¹⁰ Approximately 11 cc of brain tissue is lost during FEP and with every subsequent relapse.⁶ Simple math shows that after 3 to 5 relapses, patients’ brains will shrink by 35 cc to 60 cc. No wonder recurrent psychoses lead to a life of permanent disability. As I have said in a past editorial,¹¹ just as cardiologists do everything they can to prevent a second myocardial infarction (“heart attack”), psychiatrists must do the same to prevent a second psychotic episode (“brain attack”).

2. Treatment resistance. With each psychotic episode, the low antipsychotic dose that worked well in FEP is no longer enough and must be increased. The neurodegenerative effects of psychosis implies that the brain structure changes with each episode. Higher and higher doses become necessary with every psychotic recurrence, and studies show that approximately 1 in 8 patients may stop responding altogether after a psychotic relapse.¹²

Continue to: Disability

3. Disability. Functional disability, both vocational and social, usually begins after the second psychotic episode, which is why it is so important to prevent the second episode.¹³ Patients usually must drop out of high school or college or quit the job they held before FEP. Most patients with multiple psychotic episodes will never be able to work, get married, have children, live independently, or develop a circle of friends. Disability in schizophrenia is essentially a functional death sentence.¹⁴

4. Incarceration and criminalization. So many of our patients with schizophrenia get arrested when they become psychotic and behave erratically due to delusions, hallucinations, or both. They typically are taken to jail instead of a hospital because almost all the state hospitals around the country have been closed. It is outrageous that a medical condition of the brain leads to criminalization of patients with schizophrenia.¹⁵ The only solution for this ongoing crisis of incarceration of our patients with schizophrenia is to prevent them from relapsing into psychosis. The so-called deinstitutionalization movement has mutated into trans-institutionalization, moving patients who are medically ill from state hospitals to more restrictive state prisons. Patients with schizophrenia should be surrounded by a mental health team, not by armed prison guards. The rate of recidivism among these individuals is extremely high because patients who are released often stop taking their medications and get re-arrested when their behavior deteriorates.

5. Suicide. The rate of suicide in the first year after FEP is astronomical. A recent study reported an unimaginably high suicide rate: 17,000% higher than that of the general population.¹⁶ Many patients with FEP commit suicide after they stop taking their antipsychotic medication, and often no antipsychotic medication is detected in their postmortem blood samples.

6. Homelessness. A disproportionate number of patients with schizophrenia become homeless.¹⁷ It started in the 1980s, when the shuttering of state hospitals began and patients with chronic illnesses were released into the community to fend for themselves. Many perished. Others became homeless, living on the streets of urban areas.

7. Early mortality. Schizophrenia has repeatedly been shown to be associated with early mortality, with a loss of approximately 25 potential years of life.¹⁷ This is attributed to lifestyle risk factors (eg, sedentary living, poor diet) and multiple medical comorbidities (eg, obesity, diabetes, hypertension). To make things worse, patients with schizophrenia do not receive basic medical care to protect them from cardiovascular morbidity, an appalling disparity of care.¹⁸ Interestingly, a recent 7-year follow-up study of patients with schizophrenia found that the lowest rate of mortality from all causes was among patients receiving a second-generation LAI.¹⁹ Relapse prevention with LAIs can reduce mortality! According to that study, the worst mortality rate was observed in patients with schizophrenia who were not receiving any antipsychotic medication.

Continue to: Posttraumatic stress disorder

8. Posttraumatic stress disorder (PTSD). Many studies report that psychosis triggers PTSD symptoms²⁰ because delusions and hallucinations can represent a life-threatening experience. The symptoms of PTSD get embedded within the positive and negative symptoms of schizophrenia, and every psychotic relapse serves as a “booster shot” for PTSD, leading to depression, anxiety, personality changes, aggressive behavior, and suicide.

9. Hopelessness, depression, and demoralization. The stigma of a severe psychiatric brain disorder such as schizophrenia, with multiple episodes, disability, incarceration, and homelessness, extends to the patients themselves, who become hopeless and demoralized by a chronic illness that marginalizes them into desperately ill individuals.²¹ The more psychotic episodes, the more intense the demoralization, hopelessness, and depression.

10. Family burden. The repercussions of psychotic relapses after FEP leads to significant financial and emotional stress on patients’ families.²² The heavy burden of caregiving among family members can be highly distressing, leading to depression and medical illness due to compromised immune functions.

Preventing relapse: It is not rocket science

It is obvious that the single most important therapeutic action for patients with schizophrenia is to prevent psychotic relapses. Even partial nonadherence must be prevented, because a drop of 25% in a patient’s serum antipsychotic level has been reported to lead to a psychotic relapse.²³ Preventing relapse after FEP is not rocket science: Switch the patient to an LAI before discharge from the hospital,²⁴ and provide the clinically necessary psychosocial treatments at every monthly follow-up visit (supportive psychotherapy, social skill training, vocational rehabilitation, and cognitive remediation). I have witnessed firsthand how stable and functional a patient who has had FEP can become when started on a second-generation LAI very soon after the onset of the illness.

I will finish with a simple question to my clinician readers: given the many devastating consequences of psychotic relapses, what would you do for your young patient with FEP? I hope you will treat them like a family member, and protect them from brain atrophy, disability, incarceration, homelessness, and suicide by starting them on an LAI antipsychotic before they leave the hospital. We must do no less for this highly vulnerable, young patient population.

I wanted to thank Dr. Nasrallah for his most important editorial, “Let’s ‘cancel’ these obsolete terms in DSM” (From the Editor, Current Psychiatry, January 2021, p. 4,9-10). Over my 40 years of clinical practice, I never cease to cringe or be pained when “clinical” diagnoses offered are nothing but thinly veiled expressions of contempt for our troubled patients. True clinical compassion honors the horizontal axis in caring for other individuals, honoring our mutually shared imperfection and humanity. The offensive “diagnoses” as delineated by Dr. Nasrallah strengthen a distorted vertical axis, speaking to a moral superiority and contempt as clinicians. If I might humbly add to this list, most personally offensive to me is oppositional defiant disorder. I see nothing of clinical or treatment value to this term, and it strikes me more as a horrible pejorative used to label a child suffering from a brain-based behavioral disorder requiring compassionate treatment. Perhaps other readers would like to add their “top hits” to this ignominious list. Many thanks, Dr. Nasrallah!

Robert Barris, MD
Nassau University Medical Center
East Meadow, New York

How sad! This is my reaction to reading Dr. Nasrallah’s January 2021 editorial. Although biological psychiatry is synonymous with brain neurotransmitters and psychopharmacology, absent from this perspective is the visible biology of the human organism, specifically Sigmund Freud’s discovery of the psychosexual development of the infant and child and Wilhelm Reich’s discovery of characterological and muscular armor. Medicine, a natural science, is founded and grounded in observation. Psychiatry, having ignored and eliminated (“canceled”) recognition of these readily observable phenomena essential to understanding psychiatric disorders, including neurosis and schizophrenia, allows Dr. Nasrallah to suggest we “cancel” what should be at the heart of psychiatric diagnosis and treatment. Sadly, this heart has been lost for decades.

Howard Chavis, MD
New York, New York

Dr. Nasrallah responds

Psychiatry, like all medical and scientific disciplines, must go through an ongoing renewal, including the update of its terminology, with or without a change in its concepts or principles. Anxiety is a more accurate description of clinical symptoms than neurosis, and psychosis spectrum is more accurate than schizophrenia. Besides the accuracy issue, “neurotic” and “schizophrenic” have unfortunately devolved into pejorative and stigmatizing terms. The lexicon of psychiatry has gone through seismic changes over the past several decades, as I described in a previous editorial.¹ Psychiatry is a vibrant, constantly evolving biopsychosocial/clinical neuroscience, not a static descriptive discipline.

Reference

1. Nasrallah HA. From bedlam to biomarkers: the transformation of psychiatry’s terminology reflects its 4 conceptual earthquakes. Current Psychiatry. 2015;14(1):5-7.

I found myself having difficulty with Dr. Nasrallah’s editorial about canceling “obsolete” terms. I agree that making a diagnosis of borderline or narcissistic personality disorder can be pejorative if the clinician is using it to manage their own unprocessed counter­transference. While all behavior is brain-mediated, human behavior is influenced by psychological events great and small. I am concerned that you seem to be reducing personality trait disturbances to biological abnormality, pure and simple. Losing psychological understanding of patients while overexplaining behavior as pathological brain dysfunction risks losing why patients see us in the first place.

Michael Friedman, DO
Cherry Hill, New Jersey

Dr. Nasrallah responds

The renaming I suggest goes beyond countertransference. It has to do with scientific validity of the diagnostic construct. And yes, personality traits are heavily genetic, but with some modulation by environmental factors. I suggest reading the seminal works of Thomas J. Bouchard Jr., PhD, and Kenneth S. Kendler, MD, on identical twins reared together or apart for more details about the genetics of personality traits.

Disclosures

The authors report no financial relationships with any companies whose products are mentioned in their letters, or with manufacturers of competing products.

I wanted to thank Dr. Nasrallah for his most important editorial, “Let’s ‘cancel’ these obsolete terms in DSM” (From the Editor, Current Psychiatry, January 2021, p. 4,9-10). Over my 40 years of clinical practice, I never cease to cringe or be pained when “clinical” diagnoses offered are nothing but thinly veiled expressions of contempt for our troubled patients. True clinical compassion honors the horizontal axis in caring for other individuals, honoring our mutually shared imperfection and humanity. The offensive “diagnoses” as delineated by Dr. Nasrallah strengthen a distorted vertical axis, speaking to a moral superiority and contempt as clinicians. If I might humbly add to this list, most personally offensive to me is oppositional defiant disorder. I see nothing of clinical or treatment value to this term, and it strikes me more as a horrible pejorative used to label a child suffering from a brain-based behavioral disorder requiring compassionate treatment. Perhaps other readers would like to add their “top hits” to this ignominious list. Many thanks, Dr. Nasrallah!

Robert Barris, MD
Nassau University Medical Center
East Meadow, New York

How sad! This is my reaction to reading Dr. Nasrallah’s January 2021 editorial. Although biological psychiatry is synonymous with brain neurotransmitters and psychopharmacology, absent from this perspective is the visible biology of the human organism, specifically Sigmund Freud’s discovery of the psychosexual development of the infant and child and Wilhelm Reich’s discovery of characterological and muscular armor. Medicine, a natural science, is founded and grounded in observation. Psychiatry, having ignored and eliminated (“canceled”) recognition of these readily observable phenomena essential to understanding psychiatric disorders, including neurosis and schizophrenia, allows Dr. Nasrallah to suggest we “cancel” what should be at the heart of psychiatric diagnosis and treatment. Sadly, this heart has been lost for decades.

Howard Chavis, MD
New York, New York

Dr. Nasrallah responds

Psychiatry, like all medical and scientific disciplines, must go through an ongoing renewal, including the update of its terminology, with or without a change in its concepts or principles. Anxiety is a more accurate description of clinical symptoms than neurosis, and psychosis spectrum is more accurate than schizophrenia. Besides the accuracy issue, “neurotic” and “schizophrenic” have unfortunately devolved into pejorative and stigmatizing terms. The lexicon of psychiatry has gone through seismic changes over the past several decades, as I described in a previous editorial.¹ Psychiatry is a vibrant, constantly evolving biopsychosocial/clinical neuroscience, not a static descriptive discipline.

Reference

1. Nasrallah HA. From bedlam to biomarkers: the transformation of psychiatry’s terminology reflects its 4 conceptual earthquakes. Current Psychiatry. 2015;14(1):5-7.

I found myself having difficulty with Dr. Nasrallah’s editorial about canceling “obsolete” terms. I agree that making a diagnosis of borderline or narcissistic personality disorder can be pejorative if the clinician is using it to manage their own unprocessed counter­transference. While all behavior is brain-mediated, human behavior is influenced by psychological events great and small. I am concerned that you seem to be reducing personality trait disturbances to biological abnormality, pure and simple. Losing psychological understanding of patients while overexplaining behavior as pathological brain dysfunction risks losing why patients see us in the first place.

Michael Friedman, DO
Cherry Hill, New Jersey

Dr. Nasrallah responds

The renaming I suggest goes beyond countertransference. It has to do with scientific validity of the diagnostic construct. And yes, personality traits are heavily genetic, but with some modulation by environmental factors. I suggest reading the seminal works of Thomas J. Bouchard Jr., PhD, and Kenneth S. Kendler, MD, on identical twins reared together or apart for more details about the genetics of personality traits.

Disclosures

The authors report no financial relationships with any companies whose products are mentioned in their letters, or with manufacturers of competing products.

I wanted to thank Dr. Nasrallah for his most important editorial, “Let’s ‘cancel’ these obsolete terms in DSM” (From the Editor, Current Psychiatry, January 2021, p. 4,9-10). Over my 40 years of clinical practice, I never cease to cringe or be pained when “clinical” diagnoses offered are nothing but thinly veiled expressions of contempt for our troubled patients. True clinical compassion honors the horizontal axis in caring for other individuals, honoring our mutually shared imperfection and humanity. The offensive “diagnoses” as delineated by Dr. Nasrallah strengthen a distorted vertical axis, speaking to a moral superiority and contempt as clinicians. If I might humbly add to this list, most personally offensive to me is oppositional defiant disorder. I see nothing of clinical or treatment value to this term, and it strikes me more as a horrible pejorative used to label a child suffering from a brain-based behavioral disorder requiring compassionate treatment. Perhaps other readers would like to add their “top hits” to this ignominious list. Many thanks, Dr. Nasrallah!

Robert Barris, MD
Nassau University Medical Center
East Meadow, New York

How sad! This is my reaction to reading Dr. Nasrallah’s January 2021 editorial. Although biological psychiatry is synonymous with brain neurotransmitters and psychopharmacology, absent from this perspective is the visible biology of the human organism, specifically Sigmund Freud’s discovery of the psychosexual development of the infant and child and Wilhelm Reich’s discovery of characterological and muscular armor. Medicine, a natural science, is founded and grounded in observation. Psychiatry, having ignored and eliminated (“canceled”) recognition of these readily observable phenomena essential to understanding psychiatric disorders, including neurosis and schizophrenia, allows Dr. Nasrallah to suggest we “cancel” what should be at the heart of psychiatric diagnosis and treatment. Sadly, this heart has been lost for decades.

Howard Chavis, MD
New York, New York

Dr. Nasrallah responds

Psychiatry, like all medical and scientific disciplines, must go through an ongoing renewal, including the update of its terminology, with or without a change in its concepts or principles. Anxiety is a more accurate description of clinical symptoms than neurosis, and psychosis spectrum is more accurate than schizophrenia. Besides the accuracy issue, “neurotic” and “schizophrenic” have unfortunately devolved into pejorative and stigmatizing terms. The lexicon of psychiatry has gone through seismic changes over the past several decades, as I described in a previous editorial.¹ Psychiatry is a vibrant, constantly evolving biopsychosocial/clinical neuroscience, not a static descriptive discipline.

Reference

1. Nasrallah HA. From bedlam to biomarkers: the transformation of psychiatry’s terminology reflects its 4 conceptual earthquakes. Current Psychiatry. 2015;14(1):5-7.

I found myself having difficulty with Dr. Nasrallah’s editorial about canceling “obsolete” terms. I agree that making a diagnosis of borderline or narcissistic personality disorder can be pejorative if the clinician is using it to manage their own unprocessed counter­transference. While all behavior is brain-mediated, human behavior is influenced by psychological events great and small. I am concerned that you seem to be reducing personality trait disturbances to biological abnormality, pure and simple. Losing psychological understanding of patients while overexplaining behavior as pathological brain dysfunction risks losing why patients see us in the first place.

Michael Friedman, DO
Cherry Hill, New Jersey

Dr. Nasrallah responds

The renaming I suggest goes beyond countertransference. It has to do with scientific validity of the diagnostic construct. And yes, personality traits are heavily genetic, but with some modulation by environmental factors. I suggest reading the seminal works of Thomas J. Bouchard Jr., PhD, and Kenneth S. Kendler, MD, on identical twins reared together or apart for more details about the genetics of personality traits.

Disclosures

The authors report no financial relationships with any companies whose products are mentioned in their letters, or with manufacturers of competing products.

New data from the IMvigor130 trial have augmented oncologists’ knowledge about the treatment of locally advanced or metastatic urothelial carcinoma (mUC) with the immune checkpoint inhibitor atezolizumab.

A second interim overall survival (OS) analysis suggested that atezolizumab monotherapy provides a clinical benefit as first-line treatment for mUC patients with PD-L1–expressing immune cells representing at least 5% of the tumor area (IC2/3), including patients who are cisplatin ineligible.

The analysis also suggested that atezolizumab plus chemotherapy produces similar OS results as chemotherapy plus placebo, but patients receiving atezolizumab may do better with cisplatin-based chemotherapy than with carboplatin-based chemotherapy.

These results were reported in two presentations at the American Association for Cancer Research Annual Meeting 2021: Week 1.

Current guidelines from the National Comprehensive Cancer Network and the European Society for Medical Oncology recommend atezolizumab monotherapy for cisplatin-ineligible patients with mUC and PD-L1 IC2/3.

The ongoing phase 3 IMvigor130 trial was designed to compare atezolizumab plus gemcitabine/platinum chemotherapy, atezolizumab monotherapy, and placebo plus chemotherapy. Platinum-based chemotherapy included either cisplatin or carboplatin, per investigator choice.

Coprimary endpoints for IMvigor130 were progression-free survival (PFS) and OS for atezolizumab plus chemotherapy versus placebo plus chemotherapy. The hierarchical study design dictated that OS would only be assessed for the comparison of atezolizumab monotherapy versus placebo-chemotherapy in the overall and PD-L1 IC2/3 populations if there was statistical improvement in OS for the atezolizumab-chemotherapy arm over the placebo-chemotherapy arm.

Secondary endpoints were overall response rate (ORR; per RECIST 1.1), duration of response (DOR) for all patients, and PFS for the comparison between atezolizumab monotherapy and placebo-chemotherapy. Exploratory analyses were performed on cisplatin-ineligible patients by PD-L1 status.

At the time of the primary analysis, an OS benefit for atezolizumab-chemotherapy over placebo-chemotherapy was not observed. Therefore, the OS benefit of atezolizumab monotherapy versus placebo-chemotherapy was not assessed. However, a trend toward improved OS was noted with atezolizumab for PD-L1 IC2/3 patients, including cisplatin-ineligible patients.
 

Atezolizumab vs. placebo-chemo

Ian D. Davis, MBBS, PhD, of Monash University in Melbourne, presented the second interim analysis of OS with atezolizumab monotherapy versus placebo plus chemotherapy (Abstract CT040).

The median follow-up was 14.9 months for atezolizumab monotherapy (n = 360) and 11.8 months for placebo-chemotherapy (n = 359). The median OS was 15.2 months and 13.1 months, respectively (hazard ratio, 0.99; 95% confidence interval, 0.83-1.19). There was no apparent OS benefit of atezolizumab for any clinically selected subgroup.

The ORR was 23.4% for atezolizumab monotherapy and 44.1% for placebo-chemotherapy. The median DOR was more than 3.5 times longer for atezolizumab monotherapy than for placebo-chemotherapy – 29.6 months and 8.1 months, respectively.

Although there was no formal statistical comparison, exploratory subgroup analyses demonstrated that the median OS for the PD-L1 IC2/3 patients appeared higher in the atezolizumab monotherapy arm than in the placebo-chemotherapy arm – 27.5 months and 16.7 months, respectively.

Similarly, the median OS for cisplatin-ineligible PD-L1 IC2/3 patients appeared higher for atezolizumab monotherapy than for placebo-chemotherapy – 18.6 months and 10.0 months, respectively.

In terms of safety, atezolizumab monotherapy compared favorably with placebo plus chemotherapy. There were similar numbers of grade 3/4 adverse events and comparable adverse events leading to discontinuation of treatment in both arms.

The atezolizumab monotherapy arm had fewer adverse events leading to withdrawal from any treatment, when compared with the placebo-chemotherapy arm – 7% and 34%, respectively. Two patients in the atezolizumab arm and one in the placebo-chemotherapy died of treatment-related causes.
 

Atezolizumab-chemo vs. placebo-chemo

Matthew D. Galsky, MD, of Mount Sinai Health System and Icahn School of Medicine at Mount Sinai in New York, presented the second interim OS comparison of atezolizumab plus chemotherapy with placebo plus chemotherapy (Abstract CT042).

The primary analysis had shown a statistically significant improvement in PFS for patients on atezolizumab-chemotherapy, in comparison with placebo-chemotherapy, with encouraging OS improvement, but the boundary for declaring significance for the OS endpoint was not crossed (Lancet. 2020 May 16;395[10236]:1547-1557).

Because IMvigor130 included both patients who received cisplatin and patients who investigators deemed cisplatin ineligible, the second interim analysis included an exploratory analysis of whether there was a difference in outcome between patients who received or did not receive cisplatin.

At a median follow-up of 13.3 months, the median OS was not significantly different in the atezolizumab-chemotherapy arm (n = 451) and the placebo-chemotherapy arm (n = 400) – 16.1 months and 13.4 months, respectively (HR, 0.84; 95% CI, 0.71-1.00; P = .026).

There were no clinically or pathologically defined subgroups that experienced an OS benefit from atezolizumab-chemotherapy over placebo-chemotherapy.

As for subsequent nonprotocol therapy, 24% of the placebo-chemotherapy arm received an immune checkpoint inhibitor at progression, as did 7% of the atezolizumab-chemotherapy arm. There was no difference in receipt of an immune checkpoint inhibitor post progression among patients treated with cisplatin versus carboplatin.

The benefit of combining atezolizumab with chemotherapy appeared more substantial with cisplatin-based chemotherapy than with carboplatin-based treatment. With cisplatin, the median OS was 21.6 months for the atezolizumab-chemotherapy arm and 14.6 months for the placebo-chemotherapy arm. With carboplatin, the median OS was 14.3 months and 13.0 months, respectively.

PD-L1 status was prognostic for patients who received cisplatin, with lower OS being observed for patients with PD-L1 IC0/1 status and higher OS observed for patients with PD-L1 IC2/3 status. Atezolizumab plus cisplatin-based chemotherapy appeared superior to cisplatin-based chemotherapy alone in both PD-L1–low and –high groups.

Atezolizumab did not seem to benefit patients who were treated with carboplatin, and PD-L1 status did not seem to influence OS among the carboplatin-treated patients.

Although similar ORR results were seen with cisplatin and carboplatin, there appeared to be a longer median DOR among cisplatin-treated patients who received atezolizumab than among those who did not – 13.2 months and 8.3 months, respectively.

No such benefit from atezolizumab was seen in carboplatin-treated patients. The median DOR was 8.1 months among patients who received atezolizumab and 7.1 months among those who did not.

The overall safety profile for atezolizumab plus chemotherapy was consistent with prior reports of the combination. Treatment-related grade 3-5 adverse events were similar on the atezolizumab-chemotherapy arm and the placebo-chemotherapy arm.
 

The present and future

The investigators who presented the second interim analysis for OS of the IMvigor130 trial were appropriately modest in their conclusions. After all, the prespecified boundary for significant improvement in OS for the addition of atezolizumab to chemotherapy was not crossed. No change in guideline-based clinical practice would be appropriate at the present time.

The various exploratory analyses are hypothesis generating and invite potential mechanistic explanations. However, given the nonrandom allocation of patients to cisplatin- or carboplatin-based chemotherapy, unrecognized variables may have influenced any appearance of a difference in OS between the regimens.

In IMvigor130, treatment was given until unacceptable toxicity or disease progression. It is uncertain whether the current National Comprehensive Cancer Network category 1 recommendation of chemotherapy induction followed by immune checkpoint inhibitor maintenance therapy will prove superior to the IMvigor130 strategy.

Clearly – and concordant with current treatment guidelines – atezolizumab monotherapy can benefit some patients, though the response rate for atezolizumab monotherapy was lower than for chemotherapy (23.4% vs. 44.1%).

As noted by the session chair, Marina Chiara Garassino, MD, of the University of Chicago, the OS curves were initially superior for chemotherapy over atezolizumab. However, the apparent early OS benefit for chemotherapy dissipated over time and, among responders to atezolizumab, response duration was considerably longer than for chemotherapy.

IMvigor130 will ultimately have a final OS analysis to clarify the relative benefits of the various treatment strategies. Fortunately, this large phase 3 study will yield a treasure trove of data to inform future research and build on the advances of recent years for patients with advanced urothelial cancer.

IMvigor130 is sponsored by Hoffmann-La Roche. Dr. Davis, Dr. Galsky, and Dr. Garassino disclosed relationships with Hoffmann-La Roche and many other companies.
 

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

New data from the IMvigor130 trial have augmented oncologists’ knowledge about the treatment of locally advanced or metastatic urothelial carcinoma (mUC) with the immune checkpoint inhibitor atezolizumab.

A second interim overall survival (OS) analysis suggested that atezolizumab monotherapy provides a clinical benefit as first-line treatment for mUC patients with PD-L1–expressing immune cells representing at least 5% of the tumor area (IC2/3), including patients who are cisplatin ineligible.

The analysis also suggested that atezolizumab plus chemotherapy produces similar OS results as chemotherapy plus placebo, but patients receiving atezolizumab may do better with cisplatin-based chemotherapy than with carboplatin-based chemotherapy.

These results were reported in two presentations at the American Association for Cancer Research Annual Meeting 2021: Week 1.

Current guidelines from the National Comprehensive Cancer Network and the European Society for Medical Oncology recommend atezolizumab monotherapy for cisplatin-ineligible patients with mUC and PD-L1 IC2/3.

The ongoing phase 3 IMvigor130 trial was designed to compare atezolizumab plus gemcitabine/platinum chemotherapy, atezolizumab monotherapy, and placebo plus chemotherapy. Platinum-based chemotherapy included either cisplatin or carboplatin, per investigator choice.

Coprimary endpoints for IMvigor130 were progression-free survival (PFS) and OS for atezolizumab plus chemotherapy versus placebo plus chemotherapy. The hierarchical study design dictated that OS would only be assessed for the comparison of atezolizumab monotherapy versus placebo-chemotherapy in the overall and PD-L1 IC2/3 populations if there was statistical improvement in OS for the atezolizumab-chemotherapy arm over the placebo-chemotherapy arm.

Secondary endpoints were overall response rate (ORR; per RECIST 1.1), duration of response (DOR) for all patients, and PFS for the comparison between atezolizumab monotherapy and placebo-chemotherapy. Exploratory analyses were performed on cisplatin-ineligible patients by PD-L1 status.

At the time of the primary analysis, an OS benefit for atezolizumab-chemotherapy over placebo-chemotherapy was not observed. Therefore, the OS benefit of atezolizumab monotherapy versus placebo-chemotherapy was not assessed. However, a trend toward improved OS was noted with atezolizumab for PD-L1 IC2/3 patients, including cisplatin-ineligible patients.
 

Atezolizumab vs. placebo-chemo

Ian D. Davis, MBBS, PhD, of Monash University in Melbourne, presented the second interim analysis of OS with atezolizumab monotherapy versus placebo plus chemotherapy (Abstract CT040).

The median follow-up was 14.9 months for atezolizumab monotherapy (n = 360) and 11.8 months for placebo-chemotherapy (n = 359). The median OS was 15.2 months and 13.1 months, respectively (hazard ratio, 0.99; 95% confidence interval, 0.83-1.19). There was no apparent OS benefit of atezolizumab for any clinically selected subgroup.

The ORR was 23.4% for atezolizumab monotherapy and 44.1% for placebo-chemotherapy. The median DOR was more than 3.5 times longer for atezolizumab monotherapy than for placebo-chemotherapy – 29.6 months and 8.1 months, respectively.

Although there was no formal statistical comparison, exploratory subgroup analyses demonstrated that the median OS for the PD-L1 IC2/3 patients appeared higher in the atezolizumab monotherapy arm than in the placebo-chemotherapy arm – 27.5 months and 16.7 months, respectively.

Similarly, the median OS for cisplatin-ineligible PD-L1 IC2/3 patients appeared higher for atezolizumab monotherapy than for placebo-chemotherapy – 18.6 months and 10.0 months, respectively.

In terms of safety, atezolizumab monotherapy compared favorably with placebo plus chemotherapy. There were similar numbers of grade 3/4 adverse events and comparable adverse events leading to discontinuation of treatment in both arms.

The atezolizumab monotherapy arm had fewer adverse events leading to withdrawal from any treatment, when compared with the placebo-chemotherapy arm – 7% and 34%, respectively. Two patients in the atezolizumab arm and one in the placebo-chemotherapy died of treatment-related causes.
 

Atezolizumab-chemo vs. placebo-chemo

Matthew D. Galsky, MD, of Mount Sinai Health System and Icahn School of Medicine at Mount Sinai in New York, presented the second interim OS comparison of atezolizumab plus chemotherapy with placebo plus chemotherapy (Abstract CT042).

The primary analysis had shown a statistically significant improvement in PFS for patients on atezolizumab-chemotherapy, in comparison with placebo-chemotherapy, with encouraging OS improvement, but the boundary for declaring significance for the OS endpoint was not crossed (Lancet. 2020 May 16;395[10236]:1547-1557).

Because IMvigor130 included both patients who received cisplatin and patients who investigators deemed cisplatin ineligible, the second interim analysis included an exploratory analysis of whether there was a difference in outcome between patients who received or did not receive cisplatin.

At a median follow-up of 13.3 months, the median OS was not significantly different in the atezolizumab-chemotherapy arm (n = 451) and the placebo-chemotherapy arm (n = 400) – 16.1 months and 13.4 months, respectively (HR, 0.84; 95% CI, 0.71-1.00; P = .026).

There were no clinically or pathologically defined subgroups that experienced an OS benefit from atezolizumab-chemotherapy over placebo-chemotherapy.

As for subsequent nonprotocol therapy, 24% of the placebo-chemotherapy arm received an immune checkpoint inhibitor at progression, as did 7% of the atezolizumab-chemotherapy arm. There was no difference in receipt of an immune checkpoint inhibitor post progression among patients treated with cisplatin versus carboplatin.

The benefit of combining atezolizumab with chemotherapy appeared more substantial with cisplatin-based chemotherapy than with carboplatin-based treatment. With cisplatin, the median OS was 21.6 months for the atezolizumab-chemotherapy arm and 14.6 months for the placebo-chemotherapy arm. With carboplatin, the median OS was 14.3 months and 13.0 months, respectively.

PD-L1 status was prognostic for patients who received cisplatin, with lower OS being observed for patients with PD-L1 IC0/1 status and higher OS observed for patients with PD-L1 IC2/3 status. Atezolizumab plus cisplatin-based chemotherapy appeared superior to cisplatin-based chemotherapy alone in both PD-L1–low and –high groups.

Atezolizumab did not seem to benefit patients who were treated with carboplatin, and PD-L1 status did not seem to influence OS among the carboplatin-treated patients.

Although similar ORR results were seen with cisplatin and carboplatin, there appeared to be a longer median DOR among cisplatin-treated patients who received atezolizumab than among those who did not – 13.2 months and 8.3 months, respectively.

No such benefit from atezolizumab was seen in carboplatin-treated patients. The median DOR was 8.1 months among patients who received atezolizumab and 7.1 months among those who did not.

The overall safety profile for atezolizumab plus chemotherapy was consistent with prior reports of the combination. Treatment-related grade 3-5 adverse events were similar on the atezolizumab-chemotherapy arm and the placebo-chemotherapy arm.
 

The present and future

The investigators who presented the second interim analysis for OS of the IMvigor130 trial were appropriately modest in their conclusions. After all, the prespecified boundary for significant improvement in OS for the addition of atezolizumab to chemotherapy was not crossed. No change in guideline-based clinical practice would be appropriate at the present time.

The various exploratory analyses are hypothesis generating and invite potential mechanistic explanations. However, given the nonrandom allocation of patients to cisplatin- or carboplatin-based chemotherapy, unrecognized variables may have influenced any appearance of a difference in OS between the regimens.

In IMvigor130, treatment was given until unacceptable toxicity or disease progression. It is uncertain whether the current National Comprehensive Cancer Network category 1 recommendation of chemotherapy induction followed by immune checkpoint inhibitor maintenance therapy will prove superior to the IMvigor130 strategy.

Clearly – and concordant with current treatment guidelines – atezolizumab monotherapy can benefit some patients, though the response rate for atezolizumab monotherapy was lower than for chemotherapy (23.4% vs. 44.1%).

As noted by the session chair, Marina Chiara Garassino, MD, of the University of Chicago, the OS curves were initially superior for chemotherapy over atezolizumab. However, the apparent early OS benefit for chemotherapy dissipated over time and, among responders to atezolizumab, response duration was considerably longer than for chemotherapy.

IMvigor130 will ultimately have a final OS analysis to clarify the relative benefits of the various treatment strategies. Fortunately, this large phase 3 study will yield a treasure trove of data to inform future research and build on the advances of recent years for patients with advanced urothelial cancer.

IMvigor130 is sponsored by Hoffmann-La Roche. Dr. Davis, Dr. Galsky, and Dr. Garassino disclosed relationships with Hoffmann-La Roche and many other companies.
 

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

New data from the IMvigor130 trial have augmented oncologists’ knowledge about the treatment of locally advanced or metastatic urothelial carcinoma (mUC) with the immune checkpoint inhibitor atezolizumab.

A second interim overall survival (OS) analysis suggested that atezolizumab monotherapy provides a clinical benefit as first-line treatment for mUC patients with PD-L1–expressing immune cells representing at least 5% of the tumor area (IC2/3), including patients who are cisplatin ineligible.

The analysis also suggested that atezolizumab plus chemotherapy produces similar OS results as chemotherapy plus placebo, but patients receiving atezolizumab may do better with cisplatin-based chemotherapy than with carboplatin-based chemotherapy.

These results were reported in two presentations at the American Association for Cancer Research Annual Meeting 2021: Week 1.

Current guidelines from the National Comprehensive Cancer Network and the European Society for Medical Oncology recommend atezolizumab monotherapy for cisplatin-ineligible patients with mUC and PD-L1 IC2/3.

The ongoing phase 3 IMvigor130 trial was designed to compare atezolizumab plus gemcitabine/platinum chemotherapy, atezolizumab monotherapy, and placebo plus chemotherapy. Platinum-based chemotherapy included either cisplatin or carboplatin, per investigator choice.

Coprimary endpoints for IMvigor130 were progression-free survival (PFS) and OS for atezolizumab plus chemotherapy versus placebo plus chemotherapy. The hierarchical study design dictated that OS would only be assessed for the comparison of atezolizumab monotherapy versus placebo-chemotherapy in the overall and PD-L1 IC2/3 populations if there was statistical improvement in OS for the atezolizumab-chemotherapy arm over the placebo-chemotherapy arm.

Secondary endpoints were overall response rate (ORR; per RECIST 1.1), duration of response (DOR) for all patients, and PFS for the comparison between atezolizumab monotherapy and placebo-chemotherapy. Exploratory analyses were performed on cisplatin-ineligible patients by PD-L1 status.

At the time of the primary analysis, an OS benefit for atezolizumab-chemotherapy over placebo-chemotherapy was not observed. Therefore, the OS benefit of atezolizumab monotherapy versus placebo-chemotherapy was not assessed. However, a trend toward improved OS was noted with atezolizumab for PD-L1 IC2/3 patients, including cisplatin-ineligible patients.
 

Atezolizumab vs. placebo-chemo

Ian D. Davis, MBBS, PhD, of Monash University in Melbourne, presented the second interim analysis of OS with atezolizumab monotherapy versus placebo plus chemotherapy (Abstract CT040).

The median follow-up was 14.9 months for atezolizumab monotherapy (n = 360) and 11.8 months for placebo-chemotherapy (n = 359). The median OS was 15.2 months and 13.1 months, respectively (hazard ratio, 0.99; 95% confidence interval, 0.83-1.19). There was no apparent OS benefit of atezolizumab for any clinically selected subgroup.

The ORR was 23.4% for atezolizumab monotherapy and 44.1% for placebo-chemotherapy. The median DOR was more than 3.5 times longer for atezolizumab monotherapy than for placebo-chemotherapy – 29.6 months and 8.1 months, respectively.

Although there was no formal statistical comparison, exploratory subgroup analyses demonstrated that the median OS for the PD-L1 IC2/3 patients appeared higher in the atezolizumab monotherapy arm than in the placebo-chemotherapy arm – 27.5 months and 16.7 months, respectively.

Similarly, the median OS for cisplatin-ineligible PD-L1 IC2/3 patients appeared higher for atezolizumab monotherapy than for placebo-chemotherapy – 18.6 months and 10.0 months, respectively.

In terms of safety, atezolizumab monotherapy compared favorably with placebo plus chemotherapy. There were similar numbers of grade 3/4 adverse events and comparable adverse events leading to discontinuation of treatment in both arms.

The atezolizumab monotherapy arm had fewer adverse events leading to withdrawal from any treatment, when compared with the placebo-chemotherapy arm – 7% and 34%, respectively. Two patients in the atezolizumab arm and one in the placebo-chemotherapy died of treatment-related causes.
 

Atezolizumab-chemo vs. placebo-chemo

Matthew D. Galsky, MD, of Mount Sinai Health System and Icahn School of Medicine at Mount Sinai in New York, presented the second interim OS comparison of atezolizumab plus chemotherapy with placebo plus chemotherapy (Abstract CT042).

The primary analysis had shown a statistically significant improvement in PFS for patients on atezolizumab-chemotherapy, in comparison with placebo-chemotherapy, with encouraging OS improvement, but the boundary for declaring significance for the OS endpoint was not crossed (Lancet. 2020 May 16;395[10236]:1547-1557).

Because IMvigor130 included both patients who received cisplatin and patients who investigators deemed cisplatin ineligible, the second interim analysis included an exploratory analysis of whether there was a difference in outcome between patients who received or did not receive cisplatin.

At a median follow-up of 13.3 months, the median OS was not significantly different in the atezolizumab-chemotherapy arm (n = 451) and the placebo-chemotherapy arm (n = 400) – 16.1 months and 13.4 months, respectively (HR, 0.84; 95% CI, 0.71-1.00; P = .026).

There were no clinically or pathologically defined subgroups that experienced an OS benefit from atezolizumab-chemotherapy over placebo-chemotherapy.

As for subsequent nonprotocol therapy, 24% of the placebo-chemotherapy arm received an immune checkpoint inhibitor at progression, as did 7% of the atezolizumab-chemotherapy arm. There was no difference in receipt of an immune checkpoint inhibitor post progression among patients treated with cisplatin versus carboplatin.

The benefit of combining atezolizumab with chemotherapy appeared more substantial with cisplatin-based chemotherapy than with carboplatin-based treatment. With cisplatin, the median OS was 21.6 months for the atezolizumab-chemotherapy arm and 14.6 months for the placebo-chemotherapy arm. With carboplatin, the median OS was 14.3 months and 13.0 months, respectively.

PD-L1 status was prognostic for patients who received cisplatin, with lower OS being observed for patients with PD-L1 IC0/1 status and higher OS observed for patients with PD-L1 IC2/3 status. Atezolizumab plus cisplatin-based chemotherapy appeared superior to cisplatin-based chemotherapy alone in both PD-L1–low and –high groups.

Atezolizumab did not seem to benefit patients who were treated with carboplatin, and PD-L1 status did not seem to influence OS among the carboplatin-treated patients.

Although similar ORR results were seen with cisplatin and carboplatin, there appeared to be a longer median DOR among cisplatin-treated patients who received atezolizumab than among those who did not – 13.2 months and 8.3 months, respectively.

No such benefit from atezolizumab was seen in carboplatin-treated patients. The median DOR was 8.1 months among patients who received atezolizumab and 7.1 months among those who did not.

The overall safety profile for atezolizumab plus chemotherapy was consistent with prior reports of the combination. Treatment-related grade 3-5 adverse events were similar on the atezolizumab-chemotherapy arm and the placebo-chemotherapy arm.
 

The present and future

The investigators who presented the second interim analysis for OS of the IMvigor130 trial were appropriately modest in their conclusions. After all, the prespecified boundary for significant improvement in OS for the addition of atezolizumab to chemotherapy was not crossed. No change in guideline-based clinical practice would be appropriate at the present time.

The various exploratory analyses are hypothesis generating and invite potential mechanistic explanations. However, given the nonrandom allocation of patients to cisplatin- or carboplatin-based chemotherapy, unrecognized variables may have influenced any appearance of a difference in OS between the regimens.

In IMvigor130, treatment was given until unacceptable toxicity or disease progression. It is uncertain whether the current National Comprehensive Cancer Network category 1 recommendation of chemotherapy induction followed by immune checkpoint inhibitor maintenance therapy will prove superior to the IMvigor130 strategy.

Clearly – and concordant with current treatment guidelines – atezolizumab monotherapy can benefit some patients, though the response rate for atezolizumab monotherapy was lower than for chemotherapy (23.4% vs. 44.1%).

As noted by the session chair, Marina Chiara Garassino, MD, of the University of Chicago, the OS curves were initially superior for chemotherapy over atezolizumab. However, the apparent early OS benefit for chemotherapy dissipated over time and, among responders to atezolizumab, response duration was considerably longer than for chemotherapy.

IMvigor130 will ultimately have a final OS analysis to clarify the relative benefits of the various treatment strategies. Fortunately, this large phase 3 study will yield a treasure trove of data to inform future research and build on the advances of recent years for patients with advanced urothelial cancer.

IMvigor130 is sponsored by Hoffmann-La Roche. Dr. Davis, Dr. Galsky, and Dr. Garassino disclosed relationships with Hoffmann-La Roche and many other companies.
 

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Dear colleagues and friends,

The Perspectives series returns, this time with an exciting discussion about antibiotic use in acute uncomplicated diverticulitis. It has been fascinating to witness this field evolve from an era where not using antibiotics was inconceivable! Dr. Anne F. Peery and Dr. Neil Stollman, both recognized experts in the matter, provide arguments to both sides of the debate, as well as much-needed nuance. As always, I welcome your comments and suggestions for future topics at ginews@gastro.org. Thank you for your support, and I hope you will enjoy the reading and learning from this as much as I did.

Charles J. Kahi, MD, MS, AGAF, is a professor of medicine at Indiana University, Indianapolis. He is also an associate editor for GI & Hepatology News.

Think carefully about when to withhold

For decades, it was standard practice to give antibiotics to all patients with acute uncomplicated diverticulitis (AUD). While most patients with a first diagnosis of AUD recover within a few weeks, a small proportion will develop a complication.¹ Among generally healthy patients with an initial diagnosis of AUD, about 3% will progress to complicated diverticulitis, and about 1% will require emergency surgery within 6 months. Around another 6% of cases will develop chronic diverticulitis with ongoing diverticular inflammation that persists for weeks to months.

Because the complications are uncommon, we don’t know if antibiotics reduce the risk of progression to complicated diverticulitis, emergency surgery, or the development of chronic diverticulitis. Investigating these patient-centered and morbid outcomes would require trials enrolling thousands of patients and to following these patients for months. This trial hasn’t happened yet.

To date, only small studies have compared the use of antibiotics with no antibiotics in patients with AUD. A review sponsored by the Agency for Healthcare Research and Quality published last year concluded that the current evidence was too sparse or too inconsistent to make strong conclusions about the use of antibiotics for patients with uncomplicated diverticulitis.²

With little evidence for or against antibiotics, recent guidelines have begun to recommend that antibiotics be used selectively, rather than routinely, in patients with diverticulitis.³ “Selectively” clearly means that there are some patients who should receive antibiotics, but the guidelines are vague about who those patients are. To this end, it is safest to refer to those small, underpowered trials to identify which patients are at the greatest risk of developing a complication.^1,4 The authors of those trials considered a number of groups high risk and therefore excluded them from those trials. In the absence of further definitive research, it seems clear that those groups, listed below, should therefore be selected for antibiotic treatment:

• Patients with complicated diverticulitis including paracolic extraluminal air on CT scan.
• Patients who are immunocompromised.
• Patients with a high fever, affected general condition, or clinical suspicion of sepsis.
• Patients with inflammatory bowel disease.
• Patients who are pregnant or breast feeding.

As with most clinical trials, participants in these smaller trials were younger (median age, late 50s) and healthier (63% normal, healthy patient; 34% mild systemic disease; 4% severe systemic disease) than the general population. In secondary analyses, however, several factors were independently associated with a complicated disease course after an initial diagnosis of acute uncomplicated diverticulitis. As with the first list above, the following high-risk patients should also be treated with antibiotics at diagnosis:

• Patients with American Society of Anesthesiologists scores III or IV were 4.4 times more likely to have a poor outcome, compared with those with ASA score I.
• Patients with ASA score II were 2.0 times more likely to have a poor outcome, compared with ASA score I.
• Patients with symptoms for more than 5 days at diagnosis were 3.3 times more likely to have a poor outcome, compared with those with symptoms for 5 days or less.
• Patients with vomiting at diagnosis were 3.9 times more likely to have a poor outcome, compared with those who were not vomiting.
• Patients with C-reactive protein levels higher than 140 mg/L at diagnosis were 2.9 times more likely to have a poor outcome, compared with C-reactive protein level of 140 mg/L or less.
• Patients with white blood cell count greater than 15 x 10⁹ cells/L at diagnosis were 3.7 times more likely to have a poor outcome, compared with those with 15 x 10⁹ cells/L.
• Patients with a longer segment (>86mm) of inflamed colon on CT scan were more likely to have a poor outcome, compared those who had a shorter segment (<65mm).

To help clinicians think about antibiotic treatment in patients with AUD, a recent American Gastroenterological Association clinical practice update provided the following advice: First, antibiotic treatment is advised in patients with uncomplicated diverticulitis who have comorbidities or are frail, who present with refractory symptoms or vomiting, or who have a C-reactive protein level greater than 140 mg/L, or baseline white blood cell count greater than 15 x 10⁹ cells/L.⁵ Also, antibiotic treatment is advised in patients with complicated diverticulitis or uncomplicated diverticulitis with a fluid collection or longer segment of inflammation on CT scan. Finally, patients with uncomplicated diverticulitis who are immunosuppressed are high risk for progression to complicated diverticulitis or sepsis and should be treated with antibiotics.

The lists above clearly leave some patients with AUD who may be managed without antibiotics. These patients are otherwise healthy, have good social support, access to health care, and are experiencing a mild, self-limited episode. Avoiding antibiotics requires shared decision-making with a well-informed patient. I have patients who have embraced this approach, while others found this unacceptable. Given the current level of uncertainty in the literature, I make it my practice to offer antibiotics to any patient who feels strongly about receiving them.

As with many issues in modern medicine, the use of antibiotics in AUD is an unsettled question. Given the known harms of progression of diverticulitis, it is clearly safest to treat patients who were excluded from the small studies we have or flagged by those same studies as being at increased risk of progression. Our uncertainty also demands a shared decision-making model, filling in our patients on what we can and cannot say with confidence. As is often the case, further research is desperately needed. Until that happens, antibiotics for AUD will remain a regular part of my practice.

Anne F. Peery, MD, MSCR, is with the center for gastrointestinal biology and disease at the University of North Carolina at Chapel Hill. She has no conflicts to disclose.

References

1. Daniels L et al. Br J Surg. 2017 Jan;104(1):52-61.

2. Balk EM et al. Management of Colonic Diverticulitis. Comparative Effectiveness Review No. 233. Agency for Healthcare Research and Quality. 2020 Oct. doi: 10.23970/AHRQEPCCER233.

3. Stollman N et al. Gastroenterology. 2015 Dec;149(7):1944-9.

4. Chabok A et al. Br J Surg. 2012 Jan 30;99(4):532-9.

5. Peery AF et al. Gastroenterology. 2021 Feb;160(3):906-11.e1.

The data are robust for withholding more often

That we are engaged in a legitimate debate about the role of antibiotics in acute uncomplicated diverticulitis (AUD) is itself quite notable. In the 1999 American College of Gastroenterology Practice Guidelines,¹ we did not even entertain the concept of withholding antibiotics; the only discussion points were intravenous versus oral. Fast forward 15 years, and in the 2015 American Gastroenterological Association practice guidelines (which the other contributor for this installment of Perspectives, Anne F. Peery, MD, and I worked on together) our first recommendation was that antibiotics should be used “selectively,” rather than routinely.² This did generate some raised eyebrows and hand-wringing in the community, but our position was the result of a rigorous data analysis process and we stood by it.

In fact, Dr. Peery and I also coauthored an accompanying editorial that concluded with an important endorsement “allowing the clinician to consider withholding antibiotics from select uncomplicated patients with mild disease.” I suspect, then, that Dr. Peery and I are very much coincident in our overall thoughts here, and I’m pretty sure that neither of us would defend an “always” or “never” stance on this issue, so for this educational debate, we’re really talking about where in the middle to draw the line (that is, how to define “selectively”). To that end, I will defend the supposition that the subsequent data in support of withholding antibiotics remains robust and even more supportive of this practice in many (but certainly not all) patients with acute, uncomplicated diverticulitis.

The logic underlying selective use was based on two drivers over the past decade, one being an emerging concept that diverticular pathology was often inflammatory rather than solely infectious, coupled with a timely and very important worldwide push toward restraint of antibiotic use. A recent retrospective claims analysis of outpatient antibiotic use for immunocompetent patients with AUD did reported that the dominant antibiotic combination used, metronidazole plus a fluoroquinolone, was associated with an increased risk of Clostridioides difficile infection, compared with the far less frequently used amoxicillin/clavulanate regimen, which highlights that routine antibiotics are not without risk.³

Recently, the U.S. Agency for Healthcare Research and Quality performed a rigorous meta-analysis of this body of evidence, and summarized that “antibiotic treatment may not affect pain symptoms, length of hospital stay, recurrence risk, quality of life, or need for surgery, compared to no antibiotic treatment,” with an admitted low strength of evidence (based on four randomized, controlled trials).⁴

Finally, I’ll close my evidence-based case with a quote from a Clinical Practice Update just published in February 2021 in Gastroenterology: “Antibiotic treatment can be used selectively, rather than routinely, in immunocompetent patients with mild uncomplicated diverticulitis. ... Antibiotic treatment is advised in patients with uncomplicated diverticulitis who have comorbidities or are frail, who present with refractory symptoms or vomiting, or who have a [C-reactive protein] >140 mg/L or baseline [white blood cell count] > 15 x 10⁹. Antibiotic treatment is advised in patients with complicated diverticulitis or uncomplicated diverticulitis with a fluid collection or longer segment of inflammation on CT scan.”⁵ I think this is most excellent advice, providing a practical and clinically useful framework for those in whom antibiotics absolutely should be used, but permitting a fairly large group to avoid antibiotics, which may carry significant harm, based on strong consistent data that does not support a benefit.

So, practically speaking, things are a bit harder for us now when our patient shows up in the ED and if found to have AUD on CT. In the “old days” (that is, the early 2000s), a patient with either clinically suspected or CT-confirmed AUD was simply given antibiotics, mostly a fluoroquinolone, and this was community standard. The only real decision tree was inpatient or outpatient. But now, I would respectfully suggest, we need to invest a bit more time on a nuanced discussion with the potential “no antibiotics” patient (for example, one without immunosuppression, severe comorbidities, or lab or imaging markers of aggressive disease). It is now appropriate to inform such a patient that the data suggest that a conservative approach will not increase their risk of complications and may well spare them antibiotic-related morbidity.

In the context of that informed discussion, factually framed by the practitioner, many patients should (and will, in my experience, although the San Francisco Bay Area may not entirely reflect the country as a whole) choose a strategy of observation. Of course, close follow-up with such patients is required, as is clear reassurance that if things “turn bad” that we’re available and antibiotics remain a salvage option. The “write a script and be done” days are over, and while withholding antibiotics may still feel dangerous or uncomfortable to the patient (or to us), the data is the data, and our patients deserve to at least be offered that option.

Neil Stollman, MD, AGAF, FACG, is chairman of the division of gastroenterology at Alta Bates Summit Medical Center in Oakland, Calif., and an associate clinical professor of medicine in the division of gastroenterology at the University of California, San Francisco. He discloses being a consultant for Cosmo Pharmaceuticals, which has a potential future diverticulitis study of a rifampin-class antibiotic.

References

1. Stollman N and Raskin JB. Am J Gastroenterol. 1999 Nov;94(11):3110-21.

2. Peery AF and Stollman N. Gastroenterology. 2015 Dec;149(7):1944-9.

3. Gaber CE et al. Ann Intern Med. 2021 Feb 23. doi: 10.7326/M20-6315.

4. Balk EM et al. Management of Colonic Diverticulitis. Comparative Effectiveness Review No. 233. Agency for Healthcare Research and Quality. October 2020. doi: 10.23970/AHRQEPCCER233.

5. Peery AF et al. Gastroenterology. 2021 Feb;160(3):906-11.e1.

Dear colleagues and friends,

The Perspectives series returns, this time with an exciting discussion about antibiotic use in acute uncomplicated diverticulitis. It has been fascinating to witness this field evolve from an era where not using antibiotics was inconceivable! Dr. Anne F. Peery and Dr. Neil Stollman, both recognized experts in the matter, provide arguments to both sides of the debate, as well as much-needed nuance. As always, I welcome your comments and suggestions for future topics at ginews@gastro.org. Thank you for your support, and I hope you will enjoy the reading and learning from this as much as I did.

Charles J. Kahi, MD, MS, AGAF, is a professor of medicine at Indiana University, Indianapolis. He is also an associate editor for GI & Hepatology News.

Think carefully about when to withhold

For decades, it was standard practice to give antibiotics to all patients with acute uncomplicated diverticulitis (AUD). While most patients with a first diagnosis of AUD recover within a few weeks, a small proportion will develop a complication.¹ Among generally healthy patients with an initial diagnosis of AUD, about 3% will progress to complicated diverticulitis, and about 1% will require emergency surgery within 6 months. Around another 6% of cases will develop chronic diverticulitis with ongoing diverticular inflammation that persists for weeks to months.

Because the complications are uncommon, we don’t know if antibiotics reduce the risk of progression to complicated diverticulitis, emergency surgery, or the development of chronic diverticulitis. Investigating these patient-centered and morbid outcomes would require trials enrolling thousands of patients and to following these patients for months. This trial hasn’t happened yet.

To date, only small studies have compared the use of antibiotics with no antibiotics in patients with AUD. A review sponsored by the Agency for Healthcare Research and Quality published last year concluded that the current evidence was too sparse or too inconsistent to make strong conclusions about the use of antibiotics for patients with uncomplicated diverticulitis.²

With little evidence for or against antibiotics, recent guidelines have begun to recommend that antibiotics be used selectively, rather than routinely, in patients with diverticulitis.³ “Selectively” clearly means that there are some patients who should receive antibiotics, but the guidelines are vague about who those patients are. To this end, it is safest to refer to those small, underpowered trials to identify which patients are at the greatest risk of developing a complication.^1,4 The authors of those trials considered a number of groups high risk and therefore excluded them from those trials. In the absence of further definitive research, it seems clear that those groups, listed below, should therefore be selected for antibiotic treatment:

• Patients with complicated diverticulitis including paracolic extraluminal air on CT scan.
• Patients who are immunocompromised.
• Patients with a high fever, affected general condition, or clinical suspicion of sepsis.
• Patients with inflammatory bowel disease.
• Patients who are pregnant or breast feeding.

As with most clinical trials, participants in these smaller trials were younger (median age, late 50s) and healthier (63% normal, healthy patient; 34% mild systemic disease; 4% severe systemic disease) than the general population. In secondary analyses, however, several factors were independently associated with a complicated disease course after an initial diagnosis of acute uncomplicated diverticulitis. As with the first list above, the following high-risk patients should also be treated with antibiotics at diagnosis:

• Patients with American Society of Anesthesiologists scores III or IV were 4.4 times more likely to have a poor outcome, compared with those with ASA score I.
• Patients with ASA score II were 2.0 times more likely to have a poor outcome, compared with ASA score I.
• Patients with symptoms for more than 5 days at diagnosis were 3.3 times more likely to have a poor outcome, compared with those with symptoms for 5 days or less.
• Patients with vomiting at diagnosis were 3.9 times more likely to have a poor outcome, compared with those who were not vomiting.
• Patients with C-reactive protein levels higher than 140 mg/L at diagnosis were 2.9 times more likely to have a poor outcome, compared with C-reactive protein level of 140 mg/L or less.
• Patients with white blood cell count greater than 15 x 10⁹ cells/L at diagnosis were 3.7 times more likely to have a poor outcome, compared with those with 15 x 10⁹ cells/L.
• Patients with a longer segment (>86mm) of inflamed colon on CT scan were more likely to have a poor outcome, compared those who had a shorter segment (<65mm).

To help clinicians think about antibiotic treatment in patients with AUD, a recent American Gastroenterological Association clinical practice update provided the following advice: First, antibiotic treatment is advised in patients with uncomplicated diverticulitis who have comorbidities or are frail, who present with refractory symptoms or vomiting, or who have a C-reactive protein level greater than 140 mg/L, or baseline white blood cell count greater than 15 x 10⁹ cells/L.⁵ Also, antibiotic treatment is advised in patients with complicated diverticulitis or uncomplicated diverticulitis with a fluid collection or longer segment of inflammation on CT scan. Finally, patients with uncomplicated diverticulitis who are immunosuppressed are high risk for progression to complicated diverticulitis or sepsis and should be treated with antibiotics.

The lists above clearly leave some patients with AUD who may be managed without antibiotics. These patients are otherwise healthy, have good social support, access to health care, and are experiencing a mild, self-limited episode. Avoiding antibiotics requires shared decision-making with a well-informed patient. I have patients who have embraced this approach, while others found this unacceptable. Given the current level of uncertainty in the literature, I make it my practice to offer antibiotics to any patient who feels strongly about receiving them.

As with many issues in modern medicine, the use of antibiotics in AUD is an unsettled question. Given the known harms of progression of diverticulitis, it is clearly safest to treat patients who were excluded from the small studies we have or flagged by those same studies as being at increased risk of progression. Our uncertainty also demands a shared decision-making model, filling in our patients on what we can and cannot say with confidence. As is often the case, further research is desperately needed. Until that happens, antibiotics for AUD will remain a regular part of my practice.

Anne F. Peery, MD, MSCR, is with the center for gastrointestinal biology and disease at the University of North Carolina at Chapel Hill. She has no conflicts to disclose.

References

1. Daniels L et al. Br J Surg. 2017 Jan;104(1):52-61.

2. Balk EM et al. Management of Colonic Diverticulitis. Comparative Effectiveness Review No. 233. Agency for Healthcare Research and Quality. 2020 Oct. doi: 10.23970/AHRQEPCCER233.

3. Stollman N et al. Gastroenterology. 2015 Dec;149(7):1944-9.

4. Chabok A et al. Br J Surg. 2012 Jan 30;99(4):532-9.

5. Peery AF et al. Gastroenterology. 2021 Feb;160(3):906-11.e1.

The data are robust for withholding more often

That we are engaged in a legitimate debate about the role of antibiotics in acute uncomplicated diverticulitis (AUD) is itself quite notable. In the 1999 American College of Gastroenterology Practice Guidelines,¹ we did not even entertain the concept of withholding antibiotics; the only discussion points were intravenous versus oral. Fast forward 15 years, and in the 2015 American Gastroenterological Association practice guidelines (which the other contributor for this installment of Perspectives, Anne F. Peery, MD, and I worked on together) our first recommendation was that antibiotics should be used “selectively,” rather than routinely.² This did generate some raised eyebrows and hand-wringing in the community, but our position was the result of a rigorous data analysis process and we stood by it.

In fact, Dr. Peery and I also coauthored an accompanying editorial that concluded with an important endorsement “allowing the clinician to consider withholding antibiotics from select uncomplicated patients with mild disease.” I suspect, then, that Dr. Peery and I are very much coincident in our overall thoughts here, and I’m pretty sure that neither of us would defend an “always” or “never” stance on this issue, so for this educational debate, we’re really talking about where in the middle to draw the line (that is, how to define “selectively”). To that end, I will defend the supposition that the subsequent data in support of withholding antibiotics remains robust and even more supportive of this practice in many (but certainly not all) patients with acute, uncomplicated diverticulitis.

The logic underlying selective use was based on two drivers over the past decade, one being an emerging concept that diverticular pathology was often inflammatory rather than solely infectious, coupled with a timely and very important worldwide push toward restraint of antibiotic use. A recent retrospective claims analysis of outpatient antibiotic use for immunocompetent patients with AUD did reported that the dominant antibiotic combination used, metronidazole plus a fluoroquinolone, was associated with an increased risk of Clostridioides difficile infection, compared with the far less frequently used amoxicillin/clavulanate regimen, which highlights that routine antibiotics are not without risk.³

Recently, the U.S. Agency for Healthcare Research and Quality performed a rigorous meta-analysis of this body of evidence, and summarized that “antibiotic treatment may not affect pain symptoms, length of hospital stay, recurrence risk, quality of life, or need for surgery, compared to no antibiotic treatment,” with an admitted low strength of evidence (based on four randomized, controlled trials).⁴

Finally, I’ll close my evidence-based case with a quote from a Clinical Practice Update just published in February 2021 in Gastroenterology: “Antibiotic treatment can be used selectively, rather than routinely, in immunocompetent patients with mild uncomplicated diverticulitis. ... Antibiotic treatment is advised in patients with uncomplicated diverticulitis who have comorbidities or are frail, who present with refractory symptoms or vomiting, or who have a [C-reactive protein] >140 mg/L or baseline [white blood cell count] > 15 x 10⁹. Antibiotic treatment is advised in patients with complicated diverticulitis or uncomplicated diverticulitis with a fluid collection or longer segment of inflammation on CT scan.”⁵ I think this is most excellent advice, providing a practical and clinically useful framework for those in whom antibiotics absolutely should be used, but permitting a fairly large group to avoid antibiotics, which may carry significant harm, based on strong consistent data that does not support a benefit.

So, practically speaking, things are a bit harder for us now when our patient shows up in the ED and if found to have AUD on CT. In the “old days” (that is, the early 2000s), a patient with either clinically suspected or CT-confirmed AUD was simply given antibiotics, mostly a fluoroquinolone, and this was community standard. The only real decision tree was inpatient or outpatient. But now, I would respectfully suggest, we need to invest a bit more time on a nuanced discussion with the potential “no antibiotics” patient (for example, one without immunosuppression, severe comorbidities, or lab or imaging markers of aggressive disease). It is now appropriate to inform such a patient that the data suggest that a conservative approach will not increase their risk of complications and may well spare them antibiotic-related morbidity.

In the context of that informed discussion, factually framed by the practitioner, many patients should (and will, in my experience, although the San Francisco Bay Area may not entirely reflect the country as a whole) choose a strategy of observation. Of course, close follow-up with such patients is required, as is clear reassurance that if things “turn bad” that we’re available and antibiotics remain a salvage option. The “write a script and be done” days are over, and while withholding antibiotics may still feel dangerous or uncomfortable to the patient (or to us), the data is the data, and our patients deserve to at least be offered that option.

Neil Stollman, MD, AGAF, FACG, is chairman of the division of gastroenterology at Alta Bates Summit Medical Center in Oakland, Calif., and an associate clinical professor of medicine in the division of gastroenterology at the University of California, San Francisco. He discloses being a consultant for Cosmo Pharmaceuticals, which has a potential future diverticulitis study of a rifampin-class antibiotic.

References

1. Stollman N and Raskin JB. Am J Gastroenterol. 1999 Nov;94(11):3110-21.

2. Peery AF and Stollman N. Gastroenterology. 2015 Dec;149(7):1944-9.

3. Gaber CE et al. Ann Intern Med. 2021 Feb 23. doi: 10.7326/M20-6315.

4. Balk EM et al. Management of Colonic Diverticulitis. Comparative Effectiveness Review No. 233. Agency for Healthcare Research and Quality. October 2020. doi: 10.23970/AHRQEPCCER233.

5. Peery AF et al. Gastroenterology. 2021 Feb;160(3):906-11.e1.

Dear colleagues and friends,

The Perspectives series returns, this time with an exciting discussion about antibiotic use in acute uncomplicated diverticulitis. It has been fascinating to witness this field evolve from an era where not using antibiotics was inconceivable! Dr. Anne F. Peery and Dr. Neil Stollman, both recognized experts in the matter, provide arguments to both sides of the debate, as well as much-needed nuance. As always, I welcome your comments and suggestions for future topics at ginews@gastro.org. Thank you for your support, and I hope you will enjoy the reading and learning from this as much as I did.

Charles J. Kahi, MD, MS, AGAF, is a professor of medicine at Indiana University, Indianapolis. He is also an associate editor for GI & Hepatology News.

Think carefully about when to withhold

For decades, it was standard practice to give antibiotics to all patients with acute uncomplicated diverticulitis (AUD). While most patients with a first diagnosis of AUD recover within a few weeks, a small proportion will develop a complication.¹ Among generally healthy patients with an initial diagnosis of AUD, about 3% will progress to complicated diverticulitis, and about 1% will require emergency surgery within 6 months. Around another 6% of cases will develop chronic diverticulitis with ongoing diverticular inflammation that persists for weeks to months.

Because the complications are uncommon, we don’t know if antibiotics reduce the risk of progression to complicated diverticulitis, emergency surgery, or the development of chronic diverticulitis. Investigating these patient-centered and morbid outcomes would require trials enrolling thousands of patients and to following these patients for months. This trial hasn’t happened yet.

To date, only small studies have compared the use of antibiotics with no antibiotics in patients with AUD. A review sponsored by the Agency for Healthcare Research and Quality published last year concluded that the current evidence was too sparse or too inconsistent to make strong conclusions about the use of antibiotics for patients with uncomplicated diverticulitis.²

With little evidence for or against antibiotics, recent guidelines have begun to recommend that antibiotics be used selectively, rather than routinely, in patients with diverticulitis.³ “Selectively” clearly means that there are some patients who should receive antibiotics, but the guidelines are vague about who those patients are. To this end, it is safest to refer to those small, underpowered trials to identify which patients are at the greatest risk of developing a complication.^1,4 The authors of those trials considered a number of groups high risk and therefore excluded them from those trials. In the absence of further definitive research, it seems clear that those groups, listed below, should therefore be selected for antibiotic treatment:

• Patients with complicated diverticulitis including paracolic extraluminal air on CT scan.
• Patients who are immunocompromised.
• Patients with a high fever, affected general condition, or clinical suspicion of sepsis.
• Patients with inflammatory bowel disease.
• Patients who are pregnant or breast feeding.

As with most clinical trials, participants in these smaller trials were younger (median age, late 50s) and healthier (63% normal, healthy patient; 34% mild systemic disease; 4% severe systemic disease) than the general population. In secondary analyses, however, several factors were independently associated with a complicated disease course after an initial diagnosis of acute uncomplicated diverticulitis. As with the first list above, the following high-risk patients should also be treated with antibiotics at diagnosis:

• Patients with American Society of Anesthesiologists scores III or IV were 4.4 times more likely to have a poor outcome, compared with those with ASA score I.
• Patients with ASA score II were 2.0 times more likely to have a poor outcome, compared with ASA score I.
• Patients with symptoms for more than 5 days at diagnosis were 3.3 times more likely to have a poor outcome, compared with those with symptoms for 5 days or less.
• Patients with vomiting at diagnosis were 3.9 times more likely to have a poor outcome, compared with those who were not vomiting.
• Patients with C-reactive protein levels higher than 140 mg/L at diagnosis were 2.9 times more likely to have a poor outcome, compared with C-reactive protein level of 140 mg/L or less.
• Patients with white blood cell count greater than 15 x 10⁹ cells/L at diagnosis were 3.7 times more likely to have a poor outcome, compared with those with 15 x 10⁹ cells/L.
• Patients with a longer segment (>86mm) of inflamed colon on CT scan were more likely to have a poor outcome, compared those who had a shorter segment (<65mm).

To help clinicians think about antibiotic treatment in patients with AUD, a recent American Gastroenterological Association clinical practice update provided the following advice: First, antibiotic treatment is advised in patients with uncomplicated diverticulitis who have comorbidities or are frail, who present with refractory symptoms or vomiting, or who have a C-reactive protein level greater than 140 mg/L, or baseline white blood cell count greater than 15 x 10⁹ cells/L.⁵ Also, antibiotic treatment is advised in patients with complicated diverticulitis or uncomplicated diverticulitis with a fluid collection or longer segment of inflammation on CT scan. Finally, patients with uncomplicated diverticulitis who are immunosuppressed are high risk for progression to complicated diverticulitis or sepsis and should be treated with antibiotics.

The lists above clearly leave some patients with AUD who may be managed without antibiotics. These patients are otherwise healthy, have good social support, access to health care, and are experiencing a mild, self-limited episode. Avoiding antibiotics requires shared decision-making with a well-informed patient. I have patients who have embraced this approach, while others found this unacceptable. Given the current level of uncertainty in the literature, I make it my practice to offer antibiotics to any patient who feels strongly about receiving them.

As with many issues in modern medicine, the use of antibiotics in AUD is an unsettled question. Given the known harms of progression of diverticulitis, it is clearly safest to treat patients who were excluded from the small studies we have or flagged by those same studies as being at increased risk of progression. Our uncertainty also demands a shared decision-making model, filling in our patients on what we can and cannot say with confidence. As is often the case, further research is desperately needed. Until that happens, antibiotics for AUD will remain a regular part of my practice.

Anne F. Peery, MD, MSCR, is with the center for gastrointestinal biology and disease at the University of North Carolina at Chapel Hill. She has no conflicts to disclose.

References

1. Daniels L et al. Br J Surg. 2017 Jan;104(1):52-61.

2. Balk EM et al. Management of Colonic Diverticulitis. Comparative Effectiveness Review No. 233. Agency for Healthcare Research and Quality. 2020 Oct. doi: 10.23970/AHRQEPCCER233.

3. Stollman N et al. Gastroenterology. 2015 Dec;149(7):1944-9.

4. Chabok A et al. Br J Surg. 2012 Jan 30;99(4):532-9.

5. Peery AF et al. Gastroenterology. 2021 Feb;160(3):906-11.e1.

The data are robust for withholding more often

That we are engaged in a legitimate debate about the role of antibiotics in acute uncomplicated diverticulitis (AUD) is itself quite notable. In the 1999 American College of Gastroenterology Practice Guidelines,¹ we did not even entertain the concept of withholding antibiotics; the only discussion points were intravenous versus oral. Fast forward 15 years, and in the 2015 American Gastroenterological Association practice guidelines (which the other contributor for this installment of Perspectives, Anne F. Peery, MD, and I worked on together) our first recommendation was that antibiotics should be used “selectively,” rather than routinely.² This did generate some raised eyebrows and hand-wringing in the community, but our position was the result of a rigorous data analysis process and we stood by it.

In fact, Dr. Peery and I also coauthored an accompanying editorial that concluded with an important endorsement “allowing the clinician to consider withholding antibiotics from select uncomplicated patients with mild disease.” I suspect, then, that Dr. Peery and I are very much coincident in our overall thoughts here, and I’m pretty sure that neither of us would defend an “always” or “never” stance on this issue, so for this educational debate, we’re really talking about where in the middle to draw the line (that is, how to define “selectively”). To that end, I will defend the supposition that the subsequent data in support of withholding antibiotics remains robust and even more supportive of this practice in many (but certainly not all) patients with acute, uncomplicated diverticulitis.

The logic underlying selective use was based on two drivers over the past decade, one being an emerging concept that diverticular pathology was often inflammatory rather than solely infectious, coupled with a timely and very important worldwide push toward restraint of antibiotic use. A recent retrospective claims analysis of outpatient antibiotic use for immunocompetent patients with AUD did reported that the dominant antibiotic combination used, metronidazole plus a fluoroquinolone, was associated with an increased risk of Clostridioides difficile infection, compared with the far less frequently used amoxicillin/clavulanate regimen, which highlights that routine antibiotics are not without risk.³

Recently, the U.S. Agency for Healthcare Research and Quality performed a rigorous meta-analysis of this body of evidence, and summarized that “antibiotic treatment may not affect pain symptoms, length of hospital stay, recurrence risk, quality of life, or need for surgery, compared to no antibiotic treatment,” with an admitted low strength of evidence (based on four randomized, controlled trials).⁴

Finally, I’ll close my evidence-based case with a quote from a Clinical Practice Update just published in February 2021 in Gastroenterology: “Antibiotic treatment can be used selectively, rather than routinely, in immunocompetent patients with mild uncomplicated diverticulitis. ... Antibiotic treatment is advised in patients with uncomplicated diverticulitis who have comorbidities or are frail, who present with refractory symptoms or vomiting, or who have a [C-reactive protein] >140 mg/L or baseline [white blood cell count] > 15 x 10⁹. Antibiotic treatment is advised in patients with complicated diverticulitis or uncomplicated diverticulitis with a fluid collection or longer segment of inflammation on CT scan.”⁵ I think this is most excellent advice, providing a practical and clinically useful framework for those in whom antibiotics absolutely should be used, but permitting a fairly large group to avoid antibiotics, which may carry significant harm, based on strong consistent data that does not support a benefit.

So, practically speaking, things are a bit harder for us now when our patient shows up in the ED and if found to have AUD on CT. In the “old days” (that is, the early 2000s), a patient with either clinically suspected or CT-confirmed AUD was simply given antibiotics, mostly a fluoroquinolone, and this was community standard. The only real decision tree was inpatient or outpatient. But now, I would respectfully suggest, we need to invest a bit more time on a nuanced discussion with the potential “no antibiotics” patient (for example, one without immunosuppression, severe comorbidities, or lab or imaging markers of aggressive disease). It is now appropriate to inform such a patient that the data suggest that a conservative approach will not increase their risk of complications and may well spare them antibiotic-related morbidity.

In the context of that informed discussion, factually framed by the practitioner, many patients should (and will, in my experience, although the San Francisco Bay Area may not entirely reflect the country as a whole) choose a strategy of observation. Of course, close follow-up with such patients is required, as is clear reassurance that if things “turn bad” that we’re available and antibiotics remain a salvage option. The “write a script and be done” days are over, and while withholding antibiotics may still feel dangerous or uncomfortable to the patient (or to us), the data is the data, and our patients deserve to at least be offered that option.

Neil Stollman, MD, AGAF, FACG, is chairman of the division of gastroenterology at Alta Bates Summit Medical Center in Oakland, Calif., and an associate clinical professor of medicine in the division of gastroenterology at the University of California, San Francisco. He discloses being a consultant for Cosmo Pharmaceuticals, which has a potential future diverticulitis study of a rifampin-class antibiotic.

References

1. Stollman N and Raskin JB. Am J Gastroenterol. 1999 Nov;94(11):3110-21.

2. Peery AF and Stollman N. Gastroenterology. 2015 Dec;149(7):1944-9.

3. Gaber CE et al. Ann Intern Med. 2021 Feb 23. doi: 10.7326/M20-6315.

4. Balk EM et al. Management of Colonic Diverticulitis. Comparative Effectiveness Review No. 233. Agency for Healthcare Research and Quality. October 2020. doi: 10.23970/AHRQEPCCER233.

5. Peery AF et al. Gastroenterology. 2021 Feb;160(3):906-11.e1.

The United States Preventive Services Task Force recently released a draft of updated recommendations for screening for prediabetes and type 2 diabetes mellitus (DM). If accepted as written, the new recommendation will be to “screen all asymptomatic adults ages 35 to 70 years who are overweight or obese.” Upon diagnosis of prediabetes, the recommendation is to offer or refer patients to preventive interventions.

This new recommendation would replace the one from 2015, which recommended screening adults aged 40-70 who are overweight or obese, lowering the age at which screening begins by 5 years. It would also replace the recommendation of referral to intensive behavioral counseling to promote a healthy diet and exercise.¹

The American Diabetes Association (ADA) identifies A1c, fasting plasma glucose, or oral glucose tolerance tests as appropriate tests for the diagnosis of prediabetes and type 2 DM, and the new draft recommendation does not provide a preference for method of screening.²

The USPSTF’s draft recommendation could expand screening with the hope of identifying patients with prediabetes, or those with diabetes who are asymptomatic, with the intent of beginning treatment before there are serious complications.
 

Unknown diabetes or prediabetes diagnosis common

It has been estimated by the Centers for Disease Control and Prevention that 12% of U.S. adults had DM as of 2015, though nearly 24% were not aware that they had it. Also, according to the CDC, the prevalence of DM increases with age and is higher in those with less than a high school education. The same report indicates that more than 30% of U.S. adults have prediabetes, and with less than 12% of those individuals are aware of it.³ A possible explanation for a patient’s being unaware of a diagnosis could be that it has been documented in a chart but the patient does not know such information is in his or her health record. According to the evidence provided for the updated recommendation, earlier diagnosis may have an important benefit in preventing serious complications.

A modeling study compared simulated screening strategies and found that the most optimal screening strategy from a cost-effectiveness perspective begins between the ages of 30 and 45, with rescreening every 3-5 years. Further models have led researchers to conclude that early diagnosis can lead to decreased cardiovascular events as well as an opportunity for multifactorial treatment.¹ For this reason, it makes sense to expand the ages of screening for obese and overweight individuals.
 

Treatment recommendations are more flexible

The change in treatment recommendations for a new diagnosis of prediabetes is potentially more useful. It may not be feasible or reasonable for physicians to always provide or refer their patients for intensive behavior interventions. The updated recommendation would allow for the inclusion of not only behavioral counseling and health education, but also potential medication options that are currently available but not approved, or that may be available in the future. The evidence review seemed to be mixed in outcome in this area, so the increased flexibility will likely allow for future opportunities.

Screening criteria may be too narrow

This recommendation, does not, however, provide any guidance on screening of individuals who have other risk factors besides a body mass index consistent with overweight or obesity. It seems that this may be a missed opportunity.

The draft statement clearly indicates that there are other factors associated with increased risk of developing DM, but does not consider these factors in determining which patients should be screened. Both the ADA and the American Association of Clinical Endocrinology (AACE) have recommendations for universal screening for all adults 45 and older, acknowledging that incidence of DM increases with age. The ADA also recommends screening individuals who are overweight or obese and have an additional risk factor regardless of age. The AACE recommends screening all individuals for risk factors regardless of age.

The current and draft recommendations by the USPSTF do not address other risk factors and indicate only that further research is needed to understand the risk associated with DM and the natural history of pre-DM and who may progress to DM or revert to normoglycemia. Without comment on other risk factors or universal screening with age, the USPSTF recommendation potentially would not be sensitive enough to capture all those who may meet criteria for prediabetes or DM.^2,4

In addition to not addressing other risk factors and screening for those of normal and underweight BMI, the USPSTF recommendation does not address frequency of screening. The recommendations from both the ADA and the AACE indicate screening at 3-year intervals for those who are eligible – for any reason. The supporting evidence review did not seem to address this aspect, and so it is understandable that there was no comment. However, I feel this will lead physicians to turn to the other guidelines for guidance where there is disagreement in other aspects.

Ultimately, the draft updated recommendation will provide physicians with the opportunity to identify more patients with prediabetes and DM. This will be wonderful in terms of being able to offer treatments and lifestyle interventions to decrease the morbidity patients would face were these conditions not diagnosed. I hope that future recommendations will also address risk factors in addition to BMI as well as frequency of screening for those who remain at increased risk but initially screen negative.
 

Dr. Wheat is a family physician at Erie Family Health Center in Chicago. She is program director of Northwestern’s McGaw Family Medicine residency program at Humboldt Park, Chicago. Dr. Wheat serves on the editorial advisory board of Family Practice News. You can contact her at fpnews@mdedge.com.

References

1. Screening for prediabetes and type 2 diabetes mellitus. U.S. Preventive Services Task Force. 2021 Mar 16.

2. Classification and diagnosis of diabetes: Standards of medical care in diabetes – 2020. American Diabetes Association. Diabetes Care. 2020 Jan. doi: 10.2337/dc20-S002.

3. National Diabetes Statistics Report, 2020. Centers for Disease Control and Prevention.

4. American Association of Clinical Endocrinologists and American College of Endocrinology – clinical practice guidelines for developing a diabetes mellitus comprehensive care plan. Hadelsman Y et al. Endocr Pract. 2015 Apr. 1-87. doi: 10.4158/EP15672.GL.

The United States Preventive Services Task Force recently released a draft of updated recommendations for screening for prediabetes and type 2 diabetes mellitus (DM). If accepted as written, the new recommendation will be to “screen all asymptomatic adults ages 35 to 70 years who are overweight or obese.” Upon diagnosis of prediabetes, the recommendation is to offer or refer patients to preventive interventions.

This new recommendation would replace the one from 2015, which recommended screening adults aged 40-70 who are overweight or obese, lowering the age at which screening begins by 5 years. It would also replace the recommendation of referral to intensive behavioral counseling to promote a healthy diet and exercise.¹

The American Diabetes Association (ADA) identifies A1c, fasting plasma glucose, or oral glucose tolerance tests as appropriate tests for the diagnosis of prediabetes and type 2 DM, and the new draft recommendation does not provide a preference for method of screening.²

The USPSTF’s draft recommendation could expand screening with the hope of identifying patients with prediabetes, or those with diabetes who are asymptomatic, with the intent of beginning treatment before there are serious complications.
 

Unknown diabetes or prediabetes diagnosis common

It has been estimated by the Centers for Disease Control and Prevention that 12% of U.S. adults had DM as of 2015, though nearly 24% were not aware that they had it. Also, according to the CDC, the prevalence of DM increases with age and is higher in those with less than a high school education. The same report indicates that more than 30% of U.S. adults have prediabetes, and with less than 12% of those individuals are aware of it.³ A possible explanation for a patient’s being unaware of a diagnosis could be that it has been documented in a chart but the patient does not know such information is in his or her health record. According to the evidence provided for the updated recommendation, earlier diagnosis may have an important benefit in preventing serious complications.

A modeling study compared simulated screening strategies and found that the most optimal screening strategy from a cost-effectiveness perspective begins between the ages of 30 and 45, with rescreening every 3-5 years. Further models have led researchers to conclude that early diagnosis can lead to decreased cardiovascular events as well as an opportunity for multifactorial treatment.¹ For this reason, it makes sense to expand the ages of screening for obese and overweight individuals.
 

Treatment recommendations are more flexible

The change in treatment recommendations for a new diagnosis of prediabetes is potentially more useful. It may not be feasible or reasonable for physicians to always provide or refer their patients for intensive behavior interventions. The updated recommendation would allow for the inclusion of not only behavioral counseling and health education, but also potential medication options that are currently available but not approved, or that may be available in the future. The evidence review seemed to be mixed in outcome in this area, so the increased flexibility will likely allow for future opportunities.

Screening criteria may be too narrow

This recommendation, does not, however, provide any guidance on screening of individuals who have other risk factors besides a body mass index consistent with overweight or obesity. It seems that this may be a missed opportunity.

The draft statement clearly indicates that there are other factors associated with increased risk of developing DM, but does not consider these factors in determining which patients should be screened. Both the ADA and the American Association of Clinical Endocrinology (AACE) have recommendations for universal screening for all adults 45 and older, acknowledging that incidence of DM increases with age. The ADA also recommends screening individuals who are overweight or obese and have an additional risk factor regardless of age. The AACE recommends screening all individuals for risk factors regardless of age.

The current and draft recommendations by the USPSTF do not address other risk factors and indicate only that further research is needed to understand the risk associated with DM and the natural history of pre-DM and who may progress to DM or revert to normoglycemia. Without comment on other risk factors or universal screening with age, the USPSTF recommendation potentially would not be sensitive enough to capture all those who may meet criteria for prediabetes or DM.^2,4

In addition to not addressing other risk factors and screening for those of normal and underweight BMI, the USPSTF recommendation does not address frequency of screening. The recommendations from both the ADA and the AACE indicate screening at 3-year intervals for those who are eligible – for any reason. The supporting evidence review did not seem to address this aspect, and so it is understandable that there was no comment. However, I feel this will lead physicians to turn to the other guidelines for guidance where there is disagreement in other aspects.

Ultimately, the draft updated recommendation will provide physicians with the opportunity to identify more patients with prediabetes and DM. This will be wonderful in terms of being able to offer treatments and lifestyle interventions to decrease the morbidity patients would face were these conditions not diagnosed. I hope that future recommendations will also address risk factors in addition to BMI as well as frequency of screening for those who remain at increased risk but initially screen negative.
 

Dr. Wheat is a family physician at Erie Family Health Center in Chicago. She is program director of Northwestern’s McGaw Family Medicine residency program at Humboldt Park, Chicago. Dr. Wheat serves on the editorial advisory board of Family Practice News. You can contact her at fpnews@mdedge.com.

References

1. Screening for prediabetes and type 2 diabetes mellitus. U.S. Preventive Services Task Force. 2021 Mar 16.

2. Classification and diagnosis of diabetes: Standards of medical care in diabetes – 2020. American Diabetes Association. Diabetes Care. 2020 Jan. doi: 10.2337/dc20-S002.

3. National Diabetes Statistics Report, 2020. Centers for Disease Control and Prevention.

4. American Association of Clinical Endocrinologists and American College of Endocrinology – clinical practice guidelines for developing a diabetes mellitus comprehensive care plan. Hadelsman Y et al. Endocr Pract. 2015 Apr. 1-87. doi: 10.4158/EP15672.GL.

The United States Preventive Services Task Force recently released a draft of updated recommendations for screening for prediabetes and type 2 diabetes mellitus (DM). If accepted as written, the new recommendation will be to “screen all asymptomatic adults ages 35 to 70 years who are overweight or obese.” Upon diagnosis of prediabetes, the recommendation is to offer or refer patients to preventive interventions.

This new recommendation would replace the one from 2015, which recommended screening adults aged 40-70 who are overweight or obese, lowering the age at which screening begins by 5 years. It would also replace the recommendation of referral to intensive behavioral counseling to promote a healthy diet and exercise.¹

The American Diabetes Association (ADA) identifies A1c, fasting plasma glucose, or oral glucose tolerance tests as appropriate tests for the diagnosis of prediabetes and type 2 DM, and the new draft recommendation does not provide a preference for method of screening.²

The USPSTF’s draft recommendation could expand screening with the hope of identifying patients with prediabetes, or those with diabetes who are asymptomatic, with the intent of beginning treatment before there are serious complications.
 

Unknown diabetes or prediabetes diagnosis common

It has been estimated by the Centers for Disease Control and Prevention that 12% of U.S. adults had DM as of 2015, though nearly 24% were not aware that they had it. Also, according to the CDC, the prevalence of DM increases with age and is higher in those with less than a high school education. The same report indicates that more than 30% of U.S. adults have prediabetes, and with less than 12% of those individuals are aware of it.³ A possible explanation for a patient’s being unaware of a diagnosis could be that it has been documented in a chart but the patient does not know such information is in his or her health record. According to the evidence provided for the updated recommendation, earlier diagnosis may have an important benefit in preventing serious complications.

A modeling study compared simulated screening strategies and found that the most optimal screening strategy from a cost-effectiveness perspective begins between the ages of 30 and 45, with rescreening every 3-5 years. Further models have led researchers to conclude that early diagnosis can lead to decreased cardiovascular events as well as an opportunity for multifactorial treatment.¹ For this reason, it makes sense to expand the ages of screening for obese and overweight individuals.
 

Treatment recommendations are more flexible

The change in treatment recommendations for a new diagnosis of prediabetes is potentially more useful. It may not be feasible or reasonable for physicians to always provide or refer their patients for intensive behavior interventions. The updated recommendation would allow for the inclusion of not only behavioral counseling and health education, but also potential medication options that are currently available but not approved, or that may be available in the future. The evidence review seemed to be mixed in outcome in this area, so the increased flexibility will likely allow for future opportunities.

Screening criteria may be too narrow

This recommendation, does not, however, provide any guidance on screening of individuals who have other risk factors besides a body mass index consistent with overweight or obesity. It seems that this may be a missed opportunity.

The draft statement clearly indicates that there are other factors associated with increased risk of developing DM, but does not consider these factors in determining which patients should be screened. Both the ADA and the American Association of Clinical Endocrinology (AACE) have recommendations for universal screening for all adults 45 and older, acknowledging that incidence of DM increases with age. The ADA also recommends screening individuals who are overweight or obese and have an additional risk factor regardless of age. The AACE recommends screening all individuals for risk factors regardless of age.

The current and draft recommendations by the USPSTF do not address other risk factors and indicate only that further research is needed to understand the risk associated with DM and the natural history of pre-DM and who may progress to DM or revert to normoglycemia. Without comment on other risk factors or universal screening with age, the USPSTF recommendation potentially would not be sensitive enough to capture all those who may meet criteria for prediabetes or DM.^2,4

In addition to not addressing other risk factors and screening for those of normal and underweight BMI, the USPSTF recommendation does not address frequency of screening. The recommendations from both the ADA and the AACE indicate screening at 3-year intervals for those who are eligible – for any reason. The supporting evidence review did not seem to address this aspect, and so it is understandable that there was no comment. However, I feel this will lead physicians to turn to the other guidelines for guidance where there is disagreement in other aspects.

Ultimately, the draft updated recommendation will provide physicians with the opportunity to identify more patients with prediabetes and DM. This will be wonderful in terms of being able to offer treatments and lifestyle interventions to decrease the morbidity patients would face were these conditions not diagnosed. I hope that future recommendations will also address risk factors in addition to BMI as well as frequency of screening for those who remain at increased risk but initially screen negative.
 

Dr. Wheat is a family physician at Erie Family Health Center in Chicago. She is program director of Northwestern’s McGaw Family Medicine residency program at Humboldt Park, Chicago. Dr. Wheat serves on the editorial advisory board of Family Practice News. You can contact her at fpnews@mdedge.com.

References

1. Screening for prediabetes and type 2 diabetes mellitus. U.S. Preventive Services Task Force. 2021 Mar 16.

2. Classification and diagnosis of diabetes: Standards of medical care in diabetes – 2020. American Diabetes Association. Diabetes Care. 2020 Jan. doi: 10.2337/dc20-S002.

3. National Diabetes Statistics Report, 2020. Centers for Disease Control and Prevention.

4. American Association of Clinical Endocrinologists and American College of Endocrinology – clinical practice guidelines for developing a diabetes mellitus comprehensive care plan. Hadelsman Y et al. Endocr Pract. 2015 Apr. 1-87. doi: 10.4158/EP15672.GL.

The holy grail of assisted reproductive technology (ART) is the delivery of a healthy child. From the world’s first successful ART cycle of in vitro fertilization in 1978 (3 years later in the United States), the goal of every cycle is to provide the woman with an embryo that has the highest potential for implantation and, ultimately, a single live birth.

Embryo aneuploidy is a major factor in the success of human reproduction. As women age, aneuploidy is reported in less than 30% of women aged younger than 35 years but rises to 90% for those in their mid-40s. Intuitively and through randomized, controlled trials, chromosome testing of embryos is a reasonable approach toward improved cycle outcomes and allows for the transfer of a single euploid embryo.

Recently, the phrase “add-ons” has entered the vernacular of editorials on IVF. These additional procedures are offered to patients with the expectation of improving results, yet many have not been supported by rigorous scientifically controlled research trials, e.g., endometrial scratch, embryo glue, and time-lapse imaging of embryos. Where does preimplantation genetic testing (PGT) belong in the IVF armamentarium and why, after 30 years, are there two diametrically opposed views on its benefit? (We will not address testing for single gene defects or chromosome structural rearrangements.)
 

How did we get here?

The first iteration of PGT used fluorescence in situ hybridization to not only identify X-linked recessive diseases (Hum Genet. 1992;89:18-22) but also the most common chromosome disorders (13, 18, 21, X, Y) by removing one to two blastomere cells from a day 3 embryo (six- to eight-cell stage). Despite wide enthusiasm, the technique was eventually determined to reduce implantation by nearly 40% and was abandoned; presumably impairing the embryo by removing up to one-third of its make-up.

Because of extended embryo culture to the blastocyst stage along with the improved cryopreservation process of vitrification, the next generation of embryo analysis surfaced, what we now refer to as PGT 2.0. Currently, approximately five to six cells from the outer embryo trophectoderm are removed and sent to a specialized laboratory for 24-chromosome screening while the biopsied embryos are cryopreserved. Outcome data (aneuploidy rates, mosaicism) have been influenced by the evolution of genetic platforms – from array comparative genome hybridization to single-nucleotide polymorphism array, to quantitative polymerase chain reaction, to next-generation sequencing (NGS). The newest platform, NGS with high resolution, provides the most extensive degree of analysis by detecting unbalanced translocations and a low cut-off percentage for mosaicism (20%). The clinical error rate is approximately 1%-2%, improved from the 2%-4% of earlier techniques.

The phenomenon of mosaicism describes two distinct cell lines in one embryo (typically one normal and one abnormal) and is defined based on the percentage of mosaicism – currently, the lower limit is 20%. Embryos with less than 20%-30% mosaicism are considered euploid and those greater than 70%-80% are aneuploid. Of note, clinics that do not request the reporting of mosaicism can result in the potential discarding of embryos labeled as aneuploid that would otherwise have potentially resulted in a live birth. The higher the cut-off value for designating mosaicism, the lower the false-positive rate (declaring an embryo aneuploid when euploid). While there is no safe degree of mosaicism, most transfers have resulted in chromosomally normal infants despite a lower implantation rate and higher miscarriage rate.
 

Current status

The greatest advantage of PGT for aneuploidy (PGT-A) is its increase in promoting a single embryo transfer. Medical evidence supports pregnancy outcomes equivalent from a single euploid embryo transfer versus a double “untested” embryo transfer.

Only a handful of randomized, controlled trials have evaluated the efficacy of PGT-A. Outcomes have favored improved live birth rates; however, criticism exists for enrolling only good prognosis patients given their high likelihood of developing blastocyst embryos to biopsy. The only trial that used an “intention to treat” protocol (rather than randomization at the time of biopsy) did not demonstrate any difference in live birth or miscarriage comparing embryo selection by PGT-A versus embryo morphology alone. However, post hoc analysis did show a benefit with PGT-A in the 35- to 40-year-old age group, not in the less than 35-year-old group. All other trials demonstrated a reduction in miscarriage with PGT-A but only as a secondary outcome.

The medical literature does not support PGT-A to manage patients with recurrent pregnancy loss and there is no evidence for improvement in women aged less than 35 years or egg donors (F&S Reports. 2021;2:36-42). PGT-A has been effective in patients wishing family balancing.
 

Controversy

Enthusiasm for PGT-A is countered by lingering concerns. Trophectoderm cells are not in 100% concordance with the inner cell mass, which presumably explains the reports of chromosomally normal live births from the transfer of aneuploid embryos. Biopsy techniques among embryologists are not standardized. As a result, damage to the embryo has been raised as a possible explanation for equivalent pregnancy rates in studies showing no superiority of PGT-A in pregnancy outcome, although this point has recently been refuted.

PGT-A also embraces the “blast-or-bust” credo whereby no embryo transfer occurs unless a blastocyst embryo develops. This continues to beg the unanswerable question – would a woman who did not develop a blastocyst embryo for potential biopsy still conceive if she underwent a day 3 cleavage stage embryo transfer?
 

Future

Exciting iterations are encroaching for PGT 3.0. One method is blastocyst fluid aspiration to obtain DNA suitable for analysis by molecular genetic methods. Another is noninvasive PGT whereby spent media from the embryo is analyzed using cell-free DNA. Concordance with inner cell mass is reasonably good (approximately 85%) but needs to improve. A major advantage is the biopsy skill set among embryologists is eliminated. A criticism of noninvasive PGT is the risk of false-positive results from contamination of aneuploid cell secretion by physiologic apoptotic cells. Confined placental mosaicism can also increase aneuploidy in cell-free DNA thereby contributing to false positives.

Conclusion

PGT-A is robust technology that appears to benefit women aged above 35 years but not the general infertile population. Error rates must be consistent among laboratories and be lowered. Regarding mosaic embryos, the American Society for Reproductive Medicine guidelines recommend offering another egg retrieval if only mosaic embryos are available and to only consider mosaic embryo transfer following extensive genetic counseling. Long-term effects of PGT-A on children are lacking. The Cochrane Database concluded there was insufficient evidence to make PGT-A routine.

So, the debate is clear and ongoing – universal versus discretionary use of PGT-A? As in all things of life, one size does not fit all, and PGT-A is no exception.

Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. Contact him at obnews@mdedge.com.

The holy grail of assisted reproductive technology (ART) is the delivery of a healthy child. From the world’s first successful ART cycle of in vitro fertilization in 1978 (3 years later in the United States), the goal of every cycle is to provide the woman with an embryo that has the highest potential for implantation and, ultimately, a single live birth.

Embryo aneuploidy is a major factor in the success of human reproduction. As women age, aneuploidy is reported in less than 30% of women aged younger than 35 years but rises to 90% for those in their mid-40s. Intuitively and through randomized, controlled trials, chromosome testing of embryos is a reasonable approach toward improved cycle outcomes and allows for the transfer of a single euploid embryo.

Recently, the phrase “add-ons” has entered the vernacular of editorials on IVF. These additional procedures are offered to patients with the expectation of improving results, yet many have not been supported by rigorous scientifically controlled research trials, e.g., endometrial scratch, embryo glue, and time-lapse imaging of embryos. Where does preimplantation genetic testing (PGT) belong in the IVF armamentarium and why, after 30 years, are there two diametrically opposed views on its benefit? (We will not address testing for single gene defects or chromosome structural rearrangements.)
 

How did we get here?

The first iteration of PGT used fluorescence in situ hybridization to not only identify X-linked recessive diseases (Hum Genet. 1992;89:18-22) but also the most common chromosome disorders (13, 18, 21, X, Y) by removing one to two blastomere cells from a day 3 embryo (six- to eight-cell stage). Despite wide enthusiasm, the technique was eventually determined to reduce implantation by nearly 40% and was abandoned; presumably impairing the embryo by removing up to one-third of its make-up.

Because of extended embryo culture to the blastocyst stage along with the improved cryopreservation process of vitrification, the next generation of embryo analysis surfaced, what we now refer to as PGT 2.0. Currently, approximately five to six cells from the outer embryo trophectoderm are removed and sent to a specialized laboratory for 24-chromosome screening while the biopsied embryos are cryopreserved. Outcome data (aneuploidy rates, mosaicism) have been influenced by the evolution of genetic platforms – from array comparative genome hybridization to single-nucleotide polymorphism array, to quantitative polymerase chain reaction, to next-generation sequencing (NGS). The newest platform, NGS with high resolution, provides the most extensive degree of analysis by detecting unbalanced translocations and a low cut-off percentage for mosaicism (20%). The clinical error rate is approximately 1%-2%, improved from the 2%-4% of earlier techniques.

The phenomenon of mosaicism describes two distinct cell lines in one embryo (typically one normal and one abnormal) and is defined based on the percentage of mosaicism – currently, the lower limit is 20%. Embryos with less than 20%-30% mosaicism are considered euploid and those greater than 70%-80% are aneuploid. Of note, clinics that do not request the reporting of mosaicism can result in the potential discarding of embryos labeled as aneuploid that would otherwise have potentially resulted in a live birth. The higher the cut-off value for designating mosaicism, the lower the false-positive rate (declaring an embryo aneuploid when euploid). While there is no safe degree of mosaicism, most transfers have resulted in chromosomally normal infants despite a lower implantation rate and higher miscarriage rate.
 

Current status

The greatest advantage of PGT for aneuploidy (PGT-A) is its increase in promoting a single embryo transfer. Medical evidence supports pregnancy outcomes equivalent from a single euploid embryo transfer versus a double “untested” embryo transfer.

Only a handful of randomized, controlled trials have evaluated the efficacy of PGT-A. Outcomes have favored improved live birth rates; however, criticism exists for enrolling only good prognosis patients given their high likelihood of developing blastocyst embryos to biopsy. The only trial that used an “intention to treat” protocol (rather than randomization at the time of biopsy) did not demonstrate any difference in live birth or miscarriage comparing embryo selection by PGT-A versus embryo morphology alone. However, post hoc analysis did show a benefit with PGT-A in the 35- to 40-year-old age group, not in the less than 35-year-old group. All other trials demonstrated a reduction in miscarriage with PGT-A but only as a secondary outcome.

The medical literature does not support PGT-A to manage patients with recurrent pregnancy loss and there is no evidence for improvement in women aged less than 35 years or egg donors (F&S Reports. 2021;2:36-42). PGT-A has been effective in patients wishing family balancing.
 

Controversy

Enthusiasm for PGT-A is countered by lingering concerns. Trophectoderm cells are not in 100% concordance with the inner cell mass, which presumably explains the reports of chromosomally normal live births from the transfer of aneuploid embryos. Biopsy techniques among embryologists are not standardized. As a result, damage to the embryo has been raised as a possible explanation for equivalent pregnancy rates in studies showing no superiority of PGT-A in pregnancy outcome, although this point has recently been refuted.

PGT-A also embraces the “blast-or-bust” credo whereby no embryo transfer occurs unless a blastocyst embryo develops. This continues to beg the unanswerable question – would a woman who did not develop a blastocyst embryo for potential biopsy still conceive if she underwent a day 3 cleavage stage embryo transfer?
 

Future

Exciting iterations are encroaching for PGT 3.0. One method is blastocyst fluid aspiration to obtain DNA suitable for analysis by molecular genetic methods. Another is noninvasive PGT whereby spent media from the embryo is analyzed using cell-free DNA. Concordance with inner cell mass is reasonably good (approximately 85%) but needs to improve. A major advantage is the biopsy skill set among embryologists is eliminated. A criticism of noninvasive PGT is the risk of false-positive results from contamination of aneuploid cell secretion by physiologic apoptotic cells. Confined placental mosaicism can also increase aneuploidy in cell-free DNA thereby contributing to false positives.

Conclusion

PGT-A is robust technology that appears to benefit women aged above 35 years but not the general infertile population. Error rates must be consistent among laboratories and be lowered. Regarding mosaic embryos, the American Society for Reproductive Medicine guidelines recommend offering another egg retrieval if only mosaic embryos are available and to only consider mosaic embryo transfer following extensive genetic counseling. Long-term effects of PGT-A on children are lacking. The Cochrane Database concluded there was insufficient evidence to make PGT-A routine.

So, the debate is clear and ongoing – universal versus discretionary use of PGT-A? As in all things of life, one size does not fit all, and PGT-A is no exception.

Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. Contact him at obnews@mdedge.com.

The holy grail of assisted reproductive technology (ART) is the delivery of a healthy child. From the world’s first successful ART cycle of in vitro fertilization in 1978 (3 years later in the United States), the goal of every cycle is to provide the woman with an embryo that has the highest potential for implantation and, ultimately, a single live birth.

Embryo aneuploidy is a major factor in the success of human reproduction. As women age, aneuploidy is reported in less than 30% of women aged younger than 35 years but rises to 90% for those in their mid-40s. Intuitively and through randomized, controlled trials, chromosome testing of embryos is a reasonable approach toward improved cycle outcomes and allows for the transfer of a single euploid embryo.

Recently, the phrase “add-ons” has entered the vernacular of editorials on IVF. These additional procedures are offered to patients with the expectation of improving results, yet many have not been supported by rigorous scientifically controlled research trials, e.g., endometrial scratch, embryo glue, and time-lapse imaging of embryos. Where does preimplantation genetic testing (PGT) belong in the IVF armamentarium and why, after 30 years, are there two diametrically opposed views on its benefit? (We will not address testing for single gene defects or chromosome structural rearrangements.)
 

How did we get here?

The first iteration of PGT used fluorescence in situ hybridization to not only identify X-linked recessive diseases (Hum Genet. 1992;89:18-22) but also the most common chromosome disorders (13, 18, 21, X, Y) by removing one to two blastomere cells from a day 3 embryo (six- to eight-cell stage). Despite wide enthusiasm, the technique was eventually determined to reduce implantation by nearly 40% and was abandoned; presumably impairing the embryo by removing up to one-third of its make-up.

Because of extended embryo culture to the blastocyst stage along with the improved cryopreservation process of vitrification, the next generation of embryo analysis surfaced, what we now refer to as PGT 2.0. Currently, approximately five to six cells from the outer embryo trophectoderm are removed and sent to a specialized laboratory for 24-chromosome screening while the biopsied embryos are cryopreserved. Outcome data (aneuploidy rates, mosaicism) have been influenced by the evolution of genetic platforms – from array comparative genome hybridization to single-nucleotide polymorphism array, to quantitative polymerase chain reaction, to next-generation sequencing (NGS). The newest platform, NGS with high resolution, provides the most extensive degree of analysis by detecting unbalanced translocations and a low cut-off percentage for mosaicism (20%). The clinical error rate is approximately 1%-2%, improved from the 2%-4% of earlier techniques.

The phenomenon of mosaicism describes two distinct cell lines in one embryo (typically one normal and one abnormal) and is defined based on the percentage of mosaicism – currently, the lower limit is 20%. Embryos with less than 20%-30% mosaicism are considered euploid and those greater than 70%-80% are aneuploid. Of note, clinics that do not request the reporting of mosaicism can result in the potential discarding of embryos labeled as aneuploid that would otherwise have potentially resulted in a live birth. The higher the cut-off value for designating mosaicism, the lower the false-positive rate (declaring an embryo aneuploid when euploid). While there is no safe degree of mosaicism, most transfers have resulted in chromosomally normal infants despite a lower implantation rate and higher miscarriage rate.
 

Current status

The greatest advantage of PGT for aneuploidy (PGT-A) is its increase in promoting a single embryo transfer. Medical evidence supports pregnancy outcomes equivalent from a single euploid embryo transfer versus a double “untested” embryo transfer.

Only a handful of randomized, controlled trials have evaluated the efficacy of PGT-A. Outcomes have favored improved live birth rates; however, criticism exists for enrolling only good prognosis patients given their high likelihood of developing blastocyst embryos to biopsy. The only trial that used an “intention to treat” protocol (rather than randomization at the time of biopsy) did not demonstrate any difference in live birth or miscarriage comparing embryo selection by PGT-A versus embryo morphology alone. However, post hoc analysis did show a benefit with PGT-A in the 35- to 40-year-old age group, not in the less than 35-year-old group. All other trials demonstrated a reduction in miscarriage with PGT-A but only as a secondary outcome.

The medical literature does not support PGT-A to manage patients with recurrent pregnancy loss and there is no evidence for improvement in women aged less than 35 years or egg donors (F&S Reports. 2021;2:36-42). PGT-A has been effective in patients wishing family balancing.
 

Controversy

Enthusiasm for PGT-A is countered by lingering concerns. Trophectoderm cells are not in 100% concordance with the inner cell mass, which presumably explains the reports of chromosomally normal live births from the transfer of aneuploid embryos. Biopsy techniques among embryologists are not standardized. As a result, damage to the embryo has been raised as a possible explanation for equivalent pregnancy rates in studies showing no superiority of PGT-A in pregnancy outcome, although this point has recently been refuted.

PGT-A also embraces the “blast-or-bust” credo whereby no embryo transfer occurs unless a blastocyst embryo develops. This continues to beg the unanswerable question – would a woman who did not develop a blastocyst embryo for potential biopsy still conceive if she underwent a day 3 cleavage stage embryo transfer?
 

Future

Exciting iterations are encroaching for PGT 3.0. One method is blastocyst fluid aspiration to obtain DNA suitable for analysis by molecular genetic methods. Another is noninvasive PGT whereby spent media from the embryo is analyzed using cell-free DNA. Concordance with inner cell mass is reasonably good (approximately 85%) but needs to improve. A major advantage is the biopsy skill set among embryologists is eliminated. A criticism of noninvasive PGT is the risk of false-positive results from contamination of aneuploid cell secretion by physiologic apoptotic cells. Confined placental mosaicism can also increase aneuploidy in cell-free DNA thereby contributing to false positives.

Conclusion

PGT-A is robust technology that appears to benefit women aged above 35 years but not the general infertile population. Error rates must be consistent among laboratories and be lowered. Regarding mosaic embryos, the American Society for Reproductive Medicine guidelines recommend offering another egg retrieval if only mosaic embryos are available and to only consider mosaic embryo transfer following extensive genetic counseling. Long-term effects of PGT-A on children are lacking. The Cochrane Database concluded there was insufficient evidence to make PGT-A routine.

So, the debate is clear and ongoing – universal versus discretionary use of PGT-A? As in all things of life, one size does not fit all, and PGT-A is no exception.

Dr. Trolice is director of Fertility CARE – The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. Contact him at obnews@mdedge.com.