Bipolar Disorder

Since Freud, the fields of psychiatry, psychology, and psychoanalysis have grappled with trauma and its role in psychopathology. In modern times, these fields remain uncertain about the relative influence that biology, character, and environment play in disordering the lives of traumatized patients. Modern theories try to make sense of early attachment and its impact on development and resiliency. Most bluntly put, why do some soldiers go to war and return seemingly well adapted, while others can not reenter civilian life because the psychic scars are too constricting?

In the psychiatric emergency room, psychiatrists quickly take in multiple, complex facets of a patient’s life in an attempt to assess and judge the patient’s ability to withstand their predicament in the community. Our raw purpose is to assess safety and decide whether the patient needs be committed to a psychiatric inpatient facility. In that assessment, the doctor quickly tries to take in the history, biology, character, and the social milieu of the patient, and judge the degree of risk that patients pose to themselves, their families, and their communities.

The task of the psychiatrist in this job is immense. It is profoundly complicated. It is rich and riddled with considerations. It is not seen so by many in our field, and not by our patients. To patients and the public, we are at worst jailers. To our field, we are at worst crude physicians in a souped-up triage unit.

But think about what we really do. We are surveyors and judges of trauma and character.

Freud knew that sexual abuse and death on the battlefield occurred in his time. He was profoundly struck by both. He created theories to explain these dark experiences. Freud also knew that our deep human psyches contain capacities beyond immediate experience and that one could project and layer fantasy into lived experience. He grappled with the role that fantasy plays in our interpretations of experience. He angered feminists and others because his theoretical changes undermined the role of real trauma and highlighted the role the individual mind plays in repeating trauma.

In the psychiatric ER, we witness the real traumas that weave through patient lives. We often experience these traumas, even to the extent of avoiding certain patients whose realities strike too close to home. This is especially potent for psychiatrists with young children working with patients whose stories and affects stir our worst fears for our own children and families.

We also deal with patients and personalities who seem to seek repeated suffering in the form of both micro- and macrotrauma. We sympathize with the involuntary, victim-bound suffering, and we cringe at and speculate about the conscious and unconscious degrees of self-sabotage on display.

There are several forms of social, political, and historical trauma that are close to home for me and my contemporary American peers that repeatedly come up in patient narratives in the emergency room: racism, sexism, homophobia, and transphobia. In my 41 years of life, I have encountered or experienced all of these forms of oppression, trauma, and microaggressions. I know that they are "real." Many psychiatric ER psychiatrists know that they are real. But in the psych ER, where profound decisions weigh on individual assessment, what is real and what that means becomes relative.

It may be obvious upon arrival that a patient has just suffered a serious physical injury, sexual assault, or severe and obvious abandonment by a loved one. But when patients report histories of such events and a seeming pattern of repeated abuse, we naturally wonder about their perception and their own role in creating self-destructive experiences. Because we have experience and understanding of the human compulsion to repeat even painful life experiences, we are cautiously skeptical when a narrative is full of catastrophe, especially when presented as accidental or without agency.

For instance, even though we know about the depth of racism in our history and its profoundly traumatogenic potential (though this gets little or no attention in formal training!), we must be curious about the meaning an individual attaches to it, and how that meaning may serve or defeat his or her psychological existence and progression across life development.

The same goes for women, gay people, and transgender people who are so exposed and vulnerable to real and perceived physical and emotional trauma and aggression on a daily basis.

How does a person suffer in the moment after an infliction of trauma or aggression? How does a person encode that experience in her character, early in life and later in life? How does it color her experience and interactions? In the comprehensive psychiatric emergency program (CPEP), we must try to answer all these complex questions in what seems like a blink of the eye!

We only see a slice of a person’s life. We focus on the patient’s "history of present illness," the narrative history told in that moment, and the mental status exam. We rely heavily on collateral information to corroborate as much as possible. We use this to measure accuracy and distortion, always holding a skeptical lens against our patient!

While we want to believe our patients and take their histories at face value, we can’t fully do so because we know, instinctively or through training, that fantasy permeates the human mind and transforms meaning. Yet, at the same time, we assess that very idiosyncratic meaning for what it is, because that meaning stays with patients as they move from our ER to the street or the unit. And it is that meaning, embedded in an individual’s coping strategies and character that partly predicts what and how the person will do. It is an inherent consideration of risk and resilience, and we instinctively factor that into our decision making. This is the art of psychiatry at its best.

The CPEP is the frontline of psychiatry. Some residents dislike it because it vibrates with anxiety and responsibility. It is a place in which clinicians tend to come unglued behind the scenes, joking as if at a party, talking loudly and blurting out inane and obscene lines from TV shows and real life. In the back room, the burdened frontline psychiatrists and staff attempt to regain control and wrestle back their own meaning in life, in the face of withstanding traumas, distortions, and psychosis – the delinking of meaning – while rendering verdicts of risk and resilience based in rapid assessments of social, cultural, characterological, and biological factors that make up patient lives.

We swiftly analyze our patients and decide their immediate fate – street, home, unit, extended observation, needles, blood, medications, even visitors and babysitters. We hold them, or we jail them, depending on your view. But we do it with benign and perhaps grandiose intentions to protect, comfort, and quickly "know" them in order to progress them to the next most right place. And we do this almost without knowing that and how we are navigating a delicate and profoundly intricate path of evaluation and decision-making that is uniquely human in its intellectual and emotional nuance.

It is a job full of sharp edges and soft curves, a job that makes a bouncer an analyst and an analyst a bouncer. It is a job never to be reduced to algorithm or computation.

Dr. Pula is a psychiatrist at New York–Presbyterian/Columbia University Medical Center. He also is in private practice and is a psychoanalytic candidate at Columbia.

Since Freud, the fields of psychiatry, psychology, and psychoanalysis have grappled with trauma and its role in psychopathology. In modern times, these fields remain uncertain about the relative influence that biology, character, and environment play in disordering the lives of traumatized patients. Modern theories try to make sense of early attachment and its impact on development and resiliency. Most bluntly put, why do some soldiers go to war and return seemingly well adapted, while others can not reenter civilian life because the psychic scars are too constricting?

In the psychiatric emergency room, psychiatrists quickly take in multiple, complex facets of a patient’s life in an attempt to assess and judge the patient’s ability to withstand their predicament in the community. Our raw purpose is to assess safety and decide whether the patient needs be committed to a psychiatric inpatient facility. In that assessment, the doctor quickly tries to take in the history, biology, character, and the social milieu of the patient, and judge the degree of risk that patients pose to themselves, their families, and their communities.

The task of the psychiatrist in this job is immense. It is profoundly complicated. It is rich and riddled with considerations. It is not seen so by many in our field, and not by our patients. To patients and the public, we are at worst jailers. To our field, we are at worst crude physicians in a souped-up triage unit.

But think about what we really do. We are surveyors and judges of trauma and character.

Freud knew that sexual abuse and death on the battlefield occurred in his time. He was profoundly struck by both. He created theories to explain these dark experiences. Freud also knew that our deep human psyches contain capacities beyond immediate experience and that one could project and layer fantasy into lived experience. He grappled with the role that fantasy plays in our interpretations of experience. He angered feminists and others because his theoretical changes undermined the role of real trauma and highlighted the role the individual mind plays in repeating trauma.

In the psychiatric ER, we witness the real traumas that weave through patient lives. We often experience these traumas, even to the extent of avoiding certain patients whose realities strike too close to home. This is especially potent for psychiatrists with young children working with patients whose stories and affects stir our worst fears for our own children and families.

We also deal with patients and personalities who seem to seek repeated suffering in the form of both micro- and macrotrauma. We sympathize with the involuntary, victim-bound suffering, and we cringe at and speculate about the conscious and unconscious degrees of self-sabotage on display.

There are several forms of social, political, and historical trauma that are close to home for me and my contemporary American peers that repeatedly come up in patient narratives in the emergency room: racism, sexism, homophobia, and transphobia. In my 41 years of life, I have encountered or experienced all of these forms of oppression, trauma, and microaggressions. I know that they are "real." Many psychiatric ER psychiatrists know that they are real. But in the psych ER, where profound decisions weigh on individual assessment, what is real and what that means becomes relative.

It may be obvious upon arrival that a patient has just suffered a serious physical injury, sexual assault, or severe and obvious abandonment by a loved one. But when patients report histories of such events and a seeming pattern of repeated abuse, we naturally wonder about their perception and their own role in creating self-destructive experiences. Because we have experience and understanding of the human compulsion to repeat even painful life experiences, we are cautiously skeptical when a narrative is full of catastrophe, especially when presented as accidental or without agency.

For instance, even though we know about the depth of racism in our history and its profoundly traumatogenic potential (though this gets little or no attention in formal training!), we must be curious about the meaning an individual attaches to it, and how that meaning may serve or defeat his or her psychological existence and progression across life development.

The same goes for women, gay people, and transgender people who are so exposed and vulnerable to real and perceived physical and emotional trauma and aggression on a daily basis.

How does a person suffer in the moment after an infliction of trauma or aggression? How does a person encode that experience in her character, early in life and later in life? How does it color her experience and interactions? In the comprehensive psychiatric emergency program (CPEP), we must try to answer all these complex questions in what seems like a blink of the eye!

We only see a slice of a person’s life. We focus on the patient’s "history of present illness," the narrative history told in that moment, and the mental status exam. We rely heavily on collateral information to corroborate as much as possible. We use this to measure accuracy and distortion, always holding a skeptical lens against our patient!

While we want to believe our patients and take their histories at face value, we can’t fully do so because we know, instinctively or through training, that fantasy permeates the human mind and transforms meaning. Yet, at the same time, we assess that very idiosyncratic meaning for what it is, because that meaning stays with patients as they move from our ER to the street or the unit. And it is that meaning, embedded in an individual’s coping strategies and character that partly predicts what and how the person will do. It is an inherent consideration of risk and resilience, and we instinctively factor that into our decision making. This is the art of psychiatry at its best.

The CPEP is the frontline of psychiatry. Some residents dislike it because it vibrates with anxiety and responsibility. It is a place in which clinicians tend to come unglued behind the scenes, joking as if at a party, talking loudly and blurting out inane and obscene lines from TV shows and real life. In the back room, the burdened frontline psychiatrists and staff attempt to regain control and wrestle back their own meaning in life, in the face of withstanding traumas, distortions, and psychosis – the delinking of meaning – while rendering verdicts of risk and resilience based in rapid assessments of social, cultural, characterological, and biological factors that make up patient lives.

We swiftly analyze our patients and decide their immediate fate – street, home, unit, extended observation, needles, blood, medications, even visitors and babysitters. We hold them, or we jail them, depending on your view. But we do it with benign and perhaps grandiose intentions to protect, comfort, and quickly "know" them in order to progress them to the next most right place. And we do this almost without knowing that and how we are navigating a delicate and profoundly intricate path of evaluation and decision-making that is uniquely human in its intellectual and emotional nuance.

It is a job full of sharp edges and soft curves, a job that makes a bouncer an analyst and an analyst a bouncer. It is a job never to be reduced to algorithm or computation.

Dr. Pula is a psychiatrist at New York–Presbyterian/Columbia University Medical Center. He also is in private practice and is a psychoanalytic candidate at Columbia.

Since Freud, the fields of psychiatry, psychology, and psychoanalysis have grappled with trauma and its role in psychopathology. In modern times, these fields remain uncertain about the relative influence that biology, character, and environment play in disordering the lives of traumatized patients. Modern theories try to make sense of early attachment and its impact on development and resiliency. Most bluntly put, why do some soldiers go to war and return seemingly well adapted, while others can not reenter civilian life because the psychic scars are too constricting?

In the psychiatric emergency room, psychiatrists quickly take in multiple, complex facets of a patient’s life in an attempt to assess and judge the patient’s ability to withstand their predicament in the community. Our raw purpose is to assess safety and decide whether the patient needs be committed to a psychiatric inpatient facility. In that assessment, the doctor quickly tries to take in the history, biology, character, and the social milieu of the patient, and judge the degree of risk that patients pose to themselves, their families, and their communities.

The task of the psychiatrist in this job is immense. It is profoundly complicated. It is rich and riddled with considerations. It is not seen so by many in our field, and not by our patients. To patients and the public, we are at worst jailers. To our field, we are at worst crude physicians in a souped-up triage unit.

But think about what we really do. We are surveyors and judges of trauma and character.

Freud knew that sexual abuse and death on the battlefield occurred in his time. He was profoundly struck by both. He created theories to explain these dark experiences. Freud also knew that our deep human psyches contain capacities beyond immediate experience and that one could project and layer fantasy into lived experience. He grappled with the role that fantasy plays in our interpretations of experience. He angered feminists and others because his theoretical changes undermined the role of real trauma and highlighted the role the individual mind plays in repeating trauma.

In the psychiatric ER, we witness the real traumas that weave through patient lives. We often experience these traumas, even to the extent of avoiding certain patients whose realities strike too close to home. This is especially potent for psychiatrists with young children working with patients whose stories and affects stir our worst fears for our own children and families.

We also deal with patients and personalities who seem to seek repeated suffering in the form of both micro- and macrotrauma. We sympathize with the involuntary, victim-bound suffering, and we cringe at and speculate about the conscious and unconscious degrees of self-sabotage on display.

There are several forms of social, political, and historical trauma that are close to home for me and my contemporary American peers that repeatedly come up in patient narratives in the emergency room: racism, sexism, homophobia, and transphobia. In my 41 years of life, I have encountered or experienced all of these forms of oppression, trauma, and microaggressions. I know that they are "real." Many psychiatric ER psychiatrists know that they are real. But in the psych ER, where profound decisions weigh on individual assessment, what is real and what that means becomes relative.

It may be obvious upon arrival that a patient has just suffered a serious physical injury, sexual assault, or severe and obvious abandonment by a loved one. But when patients report histories of such events and a seeming pattern of repeated abuse, we naturally wonder about their perception and their own role in creating self-destructive experiences. Because we have experience and understanding of the human compulsion to repeat even painful life experiences, we are cautiously skeptical when a narrative is full of catastrophe, especially when presented as accidental or without agency.

For instance, even though we know about the depth of racism in our history and its profoundly traumatogenic potential (though this gets little or no attention in formal training!), we must be curious about the meaning an individual attaches to it, and how that meaning may serve or defeat his or her psychological existence and progression across life development.

The same goes for women, gay people, and transgender people who are so exposed and vulnerable to real and perceived physical and emotional trauma and aggression on a daily basis.

How does a person suffer in the moment after an infliction of trauma or aggression? How does a person encode that experience in her character, early in life and later in life? How does it color her experience and interactions? In the comprehensive psychiatric emergency program (CPEP), we must try to answer all these complex questions in what seems like a blink of the eye!

We only see a slice of a person’s life. We focus on the patient’s "history of present illness," the narrative history told in that moment, and the mental status exam. We rely heavily on collateral information to corroborate as much as possible. We use this to measure accuracy and distortion, always holding a skeptical lens against our patient!

While we want to believe our patients and take their histories at face value, we can’t fully do so because we know, instinctively or through training, that fantasy permeates the human mind and transforms meaning. Yet, at the same time, we assess that very idiosyncratic meaning for what it is, because that meaning stays with patients as they move from our ER to the street or the unit. And it is that meaning, embedded in an individual’s coping strategies and character that partly predicts what and how the person will do. It is an inherent consideration of risk and resilience, and we instinctively factor that into our decision making. This is the art of psychiatry at its best.

The CPEP is the frontline of psychiatry. Some residents dislike it because it vibrates with anxiety and responsibility. It is a place in which clinicians tend to come unglued behind the scenes, joking as if at a party, talking loudly and blurting out inane and obscene lines from TV shows and real life. In the back room, the burdened frontline psychiatrists and staff attempt to regain control and wrestle back their own meaning in life, in the face of withstanding traumas, distortions, and psychosis – the delinking of meaning – while rendering verdicts of risk and resilience based in rapid assessments of social, cultural, characterological, and biological factors that make up patient lives.

We swiftly analyze our patients and decide their immediate fate – street, home, unit, extended observation, needles, blood, medications, even visitors and babysitters. We hold them, or we jail them, depending on your view. But we do it with benign and perhaps grandiose intentions to protect, comfort, and quickly "know" them in order to progress them to the next most right place. And we do this almost without knowing that and how we are navigating a delicate and profoundly intricate path of evaluation and decision-making that is uniquely human in its intellectual and emotional nuance.

It is a job full of sharp edges and soft curves, a job that makes a bouncer an analyst and an analyst a bouncer. It is a job never to be reduced to algorithm or computation.

Dr. Pula is a psychiatrist at New York–Presbyterian/Columbia University Medical Center. He also is in private practice and is a psychoanalytic candidate at Columbia.

SAN FRANCISCO – Childhood neglect correlated with impaired capacity for close social relationships as an adult in a study of 114 nonpsychotic psychiatric inpatients.

The difficulty for patients with a history of childhood neglect centered more in maintaining than in starting close social relationships as adults, Thachell Tanis and Lisa J. Cohen, Ph.D., reported in a press briefing and a poster presentation at the annual meeting of the American Psychiatric Association.

The study used separate clinical self-report surveys to assess patients’ childhood histories and adult relational capacity. The Multidimensional Neglectful Behavior Scale assessed emotional, physical, cognitive, and supervisory neglect in the patients’ past. Patients also completed the relational domain of the Severity Indices of Personality Problems to assess capacity for intimacy or enduring relationships and the ability to feel recognized in relationships.

Each type of neglect significantly and negatively affected each facet in the relational domain. "Everything correlated with everything," said Ms. Tanis, a doctoral student at City College of New York.

The deficits were most striking in patients’ capacity for enduring relationships, said Dr. Cohen, professor of clinical psychiatry and behavioral sciences at Albert Einstein College of Medicine, New York. Childhood neglect as a whole, for example, correlated with an 81% greater negative effect on adult capacity for enduring relationships, compared with the negative effect on capacity for intimacy.

The cohort was 57% female, with a mean age of 39 years. Psychiatric diagnoses included depression in 55%, substance use disorder in 20%, bipolar disorder in 12%, anxiety in 10%, psychosis in 1%, and other diagnoses in 3%. The cohort was 44% white, 28% Hispanic, 16% black, 6% multiracial, 5% Asian, and 2% other ethnicities. The percentages total more than 100% because of rounding.

Prior studies have well documented the adverse effects of more dramatic forms of childhood maltreatment. Physical and sexual abuses in childhood, for example, have been associated with adult depression, eating disorders, and personality disorders, Dr. Cohen said. Only in recent years have mental health providers recognized the importance of less dramatic forms of childhood maltreatment, such as emotional abuse and neglect, and begun to study those issues.

The topic deserves further exploration, she added, because identifying these impairments in people with histories of childhood neglect might lead to better case conceptualization and possibly better treatment.

"You really do want to pay attention to your patients’ history of childhood neglect," Dr. Cohen said. "There may be more subtle types of maltreatment that have pernicious effects over time." If there is a history of neglect in childhood, pay attention not only to the patient’s ability to engage in relationships but the ability to maintain such relationships over time, she added.

The study was limited by using retrospective, self-report measures and its focus on inpatients, which might restrict the generalizability of the results.

The investigators reported having no financial disclosures.

[email protected]

On Twitter @sherryboschert

SAN FRANCISCO – Childhood neglect correlated with impaired capacity for close social relationships as an adult in a study of 114 nonpsychotic psychiatric inpatients.

The difficulty for patients with a history of childhood neglect centered more in maintaining than in starting close social relationships as adults, Thachell Tanis and Lisa J. Cohen, Ph.D., reported in a press briefing and a poster presentation at the annual meeting of the American Psychiatric Association.

The study used separate clinical self-report surveys to assess patients’ childhood histories and adult relational capacity. The Multidimensional Neglectful Behavior Scale assessed emotional, physical, cognitive, and supervisory neglect in the patients’ past. Patients also completed the relational domain of the Severity Indices of Personality Problems to assess capacity for intimacy or enduring relationships and the ability to feel recognized in relationships.

Each type of neglect significantly and negatively affected each facet in the relational domain. "Everything correlated with everything," said Ms. Tanis, a doctoral student at City College of New York.

The deficits were most striking in patients’ capacity for enduring relationships, said Dr. Cohen, professor of clinical psychiatry and behavioral sciences at Albert Einstein College of Medicine, New York. Childhood neglect as a whole, for example, correlated with an 81% greater negative effect on adult capacity for enduring relationships, compared with the negative effect on capacity for intimacy.

The cohort was 57% female, with a mean age of 39 years. Psychiatric diagnoses included depression in 55%, substance use disorder in 20%, bipolar disorder in 12%, anxiety in 10%, psychosis in 1%, and other diagnoses in 3%. The cohort was 44% white, 28% Hispanic, 16% black, 6% multiracial, 5% Asian, and 2% other ethnicities. The percentages total more than 100% because of rounding.

Prior studies have well documented the adverse effects of more dramatic forms of childhood maltreatment. Physical and sexual abuses in childhood, for example, have been associated with adult depression, eating disorders, and personality disorders, Dr. Cohen said. Only in recent years have mental health providers recognized the importance of less dramatic forms of childhood maltreatment, such as emotional abuse and neglect, and begun to study those issues.

The topic deserves further exploration, she added, because identifying these impairments in people with histories of childhood neglect might lead to better case conceptualization and possibly better treatment.

"You really do want to pay attention to your patients’ history of childhood neglect," Dr. Cohen said. "There may be more subtle types of maltreatment that have pernicious effects over time." If there is a history of neglect in childhood, pay attention not only to the patient’s ability to engage in relationships but the ability to maintain such relationships over time, she added.

The study was limited by using retrospective, self-report measures and its focus on inpatients, which might restrict the generalizability of the results.

The investigators reported having no financial disclosures.

[email protected]

On Twitter @sherryboschert

SAN FRANCISCO – Childhood neglect correlated with impaired capacity for close social relationships as an adult in a study of 114 nonpsychotic psychiatric inpatients.

The difficulty for patients with a history of childhood neglect centered more in maintaining than in starting close social relationships as adults, Thachell Tanis and Lisa J. Cohen, Ph.D., reported in a press briefing and a poster presentation at the annual meeting of the American Psychiatric Association.

The study used separate clinical self-report surveys to assess patients’ childhood histories and adult relational capacity. The Multidimensional Neglectful Behavior Scale assessed emotional, physical, cognitive, and supervisory neglect in the patients’ past. Patients also completed the relational domain of the Severity Indices of Personality Problems to assess capacity for intimacy or enduring relationships and the ability to feel recognized in relationships.

Each type of neglect significantly and negatively affected each facet in the relational domain. "Everything correlated with everything," said Ms. Tanis, a doctoral student at City College of New York.

The deficits were most striking in patients’ capacity for enduring relationships, said Dr. Cohen, professor of clinical psychiatry and behavioral sciences at Albert Einstein College of Medicine, New York. Childhood neglect as a whole, for example, correlated with an 81% greater negative effect on adult capacity for enduring relationships, compared with the negative effect on capacity for intimacy.

The cohort was 57% female, with a mean age of 39 years. Psychiatric diagnoses included depression in 55%, substance use disorder in 20%, bipolar disorder in 12%, anxiety in 10%, psychosis in 1%, and other diagnoses in 3%. The cohort was 44% white, 28% Hispanic, 16% black, 6% multiracial, 5% Asian, and 2% other ethnicities. The percentages total more than 100% because of rounding.

Prior studies have well documented the adverse effects of more dramatic forms of childhood maltreatment. Physical and sexual abuses in childhood, for example, have been associated with adult depression, eating disorders, and personality disorders, Dr. Cohen said. Only in recent years have mental health providers recognized the importance of less dramatic forms of childhood maltreatment, such as emotional abuse and neglect, and begun to study those issues.

The topic deserves further exploration, she added, because identifying these impairments in people with histories of childhood neglect might lead to better case conceptualization and possibly better treatment.

"You really do want to pay attention to your patients’ history of childhood neglect," Dr. Cohen said. "There may be more subtle types of maltreatment that have pernicious effects over time." If there is a history of neglect in childhood, pay attention not only to the patient’s ability to engage in relationships but the ability to maintain such relationships over time, she added.

The study was limited by using retrospective, self-report measures and its focus on inpatients, which might restrict the generalizability of the results.

The investigators reported having no financial disclosures.

[email protected]

On Twitter @sherryboschert

A behavioral weight-loss intervention significantly reduced excess weight in adults who had serious mental illness, according to a study published online March 21 in the New England Journal of Medicine.

This intervention, which was specifically tailored to the needs of people with mental illness, allowed steady weight loss that progressed over the 18-month duration of the study. In contrast, most studies of lifestyle interventions in the general population show an early peak in weight loss, often followed by weight regain.

These findings suggest that "despite substantial challenges, persons with serious mental illness are able to lose weight with a tailored intervention," said Dr. Gail L. Daumit of the Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, and her associates.

Courtesy of National Cancer Institute

The prevalence of obesity is nearly twice as high among people with serious mental illness as among the general population. Mortality is two to three times higher, and cardiovascular disease is the primary cause of death in the seriously mentally ill.

Several factors contribute to this high prevalence. Unhealthy diets and physical inactivity are common in this patient population, and many psychotropic medications cause weight gain. Given their often low socioeconomic status, many people with serious mental illness also have reduced access to healthier, more-expensive foods and to safe, affordable places to exercise.

In addition, the stigma associated with mental illness also might make patients reluctant to participate in mainstream physical activities. And many have impairments in memory and executive function as well as psychiatric symptoms that "impede learning and the adoption of new behaviors," said Dr. Daumit, who also is affiliated with Johns Hopkins Bloomberg School of Public Health, and her colleagues.

They tested the effectiveness of an intervention that addressed these needs in the ACHIEVE (Achieving Healthy Lifestyles in Psychiatric Rehabilitation) clinical trial. The trial involved 291 overweight or obese adults who were participating in seven community outpatient psychiatric rehabilitation programs.

Such programs typically offer vocational and skills training, case management, and other services to the mentally ill; they usually have commercial kitchens that provide meals and snacks, as well as communal spaces suitable for group exercise.

"Program enrollees often attend these programs multiple times each week, which facilitates the delivery of lifestyle interventions that involve frequent contact," the researchers said (N. Engl. J. Med. 2013 March 21 [doi:10.1056/NEJMoa1214530]).

A total of 144 study subjects were randomly assigned to receive the intervention and 147 to a control group that received no intervention. The mean subject age was 45 years. Approximately half of the subjects were men, and 38% were black.

Nearly 80% of the study population was unable to work. A total of 58% had schizophrenia or schizoaffective disorder, 22% had bipolar disorder, and 12% had major depression. Patients were taking a mean of three psychotropic medications each.

The intervention addressed deficits in memory and executive function by dividing information into small components and by frequently repeating practice of skills.

Group and individual weight-management sessions focused on cutting caloric intake, especially by avoiding sugary drinks and junk food; consuming five servings of fruits and vegetables every day; controlling portion size; and eating healthy snacks.

Group exercise sessions focused on moderate-intensity aerobic exercise that gradually increased in duration and intensity.

The mean net weight loss increased over time only for patients who participated in the intervention. This loss was 1.8 kg at 6 months, and 3.4 kg at the completion of the trial. Although modest, this amount "compares favorably with weight loss in lifestyle-intervention trials in the general population" and has been associated with benefits such as reducing the risk of cardiovascular disease, Dr. Daumit and her associates said.

Participants in the intervention group continued to lose weight after 6 months and did not regain any weight, even when they attended fewer weight-management and exercise sessions over time. "One possible explanation is that persons with serious mental illness take longer than those without serious mental illness to engage in an intervention and make requisite behavioral changes," the investigators said.

"Our results show that overweight and obese adults with serious mental illness can make substantial lifestyle changes despite the myriad challenges they face," and that similar interventions should be implemented for this high-risk population, they added.

The study was funded by the National Institute of Mental Health. No conflicts of interest were reported.

A behavioral weight-loss intervention significantly reduced excess weight in adults who had serious mental illness, according to a study published online March 21 in the New England Journal of Medicine.

This intervention, which was specifically tailored to the needs of people with mental illness, allowed steady weight loss that progressed over the 18-month duration of the study. In contrast, most studies of lifestyle interventions in the general population show an early peak in weight loss, often followed by weight regain.

These findings suggest that "despite substantial challenges, persons with serious mental illness are able to lose weight with a tailored intervention," said Dr. Gail L. Daumit of the Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, and her associates.

Courtesy of National Cancer Institute

The prevalence of obesity is nearly twice as high among people with serious mental illness as among the general population. Mortality is two to three times higher, and cardiovascular disease is the primary cause of death in the seriously mentally ill.

Several factors contribute to this high prevalence. Unhealthy diets and physical inactivity are common in this patient population, and many psychotropic medications cause weight gain. Given their often low socioeconomic status, many people with serious mental illness also have reduced access to healthier, more-expensive foods and to safe, affordable places to exercise.

In addition, the stigma associated with mental illness also might make patients reluctant to participate in mainstream physical activities. And many have impairments in memory and executive function as well as psychiatric symptoms that "impede learning and the adoption of new behaviors," said Dr. Daumit, who also is affiliated with Johns Hopkins Bloomberg School of Public Health, and her colleagues.

They tested the effectiveness of an intervention that addressed these needs in the ACHIEVE (Achieving Healthy Lifestyles in Psychiatric Rehabilitation) clinical trial. The trial involved 291 overweight or obese adults who were participating in seven community outpatient psychiatric rehabilitation programs.

Such programs typically offer vocational and skills training, case management, and other services to the mentally ill; they usually have commercial kitchens that provide meals and snacks, as well as communal spaces suitable for group exercise.

"Program enrollees often attend these programs multiple times each week, which facilitates the delivery of lifestyle interventions that involve frequent contact," the researchers said (N. Engl. J. Med. 2013 March 21 [doi:10.1056/NEJMoa1214530]).

A total of 144 study subjects were randomly assigned to receive the intervention and 147 to a control group that received no intervention. The mean subject age was 45 years. Approximately half of the subjects were men, and 38% were black.

Nearly 80% of the study population was unable to work. A total of 58% had schizophrenia or schizoaffective disorder, 22% had bipolar disorder, and 12% had major depression. Patients were taking a mean of three psychotropic medications each.

The intervention addressed deficits in memory and executive function by dividing information into small components and by frequently repeating practice of skills.

Group and individual weight-management sessions focused on cutting caloric intake, especially by avoiding sugary drinks and junk food; consuming five servings of fruits and vegetables every day; controlling portion size; and eating healthy snacks.

Group exercise sessions focused on moderate-intensity aerobic exercise that gradually increased in duration and intensity.

The mean net weight loss increased over time only for patients who participated in the intervention. This loss was 1.8 kg at 6 months, and 3.4 kg at the completion of the trial. Although modest, this amount "compares favorably with weight loss in lifestyle-intervention trials in the general population" and has been associated with benefits such as reducing the risk of cardiovascular disease, Dr. Daumit and her associates said.

Participants in the intervention group continued to lose weight after 6 months and did not regain any weight, even when they attended fewer weight-management and exercise sessions over time. "One possible explanation is that persons with serious mental illness take longer than those without serious mental illness to engage in an intervention and make requisite behavioral changes," the investigators said.

"Our results show that overweight and obese adults with serious mental illness can make substantial lifestyle changes despite the myriad challenges they face," and that similar interventions should be implemented for this high-risk population, they added.

The study was funded by the National Institute of Mental Health. No conflicts of interest were reported.

A behavioral weight-loss intervention significantly reduced excess weight in adults who had serious mental illness, according to a study published online March 21 in the New England Journal of Medicine.

This intervention, which was specifically tailored to the needs of people with mental illness, allowed steady weight loss that progressed over the 18-month duration of the study. In contrast, most studies of lifestyle interventions in the general population show an early peak in weight loss, often followed by weight regain.

These findings suggest that "despite substantial challenges, persons with serious mental illness are able to lose weight with a tailored intervention," said Dr. Gail L. Daumit of the Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, and her associates.

Courtesy of National Cancer Institute

The prevalence of obesity is nearly twice as high among people with serious mental illness as among the general population. Mortality is two to three times higher, and cardiovascular disease is the primary cause of death in the seriously mentally ill.

Several factors contribute to this high prevalence. Unhealthy diets and physical inactivity are common in this patient population, and many psychotropic medications cause weight gain. Given their often low socioeconomic status, many people with serious mental illness also have reduced access to healthier, more-expensive foods and to safe, affordable places to exercise.

In addition, the stigma associated with mental illness also might make patients reluctant to participate in mainstream physical activities. And many have impairments in memory and executive function as well as psychiatric symptoms that "impede learning and the adoption of new behaviors," said Dr. Daumit, who also is affiliated with Johns Hopkins Bloomberg School of Public Health, and her colleagues.

They tested the effectiveness of an intervention that addressed these needs in the ACHIEVE (Achieving Healthy Lifestyles in Psychiatric Rehabilitation) clinical trial. The trial involved 291 overweight or obese adults who were participating in seven community outpatient psychiatric rehabilitation programs.

Such programs typically offer vocational and skills training, case management, and other services to the mentally ill; they usually have commercial kitchens that provide meals and snacks, as well as communal spaces suitable for group exercise.

"Program enrollees often attend these programs multiple times each week, which facilitates the delivery of lifestyle interventions that involve frequent contact," the researchers said (N. Engl. J. Med. 2013 March 21 [doi:10.1056/NEJMoa1214530]).

A total of 144 study subjects were randomly assigned to receive the intervention and 147 to a control group that received no intervention. The mean subject age was 45 years. Approximately half of the subjects were men, and 38% were black.

Nearly 80% of the study population was unable to work. A total of 58% had schizophrenia or schizoaffective disorder, 22% had bipolar disorder, and 12% had major depression. Patients were taking a mean of three psychotropic medications each.

The intervention addressed deficits in memory and executive function by dividing information into small components and by frequently repeating practice of skills.

Group and individual weight-management sessions focused on cutting caloric intake, especially by avoiding sugary drinks and junk food; consuming five servings of fruits and vegetables every day; controlling portion size; and eating healthy snacks.

Group exercise sessions focused on moderate-intensity aerobic exercise that gradually increased in duration and intensity.

The mean net weight loss increased over time only for patients who participated in the intervention. This loss was 1.8 kg at 6 months, and 3.4 kg at the completion of the trial. Although modest, this amount "compares favorably with weight loss in lifestyle-intervention trials in the general population" and has been associated with benefits such as reducing the risk of cardiovascular disease, Dr. Daumit and her associates said.

Participants in the intervention group continued to lose weight after 6 months and did not regain any weight, even when they attended fewer weight-management and exercise sessions over time. "One possible explanation is that persons with serious mental illness take longer than those without serious mental illness to engage in an intervention and make requisite behavioral changes," the investigators said.

"Our results show that overweight and obese adults with serious mental illness can make substantial lifestyle changes despite the myriad challenges they face," and that similar interventions should be implemented for this high-risk population, they added.

The study was funded by the National Institute of Mental Health. No conflicts of interest were reported.

Hospital stays for bipolar disorder among children aged 1-17 years increased 434% from 1997 to 2010, the Agency for Healthcare Research and Quality reported.

In 2010, the rate of bipolar stays in children under age 18 was 8.2 per 10,000 population, compared with 1.5 per 10,000 in 1997, with the increase occurring in all ages, the AHRQ said.

The admission rate in children aged 5-9 years went from 0.4 to 3.2 per 10,000, an increase of 696%. Among children 10-14 years old, the rate was 2.0/10,000 in 1997 and 11.2/10,000 in 2010, an increase of 475%. The bipolar admission rate for those aged 15-17 years rose 345%, going from 4.8/10,000 in 1997 to 21.1/10,000 in 2010, according to the report.

In 2010, bipolar disorder accounted for 48% of hospital stays for mood disorders in children, compared with 16% in 1997, the AHRQ said.

[email protected]

Hospital stays for bipolar disorder among children aged 1-17 years increased 434% from 1997 to 2010, the Agency for Healthcare Research and Quality reported.

In 2010, the rate of bipolar stays in children under age 18 was 8.2 per 10,000 population, compared with 1.5 per 10,000 in 1997, with the increase occurring in all ages, the AHRQ said.

The admission rate in children aged 5-9 years went from 0.4 to 3.2 per 10,000, an increase of 696%. Among children 10-14 years old, the rate was 2.0/10,000 in 1997 and 11.2/10,000 in 2010, an increase of 475%. The bipolar admission rate for those aged 15-17 years rose 345%, going from 4.8/10,000 in 1997 to 21.1/10,000 in 2010, according to the report.

In 2010, bipolar disorder accounted for 48% of hospital stays for mood disorders in children, compared with 16% in 1997, the AHRQ said.

[email protected]

Hospital stays for bipolar disorder among children aged 1-17 years increased 434% from 1997 to 2010, the Agency for Healthcare Research and Quality reported.

In 2010, the rate of bipolar stays in children under age 18 was 8.2 per 10,000 population, compared with 1.5 per 10,000 in 1997, with the increase occurring in all ages, the AHRQ said.

The admission rate in children aged 5-9 years went from 0.4 to 3.2 per 10,000, an increase of 696%. Among children 10-14 years old, the rate was 2.0/10,000 in 1997 and 11.2/10,000 in 2010, an increase of 475%. The bipolar admission rate for those aged 15-17 years rose 345%, going from 4.8/10,000 in 1997 to 21.1/10,000 in 2010, according to the report.

In 2010, bipolar disorder accounted for 48% of hospital stays for mood disorders in children, compared with 16% in 1997, the AHRQ said.

[email protected]

A mountain of evidence indicates that psychosis and bipolar disorder (BD) are brain disorders with an array of thought, mood, cognition, and behavioral aberrations.

Yet the clinical assessment of those neuropsychiatric disorders predominantly is restricted to evaluating mental and behavioral signs and symptoms. It’s time we comprehensively assess our psychiatric patients’ brains, not just describe their minds. This is the only way we can eventually identify the roots of serious mental illness and develop accurate and effective therapeutic interventions and preventions.

Consider the following brain probes, measures, and assessments that are rarely done in patients with first-episode schizophrenia, BD, or major depression. These clinical and technological cerebral evaluation methods all are available and feasible and are being routinely exploited in neurology and other medical specialties. Not using them represents missed opportunities to advance the scientific underpinnings of psychiatric diagnosis and treatment.

Complete neurologic examination, including cranial nerves, motor functions, sensory status, reflexes (including primitive reflexes), and soft neurologic signs. Psychiatrists rarely perform such examinations, although they can easily relearn and incorporate them in their critical initial assessment of severe psychiatric episodes. Researchers have identified many neurologic findings in drug-naïve psychotic patients before they receive medications in whom adverse effects may mask or add to motor or sensory abnormalities.

Neurocognitive testing. An extensive body of literature has definitively demonstrated severe cognitive deficits across multiple domains in schizophrenia, BD, and major depression. Yet, inexplicably, few first-episode patients are assessed with a standard battery of tests for memory, attention, visuospatial skills, or executive functions in clinical practice. Cognitive deficits are a product of abnormal neural pathways and neurocognitive tests can provide tremendous insight into regional and overall brain functions and provide clues for etiopathology and a road map for rehabilitation.

Neuroimaging. Multiple sophisticated techniques to assess brain structure and function are used in research but rarely in clinical practice. These include:

Morphological MRI,, which can provide exquisitely detailed anatomical information about cortical and subcortical structures. This can help identify lesions that cause mania, schizophrenia-like disorders, or depression secondary to a brain pathology. Even if no lesion is found, the pattern of atrophy, hypertrophy, ectopic gray matter, or hyperplasia can help identify subtypes of heterogeneous psychotic and mood disorders, and may lead to a specific diagnosis and treatment.

Magnetic resonance spectroscopy (MRS) is essentially a living biopsy of the brain in any region, detailing the spectrum and amount of various neurochemical substances (such as glutamine, γ-aminobutyric acid, creatine, N-acetylaspartic acid, or lactate) using proton spectroscopy, high energy phosphates such as adenosine diphosphate (ADP) or adenosine triphosphate (ATP) or membrane breakdown products (such as phosphomonoester and phosphodiester) using phosphorous MRS. Researchers are gradually “mapping” the regional chemistry of the brain in health and disease, which may provide profound insights for understanding the neurobiology of serious mental disorders.

Functional MRI, which can display the underactivation or overactivation of various brain regions at rest or while experiencing severe symptoms such as hallucinations or melancholia or while performing a cognitive task. Significant insights about brain pathways can be gleaned from this test.

Diffusion tensor imaging (DTI), which can assess myelin integrity and provide critical data about white matter tract pathology and intra- and inter-hemispheric disconnectivity. Pathological myelin findings in psychotic and mood disorders already are prompting novel treatments for these disabling brain illnesses.

Cerebrospinal fluid (CSF) examination. Psychiatrists rarely perform lumbar punctures (LP) in first-episode patients, although psychotic or bipolar disorders are as severe and disabling as multiple sclerosis or meningitis, where an LP is routine. This longstanding omission is the result of the antiquated notion that CSF in psychiatric patients is not abnormal and uninformative. But the fact is that CSF in patients with psychotic or mood disorders may contain many recently discovered biomarkers that shed light on the tremendous neurochemical changes during an acute psychotic, manic, or depressive episode. So the focus in psychiatry is not simply on red blood cells, white blood cells, glucose levels, or proteins, as in a routine LP, but on the emerging biomarkers of brain pathologies that have been implicated in the psychotic and mood disorders, including:

• inflammatory signaling and biomarkers (such as cytokines, interleukins, TNF-α)
• apoptotic (such as caspase-3, Fas, ARTS) and anti-apoptotic proteins (Bcl-2)
• neurotropic (growth) factor (such as BDNF, NGF, VEGF)
• oxidative stress biomarkers (such as TBARS, TRAP, PCC, SOD, and TAOP)
• myelin byproducts (such as S100B, oligodendrocytic proteins)
• glutamate/glutamine abnormalities
• lipodomic aberrations
• metabolomic profiles
• mitochondrial deficits (such as low glutathione and GPX)
• immunoglobulins (such as IgG, IgM).

If CSF analysis is done routinely, unprecedented discoveries can be made about the nature of brain pathologies and potential diagnostic biomarkers in various subtypes of serious psychiatric disorders, leading to specific and personalized treatments.

It’s time that we go beyond the current descriptive approach that includes a brief mental status exam. We must conduct a comprehensive investigation of our patients’ abnormal brains, which are responsible for their anomalous minds and impaired functioning. It’s time to capitalize on the amazing neuroscience advances to understand our patients’ brains. It’s time that we employ translational psychiatry to guide our diagnosis and treatment of severe mental disorders.

A mountain of evidence indicates that psychosis and bipolar disorder (BD) are brain disorders with an array of thought, mood, cognition, and behavioral aberrations.

Yet the clinical assessment of those neuropsychiatric disorders predominantly is restricted to evaluating mental and behavioral signs and symptoms. It’s time we comprehensively assess our psychiatric patients’ brains, not just describe their minds. This is the only way we can eventually identify the roots of serious mental illness and develop accurate and effective therapeutic interventions and preventions.

Consider the following brain probes, measures, and assessments that are rarely done in patients with first-episode schizophrenia, BD, or major depression. These clinical and technological cerebral evaluation methods all are available and feasible and are being routinely exploited in neurology and other medical specialties. Not using them represents missed opportunities to advance the scientific underpinnings of psychiatric diagnosis and treatment.

Complete neurologic examination, including cranial nerves, motor functions, sensory status, reflexes (including primitive reflexes), and soft neurologic signs. Psychiatrists rarely perform such examinations, although they can easily relearn and incorporate them in their critical initial assessment of severe psychiatric episodes. Researchers have identified many neurologic findings in drug-naïve psychotic patients before they receive medications in whom adverse effects may mask or add to motor or sensory abnormalities.

Neurocognitive testing. An extensive body of literature has definitively demonstrated severe cognitive deficits across multiple domains in schizophrenia, BD, and major depression. Yet, inexplicably, few first-episode patients are assessed with a standard battery of tests for memory, attention, visuospatial skills, or executive functions in clinical practice. Cognitive deficits are a product of abnormal neural pathways and neurocognitive tests can provide tremendous insight into regional and overall brain functions and provide clues for etiopathology and a road map for rehabilitation.

Neuroimaging. Multiple sophisticated techniques to assess brain structure and function are used in research but rarely in clinical practice. These include:

Morphological MRI,, which can provide exquisitely detailed anatomical information about cortical and subcortical structures. This can help identify lesions that cause mania, schizophrenia-like disorders, or depression secondary to a brain pathology. Even if no lesion is found, the pattern of atrophy, hypertrophy, ectopic gray matter, or hyperplasia can help identify subtypes of heterogeneous psychotic and mood disorders, and may lead to a specific diagnosis and treatment.

Magnetic resonance spectroscopy (MRS) is essentially a living biopsy of the brain in any region, detailing the spectrum and amount of various neurochemical substances (such as glutamine, γ-aminobutyric acid, creatine, N-acetylaspartic acid, or lactate) using proton spectroscopy, high energy phosphates such as adenosine diphosphate (ADP) or adenosine triphosphate (ATP) or membrane breakdown products (such as phosphomonoester and phosphodiester) using phosphorous MRS. Researchers are gradually “mapping” the regional chemistry of the brain in health and disease, which may provide profound insights for understanding the neurobiology of serious mental disorders.

Functional MRI, which can display the underactivation or overactivation of various brain regions at rest or while experiencing severe symptoms such as hallucinations or melancholia or while performing a cognitive task. Significant insights about brain pathways can be gleaned from this test.

Diffusion tensor imaging (DTI), which can assess myelin integrity and provide critical data about white matter tract pathology and intra- and inter-hemispheric disconnectivity. Pathological myelin findings in psychotic and mood disorders already are prompting novel treatments for these disabling brain illnesses.

Cerebrospinal fluid (CSF) examination. Psychiatrists rarely perform lumbar punctures (LP) in first-episode patients, although psychotic or bipolar disorders are as severe and disabling as multiple sclerosis or meningitis, where an LP is routine. This longstanding omission is the result of the antiquated notion that CSF in psychiatric patients is not abnormal and uninformative. But the fact is that CSF in patients with psychotic or mood disorders may contain many recently discovered biomarkers that shed light on the tremendous neurochemical changes during an acute psychotic, manic, or depressive episode. So the focus in psychiatry is not simply on red blood cells, white blood cells, glucose levels, or proteins, as in a routine LP, but on the emerging biomarkers of brain pathologies that have been implicated in the psychotic and mood disorders, including:

• inflammatory signaling and biomarkers (such as cytokines, interleukins, TNF-α)
• apoptotic (such as caspase-3, Fas, ARTS) and anti-apoptotic proteins (Bcl-2)
• neurotropic (growth) factor (such as BDNF, NGF, VEGF)
• oxidative stress biomarkers (such as TBARS, TRAP, PCC, SOD, and TAOP)
• myelin byproducts (such as S100B, oligodendrocytic proteins)
• glutamate/glutamine abnormalities
• lipodomic aberrations
• metabolomic profiles
• mitochondrial deficits (such as low glutathione and GPX)
• immunoglobulins (such as IgG, IgM).

If CSF analysis is done routinely, unprecedented discoveries can be made about the nature of brain pathologies and potential diagnostic biomarkers in various subtypes of serious psychiatric disorders, leading to specific and personalized treatments.

It’s time that we go beyond the current descriptive approach that includes a brief mental status exam. We must conduct a comprehensive investigation of our patients’ abnormal brains, which are responsible for their anomalous minds and impaired functioning. It’s time to capitalize on the amazing neuroscience advances to understand our patients’ brains. It’s time that we employ translational psychiatry to guide our diagnosis and treatment of severe mental disorders.

A mountain of evidence indicates that psychosis and bipolar disorder (BD) are brain disorders with an array of thought, mood, cognition, and behavioral aberrations.

Yet the clinical assessment of those neuropsychiatric disorders predominantly is restricted to evaluating mental and behavioral signs and symptoms. It’s time we comprehensively assess our psychiatric patients’ brains, not just describe their minds. This is the only way we can eventually identify the roots of serious mental illness and develop accurate and effective therapeutic interventions and preventions.

Consider the following brain probes, measures, and assessments that are rarely done in patients with first-episode schizophrenia, BD, or major depression. These clinical and technological cerebral evaluation methods all are available and feasible and are being routinely exploited in neurology and other medical specialties. Not using them represents missed opportunities to advance the scientific underpinnings of psychiatric diagnosis and treatment.

Complete neurologic examination, including cranial nerves, motor functions, sensory status, reflexes (including primitive reflexes), and soft neurologic signs. Psychiatrists rarely perform such examinations, although they can easily relearn and incorporate them in their critical initial assessment of severe psychiatric episodes. Researchers have identified many neurologic findings in drug-naïve psychotic patients before they receive medications in whom adverse effects may mask or add to motor or sensory abnormalities.

Neurocognitive testing. An extensive body of literature has definitively demonstrated severe cognitive deficits across multiple domains in schizophrenia, BD, and major depression. Yet, inexplicably, few first-episode patients are assessed with a standard battery of tests for memory, attention, visuospatial skills, or executive functions in clinical practice. Cognitive deficits are a product of abnormal neural pathways and neurocognitive tests can provide tremendous insight into regional and overall brain functions and provide clues for etiopathology and a road map for rehabilitation.

Neuroimaging. Multiple sophisticated techniques to assess brain structure and function are used in research but rarely in clinical practice. These include:

Morphological MRI,, which can provide exquisitely detailed anatomical information about cortical and subcortical structures. This can help identify lesions that cause mania, schizophrenia-like disorders, or depression secondary to a brain pathology. Even if no lesion is found, the pattern of atrophy, hypertrophy, ectopic gray matter, or hyperplasia can help identify subtypes of heterogeneous psychotic and mood disorders, and may lead to a specific diagnosis and treatment.

Magnetic resonance spectroscopy (MRS) is essentially a living biopsy of the brain in any region, detailing the spectrum and amount of various neurochemical substances (such as glutamine, γ-aminobutyric acid, creatine, N-acetylaspartic acid, or lactate) using proton spectroscopy, high energy phosphates such as adenosine diphosphate (ADP) or adenosine triphosphate (ATP) or membrane breakdown products (such as phosphomonoester and phosphodiester) using phosphorous MRS. Researchers are gradually “mapping” the regional chemistry of the brain in health and disease, which may provide profound insights for understanding the neurobiology of serious mental disorders.

Functional MRI, which can display the underactivation or overactivation of various brain regions at rest or while experiencing severe symptoms such as hallucinations or melancholia or while performing a cognitive task. Significant insights about brain pathways can be gleaned from this test.

Diffusion tensor imaging (DTI), which can assess myelin integrity and provide critical data about white matter tract pathology and intra- and inter-hemispheric disconnectivity. Pathological myelin findings in psychotic and mood disorders already are prompting novel treatments for these disabling brain illnesses.

Cerebrospinal fluid (CSF) examination. Psychiatrists rarely perform lumbar punctures (LP) in first-episode patients, although psychotic or bipolar disorders are as severe and disabling as multiple sclerosis or meningitis, where an LP is routine. This longstanding omission is the result of the antiquated notion that CSF in psychiatric patients is not abnormal and uninformative. But the fact is that CSF in patients with psychotic or mood disorders may contain many recently discovered biomarkers that shed light on the tremendous neurochemical changes during an acute psychotic, manic, or depressive episode. So the focus in psychiatry is not simply on red blood cells, white blood cells, glucose levels, or proteins, as in a routine LP, but on the emerging biomarkers of brain pathologies that have been implicated in the psychotic and mood disorders, including:

• inflammatory signaling and biomarkers (such as cytokines, interleukins, TNF-α)
• apoptotic (such as caspase-3, Fas, ARTS) and anti-apoptotic proteins (Bcl-2)
• neurotropic (growth) factor (such as BDNF, NGF, VEGF)
• oxidative stress biomarkers (such as TBARS, TRAP, PCC, SOD, and TAOP)
• myelin byproducts (such as S100B, oligodendrocytic proteins)
• glutamate/glutamine abnormalities
• lipodomic aberrations
• metabolomic profiles
• mitochondrial deficits (such as low glutathione and GPX)
• immunoglobulins (such as IgG, IgM).

If CSF analysis is done routinely, unprecedented discoveries can be made about the nature of brain pathologies and potential diagnostic biomarkers in various subtypes of serious psychiatric disorders, leading to specific and personalized treatments.

It’s time that we go beyond the current descriptive approach that includes a brief mental status exam. We must conduct a comprehensive investigation of our patients’ abnormal brains, which are responsible for their anomalous minds and impaired functioning. It’s time to capitalize on the amazing neuroscience advances to understand our patients’ brains. It’s time that we employ translational psychiatry to guide our diagnosis and treatment of severe mental disorders.

Genetic variants at four chromosomal positions have now been linked to five diverse childhood- and adult-onset psychiatric illnesses: schizophrenia, autism spectrum disorders, attention-deficit/hyperactivity disorder, bipolar disorder, and major depressive disorder.

Two of the four loci encode for transmembranal calcium ion transport, a physiologic finding that could become a treatment target, Dr. Jordan W. Smoller and his colleagues wrote in the Feb. 28 online issue of the Lancet (2013 Feb. 28 [http://dx.doi.org/10.1016/S0140-6736(12)62129-1]).

"The finding that genetic variants have cross-disorder effects is an empirical step toward helping clinicians understand the common co-occurrence of clinical phenotypes in individual patients," wrote Dr. Smoller of the Massachusetts General Hospital, Boston, and his coauthors. "Our results implicate a specific biological pathway – voltage-gated calcium-channel signaling – as a contributor to the pathogenesis of several psychiatric disorders, and support the potential of this pathway as a therapeutic target for psychiatric disease."

The findings also could further the goal of "moving beyond descriptive syndromes in psychiatry and towards a nosology informed by disease cause," the investigators noted.

The genome-wide association study – the largest yet of its kind – analyzed single nucleotide polymorphisms (SNPs) for the five disorders among 33,332 cases and 27,888 controls, all of European ancestry. Four independent regions contained SNPs that were significantly related to the disorders. Three were related to all five disorders, and one to only bipolar disorder and schizophrenia.

The analysis also identified additional cross-disorder associations with a number of loci previously identified only with schizophrenia, although these associations were not as strong as those seen with the four primary regions.

Two of the four loci are related to voltage-gated transmembranal calcium channels, the authors noted. One of these has been previously identified as a risk gene for schizophrenia, bipolar disorder, and major depressive disorder. The gene facilitates the passage of calcium ions into the plasma membrane.

"Thus, our results suggest that voltage-gated calcium signaling, and, more broadly, calcium channel activity, could be an important biological process in psychiatric disorders," Dr. Smoller and his colleagues wrote. "Alterations in calcium channel signaling could represent a fundamental mechanism contributing to a broad vulnerability to psychopathology."

The authors cited several possible limitations. For example, diagnostic misclassification in cases of schizophrenia and bipolar disorder could produce "spurious evidence of genetic overlap between disorders." In addition, because their analyses were restricted to people of European ancestry, it is unclear whether their findings would apply to other populations.

Nevertheless, they said these result could provide "insights into the shared causation of psychiatric disorders."

Dr. Smoller and his coauthors are members of the Cross-Disorder Group of the Psychiatric Genomics Consortium. Their work was sponsored by the National Institutes of Health; none of the authors had any financial disclosures.

Genetic variants at four chromosomal positions have now been linked to five diverse childhood- and adult-onset psychiatric illnesses: schizophrenia, autism spectrum disorders, attention-deficit/hyperactivity disorder, bipolar disorder, and major depressive disorder.

Two of the four loci encode for transmembranal calcium ion transport, a physiologic finding that could become a treatment target, Dr. Jordan W. Smoller and his colleagues wrote in the Feb. 28 online issue of the Lancet (2013 Feb. 28 [http://dx.doi.org/10.1016/S0140-6736(12)62129-1]).

"The finding that genetic variants have cross-disorder effects is an empirical step toward helping clinicians understand the common co-occurrence of clinical phenotypes in individual patients," wrote Dr. Smoller of the Massachusetts General Hospital, Boston, and his coauthors. "Our results implicate a specific biological pathway – voltage-gated calcium-channel signaling – as a contributor to the pathogenesis of several psychiatric disorders, and support the potential of this pathway as a therapeutic target for psychiatric disease."

The findings also could further the goal of "moving beyond descriptive syndromes in psychiatry and towards a nosology informed by disease cause," the investigators noted.

The genome-wide association study – the largest yet of its kind – analyzed single nucleotide polymorphisms (SNPs) for the five disorders among 33,332 cases and 27,888 controls, all of European ancestry. Four independent regions contained SNPs that were significantly related to the disorders. Three were related to all five disorders, and one to only bipolar disorder and schizophrenia.

The analysis also identified additional cross-disorder associations with a number of loci previously identified only with schizophrenia, although these associations were not as strong as those seen with the four primary regions.

Two of the four loci are related to voltage-gated transmembranal calcium channels, the authors noted. One of these has been previously identified as a risk gene for schizophrenia, bipolar disorder, and major depressive disorder. The gene facilitates the passage of calcium ions into the plasma membrane.

"Thus, our results suggest that voltage-gated calcium signaling, and, more broadly, calcium channel activity, could be an important biological process in psychiatric disorders," Dr. Smoller and his colleagues wrote. "Alterations in calcium channel signaling could represent a fundamental mechanism contributing to a broad vulnerability to psychopathology."

The authors cited several possible limitations. For example, diagnostic misclassification in cases of schizophrenia and bipolar disorder could produce "spurious evidence of genetic overlap between disorders." In addition, because their analyses were restricted to people of European ancestry, it is unclear whether their findings would apply to other populations.

Nevertheless, they said these result could provide "insights into the shared causation of psychiatric disorders."

Dr. Smoller and his coauthors are members of the Cross-Disorder Group of the Psychiatric Genomics Consortium. Their work was sponsored by the National Institutes of Health; none of the authors had any financial disclosures.

Genetic variants at four chromosomal positions have now been linked to five diverse childhood- and adult-onset psychiatric illnesses: schizophrenia, autism spectrum disorders, attention-deficit/hyperactivity disorder, bipolar disorder, and major depressive disorder.

Two of the four loci encode for transmembranal calcium ion transport, a physiologic finding that could become a treatment target, Dr. Jordan W. Smoller and his colleagues wrote in the Feb. 28 online issue of the Lancet (2013 Feb. 28 [http://dx.doi.org/10.1016/S0140-6736(12)62129-1]).

"The finding that genetic variants have cross-disorder effects is an empirical step toward helping clinicians understand the common co-occurrence of clinical phenotypes in individual patients," wrote Dr. Smoller of the Massachusetts General Hospital, Boston, and his coauthors. "Our results implicate a specific biological pathway – voltage-gated calcium-channel signaling – as a contributor to the pathogenesis of several psychiatric disorders, and support the potential of this pathway as a therapeutic target for psychiatric disease."

The findings also could further the goal of "moving beyond descriptive syndromes in psychiatry and towards a nosology informed by disease cause," the investigators noted.

The genome-wide association study – the largest yet of its kind – analyzed single nucleotide polymorphisms (SNPs) for the five disorders among 33,332 cases and 27,888 controls, all of European ancestry. Four independent regions contained SNPs that were significantly related to the disorders. Three were related to all five disorders, and one to only bipolar disorder and schizophrenia.

The analysis also identified additional cross-disorder associations with a number of loci previously identified only with schizophrenia, although these associations were not as strong as those seen with the four primary regions.

Two of the four loci are related to voltage-gated transmembranal calcium channels, the authors noted. One of these has been previously identified as a risk gene for schizophrenia, bipolar disorder, and major depressive disorder. The gene facilitates the passage of calcium ions into the plasma membrane.

"Thus, our results suggest that voltage-gated calcium signaling, and, more broadly, calcium channel activity, could be an important biological process in psychiatric disorders," Dr. Smoller and his colleagues wrote. "Alterations in calcium channel signaling could represent a fundamental mechanism contributing to a broad vulnerability to psychopathology."

The authors cited several possible limitations. For example, diagnostic misclassification in cases of schizophrenia and bipolar disorder could produce "spurious evidence of genetic overlap between disorders." In addition, because their analyses were restricted to people of European ancestry, it is unclear whether their findings would apply to other populations.

Nevertheless, they said these result could provide "insights into the shared causation of psychiatric disorders."

Dr. Smoller and his coauthors are members of the Cross-Disorder Group of the Psychiatric Genomics Consortium. Their work was sponsored by the National Institutes of Health; none of the authors had any financial disclosures.

LAS VEGAS – Differences in drug responses probably offer the strongest evidence that bipolar disorder and schizophrenia may be separate entities, according to Dr. Charles B. Nemeroff.

The notion that the two are different manifestations of the same disease has gained traction in some quarters because, at least superficially, the two illnesses have quite a bit in common, including age of onset, response to atypical antipsychotics, ventricular enlargement, and shared genetic characteristics.

Early childhood abuse and neglect can increase the risk of both in vulnerable people, as well, and bipolar disorder patients can have auditory hallucinations and paranoid delusions, just as those with schizophrenia do, Dr. Nemeroff said at the Nevada Psychiatric Association’s annual psychopharmacology update.

Indeed, the possibility that they are even on the same spectrum has "implications in terms of current treatment and treatment development," but Dr. Nemeroff said he has his doubts. "The last chapter to this debate has not yet been written," he said.

That both respond to atypicals could be a red herring, for instance. "Imipramine is effective for treating both depression and enuresis, but I don’t think they’re the same thing," said Dr. Nemeroff, Leonard M. Miller Professor and chairman of the department of psychiatry and behavioral sciences at the University of Miami.

Regarding genes, some indeed are associated with both schizophrenia and bipolar disorder, but others appear to increase risk for one but not the other. Overall, genes account for about two-thirds of the risk for bipolar disorder, but only about half the risk for schizophrenia, he said (Neurosci. Biobehav. Rev. 2012;36:556-71).

Bipolar patients also do not lose brain volume over time, unlike patients with schizophrenia, and they often report an early onset of depression, sometimes before puberty. "We often don’t hear that in patients with schizophrenia, even when you talk to family members. There may have been something [odd] going on in those early years, but it doesn’t look like early-onset depression," he said.

Atypicals aside, differences in drug responses probably offer the strongest evidence that the two illnesses are separate entities.

Although of great help in manic patients, anticonvulsants "have no efficacy whatsoever in schizophrenia." Likewise, antidepressants can "rocket" bipolar patients into mania, but "have you ever seen a schizophrenic patient given an antidepressant become acutely manic? I haven’t," Dr. Nemeroff said.

Perhaps the response to lithium is the most telling of all. It remains one of the most effective treatments for bipolar disorder but "just does not work" for schizophrenia, according to numerous trials as both monotherapy and add-on therapy, he said.

"I’ve seen dozens of [bipolar] patients" struggle for years despite treatment with newer agents, but who have never had a lithium trial. When it’s finally tried, they often have "phenomenal response[s]. They became euthymic and remain euthymic for years, and never suffer an episode. I’ve rarely ever seen that with any other treatment for bipolar disorder. [Lithium is] a great drug; it’s also cheap," he said. "Cheap is good for our patients."

Lithium is underused because "nobody’s marketing it to you," he said.

Ongoing monitoring for kidney, thyroid, and other side effects probably puts some psychiatrists off, as well, but it’s really not any more complicated than the ongoing monitoring needed with atypicals and anticonvulsants, he said.

Plus, "there’s pretty good data that if you check TSH [thyroid-stimulating hormone] every 6 months, you’ll be able to catch any incipient hyperthyroidism. Patients who have [thyroid] antibodies at baseline are generally the ones who go on to develop thyroid problems, so you can check that at baseline," he said.

For patients with refractory bipolar depression, "my favorite combination has been lamotrigine and MAO inhibitors," particularly tranylcypromine. "I’ve probably gotten more people [out of] bipolar depression with that – after they’ve been marinated in everything else – than any other strategy besides [electroconvulsive therapy]."

And "lamotrigine doesn’t work in patients with schizophrenia," he noted.

Dr. Nemeroff reported stock ownership, consultant fees, or other income from Allergan, Lilly, Shire, Roche, NovaDel Pharma, BioPharma, AstraZeneca, and other companies.

[email protected]

LAS VEGAS – Differences in drug responses probably offer the strongest evidence that bipolar disorder and schizophrenia may be separate entities, according to Dr. Charles B. Nemeroff.

The notion that the two are different manifestations of the same disease has gained traction in some quarters because, at least superficially, the two illnesses have quite a bit in common, including age of onset, response to atypical antipsychotics, ventricular enlargement, and shared genetic characteristics.

Early childhood abuse and neglect can increase the risk of both in vulnerable people, as well, and bipolar disorder patients can have auditory hallucinations and paranoid delusions, just as those with schizophrenia do, Dr. Nemeroff said at the Nevada Psychiatric Association’s annual psychopharmacology update.

Indeed, the possibility that they are even on the same spectrum has "implications in terms of current treatment and treatment development," but Dr. Nemeroff said he has his doubts. "The last chapter to this debate has not yet been written," he said.

That both respond to atypicals could be a red herring, for instance. "Imipramine is effective for treating both depression and enuresis, but I don’t think they’re the same thing," said Dr. Nemeroff, Leonard M. Miller Professor and chairman of the department of psychiatry and behavioral sciences at the University of Miami.

Regarding genes, some indeed are associated with both schizophrenia and bipolar disorder, but others appear to increase risk for one but not the other. Overall, genes account for about two-thirds of the risk for bipolar disorder, but only about half the risk for schizophrenia, he said (Neurosci. Biobehav. Rev. 2012;36:556-71).

Bipolar patients also do not lose brain volume over time, unlike patients with schizophrenia, and they often report an early onset of depression, sometimes before puberty. "We often don’t hear that in patients with schizophrenia, even when you talk to family members. There may have been something [odd] going on in those early years, but it doesn’t look like early-onset depression," he said.

Atypicals aside, differences in drug responses probably offer the strongest evidence that the two illnesses are separate entities.

Although of great help in manic patients, anticonvulsants "have no efficacy whatsoever in schizophrenia." Likewise, antidepressants can "rocket" bipolar patients into mania, but "have you ever seen a schizophrenic patient given an antidepressant become acutely manic? I haven’t," Dr. Nemeroff said.

Perhaps the response to lithium is the most telling of all. It remains one of the most effective treatments for bipolar disorder but "just does not work" for schizophrenia, according to numerous trials as both monotherapy and add-on therapy, he said.

"I’ve seen dozens of [bipolar] patients" struggle for years despite treatment with newer agents, but who have never had a lithium trial. When it’s finally tried, they often have "phenomenal response[s]. They became euthymic and remain euthymic for years, and never suffer an episode. I’ve rarely ever seen that with any other treatment for bipolar disorder. [Lithium is] a great drug; it’s also cheap," he said. "Cheap is good for our patients."

Lithium is underused because "nobody’s marketing it to you," he said.

Ongoing monitoring for kidney, thyroid, and other side effects probably puts some psychiatrists off, as well, but it’s really not any more complicated than the ongoing monitoring needed with atypicals and anticonvulsants, he said.

Plus, "there’s pretty good data that if you check TSH [thyroid-stimulating hormone] every 6 months, you’ll be able to catch any incipient hyperthyroidism. Patients who have [thyroid] antibodies at baseline are generally the ones who go on to develop thyroid problems, so you can check that at baseline," he said.

For patients with refractory bipolar depression, "my favorite combination has been lamotrigine and MAO inhibitors," particularly tranylcypromine. "I’ve probably gotten more people [out of] bipolar depression with that – after they’ve been marinated in everything else – than any other strategy besides [electroconvulsive therapy]."

And "lamotrigine doesn’t work in patients with schizophrenia," he noted.

Dr. Nemeroff reported stock ownership, consultant fees, or other income from Allergan, Lilly, Shire, Roche, NovaDel Pharma, BioPharma, AstraZeneca, and other companies.

[email protected]

LAS VEGAS – Differences in drug responses probably offer the strongest evidence that bipolar disorder and schizophrenia may be separate entities, according to Dr. Charles B. Nemeroff.

The notion that the two are different manifestations of the same disease has gained traction in some quarters because, at least superficially, the two illnesses have quite a bit in common, including age of onset, response to atypical antipsychotics, ventricular enlargement, and shared genetic characteristics.

Early childhood abuse and neglect can increase the risk of both in vulnerable people, as well, and bipolar disorder patients can have auditory hallucinations and paranoid delusions, just as those with schizophrenia do, Dr. Nemeroff said at the Nevada Psychiatric Association’s annual psychopharmacology update.

Indeed, the possibility that they are even on the same spectrum has "implications in terms of current treatment and treatment development," but Dr. Nemeroff said he has his doubts. "The last chapter to this debate has not yet been written," he said.

That both respond to atypicals could be a red herring, for instance. "Imipramine is effective for treating both depression and enuresis, but I don’t think they’re the same thing," said Dr. Nemeroff, Leonard M. Miller Professor and chairman of the department of psychiatry and behavioral sciences at the University of Miami.

Regarding genes, some indeed are associated with both schizophrenia and bipolar disorder, but others appear to increase risk for one but not the other. Overall, genes account for about two-thirds of the risk for bipolar disorder, but only about half the risk for schizophrenia, he said (Neurosci. Biobehav. Rev. 2012;36:556-71).

Bipolar patients also do not lose brain volume over time, unlike patients with schizophrenia, and they often report an early onset of depression, sometimes before puberty. "We often don’t hear that in patients with schizophrenia, even when you talk to family members. There may have been something [odd] going on in those early years, but it doesn’t look like early-onset depression," he said.

Atypicals aside, differences in drug responses probably offer the strongest evidence that the two illnesses are separate entities.

Although of great help in manic patients, anticonvulsants "have no efficacy whatsoever in schizophrenia." Likewise, antidepressants can "rocket" bipolar patients into mania, but "have you ever seen a schizophrenic patient given an antidepressant become acutely manic? I haven’t," Dr. Nemeroff said.

Perhaps the response to lithium is the most telling of all. It remains one of the most effective treatments for bipolar disorder but "just does not work" for schizophrenia, according to numerous trials as both monotherapy and add-on therapy, he said.

"I’ve seen dozens of [bipolar] patients" struggle for years despite treatment with newer agents, but who have never had a lithium trial. When it’s finally tried, they often have "phenomenal response[s]. They became euthymic and remain euthymic for years, and never suffer an episode. I’ve rarely ever seen that with any other treatment for bipolar disorder. [Lithium is] a great drug; it’s also cheap," he said. "Cheap is good for our patients."

Lithium is underused because "nobody’s marketing it to you," he said.

Ongoing monitoring for kidney, thyroid, and other side effects probably puts some psychiatrists off, as well, but it’s really not any more complicated than the ongoing monitoring needed with atypicals and anticonvulsants, he said.

Plus, "there’s pretty good data that if you check TSH [thyroid-stimulating hormone] every 6 months, you’ll be able to catch any incipient hyperthyroidism. Patients who have [thyroid] antibodies at baseline are generally the ones who go on to develop thyroid problems, so you can check that at baseline," he said.

For patients with refractory bipolar depression, "my favorite combination has been lamotrigine and MAO inhibitors," particularly tranylcypromine. "I’ve probably gotten more people [out of] bipolar depression with that – after they’ve been marinated in everything else – than any other strategy besides [electroconvulsive therapy]."

And "lamotrigine doesn’t work in patients with schizophrenia," he noted.

Dr. Nemeroff reported stock ownership, consultant fees, or other income from Allergan, Lilly, Shire, Roche, NovaDel Pharma, BioPharma, AstraZeneca, and other companies.

[email protected]

Discuss this article at www.facebook.com/CurrentPsychiatry

Approved by the FDA on December 21, 2012, loxapine inhalation powder is the newest agent commercialized for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults (Table 1).^1,2 Loxapine is a first-generation antipsychotic that garnered newfound interest because of its potential atypical properties.³ Loxapine’s reformulation allows for direct administration to the lungs, resulting in rapid absorption into systemic circulation. This formulation offers a different method to manage agitation, for which IM formulations of other antipsychotics have been approved.⁴

Inhaled loxapine is delivered using a handheld device that produces a thermally-generated condensation aerosol.^5,6 A single inhalation is sufficient to activate the controlled rapid heating (300 to 500°C in approximately 100 ms) of a thin layer of excipient-free loxapine on a metal substrate. Once vaporized, the medication cools down rapidly and aggregates into particles. The 1- to 3.5-micron aerosol particles of loxapine enter the respiratory track in 7

Table 1

Inhaled loxapine: Fast facts

How it works

As with all antipsychotics, loxapine is an antagonist at the dopamine D2 receptor. However, loxapine also has clinically relevant serotonin-2A antagonism.³ Pharmacologic effects for loxapine and its metabolites include biogenic amine transporter inhibitor activity, alpha adrenergic blocking effects, and histaminergic and muscarinic receptor affinity.^3,8

Clinical pharmacokinetics

In a phase I study of healthy volunteers, inhaled loxapine produced IV administration-type kinetics, with maximum plasma concentration achieved in approximately 2 minutes.⁶ Plasma exposure to loxapine was dose-proportional. Half-life for the 5- and 10-mg doses was approximately 6 hours. In these patients, exposure to loxapine’s metabolites as a percentage of exposure to the parent compound were 8.79% for 7-OH loxapine, 52.6% for 8-OH loxapine, and 3.96% for amoxapine (all produced as a result of metabolism via liver cytochrome P450 [CYP] enzymes CYP1A2, CYP2D6, and/or CYP3A4⁶). 7-OH loxapine has a 5-fold higher affinity for the dopamine D2 receptor compared with loxapine, and may contribute to the drug’s clinical effect.⁶

Based on loxapine levels observed in the pharmacokinetic study,⁶ loxapine is not extensively metabolized in the lungs. Peak plasma concentrations immediately after inhalation are higher than for oral loxapine, but concentration of loxapine and its metabolites after the initial distribution phase is similar to that of oral loxapine.⁶ Loxapine and its metabolites are excreted through the kidneys.

Efficacy

Three efficacy studies were completed (Table 2)^9-11; all were double-blind randomized controlled trials that compared inhaled loxapine, 5 or 10 mg, with placebo. Patients were required to be clinically agitated at baseline, with a score of ≥14 on the Positive and Negative Syndrome Scale Excited Component (PANSS-EC)—which consists of the PANSS items of tension, excitement, hostility, uncooperativeness, and poor impulse control; each item is rated from 1 (absent) to 7 (extreme)—and a score of ≥4 (moderate) on ≥1 item. Patients who were intoxicated or had a positive drug screen for psychostimulants were excluded. Lorazepam was allowed ≥2 hours after the study drug was administered. Change in the PANSS-EC was measured 10 minutes to 24 hours post-dose. The primary endpoint used to statistically test loxapine vs placebo was 2 hours post-dose.

In the initial phase II trial, loxapine 10 mg, but not 5 mg, was superior to placebo on the PANSS-EC at 2 hours.⁹ The authors described the 5-mg dose effect size as intermediate between placebo and the 10-mg dose, suggesting a possible dose response relationship. The 10-mg dose did separate from placebo as early as 20 minutes post-dose. The small number of patients enrolled is a limitation of this trial, but this was addressed in studies in the phase III program, which were considerably larger. For each of the 2 phase III trials—1 for patients with schizophrenia¹⁰ and the other for those with bipolar disorder (BD)¹¹—both doses of loxapine were superior to placebo starting at 10 minutes post-dose. The number needed to treat (NNT) for response—as defined by a Clinical Global Impressions-Improvement score of much improved or very much improved—for loxapine vs placebo is included in Table 2.^9-11 NNT for other outcomes, such as reduction on the PANSS-EC by at least 40% from baseline, demonstrated similar results.

When examining each individual item on the PANSS-EC in each of the phase III trials, every item improved with treatment, starting 10 to 20 minutes after dosing.¹⁴ Each item improved an average of 1 to 2 units from baseline over the first 2 hours post-dose. Moreover, inhaled loxapine appears to reduce agitation equally well in patients with higher or lower levels of agitation at baseline.

Another clinically relevant outcome is whether or not a patient required an additional dose or rescue medication within 24 hours. In the phase III schizophrenia trial,¹⁰ 60.9% of patients randomized to loxapine, 10 mg, did not require an additional dose or rescue medication, compared with 54.4% and 46.1% for loxapine, 5 mg, and placebo, respectively. This yielded an NNT of 7 when comparing loxapine, 10 mg, with placebo.¹² In the BD study,¹⁰ 61.5%, 41.3%, and 26.7% did not require an additional dose or rescue medication within 24 hours for loxapine, 10 mg, 5 mg, and placebo, respectively. In this study, the NNT for loxapine, 10 mg, vs placebo was 3.¹²

In general, there appears to be a dose response for efficacy with inhaled loxapine, and therefore the FDA approved the 10-mg dose.²

Table 2

Summary of double-blind RCTs for inhaled loxapine vs inhaled placebo

Box

Tolerability and safety

Combined safety results from phase III trials^10,11 as well as information about a phase I ECG QT interval study were presented in a poster.¹⁵ Among 524 patients receiving loxapine vs 263 receiving placebo, there were no significant differences in the likelihood of experiencing any adverse event, a nervous system adverse event, sedation, sedation or somnolence, or sedation, somnolence or dizziness, when stratified by lorazepam rescue.¹⁶ Adverse events that were more frequently encountered with both doses of loxapine (ie, 5 and 10 mg) than placebo are listed in Table 3,¹⁵ along with the number needed to harm (NNH). The most commonly encountered adverse event was dysgeusia. The NNH of 10 for dysgeusia for loxapine, 10 mg, vs placebo means that for every 10 patients receiving inhaled loxapine, 10 mg, instead of inhaled placebo, you would encounter 1 additional case of dysgeusia. This contrasts with the NNT for response of 4 and 3 for agitation associated with schizophrenia and BD, respectively. Therefore, one would encounter response more often than dysgeusia when comparing loxapine with placebo.

No important changes in the ECG QT interval after inhaled loxapine, 10 mg, were observed in a phase I study with healthy volunteers.¹⁵ Difference from placebo in change from baseline for QTc was

Additional details regarding overall safety and tolerability can be found in a previously published review.¹⁷

Table 3

Inhaled loxapine: Incidence of adverse events

Pulmonary safety

Because this product is inhaled, additional information on pulmonary safety was gathered.^18,19 Among 1,095 patients without active airways disease, 1 (0.09%) required treatment for post-treatment airway-related symptoms (bronchospasm). In the agitated patient population, the rate of airway adverse events was 0.4% of loxapine exposures among 524 patients, in which 6.7% had a history of asthma or chronic obstructive pulmonary disease (COPD). Others were likely to have some respiratory impairment because of a history of cigarette smoking, but they did not have active respiratory symptoms that required treatment because such patients were excluded from the trials.¹² Phase I spirometry-based studies also were completed in healthy nonsmoking volunteers, in patients with asthma, and in patients with COPD. No clinically relevant effects were observed in healthy volunteers, but in patients with asthma or COPD a reduction in forced expiratory volume was observed. In patients with asthma, rates of bronchospasm as an adverse event were 26.9% for loxapine vs 3.8% for placebo, for a NNH of 5.¹² Bronchospasm was not reported for patients with COPD receiving loxapine but was observed in 1 patient who received placebo. All airway adverse events in patients with asthma or COPD were mild or moderate. All respiratory signs or symptoms requiring treatment in the phase I asthma and COPD studies were managed with an inhaled bronchodilator.

Product labeling notes in a warning that inhaled loxapine can cause bronchospasm that has the potential to lead to respiratory distress and respiratory arrest.² Therefore, inhaled loxapine is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the “ADASUVE REMS.” Enrolled health care facilities are required to have immediate, on-site access to equipment and personnel trained to manage acute bronchospasm, including advanced airway management (intubation and mechanical ventilation). Inhaled loxapine is contraindicated in patients with a current diagnosis or history of asthma, COPD, or other lung diseases associated with bronchospasm; acute respiratory signs or symptoms such as wheezing; current use of medications to treat airway diseases such as asthma or COPD; history of bronchospasm following inhaled loxapine treatment; or known hypersensitivity to loxapine and amoxapine.

Only a single dose within a 24-hour period is recommended. Before administration, patients should be screened for a history of pulmonary disease and examined (including chest auscultation) for respiratory abnormalities (eg, wheezing). After administration, patients require monitoring for signs and symptoms of bronchospasm at least every 15 minutes for ≥1 hour.

Related Resource

• Dinh K, Myers DJ, Glazer M, et al. In vitro aerosol characterization of Staccato(®) Loxapine. Int J Pharm. 2011; 403(1-2):101-108.

Drug Brand Names

• Haloperidol • Haldol
• Lorazepam • Ativan
• Loxapine • Loxitane
• Loxapine inhalation powder • Adasuve

Disclosure

In the past 36 months, Dr. Citrome has engaged in collaborative research with or received consulting or speaking fees from Alexza Pharmaceuticals, Alkermes, AstraZeneca, Avanir Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly and Company, EnVivo Pharmaceuticals, Forest Pharmaceuticals, Genentech, Janssen, L.P., Lundbeck, Merck, Mylan, Novartis, Noven, Otsuka, Pfizer Inc., Shire, Sunovion, and Valeant.

Discuss this article at www.facebook.com/CurrentPsychiatry

Approved by the FDA on December 21, 2012, loxapine inhalation powder is the newest agent commercialized for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults (Table 1).^1,2 Loxapine is a first-generation antipsychotic that garnered newfound interest because of its potential atypical properties.³ Loxapine’s reformulation allows for direct administration to the lungs, resulting in rapid absorption into systemic circulation. This formulation offers a different method to manage agitation, for which IM formulations of other antipsychotics have been approved.⁴

Inhaled loxapine is delivered using a handheld device that produces a thermally-generated condensation aerosol.^5,6 A single inhalation is sufficient to activate the controlled rapid heating (300 to 500°C in approximately 100 ms) of a thin layer of excipient-free loxapine on a metal substrate. Once vaporized, the medication cools down rapidly and aggregates into particles. The 1- to 3.5-micron aerosol particles of loxapine enter the respiratory track in 7

Table 1

Inhaled loxapine: Fast facts

How it works

As with all antipsychotics, loxapine is an antagonist at the dopamine D2 receptor. However, loxapine also has clinically relevant serotonin-2A antagonism.³ Pharmacologic effects for loxapine and its metabolites include biogenic amine transporter inhibitor activity, alpha adrenergic blocking effects, and histaminergic and muscarinic receptor affinity.^3,8

Clinical pharmacokinetics

In a phase I study of healthy volunteers, inhaled loxapine produced IV administration-type kinetics, with maximum plasma concentration achieved in approximately 2 minutes.⁶ Plasma exposure to loxapine was dose-proportional. Half-life for the 5- and 10-mg doses was approximately 6 hours. In these patients, exposure to loxapine’s metabolites as a percentage of exposure to the parent compound were 8.79% for 7-OH loxapine, 52.6% for 8-OH loxapine, and 3.96% for amoxapine (all produced as a result of metabolism via liver cytochrome P450 [CYP] enzymes CYP1A2, CYP2D6, and/or CYP3A4⁶). 7-OH loxapine has a 5-fold higher affinity for the dopamine D2 receptor compared with loxapine, and may contribute to the drug’s clinical effect.⁶

Based on loxapine levels observed in the pharmacokinetic study,⁶ loxapine is not extensively metabolized in the lungs. Peak plasma concentrations immediately after inhalation are higher than for oral loxapine, but concentration of loxapine and its metabolites after the initial distribution phase is similar to that of oral loxapine.⁶ Loxapine and its metabolites are excreted through the kidneys.

Efficacy

Three efficacy studies were completed (Table 2)^9-11; all were double-blind randomized controlled trials that compared inhaled loxapine, 5 or 10 mg, with placebo. Patients were required to be clinically agitated at baseline, with a score of ≥14 on the Positive and Negative Syndrome Scale Excited Component (PANSS-EC)—which consists of the PANSS items of tension, excitement, hostility, uncooperativeness, and poor impulse control; each item is rated from 1 (absent) to 7 (extreme)—and a score of ≥4 (moderate) on ≥1 item. Patients who were intoxicated or had a positive drug screen for psychostimulants were excluded. Lorazepam was allowed ≥2 hours after the study drug was administered. Change in the PANSS-EC was measured 10 minutes to 24 hours post-dose. The primary endpoint used to statistically test loxapine vs placebo was 2 hours post-dose.

In the initial phase II trial, loxapine 10 mg, but not 5 mg, was superior to placebo on the PANSS-EC at 2 hours.⁹ The authors described the 5-mg dose effect size as intermediate between placebo and the 10-mg dose, suggesting a possible dose response relationship. The 10-mg dose did separate from placebo as early as 20 minutes post-dose. The small number of patients enrolled is a limitation of this trial, but this was addressed in studies in the phase III program, which were considerably larger. For each of the 2 phase III trials—1 for patients with schizophrenia¹⁰ and the other for those with bipolar disorder (BD)¹¹—both doses of loxapine were superior to placebo starting at 10 minutes post-dose. The number needed to treat (NNT) for response—as defined by a Clinical Global Impressions-Improvement score of much improved or very much improved—for loxapine vs placebo is included in Table 2.^9-11 NNT for other outcomes, such as reduction on the PANSS-EC by at least 40% from baseline, demonstrated similar results.

When examining each individual item on the PANSS-EC in each of the phase III trials, every item improved with treatment, starting 10 to 20 minutes after dosing.¹⁴ Each item improved an average of 1 to 2 units from baseline over the first 2 hours post-dose. Moreover, inhaled loxapine appears to reduce agitation equally well in patients with higher or lower levels of agitation at baseline.

Another clinically relevant outcome is whether or not a patient required an additional dose or rescue medication within 24 hours. In the phase III schizophrenia trial,¹⁰ 60.9% of patients randomized to loxapine, 10 mg, did not require an additional dose or rescue medication, compared with 54.4% and 46.1% for loxapine, 5 mg, and placebo, respectively. This yielded an NNT of 7 when comparing loxapine, 10 mg, with placebo.¹² In the BD study,¹⁰ 61.5%, 41.3%, and 26.7% did not require an additional dose or rescue medication within 24 hours for loxapine, 10 mg, 5 mg, and placebo, respectively. In this study, the NNT for loxapine, 10 mg, vs placebo was 3.¹²

In general, there appears to be a dose response for efficacy with inhaled loxapine, and therefore the FDA approved the 10-mg dose.²

Table 2

Summary of double-blind RCTs for inhaled loxapine vs inhaled placebo

Box

Tolerability and safety

Combined safety results from phase III trials^10,11 as well as information about a phase I ECG QT interval study were presented in a poster.¹⁵ Among 524 patients receiving loxapine vs 263 receiving placebo, there were no significant differences in the likelihood of experiencing any adverse event, a nervous system adverse event, sedation, sedation or somnolence, or sedation, somnolence or dizziness, when stratified by lorazepam rescue.¹⁶ Adverse events that were more frequently encountered with both doses of loxapine (ie, 5 and 10 mg) than placebo are listed in Table 3,¹⁵ along with the number needed to harm (NNH). The most commonly encountered adverse event was dysgeusia. The NNH of 10 for dysgeusia for loxapine, 10 mg, vs placebo means that for every 10 patients receiving inhaled loxapine, 10 mg, instead of inhaled placebo, you would encounter 1 additional case of dysgeusia. This contrasts with the NNT for response of 4 and 3 for agitation associated with schizophrenia and BD, respectively. Therefore, one would encounter response more often than dysgeusia when comparing loxapine with placebo.

No important changes in the ECG QT interval after inhaled loxapine, 10 mg, were observed in a phase I study with healthy volunteers.¹⁵ Difference from placebo in change from baseline for QTc was

Additional details regarding overall safety and tolerability can be found in a previously published review.¹⁷

Table 3

Inhaled loxapine: Incidence of adverse events

Pulmonary safety

Because this product is inhaled, additional information on pulmonary safety was gathered.^18,19 Among 1,095 patients without active airways disease, 1 (0.09%) required treatment for post-treatment airway-related symptoms (bronchospasm). In the agitated patient population, the rate of airway adverse events was 0.4% of loxapine exposures among 524 patients, in which 6.7% had a history of asthma or chronic obstructive pulmonary disease (COPD). Others were likely to have some respiratory impairment because of a history of cigarette smoking, but they did not have active respiratory symptoms that required treatment because such patients were excluded from the trials.¹² Phase I spirometry-based studies also were completed in healthy nonsmoking volunteers, in patients with asthma, and in patients with COPD. No clinically relevant effects were observed in healthy volunteers, but in patients with asthma or COPD a reduction in forced expiratory volume was observed. In patients with asthma, rates of bronchospasm as an adverse event were 26.9% for loxapine vs 3.8% for placebo, for a NNH of 5.¹² Bronchospasm was not reported for patients with COPD receiving loxapine but was observed in 1 patient who received placebo. All airway adverse events in patients with asthma or COPD were mild or moderate. All respiratory signs or symptoms requiring treatment in the phase I asthma and COPD studies were managed with an inhaled bronchodilator.

Product labeling notes in a warning that inhaled loxapine can cause bronchospasm that has the potential to lead to respiratory distress and respiratory arrest.² Therefore, inhaled loxapine is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the “ADASUVE REMS.” Enrolled health care facilities are required to have immediate, on-site access to equipment and personnel trained to manage acute bronchospasm, including advanced airway management (intubation and mechanical ventilation). Inhaled loxapine is contraindicated in patients with a current diagnosis or history of asthma, COPD, or other lung diseases associated with bronchospasm; acute respiratory signs or symptoms such as wheezing; current use of medications to treat airway diseases such as asthma or COPD; history of bronchospasm following inhaled loxapine treatment; or known hypersensitivity to loxapine and amoxapine.

Only a single dose within a 24-hour period is recommended. Before administration, patients should be screened for a history of pulmonary disease and examined (including chest auscultation) for respiratory abnormalities (eg, wheezing). After administration, patients require monitoring for signs and symptoms of bronchospasm at least every 15 minutes for ≥1 hour.

Related Resource

• Dinh K, Myers DJ, Glazer M, et al. In vitro aerosol characterization of Staccato(®) Loxapine. Int J Pharm. 2011; 403(1-2):101-108.

Drug Brand Names

• Haloperidol • Haldol
• Lorazepam • Ativan
• Loxapine • Loxitane
• Loxapine inhalation powder • Adasuve

Disclosure

In the past 36 months, Dr. Citrome has engaged in collaborative research with or received consulting or speaking fees from Alexza Pharmaceuticals, Alkermes, AstraZeneca, Avanir Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly and Company, EnVivo Pharmaceuticals, Forest Pharmaceuticals, Genentech, Janssen, L.P., Lundbeck, Merck, Mylan, Novartis, Noven, Otsuka, Pfizer Inc., Shire, Sunovion, and Valeant.

Discuss this article at www.facebook.com/CurrentPsychiatry

Approved by the FDA on December 21, 2012, loxapine inhalation powder is the newest agent commercialized for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults (Table 1).^1,2 Loxapine is a first-generation antipsychotic that garnered newfound interest because of its potential atypical properties.³ Loxapine’s reformulation allows for direct administration to the lungs, resulting in rapid absorption into systemic circulation. This formulation offers a different method to manage agitation, for which IM formulations of other antipsychotics have been approved.⁴

Inhaled loxapine is delivered using a handheld device that produces a thermally-generated condensation aerosol.^5,6 A single inhalation is sufficient to activate the controlled rapid heating (300 to 500°C in approximately 100 ms) of a thin layer of excipient-free loxapine on a metal substrate. Once vaporized, the medication cools down rapidly and aggregates into particles. The 1- to 3.5-micron aerosol particles of loxapine enter the respiratory track in 7

Table 1

Inhaled loxapine: Fast facts

How it works

As with all antipsychotics, loxapine is an antagonist at the dopamine D2 receptor. However, loxapine also has clinically relevant serotonin-2A antagonism.³ Pharmacologic effects for loxapine and its metabolites include biogenic amine transporter inhibitor activity, alpha adrenergic blocking effects, and histaminergic and muscarinic receptor affinity.^3,8

Clinical pharmacokinetics

In a phase I study of healthy volunteers, inhaled loxapine produced IV administration-type kinetics, with maximum plasma concentration achieved in approximately 2 minutes.⁶ Plasma exposure to loxapine was dose-proportional. Half-life for the 5- and 10-mg doses was approximately 6 hours. In these patients, exposure to loxapine’s metabolites as a percentage of exposure to the parent compound were 8.79% for 7-OH loxapine, 52.6% for 8-OH loxapine, and 3.96% for amoxapine (all produced as a result of metabolism via liver cytochrome P450 [CYP] enzymes CYP1A2, CYP2D6, and/or CYP3A4⁶). 7-OH loxapine has a 5-fold higher affinity for the dopamine D2 receptor compared with loxapine, and may contribute to the drug’s clinical effect.⁶

Based on loxapine levels observed in the pharmacokinetic study,⁶ loxapine is not extensively metabolized in the lungs. Peak plasma concentrations immediately after inhalation are higher than for oral loxapine, but concentration of loxapine and its metabolites after the initial distribution phase is similar to that of oral loxapine.⁶ Loxapine and its metabolites are excreted through the kidneys.

Efficacy

Three efficacy studies were completed (Table 2)^9-11; all were double-blind randomized controlled trials that compared inhaled loxapine, 5 or 10 mg, with placebo. Patients were required to be clinically agitated at baseline, with a score of ≥14 on the Positive and Negative Syndrome Scale Excited Component (PANSS-EC)—which consists of the PANSS items of tension, excitement, hostility, uncooperativeness, and poor impulse control; each item is rated from 1 (absent) to 7 (extreme)—and a score of ≥4 (moderate) on ≥1 item. Patients who were intoxicated or had a positive drug screen for psychostimulants were excluded. Lorazepam was allowed ≥2 hours after the study drug was administered. Change in the PANSS-EC was measured 10 minutes to 24 hours post-dose. The primary endpoint used to statistically test loxapine vs placebo was 2 hours post-dose.

In the initial phase II trial, loxapine 10 mg, but not 5 mg, was superior to placebo on the PANSS-EC at 2 hours.⁹ The authors described the 5-mg dose effect size as intermediate between placebo and the 10-mg dose, suggesting a possible dose response relationship. The 10-mg dose did separate from placebo as early as 20 minutes post-dose. The small number of patients enrolled is a limitation of this trial, but this was addressed in studies in the phase III program, which were considerably larger. For each of the 2 phase III trials—1 for patients with schizophrenia¹⁰ and the other for those with bipolar disorder (BD)¹¹—both doses of loxapine were superior to placebo starting at 10 minutes post-dose. The number needed to treat (NNT) for response—as defined by a Clinical Global Impressions-Improvement score of much improved or very much improved—for loxapine vs placebo is included in Table 2.^9-11 NNT for other outcomes, such as reduction on the PANSS-EC by at least 40% from baseline, demonstrated similar results.

When examining each individual item on the PANSS-EC in each of the phase III trials, every item improved with treatment, starting 10 to 20 minutes after dosing.¹⁴ Each item improved an average of 1 to 2 units from baseline over the first 2 hours post-dose. Moreover, inhaled loxapine appears to reduce agitation equally well in patients with higher or lower levels of agitation at baseline.

Another clinically relevant outcome is whether or not a patient required an additional dose or rescue medication within 24 hours. In the phase III schizophrenia trial,¹⁰ 60.9% of patients randomized to loxapine, 10 mg, did not require an additional dose or rescue medication, compared with 54.4% and 46.1% for loxapine, 5 mg, and placebo, respectively. This yielded an NNT of 7 when comparing loxapine, 10 mg, with placebo.¹² In the BD study,¹⁰ 61.5%, 41.3%, and 26.7% did not require an additional dose or rescue medication within 24 hours for loxapine, 10 mg, 5 mg, and placebo, respectively. In this study, the NNT for loxapine, 10 mg, vs placebo was 3.¹²

In general, there appears to be a dose response for efficacy with inhaled loxapine, and therefore the FDA approved the 10-mg dose.²

Table 2

Summary of double-blind RCTs for inhaled loxapine vs inhaled placebo

Box

Tolerability and safety

Combined safety results from phase III trials^10,11 as well as information about a phase I ECG QT interval study were presented in a poster.¹⁵ Among 524 patients receiving loxapine vs 263 receiving placebo, there were no significant differences in the likelihood of experiencing any adverse event, a nervous system adverse event, sedation, sedation or somnolence, or sedation, somnolence or dizziness, when stratified by lorazepam rescue.¹⁶ Adverse events that were more frequently encountered with both doses of loxapine (ie, 5 and 10 mg) than placebo are listed in Table 3,¹⁵ along with the number needed to harm (NNH). The most commonly encountered adverse event was dysgeusia. The NNH of 10 for dysgeusia for loxapine, 10 mg, vs placebo means that for every 10 patients receiving inhaled loxapine, 10 mg, instead of inhaled placebo, you would encounter 1 additional case of dysgeusia. This contrasts with the NNT for response of 4 and 3 for agitation associated with schizophrenia and BD, respectively. Therefore, one would encounter response more often than dysgeusia when comparing loxapine with placebo.

No important changes in the ECG QT interval after inhaled loxapine, 10 mg, were observed in a phase I study with healthy volunteers.¹⁵ Difference from placebo in change from baseline for QTc was

Additional details regarding overall safety and tolerability can be found in a previously published review.¹⁷

Table 3

Inhaled loxapine: Incidence of adverse events

Pulmonary safety

Because this product is inhaled, additional information on pulmonary safety was gathered.^18,19 Among 1,095 patients without active airways disease, 1 (0.09%) required treatment for post-treatment airway-related symptoms (bronchospasm). In the agitated patient population, the rate of airway adverse events was 0.4% of loxapine exposures among 524 patients, in which 6.7% had a history of asthma or chronic obstructive pulmonary disease (COPD). Others were likely to have some respiratory impairment because of a history of cigarette smoking, but they did not have active respiratory symptoms that required treatment because such patients were excluded from the trials.¹² Phase I spirometry-based studies also were completed in healthy nonsmoking volunteers, in patients with asthma, and in patients with COPD. No clinically relevant effects were observed in healthy volunteers, but in patients with asthma or COPD a reduction in forced expiratory volume was observed. In patients with asthma, rates of bronchospasm as an adverse event were 26.9% for loxapine vs 3.8% for placebo, for a NNH of 5.¹² Bronchospasm was not reported for patients with COPD receiving loxapine but was observed in 1 patient who received placebo. All airway adverse events in patients with asthma or COPD were mild or moderate. All respiratory signs or symptoms requiring treatment in the phase I asthma and COPD studies were managed with an inhaled bronchodilator.

Product labeling notes in a warning that inhaled loxapine can cause bronchospasm that has the potential to lead to respiratory distress and respiratory arrest.² Therefore, inhaled loxapine is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the “ADASUVE REMS.” Enrolled health care facilities are required to have immediate, on-site access to equipment and personnel trained to manage acute bronchospasm, including advanced airway management (intubation and mechanical ventilation). Inhaled loxapine is contraindicated in patients with a current diagnosis or history of asthma, COPD, or other lung diseases associated with bronchospasm; acute respiratory signs or symptoms such as wheezing; current use of medications to treat airway diseases such as asthma or COPD; history of bronchospasm following inhaled loxapine treatment; or known hypersensitivity to loxapine and amoxapine.

Only a single dose within a 24-hour period is recommended. Before administration, patients should be screened for a history of pulmonary disease and examined (including chest auscultation) for respiratory abnormalities (eg, wheezing). After administration, patients require monitoring for signs and symptoms of bronchospasm at least every 15 minutes for ≥1 hour.

Related Resource

• Dinh K, Myers DJ, Glazer M, et al. In vitro aerosol characterization of Staccato(®) Loxapine. Int J Pharm. 2011; 403(1-2):101-108.

Drug Brand Names

• Haloperidol • Haldol
• Lorazepam • Ativan
• Loxapine • Loxitane
• Loxapine inhalation powder • Adasuve

Disclosure

In the past 36 months, Dr. Citrome has engaged in collaborative research with or received consulting or speaking fees from Alexza Pharmaceuticals, Alkermes, AstraZeneca, Avanir Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly and Company, EnVivo Pharmaceuticals, Forest Pharmaceuticals, Genentech, Janssen, L.P., Lundbeck, Merck, Mylan, Novartis, Noven, Otsuka, Pfizer Inc., Shire, Sunovion, and Valeant.