Imagine being able to precisely select the medication with the optimal efficacy, safety, and tolerability at the outset of treatment for every psychiatric patient who needs pharma­cotherapy. Imagine how much the patient would appreciate not receiving a series of drugs and suffering multiple adverse effects and unremitting symptoms until the “right medication” is identified. Imagine how gratifying it would be for you as a psychiatrist to watch every one of your patients improve rapidly with minimal complaints or adverse effects.

Precision psychiatry is the indispensable vehicle to achieve personalized medicine for psychiatric patients. Precision psychiatry is a cherished goal, but it remains an aspirational objective. Other medical specialties, especially oncology and cardiology, have made remarkable strides in precision medicine, but the journey to precision psychiatry is still in its early stages. Yet there is every reason to believe that we are making progress toward that cherished goal.

To implement precision psychiatry, we must be able to identify the biosignature of each patient’s psychiatric brain disorder. But there is a formidable challenge to overcome: the complex, extensive heterogeneity of psychiatric disorders, which requires intense and inspired neurobiology research. So, while clinicians go on with the mundane trial-and-error approach of contemporary psychopharmacology, psychiatric neuroscientists are diligently deconstructing major psychiatric disorders into specific biotypes with unique biosignatures that will one day guide accurate and prompt clinical management.

Psychiatric practitioners may be too busy to keep tabs on the progress being made in identifying various biomarkers that are the key ingredients to decoding the biosignature of each psychiatric patient. Take schizophrenia, for example. There are myriad clinical variations that comprise this heterogeneous brain syndrome, including level of premorbid functioning; acute vs gradual onset of psychosis; the type and severity of hallucinations or delusions; the dimensional spectrum of negative symptoms and cognitive impairments; the presence and intensity of suicidal or homicidal urges; and the type of medical and psychiatric comorbidities. No wonder every patient is a unique and fascinating clinical puzzle, and yet, patients with schizophrenia are still being homogenized under a single DSM diagnostic category.

Precision psychiatry will ultimately enable practitioners to recognize various psychotic diseases that are more specific than the current DSM psychosis categories. Further, precision psychiatry will provide guidance as to which member within a class of so-called “me-too” drugs is the optimal match for each patient. This will stand in stark contrast to the chaotic hit-or-miss approach.

Precision psychiatry also will reveal the absurdity of current FDA clinical trials design for drug development. How can a molecule with a putative mechanism of action relevant to a specific biotype be administered to a hodgepodge of heterogeneous biotypes that have been lumped in 1 clinical category, and yet be expected to exert efficacy in most biotypes? It is a small miracle that some new drugs beat placebo despite the extensive variability in both placebo responses and drug responses. But it is well known that in all FDA placebo-controlled trials, the therapeutic response across the patient population varies from extremely high to extremely low, and worsening may even occur in a subset of patients receiving either the active drug or placebo. Perhaps drug response should be used as 1 methodology to classify biotypes of patients encompassed within a heterogeneous syndrome such as schizophrenia.

Precision psychiatry will represent a huge paradigm shift in the science and practice of our specialty. In his landmark book, Thomas Kuhn defined a paradigm as “an entire worldview in which a theory exists and all the implications that come from that view.”² Precision psychiatry will completely disrupt the current antiquated clinical paradigm, transforming psychiatry into the clinical neuroscience it is. Many “omics,” such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, and metagenomics, will inevitably find their way into the jargon of psychiatrists.³

A marriage of science and technology is essential for the emergence of precision psychiatry. To achieve this transformative amalgamation, we need to reconfigure our concepts, reengineer our methods, reinvent our models, and redesign our approaches to patient care.

As Peter Drucker said, “The best way to predict the future is to create it.”⁴ Precision psychiatry is our future. Let’s create it!

Imagine being able to precisely select the medication with the optimal efficacy, safety, and tolerability at the outset of treatment for every psychiatric patient who needs pharma­cotherapy. Imagine how much the patient would appreciate not receiving a series of drugs and suffering multiple adverse effects and unremitting symptoms until the “right medication” is identified. Imagine how gratifying it would be for you as a psychiatrist to watch every one of your patients improve rapidly with minimal complaints or adverse effects.

Precision psychiatry is the indispensable vehicle to achieve personalized medicine for psychiatric patients. Precision psychiatry is a cherished goal, but it remains an aspirational objective. Other medical specialties, especially oncology and cardiology, have made remarkable strides in precision medicine, but the journey to precision psychiatry is still in its early stages. Yet there is every reason to believe that we are making progress toward that cherished goal.

To implement precision psychiatry, we must be able to identify the biosignature of each patient’s psychiatric brain disorder. But there is a formidable challenge to overcome: the complex, extensive heterogeneity of psychiatric disorders, which requires intense and inspired neurobiology research. So, while clinicians go on with the mundane trial-and-error approach of contemporary psychopharmacology, psychiatric neuroscientists are diligently deconstructing major psychiatric disorders into specific biotypes with unique biosignatures that will one day guide accurate and prompt clinical management.

Psychiatric practitioners may be too busy to keep tabs on the progress being made in identifying various biomarkers that are the key ingredients to decoding the biosignature of each psychiatric patient. Take schizophrenia, for example. There are myriad clinical variations that comprise this heterogeneous brain syndrome, including level of premorbid functioning; acute vs gradual onset of psychosis; the type and severity of hallucinations or delusions; the dimensional spectrum of negative symptoms and cognitive impairments; the presence and intensity of suicidal or homicidal urges; and the type of medical and psychiatric comorbidities. No wonder every patient is a unique and fascinating clinical puzzle, and yet, patients with schizophrenia are still being homogenized under a single DSM diagnostic category.

Precision psychiatry will ultimately enable practitioners to recognize various psychotic diseases that are more specific than the current DSM psychosis categories. Further, precision psychiatry will provide guidance as to which member within a class of so-called “me-too” drugs is the optimal match for each patient. This will stand in stark contrast to the chaotic hit-or-miss approach.

Precision psychiatry also will reveal the absurdity of current FDA clinical trials design for drug development. How can a molecule with a putative mechanism of action relevant to a specific biotype be administered to a hodgepodge of heterogeneous biotypes that have been lumped in 1 clinical category, and yet be expected to exert efficacy in most biotypes? It is a small miracle that some new drugs beat placebo despite the extensive variability in both placebo responses and drug responses. But it is well known that in all FDA placebo-controlled trials, the therapeutic response across the patient population varies from extremely high to extremely low, and worsening may even occur in a subset of patients receiving either the active drug or placebo. Perhaps drug response should be used as 1 methodology to classify biotypes of patients encompassed within a heterogeneous syndrome such as schizophrenia.

Precision psychiatry will represent a huge paradigm shift in the science and practice of our specialty. In his landmark book, Thomas Kuhn defined a paradigm as “an entire worldview in which a theory exists and all the implications that come from that view.”² Precision psychiatry will completely disrupt the current antiquated clinical paradigm, transforming psychiatry into the clinical neuroscience it is. Many “omics,” such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, and metagenomics, will inevitably find their way into the jargon of psychiatrists.³

A marriage of science and technology is essential for the emergence of precision psychiatry. To achieve this transformative amalgamation, we need to reconfigure our concepts, reengineer our methods, reinvent our models, and redesign our approaches to patient care.

As Peter Drucker said, “The best way to predict the future is to create it.”⁴ Precision psychiatry is our future. Let’s create it!

Imagine being able to precisely select the medication with the optimal efficacy, safety, and tolerability at the outset of treatment for every psychiatric patient who needs pharma­cotherapy. Imagine how much the patient would appreciate not receiving a series of drugs and suffering multiple adverse effects and unremitting symptoms until the “right medication” is identified. Imagine how gratifying it would be for you as a psychiatrist to watch every one of your patients improve rapidly with minimal complaints or adverse effects.

Precision psychiatry is the indispensable vehicle to achieve personalized medicine for psychiatric patients. Precision psychiatry is a cherished goal, but it remains an aspirational objective. Other medical specialties, especially oncology and cardiology, have made remarkable strides in precision medicine, but the journey to precision psychiatry is still in its early stages. Yet there is every reason to believe that we are making progress toward that cherished goal.

To implement precision psychiatry, we must be able to identify the biosignature of each patient’s psychiatric brain disorder. But there is a formidable challenge to overcome: the complex, extensive heterogeneity of psychiatric disorders, which requires intense and inspired neurobiology research. So, while clinicians go on with the mundane trial-and-error approach of contemporary psychopharmacology, psychiatric neuroscientists are diligently deconstructing major psychiatric disorders into specific biotypes with unique biosignatures that will one day guide accurate and prompt clinical management.

Psychiatric practitioners may be too busy to keep tabs on the progress being made in identifying various biomarkers that are the key ingredients to decoding the biosignature of each psychiatric patient. Take schizophrenia, for example. There are myriad clinical variations that comprise this heterogeneous brain syndrome, including level of premorbid functioning; acute vs gradual onset of psychosis; the type and severity of hallucinations or delusions; the dimensional spectrum of negative symptoms and cognitive impairments; the presence and intensity of suicidal or homicidal urges; and the type of medical and psychiatric comorbidities. No wonder every patient is a unique and fascinating clinical puzzle, and yet, patients with schizophrenia are still being homogenized under a single DSM diagnostic category.

Precision psychiatry will ultimately enable practitioners to recognize various psychotic diseases that are more specific than the current DSM psychosis categories. Further, precision psychiatry will provide guidance as to which member within a class of so-called “me-too” drugs is the optimal match for each patient. This will stand in stark contrast to the chaotic hit-or-miss approach.

Precision psychiatry also will reveal the absurdity of current FDA clinical trials design for drug development. How can a molecule with a putative mechanism of action relevant to a specific biotype be administered to a hodgepodge of heterogeneous biotypes that have been lumped in 1 clinical category, and yet be expected to exert efficacy in most biotypes? It is a small miracle that some new drugs beat placebo despite the extensive variability in both placebo responses and drug responses. But it is well known that in all FDA placebo-controlled trials, the therapeutic response across the patient population varies from extremely high to extremely low, and worsening may even occur in a subset of patients receiving either the active drug or placebo. Perhaps drug response should be used as 1 methodology to classify biotypes of patients encompassed within a heterogeneous syndrome such as schizophrenia.

Precision psychiatry will represent a huge paradigm shift in the science and practice of our specialty. In his landmark book, Thomas Kuhn defined a paradigm as “an entire worldview in which a theory exists and all the implications that come from that view.”² Precision psychiatry will completely disrupt the current antiquated clinical paradigm, transforming psychiatry into the clinical neuroscience it is. Many “omics,” such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics, and metagenomics, will inevitably find their way into the jargon of psychiatrists.³

A marriage of science and technology is essential for the emergence of precision psychiatry. To achieve this transformative amalgamation, we need to reconfigure our concepts, reengineer our methods, reinvent our models, and redesign our approaches to patient care.

As Peter Drucker said, “The best way to predict the future is to create it.”⁴ Precision psychiatry is our future. Let’s create it!

Dear Dr. Mossman,
I have a possibly fatal disease. So far, my symptoms and treatment haven’t kept me from my usual activities. But if my illness worsens, I’ll have to quit practicing psychiatry. What should I be doing now to make sure I fulfill my ethical and legal obligations to my patients?
Submitted by “Dr. F”

“Remember, with great power comes great responsibility.”

- Peter Parker, Spider-Man (2002)

Peter Parker’s movie-ending statement applies to doctors as well as Spider-Man. Although we don’t swing from building to building to save cities from heinous villains, practicing medicine is a privilege that society bestows only upon physicians who retain the knowledge, skills, and ability to treat patients competently.

Doctors retire from practice for many reasons, including when deteriorating physical health or cognitive capacity prevents them from performing clinical duties properly. Dr. F’s situation is not rare. As the physician population ages,^1,2 a growing number of his colleagues will face similar circumstances,^3,4 and with them, the responsibility and emotional turmoil of arranging to end their medical practices.

In many ways, concluding a psychiatric practice is similar to retiring from practice in other specialties. But because we care for patients’ minds as well as their bodies, retirement affects psychiatrists in distinctive ways that reflect our patients’ feelings toward us and our feelings toward them. To answer Dr. F’s question, this article considers having to stop practicing from 3 vantage points:

• the emotional impact on patients
• the emotional impact on the psychiatrist
• fulfilling one’s legal obligations while attending to the emotions of patients as well as oneself.

Emotional impact on patients

A content analysis study suggests that the traits patients appreciate in family physicians include the availability to listen, caring and compassion, trusted medical judgment, conveying the patient’s importance during encounters, feelings of connectedness, knowledge and understanding of the patient’s family, and relationship longevity.⁵ The same factors likely apply to relationships between psychiatrists and their patients, particularly if treatment encounters have extended over years and have involved conversations beyond those needed merely to write prescriptions.

Psychoanalytic publications offer many descriptions of patients’ reactions to the illness or death of their mental health professional. A 1978 study of 27 analysands whose physicians died during ongoing therapy reported reactions that ranged from a minimal impact to protracted mourning accompanied by helplessness, intense crying, and recurrent dreams about the analyst.⁶ Although a few patients were relieved that death had ended a difficult treatment, many were angry at their doctor for not attending to self-care and for breaking their treatment agreement, or because they had missed out on hoped-for benefits.

A 2010 study described the pain and distress that patients may experience following the death of their analyst or psychotherapist. These accounts emphasized the emotional isolation of grieving patients, who do not have the social support that bereaved persons receive after losing a loved one.⁷ Successful psychotherapy provides a special relationship characterized by trust, intimacy, and safety. But if the therapist suddenly dies, this relationship “is transformed into a solitude like no other.”⁸

Because the sudden “rupture of an analytic process is bound to be traumatic and may cause iatrogenic injury to the patient,” Traesdal⁹ advocates that therapists in situations similar to Dr. F’s discuss their possible death “on the reality level at least once during any analysis or psychotherapy.… It is extremely helpful to a patient to have discussed … how to handle the situation” if the therapist dies. This discussion also offers the patient an opportunity to confront a cultural taboo around death and to increase capacity to tolerate pain, illness, and aging.^10,11

Most psychiatric care today is not psychoanalysis; psychiatrists provide other forms of care that create less intense doctor–patient relationships. Yet knowledge of these kinds of reactions may help Dr. F stay attuned to his patients’ concerns and to contemplate what they may experience, to greater or lesser degrees, if his health declines.

Retirement’s emotional impact on the psychiatrist

Published guidance on concluding a psychiatric practice is sparse, considering that all psychiatrists are mortal and stop practicing at some point.¹²Not thinking about or planning for retirement is a psychiatric tradition that started with Freud. He saw patients until shortly before his death and did not seem to have planned for ending his practice, despite suffering with jaw cancer for 16 years.¹³

Practicing medicine often is more than just a career; it is a core aspect of many physicians’ identity.¹⁴ Most of us spend a large fraction of our waking hours caring for patients and meeting other job requirements (eg, teaching, maintaining knowledge and skills), and many of us have scant time to pursue nonmedical interests. An intense prioritization of one’s “medical identity” makes retirement a blow to a doctor’s self-worth and sense of meaning in life.^15,16

Because their work is not physically demanding, most psychiatrists continue to practice beyond the age of 65 years.^12,17 More important, perhaps, is that being a psychiatrist is uniquely rewarding. As Benjamin Rush observed in an 1810 letter to Pennsylvania Hospital, successfully treating any medical disease is gratifying, but “what is this pleasure compared with that of restoring a fellow creature from the anguish and folly of madness and of reviving in him the knowledge of himself, his family, his friends, and his God!”¹⁸

Physicians in any specialty that involves repeated contact with the same patients form emotional bonds with their patients that retirement breaks.¹⁴ Psychiatrists’ interest in how patients think, feel, and cope with problems creates special attachments¹⁷ that can make some terminations “emotionally excruciating.”¹²

Psychiatrists with serious illness

What guidance might Dr. F find regarding whether to broach the subject of his illness with patients, and if so, how? No one has conducted controlled trials to answer these questions. Rather, published discussion of psychiatrists’ serious illness is found mainly in the psychotherapy literature. What’s available consists of individual accounts and case series that lack scientific rigor and offer little clarity about what the therapist should say, when to say it, and how to initiate the discussion.^19,20 Yet Dr. F may find some of these authors’ ideas and suggestions helpful, particularly if his psychiatric practice includes providing psychotherapy.

As a rule, psychiatrists avoid talking about themselves, but having a serious illness that could affect treatment often justifies deviating from this practice. Although Dr. F (like many psychiatrists) may be concerned that discussing his health will make patients anxious or “contaminate” what they are able or willing to say,²¹ not providing information or avoiding discussion (especially if a patient asks about your health) may quickly undermine a patient’s trust.^21,22 Even in psycho­analytic treatment, it makes little sense to encourage patients “to speak freely on the pretense that all is well, despite obvious evidence to the contrary.”¹⁹

Physicians often deny—or at least avoid thinking about—their own mortality.²³ But avoiding talking about something so important (and often so obvious) as one’s illness may risk supporting patients’ denial of crucial matters in their own lives.^19,21 Moreover, Dr. F’s inadvertent self-disclosure (eg, by displaying obvious signs of illness) may do more harm to therapy than a planned statement in which Dr. F has prepared what he’ll say to answer his patients’ questions.²⁰

That Dr. F has continued working while suffering from a potentially fatal illness seems noble. Yet by doing so, he accepts not only the burdens of his illness but also the obligation to continue to serve his patients competently. This requires maintaining emotional steadiness and not using patients for emotional support, but instead obtaining and using the support of his friends, colleagues, family, consultants, and caregivers.²⁰

Legal obligations

Retirement does not end a physician’s professional legal obligations.²⁴ The legal rules and duties for psychiatrists who leave their practices are similar to those that apply to other physicians. Mishandling these aspects of retirement can result in various legal, licensure-related, or economic consequences, depending on your circumstances and employment arrangements.

Employment contracts in hospital or group practices often require notice of impending departures. If applicable to Dr. F’s situation, failure to comply with such conditions may lead to forfeiture of buyout payments, paying for malpractice tail coverage, or lawsuits claiming violation of contractual agreements.²⁵

Retirement also creates practical and legal responsibilities to patients that are separate from the interpersonal and emotional issues previously discussed. How will those who need ongoing care and coverage be cared for? When withdrawing from a patient’s care (because of retirement or other reasons), a physician should give the patient enough advance notice to set up satisfactory treatment arrangements elsewhere and should facilitate transfer of the patient’s care, if appropriate.²⁶ Failure to meet this ethical obligation may lead to a malpractice action alleging abandonment, which is defined as “the unilateral severance of the professional relationship … without reasonable notice at a time when there is still the necessity of continuing medical attention.”²⁷

Further obligations come from medical licensing boards, which, in many states, have established time frames and specific procedures for informing patients and the public when a physician is leaving practice. Table 1^24,28-31 lists examples of these. If Dr. F works in a state where the board hasn’t promulgated such regulations, Table 1^24,28-31 may still help him think through how to discharge his ethical responsibilities to notify patients, colleagues, and business entities that he is ending his practice. References 28-30 and 32 discuss several of these matters, suggest timetables for various steps of a practice closure, and provide sample letters for notifying patients.

Physicians also must preserve their medical records for a certain period after they retire. States with rules on this matter require record preservation for 5 to 10 years or until 2 or 3 years after minor patients reach the age of majority.³³ The Health Insurance Portability and Accountability Act of 1996 requires covered entities, which include most psychiatrists, to retain records for 6 years,³⁴ and certain Medicare programs require retention for 10 years.³⁵

Depending on Dr. F’s location and type of practice, his records should be preserved for the longest period that applies. If he is leaving a group practice that owns the records, arranging for this should be easy. If leaving an independent practice, he may need to ask another practice to perform this function.²⁵

A ‘professional will’

Dr. F also might consider a measure that many psychotherapists recommend^13,19,36 and that in some states is required by mental health licensing boards or professional codes^37,38: creating a “professional will” that contains instructions for handling practice matters in case of death or disability.³⁹

Dear Dr. Mossman,
I have a possibly fatal disease. So far, my symptoms and treatment haven’t kept me from my usual activities. But if my illness worsens, I’ll have to quit practicing psychiatry. What should I be doing now to make sure I fulfill my ethical and legal obligations to my patients?
Submitted by “Dr. F”

“Remember, with great power comes great responsibility.”

- Peter Parker, Spider-Man (2002)

Peter Parker’s movie-ending statement applies to doctors as well as Spider-Man. Although we don’t swing from building to building to save cities from heinous villains, practicing medicine is a privilege that society bestows only upon physicians who retain the knowledge, skills, and ability to treat patients competently.

Doctors retire from practice for many reasons, including when deteriorating physical health or cognitive capacity prevents them from performing clinical duties properly. Dr. F’s situation is not rare. As the physician population ages,^1,2 a growing number of his colleagues will face similar circumstances,^3,4 and with them, the responsibility and emotional turmoil of arranging to end their medical practices.

In many ways, concluding a psychiatric practice is similar to retiring from practice in other specialties. But because we care for patients’ minds as well as their bodies, retirement affects psychiatrists in distinctive ways that reflect our patients’ feelings toward us and our feelings toward them. To answer Dr. F’s question, this article considers having to stop practicing from 3 vantage points:

• the emotional impact on patients
• the emotional impact on the psychiatrist
• fulfilling one’s legal obligations while attending to the emotions of patients as well as oneself.

Emotional impact on patients

A content analysis study suggests that the traits patients appreciate in family physicians include the availability to listen, caring and compassion, trusted medical judgment, conveying the patient’s importance during encounters, feelings of connectedness, knowledge and understanding of the patient’s family, and relationship longevity.⁵ The same factors likely apply to relationships between psychiatrists and their patients, particularly if treatment encounters have extended over years and have involved conversations beyond those needed merely to write prescriptions.

Psychoanalytic publications offer many descriptions of patients’ reactions to the illness or death of their mental health professional. A 1978 study of 27 analysands whose physicians died during ongoing therapy reported reactions that ranged from a minimal impact to protracted mourning accompanied by helplessness, intense crying, and recurrent dreams about the analyst.⁶ Although a few patients were relieved that death had ended a difficult treatment, many were angry at their doctor for not attending to self-care and for breaking their treatment agreement, or because they had missed out on hoped-for benefits.

A 2010 study described the pain and distress that patients may experience following the death of their analyst or psychotherapist. These accounts emphasized the emotional isolation of grieving patients, who do not have the social support that bereaved persons receive after losing a loved one.⁷ Successful psychotherapy provides a special relationship characterized by trust, intimacy, and safety. But if the therapist suddenly dies, this relationship “is transformed into a solitude like no other.”⁸

Because the sudden “rupture of an analytic process is bound to be traumatic and may cause iatrogenic injury to the patient,” Traesdal⁹ advocates that therapists in situations similar to Dr. F’s discuss their possible death “on the reality level at least once during any analysis or psychotherapy.… It is extremely helpful to a patient to have discussed … how to handle the situation” if the therapist dies. This discussion also offers the patient an opportunity to confront a cultural taboo around death and to increase capacity to tolerate pain, illness, and aging.^10,11

Most psychiatric care today is not psychoanalysis; psychiatrists provide other forms of care that create less intense doctor–patient relationships. Yet knowledge of these kinds of reactions may help Dr. F stay attuned to his patients’ concerns and to contemplate what they may experience, to greater or lesser degrees, if his health declines.

Retirement’s emotional impact on the psychiatrist

Published guidance on concluding a psychiatric practice is sparse, considering that all psychiatrists are mortal and stop practicing at some point.¹²Not thinking about or planning for retirement is a psychiatric tradition that started with Freud. He saw patients until shortly before his death and did not seem to have planned for ending his practice, despite suffering with jaw cancer for 16 years.¹³

Practicing medicine often is more than just a career; it is a core aspect of many physicians’ identity.¹⁴ Most of us spend a large fraction of our waking hours caring for patients and meeting other job requirements (eg, teaching, maintaining knowledge and skills), and many of us have scant time to pursue nonmedical interests. An intense prioritization of one’s “medical identity” makes retirement a blow to a doctor’s self-worth and sense of meaning in life.^15,16

Because their work is not physically demanding, most psychiatrists continue to practice beyond the age of 65 years.^12,17 More important, perhaps, is that being a psychiatrist is uniquely rewarding. As Benjamin Rush observed in an 1810 letter to Pennsylvania Hospital, successfully treating any medical disease is gratifying, but “what is this pleasure compared with that of restoring a fellow creature from the anguish and folly of madness and of reviving in him the knowledge of himself, his family, his friends, and his God!”¹⁸

Physicians in any specialty that involves repeated contact with the same patients form emotional bonds with their patients that retirement breaks.¹⁴ Psychiatrists’ interest in how patients think, feel, and cope with problems creates special attachments¹⁷ that can make some terminations “emotionally excruciating.”¹²

Psychiatrists with serious illness

What guidance might Dr. F find regarding whether to broach the subject of his illness with patients, and if so, how? No one has conducted controlled trials to answer these questions. Rather, published discussion of psychiatrists’ serious illness is found mainly in the psychotherapy literature. What’s available consists of individual accounts and case series that lack scientific rigor and offer little clarity about what the therapist should say, when to say it, and how to initiate the discussion.^19,20 Yet Dr. F may find some of these authors’ ideas and suggestions helpful, particularly if his psychiatric practice includes providing psychotherapy.

As a rule, psychiatrists avoid talking about themselves, but having a serious illness that could affect treatment often justifies deviating from this practice. Although Dr. F (like many psychiatrists) may be concerned that discussing his health will make patients anxious or “contaminate” what they are able or willing to say,²¹ not providing information or avoiding discussion (especially if a patient asks about your health) may quickly undermine a patient’s trust.^21,22 Even in psycho­analytic treatment, it makes little sense to encourage patients “to speak freely on the pretense that all is well, despite obvious evidence to the contrary.”¹⁹

Physicians often deny—or at least avoid thinking about—their own mortality.²³ But avoiding talking about something so important (and often so obvious) as one’s illness may risk supporting patients’ denial of crucial matters in their own lives.^19,21 Moreover, Dr. F’s inadvertent self-disclosure (eg, by displaying obvious signs of illness) may do more harm to therapy than a planned statement in which Dr. F has prepared what he’ll say to answer his patients’ questions.²⁰

That Dr. F has continued working while suffering from a potentially fatal illness seems noble. Yet by doing so, he accepts not only the burdens of his illness but also the obligation to continue to serve his patients competently. This requires maintaining emotional steadiness and not using patients for emotional support, but instead obtaining and using the support of his friends, colleagues, family, consultants, and caregivers.²⁰

Legal obligations

Retirement does not end a physician’s professional legal obligations.²⁴ The legal rules and duties for psychiatrists who leave their practices are similar to those that apply to other physicians. Mishandling these aspects of retirement can result in various legal, licensure-related, or economic consequences, depending on your circumstances and employment arrangements.

Employment contracts in hospital or group practices often require notice of impending departures. If applicable to Dr. F’s situation, failure to comply with such conditions may lead to forfeiture of buyout payments, paying for malpractice tail coverage, or lawsuits claiming violation of contractual agreements.²⁵

Retirement also creates practical and legal responsibilities to patients that are separate from the interpersonal and emotional issues previously discussed. How will those who need ongoing care and coverage be cared for? When withdrawing from a patient’s care (because of retirement or other reasons), a physician should give the patient enough advance notice to set up satisfactory treatment arrangements elsewhere and should facilitate transfer of the patient’s care, if appropriate.²⁶ Failure to meet this ethical obligation may lead to a malpractice action alleging abandonment, which is defined as “the unilateral severance of the professional relationship … without reasonable notice at a time when there is still the necessity of continuing medical attention.”²⁷

Further obligations come from medical licensing boards, which, in many states, have established time frames and specific procedures for informing patients and the public when a physician is leaving practice. Table 1^24,28-31 lists examples of these. If Dr. F works in a state where the board hasn’t promulgated such regulations, Table 1^24,28-31 may still help him think through how to discharge his ethical responsibilities to notify patients, colleagues, and business entities that he is ending his practice. References 28-30 and 32 discuss several of these matters, suggest timetables for various steps of a practice closure, and provide sample letters for notifying patients.

Physicians also must preserve their medical records for a certain period after they retire. States with rules on this matter require record preservation for 5 to 10 years or until 2 or 3 years after minor patients reach the age of majority.³³ The Health Insurance Portability and Accountability Act of 1996 requires covered entities, which include most psychiatrists, to retain records for 6 years,³⁴ and certain Medicare programs require retention for 10 years.³⁵

Depending on Dr. F’s location and type of practice, his records should be preserved for the longest period that applies. If he is leaving a group practice that owns the records, arranging for this should be easy. If leaving an independent practice, he may need to ask another practice to perform this function.²⁵

A ‘professional will’

Dr. F also might consider a measure that many psychotherapists recommend^13,19,36 and that in some states is required by mental health licensing boards or professional codes^37,38: creating a “professional will” that contains instructions for handling practice matters in case of death or disability.³⁹

Dear Dr. Mossman,
I have a possibly fatal disease. So far, my symptoms and treatment haven’t kept me from my usual activities. But if my illness worsens, I’ll have to quit practicing psychiatry. What should I be doing now to make sure I fulfill my ethical and legal obligations to my patients?
Submitted by “Dr. F”

“Remember, with great power comes great responsibility.”

- Peter Parker, Spider-Man (2002)

Peter Parker’s movie-ending statement applies to doctors as well as Spider-Man. Although we don’t swing from building to building to save cities from heinous villains, practicing medicine is a privilege that society bestows only upon physicians who retain the knowledge, skills, and ability to treat patients competently.

Doctors retire from practice for many reasons, including when deteriorating physical health or cognitive capacity prevents them from performing clinical duties properly. Dr. F’s situation is not rare. As the physician population ages,^1,2 a growing number of his colleagues will face similar circumstances,^3,4 and with them, the responsibility and emotional turmoil of arranging to end their medical practices.

In many ways, concluding a psychiatric practice is similar to retiring from practice in other specialties. But because we care for patients’ minds as well as their bodies, retirement affects psychiatrists in distinctive ways that reflect our patients’ feelings toward us and our feelings toward them. To answer Dr. F’s question, this article considers having to stop practicing from 3 vantage points:

• the emotional impact on patients
• the emotional impact on the psychiatrist
• fulfilling one’s legal obligations while attending to the emotions of patients as well as oneself.

Emotional impact on patients

A content analysis study suggests that the traits patients appreciate in family physicians include the availability to listen, caring and compassion, trusted medical judgment, conveying the patient’s importance during encounters, feelings of connectedness, knowledge and understanding of the patient’s family, and relationship longevity.⁵ The same factors likely apply to relationships between psychiatrists and their patients, particularly if treatment encounters have extended over years and have involved conversations beyond those needed merely to write prescriptions.

Psychoanalytic publications offer many descriptions of patients’ reactions to the illness or death of their mental health professional. A 1978 study of 27 analysands whose physicians died during ongoing therapy reported reactions that ranged from a minimal impact to protracted mourning accompanied by helplessness, intense crying, and recurrent dreams about the analyst.⁶ Although a few patients were relieved that death had ended a difficult treatment, many were angry at their doctor for not attending to self-care and for breaking their treatment agreement, or because they had missed out on hoped-for benefits.

A 2010 study described the pain and distress that patients may experience following the death of their analyst or psychotherapist. These accounts emphasized the emotional isolation of grieving patients, who do not have the social support that bereaved persons receive after losing a loved one.⁷ Successful psychotherapy provides a special relationship characterized by trust, intimacy, and safety. But if the therapist suddenly dies, this relationship “is transformed into a solitude like no other.”⁸

Because the sudden “rupture of an analytic process is bound to be traumatic and may cause iatrogenic injury to the patient,” Traesdal⁹ advocates that therapists in situations similar to Dr. F’s discuss their possible death “on the reality level at least once during any analysis or psychotherapy.… It is extremely helpful to a patient to have discussed … how to handle the situation” if the therapist dies. This discussion also offers the patient an opportunity to confront a cultural taboo around death and to increase capacity to tolerate pain, illness, and aging.^10,11

Most psychiatric care today is not psychoanalysis; psychiatrists provide other forms of care that create less intense doctor–patient relationships. Yet knowledge of these kinds of reactions may help Dr. F stay attuned to his patients’ concerns and to contemplate what they may experience, to greater or lesser degrees, if his health declines.

Retirement’s emotional impact on the psychiatrist

Published guidance on concluding a psychiatric practice is sparse, considering that all psychiatrists are mortal and stop practicing at some point.¹²Not thinking about or planning for retirement is a psychiatric tradition that started with Freud. He saw patients until shortly before his death and did not seem to have planned for ending his practice, despite suffering with jaw cancer for 16 years.¹³

Practicing medicine often is more than just a career; it is a core aspect of many physicians’ identity.¹⁴ Most of us spend a large fraction of our waking hours caring for patients and meeting other job requirements (eg, teaching, maintaining knowledge and skills), and many of us have scant time to pursue nonmedical interests. An intense prioritization of one’s “medical identity” makes retirement a blow to a doctor’s self-worth and sense of meaning in life.^15,16

Because their work is not physically demanding, most psychiatrists continue to practice beyond the age of 65 years.^12,17 More important, perhaps, is that being a psychiatrist is uniquely rewarding. As Benjamin Rush observed in an 1810 letter to Pennsylvania Hospital, successfully treating any medical disease is gratifying, but “what is this pleasure compared with that of restoring a fellow creature from the anguish and folly of madness and of reviving in him the knowledge of himself, his family, his friends, and his God!”¹⁸

Physicians in any specialty that involves repeated contact with the same patients form emotional bonds with their patients that retirement breaks.¹⁴ Psychiatrists’ interest in how patients think, feel, and cope with problems creates special attachments¹⁷ that can make some terminations “emotionally excruciating.”¹²

Psychiatrists with serious illness

What guidance might Dr. F find regarding whether to broach the subject of his illness with patients, and if so, how? No one has conducted controlled trials to answer these questions. Rather, published discussion of psychiatrists’ serious illness is found mainly in the psychotherapy literature. What’s available consists of individual accounts and case series that lack scientific rigor and offer little clarity about what the therapist should say, when to say it, and how to initiate the discussion.^19,20 Yet Dr. F may find some of these authors’ ideas and suggestions helpful, particularly if his psychiatric practice includes providing psychotherapy.

As a rule, psychiatrists avoid talking about themselves, but having a serious illness that could affect treatment often justifies deviating from this practice. Although Dr. F (like many psychiatrists) may be concerned that discussing his health will make patients anxious or “contaminate” what they are able or willing to say,²¹ not providing information or avoiding discussion (especially if a patient asks about your health) may quickly undermine a patient’s trust.^21,22 Even in psycho­analytic treatment, it makes little sense to encourage patients “to speak freely on the pretense that all is well, despite obvious evidence to the contrary.”¹⁹

Physicians often deny—or at least avoid thinking about—their own mortality.²³ But avoiding talking about something so important (and often so obvious) as one’s illness may risk supporting patients’ denial of crucial matters in their own lives.^19,21 Moreover, Dr. F’s inadvertent self-disclosure (eg, by displaying obvious signs of illness) may do more harm to therapy than a planned statement in which Dr. F has prepared what he’ll say to answer his patients’ questions.²⁰

That Dr. F has continued working while suffering from a potentially fatal illness seems noble. Yet by doing so, he accepts not only the burdens of his illness but also the obligation to continue to serve his patients competently. This requires maintaining emotional steadiness and not using patients for emotional support, but instead obtaining and using the support of his friends, colleagues, family, consultants, and caregivers.²⁰

Legal obligations

Retirement does not end a physician’s professional legal obligations.²⁴ The legal rules and duties for psychiatrists who leave their practices are similar to those that apply to other physicians. Mishandling these aspects of retirement can result in various legal, licensure-related, or economic consequences, depending on your circumstances and employment arrangements.

Employment contracts in hospital or group practices often require notice of impending departures. If applicable to Dr. F’s situation, failure to comply with such conditions may lead to forfeiture of buyout payments, paying for malpractice tail coverage, or lawsuits claiming violation of contractual agreements.²⁵

Retirement also creates practical and legal responsibilities to patients that are separate from the interpersonal and emotional issues previously discussed. How will those who need ongoing care and coverage be cared for? When withdrawing from a patient’s care (because of retirement or other reasons), a physician should give the patient enough advance notice to set up satisfactory treatment arrangements elsewhere and should facilitate transfer of the patient’s care, if appropriate.²⁶ Failure to meet this ethical obligation may lead to a malpractice action alleging abandonment, which is defined as “the unilateral severance of the professional relationship … without reasonable notice at a time when there is still the necessity of continuing medical attention.”²⁷

Further obligations come from medical licensing boards, which, in many states, have established time frames and specific procedures for informing patients and the public when a physician is leaving practice. Table 1^24,28-31 lists examples of these. If Dr. F works in a state where the board hasn’t promulgated such regulations, Table 1^24,28-31 may still help him think through how to discharge his ethical responsibilities to notify patients, colleagues, and business entities that he is ending his practice. References 28-30 and 32 discuss several of these matters, suggest timetables for various steps of a practice closure, and provide sample letters for notifying patients.

Physicians also must preserve their medical records for a certain period after they retire. States with rules on this matter require record preservation for 5 to 10 years or until 2 or 3 years after minor patients reach the age of majority.³³ The Health Insurance Portability and Accountability Act of 1996 requires covered entities, which include most psychiatrists, to retain records for 6 years,³⁴ and certain Medicare programs require retention for 10 years.³⁵

Depending on Dr. F’s location and type of practice, his records should be preserved for the longest period that applies. If he is leaving a group practice that owns the records, arranging for this should be easy. If leaving an independent practice, he may need to ask another practice to perform this function.²⁵

A ‘professional will’

Dr. F also might consider a measure that many psychotherapists recommend^13,19,36 and that in some states is required by mental health licensing boards or professional codes^37,38: creating a “professional will” that contains instructions for handling practice matters in case of death or disability.³⁹

CASE Bleeding, bewildered

Mr. K, age 23, a South Asian male, is discovered in the bathroom bleeding profusely. Mr. K’s parents inform emergency medical services (EMS) personnel that Mr. K is “not in his right mind” and speculate that he is depressed. EMS personnel find Mr. K sitting in a pool of blood in the bathtub, holding a cloth over his pubic area and complaining of significant pain. They estimate that Mr. K has lost approximately 1 L of blood. Cursory evaluation reveals that his penis is severed; no other injuries or lacerations are notable. Mr. K states, “I did not want it anymore.” A kitchen knife that he used to self-amputate is found nearby. He is awake, alert, and able to follow simple directives.

In the emergency room, Mr. K is in mild-to-moderate distress. He has no history of medical illness, but his parents report that he previously required psychiatric treatment. Mr. K is not able to elaborate. He reluctantly discloses an intermittent history of Cannabis use. Physical examination reveals tachycardia (heart rate: 115 to 120 beats per minute), and despite blood loss, systolic hypertension (blood pressure: 142/70 to 167/70 mm Hg). His pulse oximetry is 97% to 99%; he is afebrile. Laboratory tests are notable for anemia (hemoglobin, 7.2 g/dL [reference range, 14.0 to 17.5 g/dL]; hematocrit, 21.2% [reference range, 41% to 50%]) and serum toxicology screen is positive for benzodiazepines, which had been administered en route to allay his distress.

Mr. K continues to hold pressure on his pubic area. When pressure is released, active arterial spurting of bright red blood is notable. Genital examination reveals a cleanly amputated phallus. Emergent surgical intervention is required to stop the hemorrhage and reattach the penis. Initially, Mr. K is opposed to reattachment, but after a brief discussion with his parents, he consents to surgery. Urology and plastic surgery consultations are elicited to perform the microvascular portion of the procedure.

[polldaddy:9881368]

The authors’ observations

Self-injurious behaviors occur in approximately 1% to 4% of adults in the United States, with chronic and severe self-injury occurring among approximately 1% of the U.S. population.^1,2 Intentional GSM is a relatively rare catastrophic event that is often, but not solely, associated with severe mental illness. Because many cases go unreported, the prevalence of GSM is difficult to estimate.^3,4 Although GSM has been described in both men and women, the literature has predominantly focused on GSM among men.⁵ Genital self-injury has been described in several (ie, ethnic/racial and religious) contexts and has been legally sanctioned.^6-8

Psychiatric disorders associated with, and precipitating factors underlying, GSM have long remained elusive.⁸ GSM has been described in case reports and small case series in both psychiatric and urologic literature. These reports provide incomplete descriptions of the diagnostic conditions and psychosocial factors underlying male GSM.

A recent systematic review of 173 cases of men who engaged in GSM published in the past 115 years (since the first case of GSM was published in the psychiatric literature⁹) revealed that having some form of psychopathology elevates the probability of GSM^10,11; rarely the individual did not have a psychiatric condition.^11-17 Nearly one-half of the men had psychosis; most had a schizophrenia spectrum disorder diagnosis. Other psychiatric conditions associated with GSM include personality disorders, substance use disorder, and gender dysphoria. GSM is rarely associated with anxiety or mood disorders.

GSM is a heterogeneous form of self-injury that ranges from superficial genital lacerations, amputation, or castration to combinations of these injuries. Compared with individuals with other psychiatric disorders, a significantly greater proportion of individuals with schizophrenia spectrum disorders engage in self-amputation (auto-penectomy). By contrast, persons with gender dysphoria tend to engage in self-castration at significantly higher rates than those with other psychiatric conditions.¹¹ Despite these trends, clinicians should not infer a specific psychiatric diagnosis based on the severity or type of self-inflicted injury.

HISTORY Command hallucinations

Postoperatively, Mr. K is managed in the trauma intensive care unit. During psychiatric consultation, Mr. K demonstrates a blunted affect. His speech is low in volume but clear and coherent. His thoughts are generally linear for specific lines of inquiry (eg, about perceived level of pain) but otherwise are impoverished. Mr. K often digresses into repetitively mumbled prayers. He appears distracted, as if responding to internal stimuli. Although he acknowledges the GSM, he does not discuss the factors underlying his decision to proceed with auto-penectomy. Over successive evaluations, he reluctantly discloses that he had been experiencing disparaging auditory hallucinations that told him that his penis “was too small” and commanded him to “cut it off.”

Psychiatric history reveals that Mr. K required psychiatric hospitalization 7 months earlier due to new-onset auditory hallucinations, paranoia, and thought disorganization, in the context of daily Cannabis use. At the time, the differential diagnosis included new-onset schizophrenia and substance-induced psychosis. His symptoms improved quickly with risperidone, 2 mg/d, and he was discharged in a stable condition with referrals for outpatient care. Mr. K admits he had stopped taking risperidone several weeks before the GSM because he was convinced that he had been cured. At that time, Mr. K had told his parents he was no longer required to take medication or engage in outpatient psychiatric treatment, and they did not question this. Mr. K struggled to sustain part-time employment (in a family business), having taken a leave of absence from graduate school after his first hospitalization. He continued to use Cannabis regularly but denies being intoxicated at the time of the GSM. Throughout his surgical hospitalization, Mr. K’s thoughts remain disorganized. He denies that the GSM was a suicide attempt or having current suicidal thoughts, intent, or plans. He also denies having religious preoccupations, over-valued religious beliefs, or delusions.

Mr. K identifies as heterosexual, and denies experiencing distress related to sexual orientation or gender identity or guilt related to sexual impulses or actions. He also denies having a history of trauma or victimization and does not report any symptoms of posttraumatic stress disorder or body dysmorphic disorder.

The authors’ observations

Self-injury elicits strong, emotional responses from health care professionals, including fascination, apprehension, and hopelessness. Psychiatrists who care for such patients should monitor members of the patient’s treatment team for psychological reactions. In addition, the patient’s behavior while hospitalized may stir feelings of retaliation, anger, fear, and frustration.^11,24,37 Collaborative relationships with medical and surgical specialties can help staff manage emotional reactions and avoid the inadvertent expression of those feelings in their interactions with the patient; these reactions might otherwise undermine treatment.^24,34 Family education can help mitigate any guilt family members may harbor for not preventing the injury.³⁷

Although efforts to understand the intended goal(s) and precipitants of the self-injury are likely to be worthwhile, the overwhelming distress associated with GSM and its emergent treatment may preclude intensive exploration. Assessing precipitants of self-injury should be approached using a nonjudgmental, dispassionate, matter-of-fact manner that conveys concern for the patient³⁸ and reassures the patient that the clinician has heard and, ideally, understands the patient’s distress.³⁹ Forced exploration during the prevailing stress of treatment may overwhelm the patient, prove to be overly distressing, and compel the patient to act out in self-injurious ways. Therefore, exploration of the underpinnings of GSM may need to be postponed until surgical treatment is completed, the patient’s symptoms have been managed with psychopharmacologic intervention, and the patient has been transitioned to the safety and close monitoring of an acute psychiatric inpatient setting.

TREATMENT Restarting medication

While on the surgical unit, Mr. K is restarted on risperidone, 2 mg/d. He appears to tolerate the medication without adverse effects. However, because Mr. K continues to experience auditory hallucinations, and the treatment team remains concerned that he might again experience commands to harm himself, he is transferred to an acute psychiatric inpatient setting.

Urology follow-up reveals necrosis/mummification of the replanted penis and an open scrotal wound. After discussing options with the patient and family, the urologist transfers Mr. K back to the surgical unit for wound closure and removal of the replanted penis. A urethrostomy is performed to allow for bladder emptying.

[polldaddy:9881371]

The authors’ observations

Because most published case reports of GSM among men have focused on acute treatment, there is a dearth of literature available on the long-term course of GSM to inform treatment strategies. Because recovery is a non-static process and a patient’s reactions to his injury will likely evolve over time, a multifaceted approach invoking psychiatric and psychotherapeutic interventions is necessary to help patients after initial injury and surgical management^37,40-43 (Table 2^11,20,27,41).

OUTCOME Return to school, work

Mr. K is discharged with close follow-up at a specialized clinic for new-onset psychosis. Post-discharge treatment consists of education about the course of schizophrenia and the need for medication adherence to prevent relapse. Mr. K also is educated on the relationship between Cannabis use and psychosis, and he abstains from illicit substance use. Family involvement is encouraged to help with medication compliance and monitoring for symptom reemergence.

Therapy focuses on exploring the antecedents of the auto-penectomy, Mr. K’s body image issue concerns, and his feelings related to eventual prosthesis implantation. He insists that he cannot recall any precipitating factors for his self-injury other than the command hallucinations. He does not report sexual guilt, although he had been sexually active with his girlfriend in the months prior to his GSM, which goes against his family’s religious beliefs. He reports significant regret and shame for the self-mutilation, and blames himself for not informing family members about his hallucinations. Therapy involves addressing his attribution of blame using cognitive techniques and focuses on measures that can be taken to prevent further self-harm. Efforts are directed at exploring whether cultural and religious traditions impacted the therapeutic alliance, medication adherence, self-esteem and body image, sexuality, and future goals. Over the course of 1 year, he resumes his graduate studies and part-time work, and explores prosthetic placement for cosmetic purposes.

The authors’ observations

Research suggests that major self-mutilation among patients with psychotic illness is likely to occur during the first episode or early in the course of illness and/or with suboptimal treatment.^44,45 Mr. K was enlisted in an intensive outpatient treatment program involving biweekly psychotherapy sessions and psychiatric follow-up. Initial sessions focused on education regarding the importance of medication adherence and exploration of signs and symptoms that might suggest reemergence of a psycho­tic decompensation. The psychiatrist monitored Mr. K closely to ensure he was able to tolerate his medications to mitigate the possibility that adverse effects would undermine adherence. Mr. K’s reactions to having a psychiatric illness also were explored because of concerns that such self-appraisals might trigger shame, embarrassment, denial, and other responses that might undermine treatment adherence. His family members were apprised of treatment goals and enlisted to foster adherence with medication and follow-up appointments.

Mr. K’s Cannabis use was addressed because ongoing use likely had a negative impact on his schizophrenia (ie, a greater propensity toward relapse and rehospitalization and a poorer ther­apeutic response to antipsychotic medication).^46,47 He was strongly encouraged to avoid Cannabis and other illicit substances.

Psychiatrists can help in examining the meaning behind the injury while helping the patient to adapt to the sequelae and cultivate skills to meet functional demands.⁴¹ Once Mr. K’s psychotic symptoms were in remission, treatment began to address the antecedents of the GSM, as well as the resultant physical consequences. It was reasonable to explore how Mr. K now viewed his actions, as well as the consequences that his actions produced in terms of his physical appearance, sexual functioning, capacity for sexual intimacy, and reproductive potential. It was also important to recognize how such highly intimate and deeply personal self-schema are framed and organized against his cultural and religious background.^27,33

Body image concerns and expectations for future urologic intervention also should be explored. Although Mr. K was not averse to such exploration, he did not spontaneously address such topics in great depth. The discussion was unforced and effectively left open as an issue that could be explored in future sessions.

CASE Bleeding, bewildered

Mr. K, age 23, a South Asian male, is discovered in the bathroom bleeding profusely. Mr. K’s parents inform emergency medical services (EMS) personnel that Mr. K is “not in his right mind” and speculate that he is depressed. EMS personnel find Mr. K sitting in a pool of blood in the bathtub, holding a cloth over his pubic area and complaining of significant pain. They estimate that Mr. K has lost approximately 1 L of blood. Cursory evaluation reveals that his penis is severed; no other injuries or lacerations are notable. Mr. K states, “I did not want it anymore.” A kitchen knife that he used to self-amputate is found nearby. He is awake, alert, and able to follow simple directives.

In the emergency room, Mr. K is in mild-to-moderate distress. He has no history of medical illness, but his parents report that he previously required psychiatric treatment. Mr. K is not able to elaborate. He reluctantly discloses an intermittent history of Cannabis use. Physical examination reveals tachycardia (heart rate: 115 to 120 beats per minute), and despite blood loss, systolic hypertension (blood pressure: 142/70 to 167/70 mm Hg). His pulse oximetry is 97% to 99%; he is afebrile. Laboratory tests are notable for anemia (hemoglobin, 7.2 g/dL [reference range, 14.0 to 17.5 g/dL]; hematocrit, 21.2% [reference range, 41% to 50%]) and serum toxicology screen is positive for benzodiazepines, which had been administered en route to allay his distress.

Mr. K continues to hold pressure on his pubic area. When pressure is released, active arterial spurting of bright red blood is notable. Genital examination reveals a cleanly amputated phallus. Emergent surgical intervention is required to stop the hemorrhage and reattach the penis. Initially, Mr. K is opposed to reattachment, but after a brief discussion with his parents, he consents to surgery. Urology and plastic surgery consultations are elicited to perform the microvascular portion of the procedure.

[polldaddy:9881368]

The authors’ observations

Self-injurious behaviors occur in approximately 1% to 4% of adults in the United States, with chronic and severe self-injury occurring among approximately 1% of the U.S. population.^1,2 Intentional GSM is a relatively rare catastrophic event that is often, but not solely, associated with severe mental illness. Because many cases go unreported, the prevalence of GSM is difficult to estimate.^3,4 Although GSM has been described in both men and women, the literature has predominantly focused on GSM among men.⁵ Genital self-injury has been described in several (ie, ethnic/racial and religious) contexts and has been legally sanctioned.^6-8

Psychiatric disorders associated with, and precipitating factors underlying, GSM have long remained elusive.⁸ GSM has been described in case reports and small case series in both psychiatric and urologic literature. These reports provide incomplete descriptions of the diagnostic conditions and psychosocial factors underlying male GSM.

A recent systematic review of 173 cases of men who engaged in GSM published in the past 115 years (since the first case of GSM was published in the psychiatric literature⁹) revealed that having some form of psychopathology elevates the probability of GSM^10,11; rarely the individual did not have a psychiatric condition.^11-17 Nearly one-half of the men had psychosis; most had a schizophrenia spectrum disorder diagnosis. Other psychiatric conditions associated with GSM include personality disorders, substance use disorder, and gender dysphoria. GSM is rarely associated with anxiety or mood disorders.

GSM is a heterogeneous form of self-injury that ranges from superficial genital lacerations, amputation, or castration to combinations of these injuries. Compared with individuals with other psychiatric disorders, a significantly greater proportion of individuals with schizophrenia spectrum disorders engage in self-amputation (auto-penectomy). By contrast, persons with gender dysphoria tend to engage in self-castration at significantly higher rates than those with other psychiatric conditions.¹¹ Despite these trends, clinicians should not infer a specific psychiatric diagnosis based on the severity or type of self-inflicted injury.

HISTORY Command hallucinations

Postoperatively, Mr. K is managed in the trauma intensive care unit. During psychiatric consultation, Mr. K demonstrates a blunted affect. His speech is low in volume but clear and coherent. His thoughts are generally linear for specific lines of inquiry (eg, about perceived level of pain) but otherwise are impoverished. Mr. K often digresses into repetitively mumbled prayers. He appears distracted, as if responding to internal stimuli. Although he acknowledges the GSM, he does not discuss the factors underlying his decision to proceed with auto-penectomy. Over successive evaluations, he reluctantly discloses that he had been experiencing disparaging auditory hallucinations that told him that his penis “was too small” and commanded him to “cut it off.”

Psychiatric history reveals that Mr. K required psychiatric hospitalization 7 months earlier due to new-onset auditory hallucinations, paranoia, and thought disorganization, in the context of daily Cannabis use. At the time, the differential diagnosis included new-onset schizophrenia and substance-induced psychosis. His symptoms improved quickly with risperidone, 2 mg/d, and he was discharged in a stable condition with referrals for outpatient care. Mr. K admits he had stopped taking risperidone several weeks before the GSM because he was convinced that he had been cured. At that time, Mr. K had told his parents he was no longer required to take medication or engage in outpatient psychiatric treatment, and they did not question this. Mr. K struggled to sustain part-time employment (in a family business), having taken a leave of absence from graduate school after his first hospitalization. He continued to use Cannabis regularly but denies being intoxicated at the time of the GSM. Throughout his surgical hospitalization, Mr. K’s thoughts remain disorganized. He denies that the GSM was a suicide attempt or having current suicidal thoughts, intent, or plans. He also denies having religious preoccupations, over-valued religious beliefs, or delusions.

Mr. K identifies as heterosexual, and denies experiencing distress related to sexual orientation or gender identity or guilt related to sexual impulses or actions. He also denies having a history of trauma or victimization and does not report any symptoms of posttraumatic stress disorder or body dysmorphic disorder.

The authors’ observations

Self-injury elicits strong, emotional responses from health care professionals, including fascination, apprehension, and hopelessness. Psychiatrists who care for such patients should monitor members of the patient’s treatment team for psychological reactions. In addition, the patient’s behavior while hospitalized may stir feelings of retaliation, anger, fear, and frustration.^11,24,37 Collaborative relationships with medical and surgical specialties can help staff manage emotional reactions and avoid the inadvertent expression of those feelings in their interactions with the patient; these reactions might otherwise undermine treatment.^24,34 Family education can help mitigate any guilt family members may harbor for not preventing the injury.³⁷

Although efforts to understand the intended goal(s) and precipitants of the self-injury are likely to be worthwhile, the overwhelming distress associated with GSM and its emergent treatment may preclude intensive exploration. Assessing precipitants of self-injury should be approached using a nonjudgmental, dispassionate, matter-of-fact manner that conveys concern for the patient³⁸ and reassures the patient that the clinician has heard and, ideally, understands the patient’s distress.³⁹ Forced exploration during the prevailing stress of treatment may overwhelm the patient, prove to be overly distressing, and compel the patient to act out in self-injurious ways. Therefore, exploration of the underpinnings of GSM may need to be postponed until surgical treatment is completed, the patient’s symptoms have been managed with psychopharmacologic intervention, and the patient has been transitioned to the safety and close monitoring of an acute psychiatric inpatient setting.

TREATMENT Restarting medication

While on the surgical unit, Mr. K is restarted on risperidone, 2 mg/d. He appears to tolerate the medication without adverse effects. However, because Mr. K continues to experience auditory hallucinations, and the treatment team remains concerned that he might again experience commands to harm himself, he is transferred to an acute psychiatric inpatient setting.

Urology follow-up reveals necrosis/mummification of the replanted penis and an open scrotal wound. After discussing options with the patient and family, the urologist transfers Mr. K back to the surgical unit for wound closure and removal of the replanted penis. A urethrostomy is performed to allow for bladder emptying.

[polldaddy:9881371]

The authors’ observations

Because most published case reports of GSM among men have focused on acute treatment, there is a dearth of literature available on the long-term course of GSM to inform treatment strategies. Because recovery is a non-static process and a patient’s reactions to his injury will likely evolve over time, a multifaceted approach invoking psychiatric and psychotherapeutic interventions is necessary to help patients after initial injury and surgical management^37,40-43 (Table 2^11,20,27,41).

OUTCOME Return to school, work

Mr. K is discharged with close follow-up at a specialized clinic for new-onset psychosis. Post-discharge treatment consists of education about the course of schizophrenia and the need for medication adherence to prevent relapse. Mr. K also is educated on the relationship between Cannabis use and psychosis, and he abstains from illicit substance use. Family involvement is encouraged to help with medication compliance and monitoring for symptom reemergence.

Therapy focuses on exploring the antecedents of the auto-penectomy, Mr. K’s body image issue concerns, and his feelings related to eventual prosthesis implantation. He insists that he cannot recall any precipitating factors for his self-injury other than the command hallucinations. He does not report sexual guilt, although he had been sexually active with his girlfriend in the months prior to his GSM, which goes against his family’s religious beliefs. He reports significant regret and shame for the self-mutilation, and blames himself for not informing family members about his hallucinations. Therapy involves addressing his attribution of blame using cognitive techniques and focuses on measures that can be taken to prevent further self-harm. Efforts are directed at exploring whether cultural and religious traditions impacted the therapeutic alliance, medication adherence, self-esteem and body image, sexuality, and future goals. Over the course of 1 year, he resumes his graduate studies and part-time work, and explores prosthetic placement for cosmetic purposes.

The authors’ observations

Research suggests that major self-mutilation among patients with psychotic illness is likely to occur during the first episode or early in the course of illness and/or with suboptimal treatment.^44,45 Mr. K was enlisted in an intensive outpatient treatment program involving biweekly psychotherapy sessions and psychiatric follow-up. Initial sessions focused on education regarding the importance of medication adherence and exploration of signs and symptoms that might suggest reemergence of a psycho­tic decompensation. The psychiatrist monitored Mr. K closely to ensure he was able to tolerate his medications to mitigate the possibility that adverse effects would undermine adherence. Mr. K’s reactions to having a psychiatric illness also were explored because of concerns that such self-appraisals might trigger shame, embarrassment, denial, and other responses that might undermine treatment adherence. His family members were apprised of treatment goals and enlisted to foster adherence with medication and follow-up appointments.

Mr. K’s Cannabis use was addressed because ongoing use likely had a negative impact on his schizophrenia (ie, a greater propensity toward relapse and rehospitalization and a poorer ther­apeutic response to antipsychotic medication).^46,47 He was strongly encouraged to avoid Cannabis and other illicit substances.

Psychiatrists can help in examining the meaning behind the injury while helping the patient to adapt to the sequelae and cultivate skills to meet functional demands.⁴¹ Once Mr. K’s psychotic symptoms were in remission, treatment began to address the antecedents of the GSM, as well as the resultant physical consequences. It was reasonable to explore how Mr. K now viewed his actions, as well as the consequences that his actions produced in terms of his physical appearance, sexual functioning, capacity for sexual intimacy, and reproductive potential. It was also important to recognize how such highly intimate and deeply personal self-schema are framed and organized against his cultural and religious background.^27,33

Body image concerns and expectations for future urologic intervention also should be explored. Although Mr. K was not averse to such exploration, he did not spontaneously address such topics in great depth. The discussion was unforced and effectively left open as an issue that could be explored in future sessions.

CASE Bleeding, bewildered

Mr. K, age 23, a South Asian male, is discovered in the bathroom bleeding profusely. Mr. K’s parents inform emergency medical services (EMS) personnel that Mr. K is “not in his right mind” and speculate that he is depressed. EMS personnel find Mr. K sitting in a pool of blood in the bathtub, holding a cloth over his pubic area and complaining of significant pain. They estimate that Mr. K has lost approximately 1 L of blood. Cursory evaluation reveals that his penis is severed; no other injuries or lacerations are notable. Mr. K states, “I did not want it anymore.” A kitchen knife that he used to self-amputate is found nearby. He is awake, alert, and able to follow simple directives.

In the emergency room, Mr. K is in mild-to-moderate distress. He has no history of medical illness, but his parents report that he previously required psychiatric treatment. Mr. K is not able to elaborate. He reluctantly discloses an intermittent history of Cannabis use. Physical examination reveals tachycardia (heart rate: 115 to 120 beats per minute), and despite blood loss, systolic hypertension (blood pressure: 142/70 to 167/70 mm Hg). His pulse oximetry is 97% to 99%; he is afebrile. Laboratory tests are notable for anemia (hemoglobin, 7.2 g/dL [reference range, 14.0 to 17.5 g/dL]; hematocrit, 21.2% [reference range, 41% to 50%]) and serum toxicology screen is positive for benzodiazepines, which had been administered en route to allay his distress.

Mr. K continues to hold pressure on his pubic area. When pressure is released, active arterial spurting of bright red blood is notable. Genital examination reveals a cleanly amputated phallus. Emergent surgical intervention is required to stop the hemorrhage and reattach the penis. Initially, Mr. K is opposed to reattachment, but after a brief discussion with his parents, he consents to surgery. Urology and plastic surgery consultations are elicited to perform the microvascular portion of the procedure.

[polldaddy:9881368]

The authors’ observations

Self-injurious behaviors occur in approximately 1% to 4% of adults in the United States, with chronic and severe self-injury occurring among approximately 1% of the U.S. population.^1,2 Intentional GSM is a relatively rare catastrophic event that is often, but not solely, associated with severe mental illness. Because many cases go unreported, the prevalence of GSM is difficult to estimate.^3,4 Although GSM has been described in both men and women, the literature has predominantly focused on GSM among men.⁵ Genital self-injury has been described in several (ie, ethnic/racial and religious) contexts and has been legally sanctioned.^6-8

Psychiatric disorders associated with, and precipitating factors underlying, GSM have long remained elusive.⁸ GSM has been described in case reports and small case series in both psychiatric and urologic literature. These reports provide incomplete descriptions of the diagnostic conditions and psychosocial factors underlying male GSM.

A recent systematic review of 173 cases of men who engaged in GSM published in the past 115 years (since the first case of GSM was published in the psychiatric literature⁹) revealed that having some form of psychopathology elevates the probability of GSM^10,11; rarely the individual did not have a psychiatric condition.^11-17 Nearly one-half of the men had psychosis; most had a schizophrenia spectrum disorder diagnosis. Other psychiatric conditions associated with GSM include personality disorders, substance use disorder, and gender dysphoria. GSM is rarely associated with anxiety or mood disorders.

GSM is a heterogeneous form of self-injury that ranges from superficial genital lacerations, amputation, or castration to combinations of these injuries. Compared with individuals with other psychiatric disorders, a significantly greater proportion of individuals with schizophrenia spectrum disorders engage in self-amputation (auto-penectomy). By contrast, persons with gender dysphoria tend to engage in self-castration at significantly higher rates than those with other psychiatric conditions.¹¹ Despite these trends, clinicians should not infer a specific psychiatric diagnosis based on the severity or type of self-inflicted injury.

HISTORY Command hallucinations

Postoperatively, Mr. K is managed in the trauma intensive care unit. During psychiatric consultation, Mr. K demonstrates a blunted affect. His speech is low in volume but clear and coherent. His thoughts are generally linear for specific lines of inquiry (eg, about perceived level of pain) but otherwise are impoverished. Mr. K often digresses into repetitively mumbled prayers. He appears distracted, as if responding to internal stimuli. Although he acknowledges the GSM, he does not discuss the factors underlying his decision to proceed with auto-penectomy. Over successive evaluations, he reluctantly discloses that he had been experiencing disparaging auditory hallucinations that told him that his penis “was too small” and commanded him to “cut it off.”

Psychiatric history reveals that Mr. K required psychiatric hospitalization 7 months earlier due to new-onset auditory hallucinations, paranoia, and thought disorganization, in the context of daily Cannabis use. At the time, the differential diagnosis included new-onset schizophrenia and substance-induced psychosis. His symptoms improved quickly with risperidone, 2 mg/d, and he was discharged in a stable condition with referrals for outpatient care. Mr. K admits he had stopped taking risperidone several weeks before the GSM because he was convinced that he had been cured. At that time, Mr. K had told his parents he was no longer required to take medication or engage in outpatient psychiatric treatment, and they did not question this. Mr. K struggled to sustain part-time employment (in a family business), having taken a leave of absence from graduate school after his first hospitalization. He continued to use Cannabis regularly but denies being intoxicated at the time of the GSM. Throughout his surgical hospitalization, Mr. K’s thoughts remain disorganized. He denies that the GSM was a suicide attempt or having current suicidal thoughts, intent, or plans. He also denies having religious preoccupations, over-valued religious beliefs, or delusions.

Mr. K identifies as heterosexual, and denies experiencing distress related to sexual orientation or gender identity or guilt related to sexual impulses or actions. He also denies having a history of trauma or victimization and does not report any symptoms of posttraumatic stress disorder or body dysmorphic disorder.

The authors’ observations

Self-injury elicits strong, emotional responses from health care professionals, including fascination, apprehension, and hopelessness. Psychiatrists who care for such patients should monitor members of the patient’s treatment team for psychological reactions. In addition, the patient’s behavior while hospitalized may stir feelings of retaliation, anger, fear, and frustration.^11,24,37 Collaborative relationships with medical and surgical specialties can help staff manage emotional reactions and avoid the inadvertent expression of those feelings in their interactions with the patient; these reactions might otherwise undermine treatment.^24,34 Family education can help mitigate any guilt family members may harbor for not preventing the injury.³⁷

Although efforts to understand the intended goal(s) and precipitants of the self-injury are likely to be worthwhile, the overwhelming distress associated with GSM and its emergent treatment may preclude intensive exploration. Assessing precipitants of self-injury should be approached using a nonjudgmental, dispassionate, matter-of-fact manner that conveys concern for the patient³⁸ and reassures the patient that the clinician has heard and, ideally, understands the patient’s distress.³⁹ Forced exploration during the prevailing stress of treatment may overwhelm the patient, prove to be overly distressing, and compel the patient to act out in self-injurious ways. Therefore, exploration of the underpinnings of GSM may need to be postponed until surgical treatment is completed, the patient’s symptoms have been managed with psychopharmacologic intervention, and the patient has been transitioned to the safety and close monitoring of an acute psychiatric inpatient setting.

TREATMENT Restarting medication

While on the surgical unit, Mr. K is restarted on risperidone, 2 mg/d. He appears to tolerate the medication without adverse effects. However, because Mr. K continues to experience auditory hallucinations, and the treatment team remains concerned that he might again experience commands to harm himself, he is transferred to an acute psychiatric inpatient setting.

Urology follow-up reveals necrosis/mummification of the replanted penis and an open scrotal wound. After discussing options with the patient and family, the urologist transfers Mr. K back to the surgical unit for wound closure and removal of the replanted penis. A urethrostomy is performed to allow for bladder emptying.

[polldaddy:9881371]

The authors’ observations

Because most published case reports of GSM among men have focused on acute treatment, there is a dearth of literature available on the long-term course of GSM to inform treatment strategies. Because recovery is a non-static process and a patient’s reactions to his injury will likely evolve over time, a multifaceted approach invoking psychiatric and psychotherapeutic interventions is necessary to help patients after initial injury and surgical management^37,40-43 (Table 2^11,20,27,41).

OUTCOME Return to school, work

Mr. K is discharged with close follow-up at a specialized clinic for new-onset psychosis. Post-discharge treatment consists of education about the course of schizophrenia and the need for medication adherence to prevent relapse. Mr. K also is educated on the relationship between Cannabis use and psychosis, and he abstains from illicit substance use. Family involvement is encouraged to help with medication compliance and monitoring for symptom reemergence.

Therapy focuses on exploring the antecedents of the auto-penectomy, Mr. K’s body image issue concerns, and his feelings related to eventual prosthesis implantation. He insists that he cannot recall any precipitating factors for his self-injury other than the command hallucinations. He does not report sexual guilt, although he had been sexually active with his girlfriend in the months prior to his GSM, which goes against his family’s religious beliefs. He reports significant regret and shame for the self-mutilation, and blames himself for not informing family members about his hallucinations. Therapy involves addressing his attribution of blame using cognitive techniques and focuses on measures that can be taken to prevent further self-harm. Efforts are directed at exploring whether cultural and religious traditions impacted the therapeutic alliance, medication adherence, self-esteem and body image, sexuality, and future goals. Over the course of 1 year, he resumes his graduate studies and part-time work, and explores prosthetic placement for cosmetic purposes.

The authors’ observations

Research suggests that major self-mutilation among patients with psychotic illness is likely to occur during the first episode or early in the course of illness and/or with suboptimal treatment.^44,45 Mr. K was enlisted in an intensive outpatient treatment program involving biweekly psychotherapy sessions and psychiatric follow-up. Initial sessions focused on education regarding the importance of medication adherence and exploration of signs and symptoms that might suggest reemergence of a psycho­tic decompensation. The psychiatrist monitored Mr. K closely to ensure he was able to tolerate his medications to mitigate the possibility that adverse effects would undermine adherence. Mr. K’s reactions to having a psychiatric illness also were explored because of concerns that such self-appraisals might trigger shame, embarrassment, denial, and other responses that might undermine treatment adherence. His family members were apprised of treatment goals and enlisted to foster adherence with medication and follow-up appointments.

Mr. K’s Cannabis use was addressed because ongoing use likely had a negative impact on his schizophrenia (ie, a greater propensity toward relapse and rehospitalization and a poorer ther­apeutic response to antipsychotic medication).^46,47 He was strongly encouraged to avoid Cannabis and other illicit substances.

Psychiatrists can help in examining the meaning behind the injury while helping the patient to adapt to the sequelae and cultivate skills to meet functional demands.⁴¹ Once Mr. K’s psychotic symptoms were in remission, treatment began to address the antecedents of the GSM, as well as the resultant physical consequences. It was reasonable to explore how Mr. K now viewed his actions, as well as the consequences that his actions produced in terms of his physical appearance, sexual functioning, capacity for sexual intimacy, and reproductive potential. It was also important to recognize how such highly intimate and deeply personal self-schema are framed and organized against his cultural and religious background.^27,33

Body image concerns and expectations for future urologic intervention also should be explored. Although Mr. K was not averse to such exploration, he did not spontaneously address such topics in great depth. The discussion was unforced and effectively left open as an issue that could be explored in future sessions.

Mindfulness is actively being aware of one’s inner and outer environments in the present moment. Core mindfulness skills include observation, description, participation, a nonjudgmental approach, focusing on 1 thing at a time, and effectiveness.¹

Psychotherapeutic interventions based on each of these skills have been developed to instill a mindful state in psychiatric patients. Evidence suggests these interventions can be helpful when treating borderline personality disorder, somatization, pain, depression, and anxiety, among other conditions.²

Elements of mindfulness can be integrated into brief interventions. The following 6 simple, practical exercises can be used to help patients develop these skills.

Observation involves noticing internal and external experiences, including thoughts and sensations, without applying words or labels. Guide your patient through the following exercise:

Focus your attention on the ground beneath your feet, feeling the pressure, temperature, and texture of this sensation. Do the same with your seat, your breath, and the sounds, sights, and smells of the room. Be aware of your thoughts and watch them come and go like fish in a fishbowl.

Description entails assigning purely descriptive words to one’s observations. To help your patient develop this skill, ask him (her) to describe the sensations he (she) observed in the previous exercise.

Participation entails immersive engagement in an activity. Ask your patient to listen to a song he has never heard before, and then play it again and dance or sing along. Instruct him to engage wholly, conscious of each step or note, without being judgmental or self-conscious. If he feels embarrassed or self-critical, tell him to observe these thoughts and emotions, put them aside, and return to the activity.

A nonjudgmental approach consists of separating out the facts and recognizing emotional responses without clinging to them. To practice this skill, ask your patient to play a song that he likes and one that he dislikes. The patient should listen to each, observing and describing the way they sound without judgment. Tell the patient that if judgmental words or phrases, such as “beautiful,” “ugly,” “I love…,” or “I hate…,” appear as thoughts, he should observe them, put them aside, and then return to nonjudgmental description and observation.

Focusing on 1 thing at a time means dedicating complete attention to a single task, activity, or thought. Give your patient a short paragraph or poem to read. Instruct him to try not to focus on recent personal events or what he will eat for dinner while reading. If he would like to switch to other tasks, then he should give his whole attention to this other task, and stop reading.

Effectiveness involves focusing on what works to attain one’s goals. For this exercise, set up a task for your patient by placing several items in a location that is neither immediately obvious nor readily accessible without an intermediate step. Instruct your patient to obtain these objects. Then guide them as follows:

What do you have to do to get them? Ask permission? Borrow a key? Recruit assistance? Determine the location? Brainstorm ways to obtain the items, and then complete the task.

Mindfulness is actively being aware of one’s inner and outer environments in the present moment. Core mindfulness skills include observation, description, participation, a nonjudgmental approach, focusing on 1 thing at a time, and effectiveness.¹

Psychotherapeutic interventions based on each of these skills have been developed to instill a mindful state in psychiatric patients. Evidence suggests these interventions can be helpful when treating borderline personality disorder, somatization, pain, depression, and anxiety, among other conditions.²

Elements of mindfulness can be integrated into brief interventions. The following 6 simple, practical exercises can be used to help patients develop these skills.

Observation involves noticing internal and external experiences, including thoughts and sensations, without applying words or labels. Guide your patient through the following exercise:

Focus your attention on the ground beneath your feet, feeling the pressure, temperature, and texture of this sensation. Do the same with your seat, your breath, and the sounds, sights, and smells of the room. Be aware of your thoughts and watch them come and go like fish in a fishbowl.

Description entails assigning purely descriptive words to one’s observations. To help your patient develop this skill, ask him (her) to describe the sensations he (she) observed in the previous exercise.

Participation entails immersive engagement in an activity. Ask your patient to listen to a song he has never heard before, and then play it again and dance or sing along. Instruct him to engage wholly, conscious of each step or note, without being judgmental or self-conscious. If he feels embarrassed or self-critical, tell him to observe these thoughts and emotions, put them aside, and return to the activity.

A nonjudgmental approach consists of separating out the facts and recognizing emotional responses without clinging to them. To practice this skill, ask your patient to play a song that he likes and one that he dislikes. The patient should listen to each, observing and describing the way they sound without judgment. Tell the patient that if judgmental words or phrases, such as “beautiful,” “ugly,” “I love…,” or “I hate…,” appear as thoughts, he should observe them, put them aside, and then return to nonjudgmental description and observation.

Focusing on 1 thing at a time means dedicating complete attention to a single task, activity, or thought. Give your patient a short paragraph or poem to read. Instruct him to try not to focus on recent personal events or what he will eat for dinner while reading. If he would like to switch to other tasks, then he should give his whole attention to this other task, and stop reading.

Effectiveness involves focusing on what works to attain one’s goals. For this exercise, set up a task for your patient by placing several items in a location that is neither immediately obvious nor readily accessible without an intermediate step. Instruct your patient to obtain these objects. Then guide them as follows:

What do you have to do to get them? Ask permission? Borrow a key? Recruit assistance? Determine the location? Brainstorm ways to obtain the items, and then complete the task.

Mindfulness is actively being aware of one’s inner and outer environments in the present moment. Core mindfulness skills include observation, description, participation, a nonjudgmental approach, focusing on 1 thing at a time, and effectiveness.¹

Psychotherapeutic interventions based on each of these skills have been developed to instill a mindful state in psychiatric patients. Evidence suggests these interventions can be helpful when treating borderline personality disorder, somatization, pain, depression, and anxiety, among other conditions.²

Elements of mindfulness can be integrated into brief interventions. The following 6 simple, practical exercises can be used to help patients develop these skills.

Observation involves noticing internal and external experiences, including thoughts and sensations, without applying words or labels. Guide your patient through the following exercise:

Focus your attention on the ground beneath your feet, feeling the pressure, temperature, and texture of this sensation. Do the same with your seat, your breath, and the sounds, sights, and smells of the room. Be aware of your thoughts and watch them come and go like fish in a fishbowl.

Description entails assigning purely descriptive words to one’s observations. To help your patient develop this skill, ask him (her) to describe the sensations he (she) observed in the previous exercise.

Participation entails immersive engagement in an activity. Ask your patient to listen to a song he has never heard before, and then play it again and dance or sing along. Instruct him to engage wholly, conscious of each step or note, without being judgmental or self-conscious. If he feels embarrassed or self-critical, tell him to observe these thoughts and emotions, put them aside, and return to the activity.

A nonjudgmental approach consists of separating out the facts and recognizing emotional responses without clinging to them. To practice this skill, ask your patient to play a song that he likes and one that he dislikes. The patient should listen to each, observing and describing the way they sound without judgment. Tell the patient that if judgmental words or phrases, such as “beautiful,” “ugly,” “I love…,” or “I hate…,” appear as thoughts, he should observe them, put them aside, and then return to nonjudgmental description and observation.

Focusing on 1 thing at a time means dedicating complete attention to a single task, activity, or thought. Give your patient a short paragraph or poem to read. Instruct him to try not to focus on recent personal events or what he will eat for dinner while reading. If he would like to switch to other tasks, then he should give his whole attention to this other task, and stop reading.

Effectiveness involves focusing on what works to attain one’s goals. For this exercise, set up a task for your patient by placing several items in a location that is neither immediately obvious nor readily accessible without an intermediate step. Instruct your patient to obtain these objects. Then guide them as follows:

What do you have to do to get them? Ask permission? Borrow a key? Recruit assistance? Determine the location? Brainstorm ways to obtain the items, and then complete the task.

Patients who are Muslim—followers of the religion of Islam—struggle with a political climate that has demonized them and the continued fallout of terrorist attacks perpetrated by individuals who identify themselves as Muslim. These patients may experience low self-esteem, bullying, depression, anxiety, or posttraumatic stress disorder.¹ Some have expressed feeling judged, labeled, attacked, and subjected to discrimination. Islamophobia and a spike in hate crimes have further marginalized this already vulnerable population.² Thus, understanding your Muslim patients is the first step to treating their mental illness.

How Muslim culture might affect care

Muslims are not a monolithic group; they vary widely in their religious adherence, cultural background, and acculturation. Some are American-born, including a significant African American Muslim population. Others are children of immigrants or have recently immigrated, including many who came to the United States because of the ongoing war in Syria. Many can trace their heritage to >50 predominantly Muslim countries. Many Muslim patients want to find a balance between their religious and American identities.

As clinicians, we should not make assumptions based on outward appearances or our preconceived notions of our patients, especially when it comes to gender roles. Our job is to ask how highly personal, individualized decisions, such as a woman’s choice to wear a hijab as an expression of her faith and a symbol of modesty, factor into our patients’ day-to-day lives. Doing so can help build the therapeutic alliance and improve the accuracy of the diagnosis and the appropriateness of treatment.

Mental health clinicians are well aware of the dangers of the social stigma that their patients may experience.³ These dangers are no different when it comes to Muslim patients, who often may face “double discrimination” for their religion and for having a mental illness. They may seek support from religious leaders, family, and friends before seeing a mental health provider. Some may view their mental illness as a weakness of faith, a punishment by God, or an affliction caused by a supernatural spirit, and therefore may feel that following religious doctrine will resolve their psychological distress.⁴ They may need additional encouragement to see a therapist or take psycho­tropics, and they may prefer specific treatments that reflect their cultural values, such as supplements.

Because some Muslim patients may be more comfortable presenting their psycho­logical concerns as somatic symptoms, they may first seek care from a primary care physician. Some patients may not be open or comfortable enough to address sensitive issues, such as substance use. Providing psychoeducation, comparing mental illness with medical illness, and emphasizing doctor–patient confidentiality may help these patients overcome the stigma that can act as a barrier to care.

Provide culturally competent care

Resources are available to help us provide the best possible care to our patients from various cultures and religions, including Muslim patients. A good starting point is the DSM-5’s Cultural Formulation Interview, which is a set of 16 questions psychiatrists can use to determine the impact of culture on a patient’s clinical presentation and care.⁵ Other resources include the American Psychiatric Association’s Assessment of Cultural Factors and the American Academy of Child and Adolescent Psychiatry’s Practice Parameter for Cultural Competence.⁶

When treating Muslim patients, remember to:

• Ask about what roles their culture and religion play
• Understand their explanation of their symptoms
• Work to overcome any stigma patients may perceive related to having a psychiatric disorder
• Engage your team to identify cultural and religious factors
• Connect to community resources, such as the patient’s family and friends.

Patients who are Muslim—followers of the religion of Islam—struggle with a political climate that has demonized them and the continued fallout of terrorist attacks perpetrated by individuals who identify themselves as Muslim. These patients may experience low self-esteem, bullying, depression, anxiety, or posttraumatic stress disorder.¹ Some have expressed feeling judged, labeled, attacked, and subjected to discrimination. Islamophobia and a spike in hate crimes have further marginalized this already vulnerable population.² Thus, understanding your Muslim patients is the first step to treating their mental illness.

How Muslim culture might affect care

Muslims are not a monolithic group; they vary widely in their religious adherence, cultural background, and acculturation. Some are American-born, including a significant African American Muslim population. Others are children of immigrants or have recently immigrated, including many who came to the United States because of the ongoing war in Syria. Many can trace their heritage to >50 predominantly Muslim countries. Many Muslim patients want to find a balance between their religious and American identities.

As clinicians, we should not make assumptions based on outward appearances or our preconceived notions of our patients, especially when it comes to gender roles. Our job is to ask how highly personal, individualized decisions, such as a woman’s choice to wear a hijab as an expression of her faith and a symbol of modesty, factor into our patients’ day-to-day lives. Doing so can help build the therapeutic alliance and improve the accuracy of the diagnosis and the appropriateness of treatment.

Mental health clinicians are well aware of the dangers of the social stigma that their patients may experience.³ These dangers are no different when it comes to Muslim patients, who often may face “double discrimination” for their religion and for having a mental illness. They may seek support from religious leaders, family, and friends before seeing a mental health provider. Some may view their mental illness as a weakness of faith, a punishment by God, or an affliction caused by a supernatural spirit, and therefore may feel that following religious doctrine will resolve their psychological distress.⁴ They may need additional encouragement to see a therapist or take psycho­tropics, and they may prefer specific treatments that reflect their cultural values, such as supplements.

Because some Muslim patients may be more comfortable presenting their psycho­logical concerns as somatic symptoms, they may first seek care from a primary care physician. Some patients may not be open or comfortable enough to address sensitive issues, such as substance use. Providing psychoeducation, comparing mental illness with medical illness, and emphasizing doctor–patient confidentiality may help these patients overcome the stigma that can act as a barrier to care.

Provide culturally competent care

Resources are available to help us provide the best possible care to our patients from various cultures and religions, including Muslim patients. A good starting point is the DSM-5’s Cultural Formulation Interview, which is a set of 16 questions psychiatrists can use to determine the impact of culture on a patient’s clinical presentation and care.⁵ Other resources include the American Psychiatric Association’s Assessment of Cultural Factors and the American Academy of Child and Adolescent Psychiatry’s Practice Parameter for Cultural Competence.⁶

When treating Muslim patients, remember to:

• Ask about what roles their culture and religion play
• Understand their explanation of their symptoms
• Work to overcome any stigma patients may perceive related to having a psychiatric disorder
• Engage your team to identify cultural and religious factors
• Connect to community resources, such as the patient’s family and friends.

Patients who are Muslim—followers of the religion of Islam—struggle with a political climate that has demonized them and the continued fallout of terrorist attacks perpetrated by individuals who identify themselves as Muslim. These patients may experience low self-esteem, bullying, depression, anxiety, or posttraumatic stress disorder.¹ Some have expressed feeling judged, labeled, attacked, and subjected to discrimination. Islamophobia and a spike in hate crimes have further marginalized this already vulnerable population.² Thus, understanding your Muslim patients is the first step to treating their mental illness.

How Muslim culture might affect care

Muslims are not a monolithic group; they vary widely in their religious adherence, cultural background, and acculturation. Some are American-born, including a significant African American Muslim population. Others are children of immigrants or have recently immigrated, including many who came to the United States because of the ongoing war in Syria. Many can trace their heritage to >50 predominantly Muslim countries. Many Muslim patients want to find a balance between their religious and American identities.

As clinicians, we should not make assumptions based on outward appearances or our preconceived notions of our patients, especially when it comes to gender roles. Our job is to ask how highly personal, individualized decisions, such as a woman’s choice to wear a hijab as an expression of her faith and a symbol of modesty, factor into our patients’ day-to-day lives. Doing so can help build the therapeutic alliance and improve the accuracy of the diagnosis and the appropriateness of treatment.

Mental health clinicians are well aware of the dangers of the social stigma that their patients may experience.³ These dangers are no different when it comes to Muslim patients, who often may face “double discrimination” for their religion and for having a mental illness. They may seek support from religious leaders, family, and friends before seeing a mental health provider. Some may view their mental illness as a weakness of faith, a punishment by God, or an affliction caused by a supernatural spirit, and therefore may feel that following religious doctrine will resolve their psychological distress.⁴ They may need additional encouragement to see a therapist or take psycho­tropics, and they may prefer specific treatments that reflect their cultural values, such as supplements.

Because some Muslim patients may be more comfortable presenting their psycho­logical concerns as somatic symptoms, they may first seek care from a primary care physician. Some patients may not be open or comfortable enough to address sensitive issues, such as substance use. Providing psychoeducation, comparing mental illness with medical illness, and emphasizing doctor–patient confidentiality may help these patients overcome the stigma that can act as a barrier to care.

Provide culturally competent care

Resources are available to help us provide the best possible care to our patients from various cultures and religions, including Muslim patients. A good starting point is the DSM-5’s Cultural Formulation Interview, which is a set of 16 questions psychiatrists can use to determine the impact of culture on a patient’s clinical presentation and care.⁵ Other resources include the American Psychiatric Association’s Assessment of Cultural Factors and the American Academy of Child and Adolescent Psychiatry’s Practice Parameter for Cultural Competence.⁶

When treating Muslim patients, remember to:

• Ask about what roles their culture and religion play
• Understand their explanation of their symptoms
• Work to overcome any stigma patients may perceive related to having a psychiatric disorder
• Engage your team to identify cultural and religious factors
• Connect to community resources, such as the patient’s family and friends.

The approval last fall by the US Food and Drug Administration (FDA) of the immune checkpoint inhibitor atezolizumab for the treatment of metastatic non–small cell lung cancer (NSCLC) marked the second approved indication for the drug in a single year. Atezolizumab, which targets the programmed cell death protein-ligand 1 (PD-L1), has a unique mechanism of action compared with other approved immune checkpoint inhibitors and had been previously approved for the treatment of patients with advanced urothelial carcinoma. The current approval was based on 2 international, randomized, open-label trials, involving more than 1,000 patients, in which atezolizumab outperformed the chemotherapeutic drug docetaxel.

The POPLAR trial¹ was a phase 2 study performed at 61 academic centers and community oncology practices across 13 countries in Europe and North America and enrolled 287 patients, while the phase 3 OAK trial² was carried out at 193 centers in 31 countries and enrolled 850 patients.

Eligibility criteria for the 2 studies were similar; patients were 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, had measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), and adequate hematologic and end-organ function. Patients with asymptomatic or treated central nervous system (CNS) metastases were also eligible.

Patients were excluded from both studies if they had a history of autoimmune disease, pneumonitis or chronic viral diseases, or had received previous treatment with docetaxel, CD137 agonists, anti-CTLA4, anti-PD-L1 or anti-PD-1 therapeutics.

Patients were randomized 1:1 to receive atezolizumab, administered intravenously at a fixed dose of 1,200 mg, or a 75 mg/m² dose of docetaxel, every 3 weeks on day 1 of each 3-week cycle. Randomization was stratified according to PD-L1 expression, number of previous chemotherapy regimens, and histology (squamous vs nonsquamous). Tumors were assessed at baseline and every 6 weeks for 36 weeks, and every 9 weeks thereafter until progression or, in patients who continued beyond progression, until discontinuation. PD-L1 expression was assessed prospectively on tumor cells and tumor-infiltrating immune cells, using the FDA-approved companion diagnostic, Ventana SP142 PD-L1 immunohistochemistry assay.

The primary endpoint in both studies was overall survival (OS), which was significantly improved in the atezolizumab treatment arm. In the POPLAR trial, over a minimum follow-up of 13 months, the median OS was 12.6 months in atezolizumab-treated patients, compared with 9.7 months in docetaxel-treated patients (hazard ratio [HR], 0.73; P = .04) and in the OAK trial, over a median follow-up of 21 months, the median OS was 15.7 months and 10.3 months, respectively.

The main difference between the 2 trials was that the OS benefit in the POPLAR trial reached statistical significance only in patients with the highest levels of PD-L1 expression, whereas in the OAK study, the OS was significantly improved regardless of PD-L1 expression status, although the greatest benefit was derived in patients with higher levels of PD-L1 expression (20.5 months and 8.9 months, respectively). The OS benefit was observed across all other prespecified subgroups, except in patients with EGFR mutation-positivity in the OAK trial. Progression-free survival and overall response rates were similar in the 2 treatment arms in both studies.

An additional 375 patients were enrolled in the OAK trial and included in the safety analyses. In both studies, the safety profile of atezolizumab was similar to that observed in previous studies of this drug. The most commonly observed adverse events (AEs) with atezolizumab treatment were fatigue, decreased appetite, dyspnea, cough, nausea, musculoskeletal pain, and constipation. Despite longer treatment duration, there were fewer incidences of grade 3/4 AEs with atezolizumab compared with docetaxel (37% vs 54%, respectively, in the OAK trial), a lower rate of discontinuation with atezolizumab treatment, and no deaths related to the study drug. The most common grade 3/4 AEs included dyspnea, pneumonia, hypoxia, hyponatremia, fatigue, and anemia. Clinically significant immune-related AEs included pneumonitis, hepatitis, colitis, and thyroid disease.

Atezolizumab is marketed as Tecentriq by Genentech and the prescribing information details warnings and precautions about immune-related AEs; pneumonitis, colitis, endocrinopathies (eg, thyroid disorders, adrenal insufficiency, and diabetes mellitus), and others, as well as infections, infusion-related reactions, and embryofetal toxicity.³

Atezolizumab treatment should be withheld for grade 2 pneumonitis; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels of >3-5 times the upper limit of normal (ULN) or total bilirubin levels of >1.5 and up to 3 times the ULN; grade 2/3 diarrhea or colitis, adrenal insufficiency, hypothyroidism, or grade 3/4 hyperglycemia; grade 2 ocular inflammatory toxicity; grade 2/3 pancreatitis or grade 3/4 increases in amylase or lipase levels; grade 3/4 infection; grade 2 infusion-related reactions; and grade 3 rash. Treatment can then be resumed in patients whose AEs recover to grade 0 or 1.

Treatment should be permanently discontinued in the event of grade 3/4 pneumonitis; AST/ALT levels of >5 times the ULN or bilirubin levels of >3 times the ULN; grade 4 diarrhea or colitis; myasthenic syndrome/myasthenia gravis, Guillain-Barre syndrome or meningoencephalitis (all grades); grade 3/4 ocular inflammatory toxicity; grade 4 or recurrent (any grade) pancreatitis; grade 3/4 infusion-related reactions; or grade 4 rash. Patients should also be advised of the risk of fetal harm.

The approval last fall by the US Food and Drug Administration (FDA) of the immune checkpoint inhibitor atezolizumab for the treatment of metastatic non–small cell lung cancer (NSCLC) marked the second approved indication for the drug in a single year. Atezolizumab, which targets the programmed cell death protein-ligand 1 (PD-L1), has a unique mechanism of action compared with other approved immune checkpoint inhibitors and had been previously approved for the treatment of patients with advanced urothelial carcinoma. The current approval was based on 2 international, randomized, open-label trials, involving more than 1,000 patients, in which atezolizumab outperformed the chemotherapeutic drug docetaxel.

The POPLAR trial¹ was a phase 2 study performed at 61 academic centers and community oncology practices across 13 countries in Europe and North America and enrolled 287 patients, while the phase 3 OAK trial² was carried out at 193 centers in 31 countries and enrolled 850 patients.

Eligibility criteria for the 2 studies were similar; patients were 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, had measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), and adequate hematologic and end-organ function. Patients with asymptomatic or treated central nervous system (CNS) metastases were also eligible.

Patients were excluded from both studies if they had a history of autoimmune disease, pneumonitis or chronic viral diseases, or had received previous treatment with docetaxel, CD137 agonists, anti-CTLA4, anti-PD-L1 or anti-PD-1 therapeutics.

Patients were randomized 1:1 to receive atezolizumab, administered intravenously at a fixed dose of 1,200 mg, or a 75 mg/m² dose of docetaxel, every 3 weeks on day 1 of each 3-week cycle. Randomization was stratified according to PD-L1 expression, number of previous chemotherapy regimens, and histology (squamous vs nonsquamous). Tumors were assessed at baseline and every 6 weeks for 36 weeks, and every 9 weeks thereafter until progression or, in patients who continued beyond progression, until discontinuation. PD-L1 expression was assessed prospectively on tumor cells and tumor-infiltrating immune cells, using the FDA-approved companion diagnostic, Ventana SP142 PD-L1 immunohistochemistry assay.

The primary endpoint in both studies was overall survival (OS), which was significantly improved in the atezolizumab treatment arm. In the POPLAR trial, over a minimum follow-up of 13 months, the median OS was 12.6 months in atezolizumab-treated patients, compared with 9.7 months in docetaxel-treated patients (hazard ratio [HR], 0.73; P = .04) and in the OAK trial, over a median follow-up of 21 months, the median OS was 15.7 months and 10.3 months, respectively.

The main difference between the 2 trials was that the OS benefit in the POPLAR trial reached statistical significance only in patients with the highest levels of PD-L1 expression, whereas in the OAK study, the OS was significantly improved regardless of PD-L1 expression status, although the greatest benefit was derived in patients with higher levels of PD-L1 expression (20.5 months and 8.9 months, respectively). The OS benefit was observed across all other prespecified subgroups, except in patients with EGFR mutation-positivity in the OAK trial. Progression-free survival and overall response rates were similar in the 2 treatment arms in both studies.

An additional 375 patients were enrolled in the OAK trial and included in the safety analyses. In both studies, the safety profile of atezolizumab was similar to that observed in previous studies of this drug. The most commonly observed adverse events (AEs) with atezolizumab treatment were fatigue, decreased appetite, dyspnea, cough, nausea, musculoskeletal pain, and constipation. Despite longer treatment duration, there were fewer incidences of grade 3/4 AEs with atezolizumab compared with docetaxel (37% vs 54%, respectively, in the OAK trial), a lower rate of discontinuation with atezolizumab treatment, and no deaths related to the study drug. The most common grade 3/4 AEs included dyspnea, pneumonia, hypoxia, hyponatremia, fatigue, and anemia. Clinically significant immune-related AEs included pneumonitis, hepatitis, colitis, and thyroid disease.

Atezolizumab is marketed as Tecentriq by Genentech and the prescribing information details warnings and precautions about immune-related AEs; pneumonitis, colitis, endocrinopathies (eg, thyroid disorders, adrenal insufficiency, and diabetes mellitus), and others, as well as infections, infusion-related reactions, and embryofetal toxicity.³

Atezolizumab treatment should be withheld for grade 2 pneumonitis; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels of >3-5 times the upper limit of normal (ULN) or total bilirubin levels of >1.5 and up to 3 times the ULN; grade 2/3 diarrhea or colitis, adrenal insufficiency, hypothyroidism, or grade 3/4 hyperglycemia; grade 2 ocular inflammatory toxicity; grade 2/3 pancreatitis or grade 3/4 increases in amylase or lipase levels; grade 3/4 infection; grade 2 infusion-related reactions; and grade 3 rash. Treatment can then be resumed in patients whose AEs recover to grade 0 or 1.

Treatment should be permanently discontinued in the event of grade 3/4 pneumonitis; AST/ALT levels of >5 times the ULN or bilirubin levels of >3 times the ULN; grade 4 diarrhea or colitis; myasthenic syndrome/myasthenia gravis, Guillain-Barre syndrome or meningoencephalitis (all grades); grade 3/4 ocular inflammatory toxicity; grade 4 or recurrent (any grade) pancreatitis; grade 3/4 infusion-related reactions; or grade 4 rash. Patients should also be advised of the risk of fetal harm.

The approval last fall by the US Food and Drug Administration (FDA) of the immune checkpoint inhibitor atezolizumab for the treatment of metastatic non–small cell lung cancer (NSCLC) marked the second approved indication for the drug in a single year. Atezolizumab, which targets the programmed cell death protein-ligand 1 (PD-L1), has a unique mechanism of action compared with other approved immune checkpoint inhibitors and had been previously approved for the treatment of patients with advanced urothelial carcinoma. The current approval was based on 2 international, randomized, open-label trials, involving more than 1,000 patients, in which atezolizumab outperformed the chemotherapeutic drug docetaxel.

The POPLAR trial¹ was a phase 2 study performed at 61 academic centers and community oncology practices across 13 countries in Europe and North America and enrolled 287 patients, while the phase 3 OAK trial² was carried out at 193 centers in 31 countries and enrolled 850 patients.

Eligibility criteria for the 2 studies were similar; patients were 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, had measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), and adequate hematologic and end-organ function. Patients with asymptomatic or treated central nervous system (CNS) metastases were also eligible.

Patients were excluded from both studies if they had a history of autoimmune disease, pneumonitis or chronic viral diseases, or had received previous treatment with docetaxel, CD137 agonists, anti-CTLA4, anti-PD-L1 or anti-PD-1 therapeutics.

Patients were randomized 1:1 to receive atezolizumab, administered intravenously at a fixed dose of 1,200 mg, or a 75 mg/m² dose of docetaxel, every 3 weeks on day 1 of each 3-week cycle. Randomization was stratified according to PD-L1 expression, number of previous chemotherapy regimens, and histology (squamous vs nonsquamous). Tumors were assessed at baseline and every 6 weeks for 36 weeks, and every 9 weeks thereafter until progression or, in patients who continued beyond progression, until discontinuation. PD-L1 expression was assessed prospectively on tumor cells and tumor-infiltrating immune cells, using the FDA-approved companion diagnostic, Ventana SP142 PD-L1 immunohistochemistry assay.

The primary endpoint in both studies was overall survival (OS), which was significantly improved in the atezolizumab treatment arm. In the POPLAR trial, over a minimum follow-up of 13 months, the median OS was 12.6 months in atezolizumab-treated patients, compared with 9.7 months in docetaxel-treated patients (hazard ratio [HR], 0.73; P = .04) and in the OAK trial, over a median follow-up of 21 months, the median OS was 15.7 months and 10.3 months, respectively.

The main difference between the 2 trials was that the OS benefit in the POPLAR trial reached statistical significance only in patients with the highest levels of PD-L1 expression, whereas in the OAK study, the OS was significantly improved regardless of PD-L1 expression status, although the greatest benefit was derived in patients with higher levels of PD-L1 expression (20.5 months and 8.9 months, respectively). The OS benefit was observed across all other prespecified subgroups, except in patients with EGFR mutation-positivity in the OAK trial. Progression-free survival and overall response rates were similar in the 2 treatment arms in both studies.

An additional 375 patients were enrolled in the OAK trial and included in the safety analyses. In both studies, the safety profile of atezolizumab was similar to that observed in previous studies of this drug. The most commonly observed adverse events (AEs) with atezolizumab treatment were fatigue, decreased appetite, dyspnea, cough, nausea, musculoskeletal pain, and constipation. Despite longer treatment duration, there were fewer incidences of grade 3/4 AEs with atezolizumab compared with docetaxel (37% vs 54%, respectively, in the OAK trial), a lower rate of discontinuation with atezolizumab treatment, and no deaths related to the study drug. The most common grade 3/4 AEs included dyspnea, pneumonia, hypoxia, hyponatremia, fatigue, and anemia. Clinically significant immune-related AEs included pneumonitis, hepatitis, colitis, and thyroid disease.

Atezolizumab is marketed as Tecentriq by Genentech and the prescribing information details warnings and precautions about immune-related AEs; pneumonitis, colitis, endocrinopathies (eg, thyroid disorders, adrenal insufficiency, and diabetes mellitus), and others, as well as infections, infusion-related reactions, and embryofetal toxicity.³

Atezolizumab treatment should be withheld for grade 2 pneumonitis; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels of >3-5 times the upper limit of normal (ULN) or total bilirubin levels of >1.5 and up to 3 times the ULN; grade 2/3 diarrhea or colitis, adrenal insufficiency, hypothyroidism, or grade 3/4 hyperglycemia; grade 2 ocular inflammatory toxicity; grade 2/3 pancreatitis or grade 3/4 increases in amylase or lipase levels; grade 3/4 infection; grade 2 infusion-related reactions; and grade 3 rash. Treatment can then be resumed in patients whose AEs recover to grade 0 or 1.

Treatment should be permanently discontinued in the event of grade 3/4 pneumonitis; AST/ALT levels of >5 times the ULN or bilirubin levels of >3 times the ULN; grade 4 diarrhea or colitis; myasthenic syndrome/myasthenia gravis, Guillain-Barre syndrome or meningoencephalitis (all grades); grade 3/4 ocular inflammatory toxicity; grade 4 or recurrent (any grade) pancreatitis; grade 3/4 infusion-related reactions; or grade 4 rash. Patients should also be advised of the risk of fetal harm.

Despite universal agreement that antibiotic overprescribing is a problem, the practice continues to vex us. Antibiotic use—whether appropriate or not—has been linked to rising rates of antimicrobial resistance, disruption of the gut microbiome leading to Clostridium difficile infections, allergic reactions, and increased health care costs (TABLE 1^1-6). And yet, physicians continue to overprescribe this class of medication.

A 2016 Centers for Disease Control and Prevention (CDC) report estimates that at least 30% of antibiotics prescribed in US outpatient settings are unnecessary.⁷ Another report cites a slightly higher figure across a variety of health care settings.⁸ Pair these findings with the fact that there are currently few new drugs in development to target resistant bacteria, and you have the potential for a post-antibiotic era in which common infections could become lethal.⁷

In 2003, the CDC launched its “Get Smart: Know When Antibiotics Work” program, focused on decreasing inappropriate antibiotic use in the outpatient setting.⁹ In 2014, the White House released the National Action Plan for Combating Antibiotic-Resistant Bacteria with a goal of decreasing inappropriate outpatient antibiotic use by 50% and inappropriate inpatient use by 20% by 2020.¹⁰ And, on an international level, the World Health Organization (WHO) developed a 5-year strategic framework in 2015 for implementing its Global Action Plan on Antimicrobial Resistance.¹¹

Family practitioners are on the front lines of this battle. Here’s what we can do now.

[polldaddy:9885811]

When and where are antibiotics most often inappropriately prescribed?

The diagnosis leading to the most frequent inappropriate prescribing of antibiotics is acute respiratory tract infection (ARTI), which includes bronchitis, otitis media, pharyngitis, sinusitis, tonsillitis, the common cold, and pneumonia. Up to 40% of antibiotic prescriptions for these conditions are unnecessary.^8,12 Bronchitis is the most common ARTI diagnosis associated with inappropriate antibiotic prescriptions, while sinusitis, suppurative otitis media, and pharyngitis are the diagnoses associated with the lion’s share of all (appropriate and inappropriate) antibiotic prescriptions within the ARTI category.^8,9,12,13 There are national clinical guidelines delineating when antibiotic treatment is appropriate for these conditions.^14-16

With respect to setting, studies have presented conflicting results as to whether there is a difference between antibiotic prescribing in office-based vs emergency department (ED) settings. Here is a sample of some of the literature to date:

• One study found a higher rate of antibiotic prescribing during ED visits (21%) than office visits (9%), despite the fact that between 2007 and 2009, more antibiotic prescriptions were written for adults in primary care offices than in either outpatient hospital clinics or EDs.¹⁷
• A cross-sectional study focused on the frequency with which antibiotics were prescribed for uncomplicated acute rhinosinusitis. Researchers analyzed data from 2005 to 2010 National Ambulatory Medical Care Surveys (NAMCS) and National Hospital Ambulatory Medical Care Surveys (NHAMCS) and found that more than half of the patients received prescriptions for antibiotics, but that there was no overall difference in antibiotic prescriptions between primary care and ED presentation.¹⁸
• A retrospective analysis that examined antibiotic prescribing found that between 2006 and 2010, outpatient hospital practices (56%) and community-practice offices (60%) prescribed more antibiotics for ARTIs than EDs (51%).¹²

Stick to narrow-spectrum agents when possible

Using broad-spectrum antibiotics, such as quinolones or imipenem, first line, contributes more to the problem of antibiotic resistance than does prescribing narrow-spectrum antibiotics such as amoxicillin, cephalexin, or trimethoprim-sulfamethoxazole.⁷ Yet between 2007 and 2009, broad-spectrum agents were prescribed for 61% of outpatient adult visits in which patients received an antibiotic prescription.¹⁷ Quinolones (25%), macrolides (20%), and aminopenicillins (12%) were most commonly prescribed, and antibiotic prescriptions were most often written for respiratory conditions, such as bronchitis, for which we now know antibiotics are rarely indicated.¹⁷

Up to 40% of antibiotic prescriptions for acute respiratory tract infections are unnecessary.

Between 2006 and 2008, pediatric patients who received antibiotic prescriptions were given broad-spectrum agents 50% of the time, of which macrolides were the class most commonly prescribed.¹³

More recently, researchers examined the frequency with which physicians prescribe narrow-spectrum, first-line antibiotics for otitis media, sinusitis, and pharyngitis using 2010 to 2011 NAMCS/NHAMCS data. They found that physicians used first-line agents recommended by professional guidelines 52% of the time, although it was estimated that they would have been appropriate in 80% of cases; pediatric patients were more likely to receive appropriate first-line antibiotics than adult patients.¹⁹ Macrolides, especially azithromycin, were the most common non–first-line antibiotics prescribed.^19,20 The bottom line is that when antibiotics are indicated for upper respiratory infections (otitis media, sinusitis, and pharyngitis), physicians should prescribe a narrow-spectrum antibiotic first.

Antibiotic overprescribing affects the gut and beyond

The human intestinal microbiome is composed of a diverse array of bacteria, viruses, and parasites.²¹ The main functions of the gut microbiome include interacting with the immune system and participating in biochemical reactions in the gut, such as absorption of fat-soluble vitamins and the production of vitamin K.

As we know, antibiotics decrease the diversity of gut bacteria, which, in turn, can cause less efficient nutrient extraction, as well as a vulnerability to enteric infections.²¹ It is well known, for example, that the bacterial gut microbiome can either inhibit or promote diarrheal illnesses such as those caused by C. difficile. C. difficile infection (CDI) is now the most common health care-related infection, accounting for approximately a half million health care facility infections a year.²² CDI extends hospital stays an average of almost 10 days and is estimated to cost the health care system $6.3 billion annually.²³

We should pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

Antibiotics can also eliminate antibiotic-susceptible organisms, allowing resistant organisms to proliferate.⁴ They also promote the transmission of genes for antibiotic resistance between gut bacteria.⁴

Beyond the gut

Less well known is that gut bacteria can promote or inhibit extraintestinal infections.

Gut bacteria and HIV. In early human immunodeficiency virus (HIV) infections, for example, gut populations of Lactobacillus and Bifidobacteria are reduced, and the gut barrier becomes compromised.²⁴ Increasing translocation of bacterial products is associated with HIV disease progression. Preservation of Lactobacillus populations in the gut is associated with markers predictive of better HIV outcomes, including a higher CD4 count, a lower viral load, and less evidence of gut microbial translocation.²⁴ This underscores the importance of maintaining a healthy gut flora in patients with HIV, using such steps as avoiding unnecessary antibiotics.

Gut bacteria and stress, depression. Antibiotics directly induce the expression of key genes that affect the stress response.²⁵ While causative studies are lacking, there is a growing body of evidence suggesting that the gut microbiome is involved in 2-way communication with the brain and can affect, and be affected by, stress and depression.^21,26-30 Diseases and conditions that seem to have a putative connection to a disordered microbiome (dysbiosis) include depression, anxiety, Crohn’s disease, type 2 diabetes, and obesity.

Gut bacteria and childhood obesity. Repeated use of broader-spectrum antibiotics in children <24 months of age increases the risk of developing childhood obesity.^1,6 One theory for the association is that the effects of broad-spectrum antibiotics on the intestinal flora of young children may alter long-term energy homeostasis resulting in a higher risk for obesity.¹

Gut bacteria and asthma. Studies demonstrate differences in the gut microbiome of asthmatic and nonasthmatic patients. These differences affect the activities of helper T-cell subsets (Th1 and Th2), which in turn affect the development of immune tolerance.³¹

Although additional studies are needed to confirm these findings, the evidence collected thus far should make us all pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

What can we do right now?

The issues created by the inappropriate prescribing of antibiotics have been known for decades, and multiple attempts have been made to find solutions and implement change. Although some small successes have occurred, little overall progress has been made in reducing antibiotic prescribing in the general population. A historical review of why physicians prescribe antibiotics inappropriately and the interventions that have successfully reduced this prescribing may prove valuable as we continue to look for new, effective answers.

Why do we overprescribe antibiotics? A 2015 systematic literature review found that patient demand, pharmaceutical company marketing activities, limited up-to-date information sources, and physician fear of losing their patients are major reasons physicians cite for prescribing antibiotics.³²

Monthly emails to physicians comparing their prescribing habits to peers and top performers reduced inappropriate antibiotic prescribing for acute respiratory tract infections.

In a separate study that explored antibiotic prescribing habits for acute bronchitis,³³ clinicians cited “patient demand” as the major reason for prescribing antibiotics. Respondents also reported that “other physicians were responsible for inappropriate antibiotic prescribing.”³³

Strategies that work

Some early intervention programs directed at reducing antibiotic prescribing demonstrated success (TABLE 2).^34-36 One example comes from a 1996 to 1998 study of 4 primary care practices.³⁴ Researchers evaluated the impact of a multidimensional intervention effort targeted at clinicians and patients and aimed at lowering the use of antimicrobial agents for acute uncomplicated bronchitis in adults. It incorporated a number of elements, including office-based and household patient educational materials, and a clinician intervention involving education, practice profiling, and academic detailing. Physicians in this program reduced their rates of antibiotic prescribing for uncomplicated bronchitis from 74% to 48%.³⁴

Employing EMRs. A more recent study focused on using electronic medical records (EMRs) and communications to modify physician antibiotic prescribing.³⁵ By sending physicians monthly emails comparing their prescribing patterns to peers and “typical top performers,” inappropriate antibiotic prescriptions for ARTIs went from 19.9% to 3.7%.³⁵

Patients and parents reported higher satisfaction with physicians who explained why antibiotics were not indicated vs physicians who simply prescribed them.

In another effort, the same researchers modified physicians’ EMRs to detect when potentially inappropriate antibiotics were prescribed. The system then prompted the physician to provide an “antibiotic justification note,” which remained visible in the patient’s chart. This approach, which encouraged physicians to follow prescribing guidelines by taking advantage of their concerns about their reputations, produced a 77% reduction in antibiotic prescribing.³⁵

Focusing on the public. Studies have also examined the effectiveness of educating the public about when antibiotics are not likely to be helpful and of the harms of unnecessary antibiotics. Studies conducted in Tennessee and Wisconsin that combined prescriber and community education about unnecessary antibiotics for children found that the intervention reduced antibiotic prescribing in both locations by about 19% compared with about a 9% reduction in the control groups.^36,37

Does prescribing antibiotics affect patient satisfaction?

The results are mixed as to whether prescribing antibiotics affects patient satisfaction. Two studies in the early 2000s found that both patients and parents reported higher satisfaction with physicians who explained why antibiotics were not indicated vs physicians who simply prescribed them, and that such explanations do not need to take a lot of time.^37,38 (See TABLE 3^9,37,38 for patient care tips.)

A more recent study found that higher antibiotic prescribing practices in Britain were associated with modestly higher patient satisfaction ratings.³⁹ The authors of this study noted, however, that reduced antibiotic prescribing may be a proxy for other practice patterns that affected satisfaction ratings.

Reducing antibiotic prescribing reduces resistance

There is also strong evidence that when physicians decrease antibiotic prescribing, antimicrobial resistance follows suit. One of the earlier landmark studies to demonstrate this was a Finnish study published in 1997.⁴⁰ The authors found that a reduction of macrolide antibiotic consumption in Finland led to a reduction in streptococci macrolide resistance from 16.5% to 8.6%.⁴⁰

There is strong evidence that when physicians decrease antibiotic prescribing, antimicrobial resistance follows suit.

Since then, multiple studies have demonstrated similar results for both respiratory and urinary tract infections.^41,42 A 2017 meta-analysis analyzing 32 studies found that antibiotic stewardship programs reduced the incidence of infections and colonization with multidrug-resistant Gram-negative bacteria (51% reduction), extended-spectrum beta-lactamase–producing Gram-negative bacteria (48%), and methicillin-resistant Staphylococcus aureus (37%). There was also a reduction in the incidence of C. difficile infections (32%).⁴³

CORRESPONDENCE
David C. Fiore, MD, Department of Family and Community Medicine, University of Nevada, Reno School of Medicine, Brigham Bldg, MS 316, Reno, NV 89557; [email protected].

Despite universal agreement that antibiotic overprescribing is a problem, the practice continues to vex us. Antibiotic use—whether appropriate or not—has been linked to rising rates of antimicrobial resistance, disruption of the gut microbiome leading to Clostridium difficile infections, allergic reactions, and increased health care costs (TABLE 1^1-6). And yet, physicians continue to overprescribe this class of medication.

A 2016 Centers for Disease Control and Prevention (CDC) report estimates that at least 30% of antibiotics prescribed in US outpatient settings are unnecessary.⁷ Another report cites a slightly higher figure across a variety of health care settings.⁸ Pair these findings with the fact that there are currently few new drugs in development to target resistant bacteria, and you have the potential for a post-antibiotic era in which common infections could become lethal.⁷

In 2003, the CDC launched its “Get Smart: Know When Antibiotics Work” program, focused on decreasing inappropriate antibiotic use in the outpatient setting.⁹ In 2014, the White House released the National Action Plan for Combating Antibiotic-Resistant Bacteria with a goal of decreasing inappropriate outpatient antibiotic use by 50% and inappropriate inpatient use by 20% by 2020.¹⁰ And, on an international level, the World Health Organization (WHO) developed a 5-year strategic framework in 2015 for implementing its Global Action Plan on Antimicrobial Resistance.¹¹

Family practitioners are on the front lines of this battle. Here’s what we can do now.

[polldaddy:9885811]

When and where are antibiotics most often inappropriately prescribed?

The diagnosis leading to the most frequent inappropriate prescribing of antibiotics is acute respiratory tract infection (ARTI), which includes bronchitis, otitis media, pharyngitis, sinusitis, tonsillitis, the common cold, and pneumonia. Up to 40% of antibiotic prescriptions for these conditions are unnecessary.^8,12 Bronchitis is the most common ARTI diagnosis associated with inappropriate antibiotic prescriptions, while sinusitis, suppurative otitis media, and pharyngitis are the diagnoses associated with the lion’s share of all (appropriate and inappropriate) antibiotic prescriptions within the ARTI category.^8,9,12,13 There are national clinical guidelines delineating when antibiotic treatment is appropriate for these conditions.^14-16

With respect to setting, studies have presented conflicting results as to whether there is a difference between antibiotic prescribing in office-based vs emergency department (ED) settings. Here is a sample of some of the literature to date:

• One study found a higher rate of antibiotic prescribing during ED visits (21%) than office visits (9%), despite the fact that between 2007 and 2009, more antibiotic prescriptions were written for adults in primary care offices than in either outpatient hospital clinics or EDs.¹⁷
• A cross-sectional study focused on the frequency with which antibiotics were prescribed for uncomplicated acute rhinosinusitis. Researchers analyzed data from 2005 to 2010 National Ambulatory Medical Care Surveys (NAMCS) and National Hospital Ambulatory Medical Care Surveys (NHAMCS) and found that more than half of the patients received prescriptions for antibiotics, but that there was no overall difference in antibiotic prescriptions between primary care and ED presentation.¹⁸
• A retrospective analysis that examined antibiotic prescribing found that between 2006 and 2010, outpatient hospital practices (56%) and community-practice offices (60%) prescribed more antibiotics for ARTIs than EDs (51%).¹²

Stick to narrow-spectrum agents when possible

Using broad-spectrum antibiotics, such as quinolones or imipenem, first line, contributes more to the problem of antibiotic resistance than does prescribing narrow-spectrum antibiotics such as amoxicillin, cephalexin, or trimethoprim-sulfamethoxazole.⁷ Yet between 2007 and 2009, broad-spectrum agents were prescribed for 61% of outpatient adult visits in which patients received an antibiotic prescription.¹⁷ Quinolones (25%), macrolides (20%), and aminopenicillins (12%) were most commonly prescribed, and antibiotic prescriptions were most often written for respiratory conditions, such as bronchitis, for which we now know antibiotics are rarely indicated.¹⁷

Up to 40% of antibiotic prescriptions for acute respiratory tract infections are unnecessary.

Between 2006 and 2008, pediatric patients who received antibiotic prescriptions were given broad-spectrum agents 50% of the time, of which macrolides were the class most commonly prescribed.¹³

More recently, researchers examined the frequency with which physicians prescribe narrow-spectrum, first-line antibiotics for otitis media, sinusitis, and pharyngitis using 2010 to 2011 NAMCS/NHAMCS data. They found that physicians used first-line agents recommended by professional guidelines 52% of the time, although it was estimated that they would have been appropriate in 80% of cases; pediatric patients were more likely to receive appropriate first-line antibiotics than adult patients.¹⁹ Macrolides, especially azithromycin, were the most common non–first-line antibiotics prescribed.^19,20 The bottom line is that when antibiotics are indicated for upper respiratory infections (otitis media, sinusitis, and pharyngitis), physicians should prescribe a narrow-spectrum antibiotic first.

Antibiotic overprescribing affects the gut and beyond

The human intestinal microbiome is composed of a diverse array of bacteria, viruses, and parasites.²¹ The main functions of the gut microbiome include interacting with the immune system and participating in biochemical reactions in the gut, such as absorption of fat-soluble vitamins and the production of vitamin K.

As we know, antibiotics decrease the diversity of gut bacteria, which, in turn, can cause less efficient nutrient extraction, as well as a vulnerability to enteric infections.²¹ It is well known, for example, that the bacterial gut microbiome can either inhibit or promote diarrheal illnesses such as those caused by C. difficile. C. difficile infection (CDI) is now the most common health care-related infection, accounting for approximately a half million health care facility infections a year.²² CDI extends hospital stays an average of almost 10 days and is estimated to cost the health care system $6.3 billion annually.²³

We should pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

Antibiotics can also eliminate antibiotic-susceptible organisms, allowing resistant organisms to proliferate.⁴ They also promote the transmission of genes for antibiotic resistance between gut bacteria.⁴

Beyond the gut

Less well known is that gut bacteria can promote or inhibit extraintestinal infections.

Gut bacteria and HIV. In early human immunodeficiency virus (HIV) infections, for example, gut populations of Lactobacillus and Bifidobacteria are reduced, and the gut barrier becomes compromised.²⁴ Increasing translocation of bacterial products is associated with HIV disease progression. Preservation of Lactobacillus populations in the gut is associated with markers predictive of better HIV outcomes, including a higher CD4 count, a lower viral load, and less evidence of gut microbial translocation.²⁴ This underscores the importance of maintaining a healthy gut flora in patients with HIV, using such steps as avoiding unnecessary antibiotics.

Gut bacteria and stress, depression. Antibiotics directly induce the expression of key genes that affect the stress response.²⁵ While causative studies are lacking, there is a growing body of evidence suggesting that the gut microbiome is involved in 2-way communication with the brain and can affect, and be affected by, stress and depression.^21,26-30 Diseases and conditions that seem to have a putative connection to a disordered microbiome (dysbiosis) include depression, anxiety, Crohn’s disease, type 2 diabetes, and obesity.

Gut bacteria and childhood obesity. Repeated use of broader-spectrum antibiotics in children <24 months of age increases the risk of developing childhood obesity.^1,6 One theory for the association is that the effects of broad-spectrum antibiotics on the intestinal flora of young children may alter long-term energy homeostasis resulting in a higher risk for obesity.¹

Gut bacteria and asthma. Studies demonstrate differences in the gut microbiome of asthmatic and nonasthmatic patients. These differences affect the activities of helper T-cell subsets (Th1 and Th2), which in turn affect the development of immune tolerance.³¹

Although additional studies are needed to confirm these findings, the evidence collected thus far should make us all pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

What can we do right now?

The issues created by the inappropriate prescribing of antibiotics have been known for decades, and multiple attempts have been made to find solutions and implement change. Although some small successes have occurred, little overall progress has been made in reducing antibiotic prescribing in the general population. A historical review of why physicians prescribe antibiotics inappropriately and the interventions that have successfully reduced this prescribing may prove valuable as we continue to look for new, effective answers.

Why do we overprescribe antibiotics? A 2015 systematic literature review found that patient demand, pharmaceutical company marketing activities, limited up-to-date information sources, and physician fear of losing their patients are major reasons physicians cite for prescribing antibiotics.³²

Monthly emails to physicians comparing their prescribing habits to peers and top performers reduced inappropriate antibiotic prescribing for acute respiratory tract infections.

In a separate study that explored antibiotic prescribing habits for acute bronchitis,³³ clinicians cited “patient demand” as the major reason for prescribing antibiotics. Respondents also reported that “other physicians were responsible for inappropriate antibiotic prescribing.”³³

Strategies that work

Some early intervention programs directed at reducing antibiotic prescribing demonstrated success (TABLE 2).^34-36 One example comes from a 1996 to 1998 study of 4 primary care practices.³⁴ Researchers evaluated the impact of a multidimensional intervention effort targeted at clinicians and patients and aimed at lowering the use of antimicrobial agents for acute uncomplicated bronchitis in adults. It incorporated a number of elements, including office-based and household patient educational materials, and a clinician intervention involving education, practice profiling, and academic detailing. Physicians in this program reduced their rates of antibiotic prescribing for uncomplicated bronchitis from 74% to 48%.³⁴

Employing EMRs. A more recent study focused on using electronic medical records (EMRs) and communications to modify physician antibiotic prescribing.³⁵ By sending physicians monthly emails comparing their prescribing patterns to peers and “typical top performers,” inappropriate antibiotic prescriptions for ARTIs went from 19.9% to 3.7%.³⁵

Patients and parents reported higher satisfaction with physicians who explained why antibiotics were not indicated vs physicians who simply prescribed them.

In another effort, the same researchers modified physicians’ EMRs to detect when potentially inappropriate antibiotics were prescribed. The system then prompted the physician to provide an “antibiotic justification note,” which remained visible in the patient’s chart. This approach, which encouraged physicians to follow prescribing guidelines by taking advantage of their concerns about their reputations, produced a 77% reduction in antibiotic prescribing.³⁵

Focusing on the public. Studies have also examined the effectiveness of educating the public about when antibiotics are not likely to be helpful and of the harms of unnecessary antibiotics. Studies conducted in Tennessee and Wisconsin that combined prescriber and community education about unnecessary antibiotics for children found that the intervention reduced antibiotic prescribing in both locations by about 19% compared with about a 9% reduction in the control groups.^36,37

Does prescribing antibiotics affect patient satisfaction?

The results are mixed as to whether prescribing antibiotics affects patient satisfaction. Two studies in the early 2000s found that both patients and parents reported higher satisfaction with physicians who explained why antibiotics were not indicated vs physicians who simply prescribed them, and that such explanations do not need to take a lot of time.^37,38 (See TABLE 3^9,37,38 for patient care tips.)

A more recent study found that higher antibiotic prescribing practices in Britain were associated with modestly higher patient satisfaction ratings.³⁹ The authors of this study noted, however, that reduced antibiotic prescribing may be a proxy for other practice patterns that affected satisfaction ratings.

Reducing antibiotic prescribing reduces resistance

There is also strong evidence that when physicians decrease antibiotic prescribing, antimicrobial resistance follows suit. One of the earlier landmark studies to demonstrate this was a Finnish study published in 1997.⁴⁰ The authors found that a reduction of macrolide antibiotic consumption in Finland led to a reduction in streptococci macrolide resistance from 16.5% to 8.6%.⁴⁰

There is strong evidence that when physicians decrease antibiotic prescribing, antimicrobial resistance follows suit.

Since then, multiple studies have demonstrated similar results for both respiratory and urinary tract infections.^41,42 A 2017 meta-analysis analyzing 32 studies found that antibiotic stewardship programs reduced the incidence of infections and colonization with multidrug-resistant Gram-negative bacteria (51% reduction), extended-spectrum beta-lactamase–producing Gram-negative bacteria (48%), and methicillin-resistant Staphylococcus aureus (37%). There was also a reduction in the incidence of C. difficile infections (32%).⁴³

CORRESPONDENCE
David C. Fiore, MD, Department of Family and Community Medicine, University of Nevada, Reno School of Medicine, Brigham Bldg, MS 316, Reno, NV 89557; [email protected].

Despite universal agreement that antibiotic overprescribing is a problem, the practice continues to vex us. Antibiotic use—whether appropriate or not—has been linked to rising rates of antimicrobial resistance, disruption of the gut microbiome leading to Clostridium difficile infections, allergic reactions, and increased health care costs (TABLE 1^1-6). And yet, physicians continue to overprescribe this class of medication.

A 2016 Centers for Disease Control and Prevention (CDC) report estimates that at least 30% of antibiotics prescribed in US outpatient settings are unnecessary.⁷ Another report cites a slightly higher figure across a variety of health care settings.⁸ Pair these findings with the fact that there are currently few new drugs in development to target resistant bacteria, and you have the potential for a post-antibiotic era in which common infections could become lethal.⁷

In 2003, the CDC launched its “Get Smart: Know When Antibiotics Work” program, focused on decreasing inappropriate antibiotic use in the outpatient setting.⁹ In 2014, the White House released the National Action Plan for Combating Antibiotic-Resistant Bacteria with a goal of decreasing inappropriate outpatient antibiotic use by 50% and inappropriate inpatient use by 20% by 2020.¹⁰ And, on an international level, the World Health Organization (WHO) developed a 5-year strategic framework in 2015 for implementing its Global Action Plan on Antimicrobial Resistance.¹¹

Family practitioners are on the front lines of this battle. Here’s what we can do now.

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When and where are antibiotics most often inappropriately prescribed?

The diagnosis leading to the most frequent inappropriate prescribing of antibiotics is acute respiratory tract infection (ARTI), which includes bronchitis, otitis media, pharyngitis, sinusitis, tonsillitis, the common cold, and pneumonia. Up to 40% of antibiotic prescriptions for these conditions are unnecessary.^8,12 Bronchitis is the most common ARTI diagnosis associated with inappropriate antibiotic prescriptions, while sinusitis, suppurative otitis media, and pharyngitis are the diagnoses associated with the lion’s share of all (appropriate and inappropriate) antibiotic prescriptions within the ARTI category.^8,9,12,13 There are national clinical guidelines delineating when antibiotic treatment is appropriate for these conditions.^14-16

With respect to setting, studies have presented conflicting results as to whether there is a difference between antibiotic prescribing in office-based vs emergency department (ED) settings. Here is a sample of some of the literature to date:

• One study found a higher rate of antibiotic prescribing during ED visits (21%) than office visits (9%), despite the fact that between 2007 and 2009, more antibiotic prescriptions were written for adults in primary care offices than in either outpatient hospital clinics or EDs.¹⁷
• A cross-sectional study focused on the frequency with which antibiotics were prescribed for uncomplicated acute rhinosinusitis. Researchers analyzed data from 2005 to 2010 National Ambulatory Medical Care Surveys (NAMCS) and National Hospital Ambulatory Medical Care Surveys (NHAMCS) and found that more than half of the patients received prescriptions for antibiotics, but that there was no overall difference in antibiotic prescriptions between primary care and ED presentation.¹⁸
• A retrospective analysis that examined antibiotic prescribing found that between 2006 and 2010, outpatient hospital practices (56%) and community-practice offices (60%) prescribed more antibiotics for ARTIs than EDs (51%).¹²

Stick to narrow-spectrum agents when possible

Using broad-spectrum antibiotics, such as quinolones or imipenem, first line, contributes more to the problem of antibiotic resistance than does prescribing narrow-spectrum antibiotics such as amoxicillin, cephalexin, or trimethoprim-sulfamethoxazole.⁷ Yet between 2007 and 2009, broad-spectrum agents were prescribed for 61% of outpatient adult visits in which patients received an antibiotic prescription.¹⁷ Quinolones (25%), macrolides (20%), and aminopenicillins (12%) were most commonly prescribed, and antibiotic prescriptions were most often written for respiratory conditions, such as bronchitis, for which we now know antibiotics are rarely indicated.¹⁷

Up to 40% of antibiotic prescriptions for acute respiratory tract infections are unnecessary.

Between 2006 and 2008, pediatric patients who received antibiotic prescriptions were given broad-spectrum agents 50% of the time, of which macrolides were the class most commonly prescribed.¹³

More recently, researchers examined the frequency with which physicians prescribe narrow-spectrum, first-line antibiotics for otitis media, sinusitis, and pharyngitis using 2010 to 2011 NAMCS/NHAMCS data. They found that physicians used first-line agents recommended by professional guidelines 52% of the time, although it was estimated that they would have been appropriate in 80% of cases; pediatric patients were more likely to receive appropriate first-line antibiotics than adult patients.¹⁹ Macrolides, especially azithromycin, were the most common non–first-line antibiotics prescribed.^19,20 The bottom line is that when antibiotics are indicated for upper respiratory infections (otitis media, sinusitis, and pharyngitis), physicians should prescribe a narrow-spectrum antibiotic first.

Antibiotic overprescribing affects the gut and beyond

The human intestinal microbiome is composed of a diverse array of bacteria, viruses, and parasites.²¹ The main functions of the gut microbiome include interacting with the immune system and participating in biochemical reactions in the gut, such as absorption of fat-soluble vitamins and the production of vitamin K.

As we know, antibiotics decrease the diversity of gut bacteria, which, in turn, can cause less efficient nutrient extraction, as well as a vulnerability to enteric infections.²¹ It is well known, for example, that the bacterial gut microbiome can either inhibit or promote diarrheal illnesses such as those caused by C. difficile. C. difficile infection (CDI) is now the most common health care-related infection, accounting for approximately a half million health care facility infections a year.²² CDI extends hospital stays an average of almost 10 days and is estimated to cost the health care system $6.3 billion annually.²³

We should pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

Antibiotics can also eliminate antibiotic-susceptible organisms, allowing resistant organisms to proliferate.⁴ They also promote the transmission of genes for antibiotic resistance between gut bacteria.⁴

Beyond the gut

Less well known is that gut bacteria can promote or inhibit extraintestinal infections.

Gut bacteria and HIV. In early human immunodeficiency virus (HIV) infections, for example, gut populations of Lactobacillus and Bifidobacteria are reduced, and the gut barrier becomes compromised.²⁴ Increasing translocation of bacterial products is associated with HIV disease progression. Preservation of Lactobacillus populations in the gut is associated with markers predictive of better HIV outcomes, including a higher CD4 count, a lower viral load, and less evidence of gut microbial translocation.²⁴ This underscores the importance of maintaining a healthy gut flora in patients with HIV, using such steps as avoiding unnecessary antibiotics.

Gut bacteria and stress, depression. Antibiotics directly induce the expression of key genes that affect the stress response.²⁵ While causative studies are lacking, there is a growing body of evidence suggesting that the gut microbiome is involved in 2-way communication with the brain and can affect, and be affected by, stress and depression.^21,26-30 Diseases and conditions that seem to have a putative connection to a disordered microbiome (dysbiosis) include depression, anxiety, Crohn’s disease, type 2 diabetes, and obesity.

Gut bacteria and childhood obesity. Repeated use of broader-spectrum antibiotics in children <24 months of age increases the risk of developing childhood obesity.^1,6 One theory for the association is that the effects of broad-spectrum antibiotics on the intestinal flora of young children may alter long-term energy homeostasis resulting in a higher risk for obesity.¹

Gut bacteria and asthma. Studies demonstrate differences in the gut microbiome of asthmatic and nonasthmatic patients. These differences affect the activities of helper T-cell subsets (Th1 and Th2), which in turn affect the development of immune tolerance.³¹

Although additional studies are needed to confirm these findings, the evidence collected thus far should make us all pause before prescribing drugs that can alter our microbiome in complex and only partially understood ways.

What can we do right now?

The issues created by the inappropriate prescribing of antibiotics have been known for decades, and multiple attempts have been made to find solutions and implement change. Although some small successes have occurred, little overall progress has been made in reducing antibiotic prescribing in the general population. A historical review of why physicians prescribe antibiotics inappropriately and the interventions that have successfully reduced this prescribing may prove valuable as we continue to look for new, effective answers.

Why do we overprescribe antibiotics? A 2015 systematic literature review found that patient demand, pharmaceutical company marketing activities, limited up-to-date information sources, and physician fear of losing their patients are major reasons physicians cite for prescribing antibiotics.³²

Monthly emails to physicians comparing their prescribing habits to peers and top performers reduced inappropriate antibiotic prescribing for acute respiratory tract infections.

In a separate study that explored antibiotic prescribing habits for acute bronchitis,³³ clinicians cited “patient demand” as the major reason for prescribing antibiotics. Respondents also reported that “other physicians were responsible for inappropriate antibiotic prescribing.”³³

Strategies that work

Some early intervention programs directed at reducing antibiotic prescribing demonstrated success (TABLE 2).^34-36 One example comes from a 1996 to 1998 study of 4 primary care practices.³⁴ Researchers evaluated the impact of a multidimensional intervention effort targeted at clinicians and patients and aimed at lowering the use of antimicrobial agents for acute uncomplicated bronchitis in adults. It incorporated a number of elements, including office-based and household patient educational materials, and a clinician intervention involving education, practice profiling, and academic detailing. Physicians in this program reduced their rates of antibiotic prescribing for uncomplicated bronchitis from 74% to 48%.³⁴

Employing EMRs. A more recent study focused on using electronic medical records (EMRs) and communications to modify physician antibiotic prescribing.³⁵ By sending physicians monthly emails comparing their prescribing patterns to peers and “typical top performers,” inappropriate antibiotic prescriptions for ARTIs went from 19.9% to 3.7%.³⁵

Patients and parents reported higher satisfaction with physicians who explained why antibiotics were not indicated vs physicians who simply prescribed them.

In another effort, the same researchers modified physicians’ EMRs to detect when potentially inappropriate antibiotics were prescribed. The system then prompted the physician to provide an “antibiotic justification note,” which remained visible in the patient’s chart. This approach, which encouraged physicians to follow prescribing guidelines by taking advantage of their concerns about their reputations, produced a 77% reduction in antibiotic prescribing.³⁵

Focusing on the public. Studies have also examined the effectiveness of educating the public about when antibiotics are not likely to be helpful and of the harms of unnecessary antibiotics. Studies conducted in Tennessee and Wisconsin that combined prescriber and community education about unnecessary antibiotics for children found that the intervention reduced antibiotic prescribing in both locations by about 19% compared with about a 9% reduction in the control groups.^36,37

Does prescribing antibiotics affect patient satisfaction?

The results are mixed as to whether prescribing antibiotics affects patient satisfaction. Two studies in the early 2000s found that both patients and parents reported higher satisfaction with physicians who explained why antibiotics were not indicated vs physicians who simply prescribed them, and that such explanations do not need to take a lot of time.^37,38 (See TABLE 3^9,37,38 for patient care tips.)

A more recent study found that higher antibiotic prescribing practices in Britain were associated with modestly higher patient satisfaction ratings.³⁹ The authors of this study noted, however, that reduced antibiotic prescribing may be a proxy for other practice patterns that affected satisfaction ratings.

Reducing antibiotic prescribing reduces resistance

There is also strong evidence that when physicians decrease antibiotic prescribing, antimicrobial resistance follows suit. One of the earlier landmark studies to demonstrate this was a Finnish study published in 1997.⁴⁰ The authors found that a reduction of macrolide antibiotic consumption in Finland led to a reduction in streptococci macrolide resistance from 16.5% to 8.6%.⁴⁰

There is strong evidence that when physicians decrease antibiotic prescribing, antimicrobial resistance follows suit.

Since then, multiple studies have demonstrated similar results for both respiratory and urinary tract infections.^41,42 A 2017 meta-analysis analyzing 32 studies found that antibiotic stewardship programs reduced the incidence of infections and colonization with multidrug-resistant Gram-negative bacteria (51% reduction), extended-spectrum beta-lactamase–producing Gram-negative bacteria (48%), and methicillin-resistant Staphylococcus aureus (37%). There was also a reduction in the incidence of C. difficile infections (32%).⁴³

CORRESPONDENCE
David C. Fiore, MD, Department of Family and Community Medicine, University of Nevada, Reno School of Medicine, Brigham Bldg, MS 316, Reno, NV 89557; [email protected].

Photo by Linda Bartlett

Combination treatment with 2 monoclonal antibodies (mAbs) has demonstrated preclinical efficacy against B-cell lymphomas, according to researchers.

The investigators tested different combinations of mAbs to see how they interact with each other and what effect this has on how the immune system fights cancer.

One combination—an anti-CD27 mAb and anti-CD20 mAb—greatly increased survival in mouse models of B-cell lymphoma.

The researchers reported these results in Cancer Cell.

“By combining 2 specific antibodies—anti-CD27 and anti-CD20—we’ve increased the ability of the immune system to destroy cancer cells,” said study author Sean Lim, MBChB, PhD, of the University of Southampton in the UK.

“It’s very exciting to see that this drug combination has an impact on survival of mice with lymphoma, as improvements in treatment are urgently needed. The next stage will be to see if what we’ve discovered can be replicated in patients.”

For this study, Dr Lim and her colleagues tested combinations of tumor-targeting mAbs and immunomodulatory mAbs. The group found that an anti-CD27 mAb enhanced anti-CD20 therapy in various preclinical models.

The investigators first tested anti-CD20 and anti-CD27 (both alone and in combination) in the murine B-cell lymphoma model BCL1.

All control BCL1 mice had died by 30 days from baseline, all mice that received anti-CD20 alone died by day 40, and 30% of mice that received anti-CD27 alone were still alive past 100 days.

In contrast, 100% of mice that received anti-CD20 and anti-CD27 in combination were still alive and lymphoma-free past the 100-day mark.

The researchers also tested the mAbs in the A31 B-cell lymphoma model and the Eµ-TCL1 B-chronic lymphocytic leukemia model.

Results were similar to those observed with the BCL1 model. The combination of anti-CD20 and anti-CD27 significantly improved survival in A31 and Eµ-TCL1 mice, with all mice that received this combination surviving past 100 days.

As far as mechanisms of action, the investigators noted that anti-CD20 binds to B cells and mediates antibody-dependent cellular phagocytosis of the mAb-opsonized cells.

The researchers said the addition of anti-CD27 stimulates CD8+ T cells and natural killer cells, which induces the release of CCL3, CCL4, and CCL5, and this potentially attracts myeloid cells.

In addition, anti-CD27 (via the stimulation of CD8+ T and natural killer cells) induces the release of interferon gamma, which activates macrophages to express more Fc gamma receptor IV and promotes their inflammatory capacity. This increases the number of macrophages available for antibody-dependent cellular phagocytosis as well as the cells’ phagocytic ability.

Based on these findings, researchers are now conducting a phase 2 trial to test the anti-CD20 mAb rituximab and the anti-CD27 mAb varililumab in patients with relapsed and/or refractory B-cell non-Hodgkin lymphoma. 

Photo by Linda Bartlett

Combination treatment with 2 monoclonal antibodies (mAbs) has demonstrated preclinical efficacy against B-cell lymphomas, according to researchers.

The investigators tested different combinations of mAbs to see how they interact with each other and what effect this has on how the immune system fights cancer.

One combination—an anti-CD27 mAb and anti-CD20 mAb—greatly increased survival in mouse models of B-cell lymphoma.

The researchers reported these results in Cancer Cell.

“By combining 2 specific antibodies—anti-CD27 and anti-CD20—we’ve increased the ability of the immune system to destroy cancer cells,” said study author Sean Lim, MBChB, PhD, of the University of Southampton in the UK.

“It’s very exciting to see that this drug combination has an impact on survival of mice with lymphoma, as improvements in treatment are urgently needed. The next stage will be to see if what we’ve discovered can be replicated in patients.”

For this study, Dr Lim and her colleagues tested combinations of tumor-targeting mAbs and immunomodulatory mAbs. The group found that an anti-CD27 mAb enhanced anti-CD20 therapy in various preclinical models.

The investigators first tested anti-CD20 and anti-CD27 (both alone and in combination) in the murine B-cell lymphoma model BCL1.

All control BCL1 mice had died by 30 days from baseline, all mice that received anti-CD20 alone died by day 40, and 30% of mice that received anti-CD27 alone were still alive past 100 days.

In contrast, 100% of mice that received anti-CD20 and anti-CD27 in combination were still alive and lymphoma-free past the 100-day mark.

The researchers also tested the mAbs in the A31 B-cell lymphoma model and the Eµ-TCL1 B-chronic lymphocytic leukemia model.

Results were similar to those observed with the BCL1 model. The combination of anti-CD20 and anti-CD27 significantly improved survival in A31 and Eµ-TCL1 mice, with all mice that received this combination surviving past 100 days.

As far as mechanisms of action, the investigators noted that anti-CD20 binds to B cells and mediates antibody-dependent cellular phagocytosis of the mAb-opsonized cells.

The researchers said the addition of anti-CD27 stimulates CD8+ T cells and natural killer cells, which induces the release of CCL3, CCL4, and CCL5, and this potentially attracts myeloid cells.

In addition, anti-CD27 (via the stimulation of CD8+ T and natural killer cells) induces the release of interferon gamma, which activates macrophages to express more Fc gamma receptor IV and promotes their inflammatory capacity. This increases the number of macrophages available for antibody-dependent cellular phagocytosis as well as the cells’ phagocytic ability.

Based on these findings, researchers are now conducting a phase 2 trial to test the anti-CD20 mAb rituximab and the anti-CD27 mAb varililumab in patients with relapsed and/or refractory B-cell non-Hodgkin lymphoma. 

Photo by Linda Bartlett

Combination treatment with 2 monoclonal antibodies (mAbs) has demonstrated preclinical efficacy against B-cell lymphomas, according to researchers.

The investigators tested different combinations of mAbs to see how they interact with each other and what effect this has on how the immune system fights cancer.

One combination—an anti-CD27 mAb and anti-CD20 mAb—greatly increased survival in mouse models of B-cell lymphoma.

The researchers reported these results in Cancer Cell.

“By combining 2 specific antibodies—anti-CD27 and anti-CD20—we’ve increased the ability of the immune system to destroy cancer cells,” said study author Sean Lim, MBChB, PhD, of the University of Southampton in the UK.

“It’s very exciting to see that this drug combination has an impact on survival of mice with lymphoma, as improvements in treatment are urgently needed. The next stage will be to see if what we’ve discovered can be replicated in patients.”

For this study, Dr Lim and her colleagues tested combinations of tumor-targeting mAbs and immunomodulatory mAbs. The group found that an anti-CD27 mAb enhanced anti-CD20 therapy in various preclinical models.

The investigators first tested anti-CD20 and anti-CD27 (both alone and in combination) in the murine B-cell lymphoma model BCL1.

All control BCL1 mice had died by 30 days from baseline, all mice that received anti-CD20 alone died by day 40, and 30% of mice that received anti-CD27 alone were still alive past 100 days.

In contrast, 100% of mice that received anti-CD20 and anti-CD27 in combination were still alive and lymphoma-free past the 100-day mark.

The researchers also tested the mAbs in the A31 B-cell lymphoma model and the Eµ-TCL1 B-chronic lymphocytic leukemia model.

Results were similar to those observed with the BCL1 model. The combination of anti-CD20 and anti-CD27 significantly improved survival in A31 and Eµ-TCL1 mice, with all mice that received this combination surviving past 100 days.

As far as mechanisms of action, the investigators noted that anti-CD20 binds to B cells and mediates antibody-dependent cellular phagocytosis of the mAb-opsonized cells.

The researchers said the addition of anti-CD27 stimulates CD8+ T cells and natural killer cells, which induces the release of CCL3, CCL4, and CCL5, and this potentially attracts myeloid cells.

In addition, anti-CD27 (via the stimulation of CD8+ T and natural killer cells) induces the release of interferon gamma, which activates macrophages to express more Fc gamma receptor IV and promotes their inflammatory capacity. This increases the number of macrophages available for antibody-dependent cellular phagocytosis as well as the cells’ phagocytic ability.

Based on these findings, researchers are now conducting a phase 2 trial to test the anti-CD20 mAb rituximab and the anti-CD27 mAb varililumab in patients with relapsed and/or refractory B-cell non-Hodgkin lymphoma. 

Red blood cells

Researchers say they have uncovered a new function of arginine vasopressin (AVP).

It seems this hormone does more than maintain fluid balance for the kidneys.

AVP also stimulates the proliferation and differentiation of red blood cell precursors and improves recovery from anemia, according to the researchers.

The group speculates that drugs targeting an AVP receptor could be used to replenish red blood cells lost due to bleeding or treatment toxicity.

Eva Mezey, MD, PhD, of the National Institutes of Health in Bethesda, Maryland, and her colleagues conducted this research and reported the results in Science Translational Medicine.

The team uncovered the unexpected role for AVP by examining clinical data from 92 patients with central diabetes insipidus, a condition that causes AVP deficiency.

Of those individuals, 87% of males and 51% of females had anemia. In comparison, anemia rates in the US general population range from 1.5% to 6% for men and 4.4% to 12% for women.

The researchers also found that all 3 AVP receptors are present on human and murine hematopoietic stem and progenitor cells.

One of these receptors, AVPR1B, plays a predominant role in red blood cell production.

Further experiments revealed that AVP-deficient rats had delayed recovery from anemia, but treatment with AVP or the AVPR1B agonist d(Leu4Lys8)VP was able to speed up anemia recovery in mice.

The researchers tested AVP and the AVPR1B agonist in mouse models of hemorrhage. Compared to vehicle-treated mice, AVP-treated mice had an increase in hematocrit and reticulocyte numbers by day 2. Mice that received d(Leu4Lys8)VP only had an increase in reticulocytes.

The team also tested mice exposed to sublethal irradiation. When the mice received AVP for 2 days, they saw increases in hematocrit and corrected reticulocyte numbers.

The researchers then tested splenectomized mice subjected to hemorrhage. AVP-treated mice had an increase in hematocrit that was similar to that observed in non-splenectomized mice.

Finally, the researchers found that AVP’s effect on hematocrit is independent of erythropoietin. The team said AVP “appears to jump-start peripheral blood cell replenishment,” but later, erythropoietin seems to take over.

Red blood cells

Researchers say they have uncovered a new function of arginine vasopressin (AVP).

It seems this hormone does more than maintain fluid balance for the kidneys.

AVP also stimulates the proliferation and differentiation of red blood cell precursors and improves recovery from anemia, according to the researchers.

The group speculates that drugs targeting an AVP receptor could be used to replenish red blood cells lost due to bleeding or treatment toxicity.

Eva Mezey, MD, PhD, of the National Institutes of Health in Bethesda, Maryland, and her colleagues conducted this research and reported the results in Science Translational Medicine.

The team uncovered the unexpected role for AVP by examining clinical data from 92 patients with central diabetes insipidus, a condition that causes AVP deficiency.

Of those individuals, 87% of males and 51% of females had anemia. In comparison, anemia rates in the US general population range from 1.5% to 6% for men and 4.4% to 12% for women.

The researchers also found that all 3 AVP receptors are present on human and murine hematopoietic stem and progenitor cells.

One of these receptors, AVPR1B, plays a predominant role in red blood cell production.

Further experiments revealed that AVP-deficient rats had delayed recovery from anemia, but treatment with AVP or the AVPR1B agonist d(Leu4Lys8)VP was able to speed up anemia recovery in mice.

The researchers tested AVP and the AVPR1B agonist in mouse models of hemorrhage. Compared to vehicle-treated mice, AVP-treated mice had an increase in hematocrit and reticulocyte numbers by day 2. Mice that received d(Leu4Lys8)VP only had an increase in reticulocytes.

The team also tested mice exposed to sublethal irradiation. When the mice received AVP for 2 days, they saw increases in hematocrit and corrected reticulocyte numbers.

The researchers then tested splenectomized mice subjected to hemorrhage. AVP-treated mice had an increase in hematocrit that was similar to that observed in non-splenectomized mice.

Finally, the researchers found that AVP’s effect on hematocrit is independent of erythropoietin. The team said AVP “appears to jump-start peripheral blood cell replenishment,” but later, erythropoietin seems to take over.

Red blood cells

Researchers say they have uncovered a new function of arginine vasopressin (AVP).

It seems this hormone does more than maintain fluid balance for the kidneys.

AVP also stimulates the proliferation and differentiation of red blood cell precursors and improves recovery from anemia, according to the researchers.

The group speculates that drugs targeting an AVP receptor could be used to replenish red blood cells lost due to bleeding or treatment toxicity.

Eva Mezey, MD, PhD, of the National Institutes of Health in Bethesda, Maryland, and her colleagues conducted this research and reported the results in Science Translational Medicine.

The team uncovered the unexpected role for AVP by examining clinical data from 92 patients with central diabetes insipidus, a condition that causes AVP deficiency.

Of those individuals, 87% of males and 51% of females had anemia. In comparison, anemia rates in the US general population range from 1.5% to 6% for men and 4.4% to 12% for women.

The researchers also found that all 3 AVP receptors are present on human and murine hematopoietic stem and progenitor cells.

One of these receptors, AVPR1B, plays a predominant role in red blood cell production.

Further experiments revealed that AVP-deficient rats had delayed recovery from anemia, but treatment with AVP or the AVPR1B agonist d(Leu4Lys8)VP was able to speed up anemia recovery in mice.

The researchers tested AVP and the AVPR1B agonist in mouse models of hemorrhage. Compared to vehicle-treated mice, AVP-treated mice had an increase in hematocrit and reticulocyte numbers by day 2. Mice that received d(Leu4Lys8)VP only had an increase in reticulocytes.

The team also tested mice exposed to sublethal irradiation. When the mice received AVP for 2 days, they saw increases in hematocrit and corrected reticulocyte numbers.

The researchers then tested splenectomized mice subjected to hemorrhage. AVP-treated mice had an increase in hematocrit that was similar to that observed in non-splenectomized mice.

Finally, the researchers found that AVP’s effect on hematocrit is independent of erythropoietin. The team said AVP “appears to jump-start peripheral blood cell replenishment,” but later, erythropoietin seems to take over.

Photo from RSNA

CHICAGO—There is no evidence to suggest that accumulation of gadolinium in the brain speeds cognitive decline, according to research presented at RSNA 2017, the annual meeting of the Radiological Society of North America.*

Recent studies have revealed that traces of the contrast agent gadolinium can be retained in the brain for years after magnetic resonance imaging (MRI).

Earlier this year, the US Food and Drug Administration recommended cautious use of gadolinium-based contrast agents due to the risk of gadolinium retention in various organs, including the brain.

The European Medicines Agency went a step further, recommending restricting the use of some linear gadolinium agents and suspending the authorization of other agents.

Still, very little is known about the health effects of gadolinium that is retained in the brain.

Robert J. McDonald, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues conducted a study to gain some insight.

The team used the Mayo Clinic Study of Aging (MCSA), the world’s largest prospective population-based cohort on aging, to study the effects of gadolinium exposure on neurologic and neurocognitive function.

All MCSA participants underwent extensive neurologic evaluation and neuropsychological testing at baseline and 15-month follow-up intervals.

The researchers compared neurologic and neurocognitive scores of patients with no history of prior gadolinium exposure and patients who underwent prior MRI with gadolinium-based contrast agents.

The team adjusted their analysis for age, sex, education level, baseline neurocognitive performance, and other factors.

The study included 4261 cognitively normal men and women with a mean age of 72 (range, 50-90). The mean duration of study participation was 3.7 years.

Roughly a quarter of the patients (25.6%, n=1092) had received gadolinium-based contrast agents. These patients received a median of 2 doses (range, 1-28), and the median time since first gadolinium exposure was 5.6 years.

The researchers found that gadolinium exposure was not a significant predictor of cognitive decline, as assessed by changes in clinical dementia rating (P=0.48), Blessed dementia scale (P=0.68), and mental status exam score (P=0.55).

Likewise, gadolinium exposure was not a significant predictor of diminished neuropsychological performance (P=0.13) or diminished motor performance (P=0.43), as assessed by the Unified Parkinson’s Disease Rating Scale.

Finally, gadolinium exposure was not an independent risk factor in the rate of cognitive decline from normal cognitive status to dementia (P=0.91).

“Right now, there is concern over the safety of gadolinium-based contrast agents, particularly relating to gadolinium retention in the brain and other tissues,” Dr McDonald said.

“This study provides useful data that, at the reasonable doses 95% of the population is likely to receive in their lifetime, there is no evidence, at this point, that gadolinium retention in the brain is associated with adverse clinical outcomes.”

*Abstract SSM16-01: Assessment of the Neurologic Effects of Intracranial Gadolinium Deposition Using a Large Population Based Cohort.

Photo from RSNA

CHICAGO—There is no evidence to suggest that accumulation of gadolinium in the brain speeds cognitive decline, according to research presented at RSNA 2017, the annual meeting of the Radiological Society of North America.*

Recent studies have revealed that traces of the contrast agent gadolinium can be retained in the brain for years after magnetic resonance imaging (MRI).

Earlier this year, the US Food and Drug Administration recommended cautious use of gadolinium-based contrast agents due to the risk of gadolinium retention in various organs, including the brain.

The European Medicines Agency went a step further, recommending restricting the use of some linear gadolinium agents and suspending the authorization of other agents.

Still, very little is known about the health effects of gadolinium that is retained in the brain.

Robert J. McDonald, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues conducted a study to gain some insight.

The team used the Mayo Clinic Study of Aging (MCSA), the world’s largest prospective population-based cohort on aging, to study the effects of gadolinium exposure on neurologic and neurocognitive function.

All MCSA participants underwent extensive neurologic evaluation and neuropsychological testing at baseline and 15-month follow-up intervals.

The researchers compared neurologic and neurocognitive scores of patients with no history of prior gadolinium exposure and patients who underwent prior MRI with gadolinium-based contrast agents.

The team adjusted their analysis for age, sex, education level, baseline neurocognitive performance, and other factors.

The study included 4261 cognitively normal men and women with a mean age of 72 (range, 50-90). The mean duration of study participation was 3.7 years.

Roughly a quarter of the patients (25.6%, n=1092) had received gadolinium-based contrast agents. These patients received a median of 2 doses (range, 1-28), and the median time since first gadolinium exposure was 5.6 years.

The researchers found that gadolinium exposure was not a significant predictor of cognitive decline, as assessed by changes in clinical dementia rating (P=0.48), Blessed dementia scale (P=0.68), and mental status exam score (P=0.55).

Likewise, gadolinium exposure was not a significant predictor of diminished neuropsychological performance (P=0.13) or diminished motor performance (P=0.43), as assessed by the Unified Parkinson’s Disease Rating Scale.

Finally, gadolinium exposure was not an independent risk factor in the rate of cognitive decline from normal cognitive status to dementia (P=0.91).

“Right now, there is concern over the safety of gadolinium-based contrast agents, particularly relating to gadolinium retention in the brain and other tissues,” Dr McDonald said.

“This study provides useful data that, at the reasonable doses 95% of the population is likely to receive in their lifetime, there is no evidence, at this point, that gadolinium retention in the brain is associated with adverse clinical outcomes.”

*Abstract SSM16-01: Assessment of the Neurologic Effects of Intracranial Gadolinium Deposition Using a Large Population Based Cohort.

Photo from RSNA

CHICAGO—There is no evidence to suggest that accumulation of gadolinium in the brain speeds cognitive decline, according to research presented at RSNA 2017, the annual meeting of the Radiological Society of North America.*

Recent studies have revealed that traces of the contrast agent gadolinium can be retained in the brain for years after magnetic resonance imaging (MRI).

Earlier this year, the US Food and Drug Administration recommended cautious use of gadolinium-based contrast agents due to the risk of gadolinium retention in various organs, including the brain.

The European Medicines Agency went a step further, recommending restricting the use of some linear gadolinium agents and suspending the authorization of other agents.

Still, very little is known about the health effects of gadolinium that is retained in the brain.

Robert J. McDonald, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, and his colleagues conducted a study to gain some insight.

The team used the Mayo Clinic Study of Aging (MCSA), the world’s largest prospective population-based cohort on aging, to study the effects of gadolinium exposure on neurologic and neurocognitive function.

All MCSA participants underwent extensive neurologic evaluation and neuropsychological testing at baseline and 15-month follow-up intervals.

The researchers compared neurologic and neurocognitive scores of patients with no history of prior gadolinium exposure and patients who underwent prior MRI with gadolinium-based contrast agents.

The team adjusted their analysis for age, sex, education level, baseline neurocognitive performance, and other factors.

The study included 4261 cognitively normal men and women with a mean age of 72 (range, 50-90). The mean duration of study participation was 3.7 years.

Roughly a quarter of the patients (25.6%, n=1092) had received gadolinium-based contrast agents. These patients received a median of 2 doses (range, 1-28), and the median time since first gadolinium exposure was 5.6 years.

The researchers found that gadolinium exposure was not a significant predictor of cognitive decline, as assessed by changes in clinical dementia rating (P=0.48), Blessed dementia scale (P=0.68), and mental status exam score (P=0.55).

Likewise, gadolinium exposure was not a significant predictor of diminished neuropsychological performance (P=0.13) or diminished motor performance (P=0.43), as assessed by the Unified Parkinson’s Disease Rating Scale.

Finally, gadolinium exposure was not an independent risk factor in the rate of cognitive decline from normal cognitive status to dementia (P=0.91).

“Right now, there is concern over the safety of gadolinium-based contrast agents, particularly relating to gadolinium retention in the brain and other tissues,” Dr McDonald said.

“This study provides useful data that, at the reasonable doses 95% of the population is likely to receive in their lifetime, there is no evidence, at this point, that gadolinium retention in the brain is associated with adverse clinical outcomes.”

*Abstract SSM16-01: Assessment of the Neurologic Effects of Intracranial Gadolinium Deposition Using a Large Population Based Cohort.