As we struggle to gradually emerge from the horrid coronavirus disease 2019 (COVID-19) pandemic that has disrupted our lives and killed hundreds of thousands of people in the United States, we harbor the hope that life will return to “normal.” But while it will certainly be a great relief to put this deadly virus behind us, many other epidemics will continue to plague our society and taint our culture.

Scientific ingenuity has led to the development of several vaccines in record time (aka “warp speed”) that will help defeat the deadly scourge of COVID-19. The pandemic is likely to peter out 2 years after its onset. We will all be grateful for such a rapid resolution of the worst health crisis the world has faced in a century, which will enable medical, economic, and social recovery. But as we eventually resume our lives and rejoice in resuming the pursuit of happiness, we will quickly realize that all is not well in our society just because the viral pandemic is gone.

Perhaps the ordeal of the COVID-19 pandemic, and the agony that was universally shared, will open our collective eyes to a jarring reality: many other epidemics will continue to permeate society and cause endless grief and suffering to many of our fellow humans. And thanks to our training as psychiatric physicians, we have developed extra “receptors” to the darker side of the human condition. As we help many of our psychiatric patients rendered sicker under the unbearable stress of the pandemic, we must not overlook the plight of so many others who do not show up in our clinics for health care, yet suffer enormously but imperceptibly. And no vaccine can come to the rescue of those who continue to live in quiet desperation.

Long-standing epidemics

It is truly unfortunate that many of the epidemics I am referring to have persisted for so long that they have become “fixtures” of contemporary societies. They have become “endemic epidemics” with no urgency to squelch them, as with the COVID-19 pandemic. The benign neglect that perpetuates these serious epidemics has had a malignant effect of “grudging resignation” that nothing can be done to reverse them. Unlike the viral epidemic that engulfed everyone around the world and triggered a massive and unified push to defeat the virus, these long-standing epidemics continue to afflict subgroups who are left to fend for themselves. These individuals deserve our empathy and warrant our determination to lift them from their miserable existence.

Consider some of the widespread epidemics that preceded the pandemic and will, in all likelihood, persist after the pandemic’s burden is lifted:

• millions of people living in poverty and hunger
• widespread racism
• smoldering social injustice
• appalling human trafficking, especially targeting children and women
• child abuse and neglect that leads to psychosis, depression, and suicide in adulthood
• gun violence, which kills many innocent people
• domestic violence that inflicts both physical and mental harm on families
• suicide, both attempts and completions, which continues to increase annually
• the festering stigma of mental illness that adds insult to injury for psychiatric patients
• alcohol and drug addictions, which destroy lives and corrode the fabric of society
• lack of access to mental health care for millions of people who need it
• lack of parity for psychiatric disorders, which is so unjust for our patients
• venomous political hatred and hyperpartisanship, which permeates our culture and can lead to violence, as we recently witnessed
• physician burnout, due to many causes, even before the stresses of COVID-19
• the ongoing agony of wars and terrorism, including dangerous cyberattacks
• the deleterious effect of social media on everyone, especially children.

Most of these epidemics claim thousands of lives each year, and yet no concerted public health effort is being mounted to counteract them, as we are seeing with the COVID-19 pandemic. Much is being written about each of them, but there has been little tangible action, so they persist. They have become a perpetual underbelly of our society that is essentially ignored or simply given the usual lip service.

It will take a herculean effort by policymakers, the judicial system, the medical establishment, and faith organizations to put an end to these life-threatening epidemics. It may appear too daunting to mount a war on so many fronts, but that should not deter us all from launching a strategic plan to create meaningful tactics and solutions. And just as was done with the COVID-19 pandemic, both mitigation measures as well as effective interventions must be employed in this campaign against the epidemic “hydra.”

Continue to: It is tragic...

It is tragic that so many fellow humans are allowed to suffer or die while the rest of us watch, or worse, turn a blind eye and never get involved. A civilized society must never neglect so many of its suffering citizens. As psychiatrists, we are aware of those human travesties around us, but we are often so overwhelmed with our work and personal responsibilities that few of us are passionately advocating or setting aside some time for those victimized by one or more of these endemic pandemics. And unless we all decide to be actively, meaningfully involved, many lives will continue to be lost every day, but without the daily “casualty count” displayed on television screens, as is the case with COVID-19 causalities.

Regrettably, maybe that old saw is true: out of sight, out of mind.

As we struggle to gradually emerge from the horrid coronavirus disease 2019 (COVID-19) pandemic that has disrupted our lives and killed hundreds of thousands of people in the United States, we harbor the hope that life will return to “normal.” But while it will certainly be a great relief to put this deadly virus behind us, many other epidemics will continue to plague our society and taint our culture.

Scientific ingenuity has led to the development of several vaccines in record time (aka “warp speed”) that will help defeat the deadly scourge of COVID-19. The pandemic is likely to peter out 2 years after its onset. We will all be grateful for such a rapid resolution of the worst health crisis the world has faced in a century, which will enable medical, economic, and social recovery. But as we eventually resume our lives and rejoice in resuming the pursuit of happiness, we will quickly realize that all is not well in our society just because the viral pandemic is gone.

Perhaps the ordeal of the COVID-19 pandemic, and the agony that was universally shared, will open our collective eyes to a jarring reality: many other epidemics will continue to permeate society and cause endless grief and suffering to many of our fellow humans. And thanks to our training as psychiatric physicians, we have developed extra “receptors” to the darker side of the human condition. As we help many of our psychiatric patients rendered sicker under the unbearable stress of the pandemic, we must not overlook the plight of so many others who do not show up in our clinics for health care, yet suffer enormously but imperceptibly. And no vaccine can come to the rescue of those who continue to live in quiet desperation.

Long-standing epidemics

It is truly unfortunate that many of the epidemics I am referring to have persisted for so long that they have become “fixtures” of contemporary societies. They have become “endemic epidemics” with no urgency to squelch them, as with the COVID-19 pandemic. The benign neglect that perpetuates these serious epidemics has had a malignant effect of “grudging resignation” that nothing can be done to reverse them. Unlike the viral epidemic that engulfed everyone around the world and triggered a massive and unified push to defeat the virus, these long-standing epidemics continue to afflict subgroups who are left to fend for themselves. These individuals deserve our empathy and warrant our determination to lift them from their miserable existence.

Consider some of the widespread epidemics that preceded the pandemic and will, in all likelihood, persist after the pandemic’s burden is lifted:

• millions of people living in poverty and hunger
• widespread racism
• smoldering social injustice
• appalling human trafficking, especially targeting children and women
• child abuse and neglect that leads to psychosis, depression, and suicide in adulthood
• gun violence, which kills many innocent people
• domestic violence that inflicts both physical and mental harm on families
• suicide, both attempts and completions, which continues to increase annually
• the festering stigma of mental illness that adds insult to injury for psychiatric patients
• alcohol and drug addictions, which destroy lives and corrode the fabric of society
• lack of access to mental health care for millions of people who need it
• lack of parity for psychiatric disorders, which is so unjust for our patients
• venomous political hatred and hyperpartisanship, which permeates our culture and can lead to violence, as we recently witnessed
• physician burnout, due to many causes, even before the stresses of COVID-19
• the ongoing agony of wars and terrorism, including dangerous cyberattacks
• the deleterious effect of social media on everyone, especially children.

Most of these epidemics claim thousands of lives each year, and yet no concerted public health effort is being mounted to counteract them, as we are seeing with the COVID-19 pandemic. Much is being written about each of them, but there has been little tangible action, so they persist. They have become a perpetual underbelly of our society that is essentially ignored or simply given the usual lip service.

It will take a herculean effort by policymakers, the judicial system, the medical establishment, and faith organizations to put an end to these life-threatening epidemics. It may appear too daunting to mount a war on so many fronts, but that should not deter us all from launching a strategic plan to create meaningful tactics and solutions. And just as was done with the COVID-19 pandemic, both mitigation measures as well as effective interventions must be employed in this campaign against the epidemic “hydra.”

Continue to: It is tragic...

It is tragic that so many fellow humans are allowed to suffer or die while the rest of us watch, or worse, turn a blind eye and never get involved. A civilized society must never neglect so many of its suffering citizens. As psychiatrists, we are aware of those human travesties around us, but we are often so overwhelmed with our work and personal responsibilities that few of us are passionately advocating or setting aside some time for those victimized by one or more of these endemic pandemics. And unless we all decide to be actively, meaningfully involved, many lives will continue to be lost every day, but without the daily “casualty count” displayed on television screens, as is the case with COVID-19 causalities.

Regrettably, maybe that old saw is true: out of sight, out of mind.

As we struggle to gradually emerge from the horrid coronavirus disease 2019 (COVID-19) pandemic that has disrupted our lives and killed hundreds of thousands of people in the United States, we harbor the hope that life will return to “normal.” But while it will certainly be a great relief to put this deadly virus behind us, many other epidemics will continue to plague our society and taint our culture.

Scientific ingenuity has led to the development of several vaccines in record time (aka “warp speed”) that will help defeat the deadly scourge of COVID-19. The pandemic is likely to peter out 2 years after its onset. We will all be grateful for such a rapid resolution of the worst health crisis the world has faced in a century, which will enable medical, economic, and social recovery. But as we eventually resume our lives and rejoice in resuming the pursuit of happiness, we will quickly realize that all is not well in our society just because the viral pandemic is gone.

Perhaps the ordeal of the COVID-19 pandemic, and the agony that was universally shared, will open our collective eyes to a jarring reality: many other epidemics will continue to permeate society and cause endless grief and suffering to many of our fellow humans. And thanks to our training as psychiatric physicians, we have developed extra “receptors” to the darker side of the human condition. As we help many of our psychiatric patients rendered sicker under the unbearable stress of the pandemic, we must not overlook the plight of so many others who do not show up in our clinics for health care, yet suffer enormously but imperceptibly. And no vaccine can come to the rescue of those who continue to live in quiet desperation.

Long-standing epidemics

It is truly unfortunate that many of the epidemics I am referring to have persisted for so long that they have become “fixtures” of contemporary societies. They have become “endemic epidemics” with no urgency to squelch them, as with the COVID-19 pandemic. The benign neglect that perpetuates these serious epidemics has had a malignant effect of “grudging resignation” that nothing can be done to reverse them. Unlike the viral epidemic that engulfed everyone around the world and triggered a massive and unified push to defeat the virus, these long-standing epidemics continue to afflict subgroups who are left to fend for themselves. These individuals deserve our empathy and warrant our determination to lift them from their miserable existence.

Consider some of the widespread epidemics that preceded the pandemic and will, in all likelihood, persist after the pandemic’s burden is lifted:

• millions of people living in poverty and hunger
• widespread racism
• smoldering social injustice
• appalling human trafficking, especially targeting children and women
• child abuse and neglect that leads to psychosis, depression, and suicide in adulthood
• gun violence, which kills many innocent people
• domestic violence that inflicts both physical and mental harm on families
• suicide, both attempts and completions, which continues to increase annually
• the festering stigma of mental illness that adds insult to injury for psychiatric patients
• alcohol and drug addictions, which destroy lives and corrode the fabric of society
• lack of access to mental health care for millions of people who need it
• lack of parity for psychiatric disorders, which is so unjust for our patients
• venomous political hatred and hyperpartisanship, which permeates our culture and can lead to violence, as we recently witnessed
• physician burnout, due to many causes, even before the stresses of COVID-19
• the ongoing agony of wars and terrorism, including dangerous cyberattacks
• the deleterious effect of social media on everyone, especially children.

Most of these epidemics claim thousands of lives each year, and yet no concerted public health effort is being mounted to counteract them, as we are seeing with the COVID-19 pandemic. Much is being written about each of them, but there has been little tangible action, so they persist. They have become a perpetual underbelly of our society that is essentially ignored or simply given the usual lip service.

It will take a herculean effort by policymakers, the judicial system, the medical establishment, and faith organizations to put an end to these life-threatening epidemics. It may appear too daunting to mount a war on so many fronts, but that should not deter us all from launching a strategic plan to create meaningful tactics and solutions. And just as was done with the COVID-19 pandemic, both mitigation measures as well as effective interventions must be employed in this campaign against the epidemic “hydra.”

Continue to: It is tragic...

It is tragic that so many fellow humans are allowed to suffer or die while the rest of us watch, or worse, turn a blind eye and never get involved. A civilized society must never neglect so many of its suffering citizens. As psychiatrists, we are aware of those human travesties around us, but we are often so overwhelmed with our work and personal responsibilities that few of us are passionately advocating or setting aside some time for those victimized by one or more of these endemic pandemics. And unless we all decide to be actively, meaningfully involved, many lives will continue to be lost every day, but without the daily “casualty count” displayed on television screens, as is the case with COVID-19 causalities.

Regrettably, maybe that old saw is true: out of sight, out of mind.

Mrs. C, age 56, has a history of major depressive disorder (MDD). She has been stable for 5 years without medication. Six months ago, she presented to you, along with her son, seeking help. She reported that she had been experiencing insomnia, fatigue, and was not engaging in hobbies. Her son told you that his mother had lost weight and had been avoiding family dinners. Mrs. C reported recurrent thoughts of dying and heard voices vividly telling her that she was a burden and that her family would be better off without her. However, there was no imminent danger of self-harm. At that appointment, you initiated sertraline, 50 mg/d titrated to 100 mg/d, and olanzapine, 5 mg/d.

Since that time, Mrs. C has followed up with you monthly with good response to the medications. Currently, she states her depression is much improved, and she denies hearing voices for approximately 5 months.

Based on her presentation and response, what do the data suggest about her length of treatment, and when should you consider tapering the antipsychotic medication?

In DSM-5, MDD with psychotic features is a severe subtype of MDD that is defined as a major depressive episode characterized by delusions and/or hallucinations.¹ In the general population, the lifetime prevalence of this disorder varies from 0.35% to 1%, and the rate is higher in older patients.² Risk factors include female gender, family history, and concomitant bipolar disorder.²

Epidemiologic studies have shown that psychotic features can occur in 15% to 20% of patients with MDD. The psychotic features that occur during these episodes are delusions and hallucinations.¹ These features can be either mood-congruent (related to the depressive themes of worthlessness or guilt) or mood-incongruent (ie, unrelated to depressive themes).¹

Treatment options: ECT or pharmacotherapy

Guidelines from the American Psychiatric Association³ and the National Institute for Clinical Excellence⁴ recommend treating depression with psychosis with electroconvulsive therapy (ECT) or with combined antidepressant and antipsychotic medications as first-line options. The Texas Medication Algorithm Project (TMAP) Algorithm for MDD,⁵ which closely focuses on treatment of MDD with psychotic features, can be used for treatment decisions (see Related Resources).

Electroconvulsive therapy is known to be efficacious in treating patients with MDD with psychotic features and should be considered as a treatment option. However, medication therapy is often chosen as the initial treatment due to the limitations of ECT, including accessibility, cost, and patient preference. However, in certain cases, ECT is the preferred option because it can provide rapid and significant improvement in patients with severe psychosis, suicidality, or risk of imminent harm.

Continue to: Pharmacotherapy

Pharmacotherapy for the treatment of MDD with psychotic features should consist of a combination of an antidepressant and antipsychotic medication. This combination has been shown to be more effective than either agent alone. Some combinations have been studied specifically for MDD with psychosis. The Study of the Pharmacotherapy of Psychotic Depression (STOP-PD), a 12-week, double-blind, randomized controlled trial, found that the combination of sertraline and olanzapine was efficacious and superior to monotherapy with olanzapine in an acute setting.⁶ In another study, the combination of olanzapine and fluoxetine was also found to be superior to olanzapine monotherapy in reducing Hamilton Depression Rating Scale (HAM-D) scores.⁷Quetiapine, when used in combination with venlafaxine, was found to be superior to venlafaxine monotherapy in response.⁸ Lastly, amitriptyline in combination with either haloperidol or perphenazine has been shown to be superior to monotherapy.^9,10 However, no medications are specifically FDA-approved for the indication of depression with psychotic features. Because none of these agents have been compared in head-to-head trials, any combination of antidepressant and antipsychotic medication can be used. Due to the greater risk of adverse effects with first-generation antipsychotics (FGAs), such as extrapyramidal symptoms (EPS), second-generation antipsychotics (SGAs) should be trialed first.

How long should treatment last?

The optimal timeline for treating patients with MDD with psychotic features is unknown. According to the TMAP algorithm and expert opinion, the continuation phase of pharmacotherapy should include treatment for at least 4 months with an antipsychotic medication and at least 2 years to lifetime treatment with an antidepressant.⁵ The STOP-PD II study, which was a continuation of the 12-week STOP-PD study, examined antipsychotic duration to determine the effects of continuing olanzapine once an episode of psychotic depression had responded to olanzapine and sertraline.¹¹ Patients who had achieved remission after receiving olanzapine and sertraline were randomized to continue to receive this combination or to receive sertraline plus placebo for 36 weeks. The primary outcome was relapse, which was broadly defined as 1 of the following¹¹:

• a Structured Clinical Interview for the DSM (SCID)-rated assessment that revealed the patient had enough symptoms to meet criteria for a DSM-IV major depressive episode
• a 17-item HAM-D scoren of ≥18
• SCID-rated psychosis
• other significant clinical worsening, defined as having a suicide plan or attempting suicide, developing SCID-rated symptoms of mania or hypomania, or being hospitalized in a psychiatric unit.

Compared with sertraline plus placebo, continuing sertraline plus olanzapine reduced the risk of relapse over 36 weeks (hazard ratio, 0.25; 95% confidence interval, 0.13 to 0.48; P < .001).¹¹ However, as expected, the incidence of adverse effects such as weight gain and parkinsonism was higher in the olanzapine group. Therefore, it is important to consider the potential long-term adverse effects of continuing antipsychotic medications. The STOP-PD II trial showed benefit in continuing antipsychotic therapy over 36 weeks, but did not answer the question of how long to continue antipsychotic therapy.

Weighing the evidence

Electroconvulsive therapy is considered a first-line treatment option for MDD with psychotic features; however, because of limitations associated with this approach, antidepressants plus antipsychotics are often utilized as an initial treatment. Essentially, any antipsychotic agent can be prescribed in conjunction with an antidepressant, but due to the greater risk of adverse effects associated with FGAs, SGAs should be trialed first. The results of the STOP-PD⁶ and STOP-PD II¹¹ studies have shown that once a patient responds to an antidepressant and antipsychotic, combination therapy needs to continue for at least 9 months to reduce the risk of relapse. Thereafter, reducing the dose of the antipsychotic can be considered after 1 year of treatment; however, no data exist about which agent and tapering schedule to consider. Because no optimal duration has been fully established, consider a slow and gradual taper when stopping antipsychotic therapy to allow for assessment of recurring symptoms.

Continue to: CASE

Based on the results of the STOP-PD and STOP-PD II trials, Mrs. C should be continued on sertraline plus olanzapine for at least another 3 to 6 months before an olanzapine taper should be considered. At that time, the risks and benefits of a taper vs continuing therapy should be considered. Given her history of MDD and the severity of this most recent episode, sertraline therapy should be continued for at least 2 years, and possibly indefinitely.

Related Resources

• Texas Medication Algorithm Project. Algorithm for the treatment of major depressive disorder with psychotic features. https://chsciowa.org/sites/chsciowa.org/files/resource/files/9_-_depression_med_algorithm_supplement.pdf
• Dold M, Bartova L, Kautzky A, et al. Psychotic features in patients with major depressive disorder: a report from the European Group for the Study of Resistant Depression. J Clin Psychiatry. 2019;80(1):17m12090. doi: 10.4088/ JCP.17m12090
• Flint AJ, Meyers BS, Rothschild AJ, et al. Effect of continuing olanzapine vs placebo on relapse among patients with psychotic depression in remission: the STOP-PD II randomized clinical trial. JAMA. 2019;322(7): 622-631.

Drug Brand Names

Amitriptyline • Elavil, Endep
Fluoxetine • Prozac
Haloperidol • Haldol
Olanzapine • Zyprexa
Quetiapine • Seroquel
Sertraline • Zoloft
Venlafaxine • Effexor

Mrs. C, age 56, has a history of major depressive disorder (MDD). She has been stable for 5 years without medication. Six months ago, she presented to you, along with her son, seeking help. She reported that she had been experiencing insomnia, fatigue, and was not engaging in hobbies. Her son told you that his mother had lost weight and had been avoiding family dinners. Mrs. C reported recurrent thoughts of dying and heard voices vividly telling her that she was a burden and that her family would be better off without her. However, there was no imminent danger of self-harm. At that appointment, you initiated sertraline, 50 mg/d titrated to 100 mg/d, and olanzapine, 5 mg/d.

Since that time, Mrs. C has followed up with you monthly with good response to the medications. Currently, she states her depression is much improved, and she denies hearing voices for approximately 5 months.

Based on her presentation and response, what do the data suggest about her length of treatment, and when should you consider tapering the antipsychotic medication?

In DSM-5, MDD with psychotic features is a severe subtype of MDD that is defined as a major depressive episode characterized by delusions and/or hallucinations.¹ In the general population, the lifetime prevalence of this disorder varies from 0.35% to 1%, and the rate is higher in older patients.² Risk factors include female gender, family history, and concomitant bipolar disorder.²

Epidemiologic studies have shown that psychotic features can occur in 15% to 20% of patients with MDD. The psychotic features that occur during these episodes are delusions and hallucinations.¹ These features can be either mood-congruent (related to the depressive themes of worthlessness or guilt) or mood-incongruent (ie, unrelated to depressive themes).¹

Treatment options: ECT or pharmacotherapy

Guidelines from the American Psychiatric Association³ and the National Institute for Clinical Excellence⁴ recommend treating depression with psychosis with electroconvulsive therapy (ECT) or with combined antidepressant and antipsychotic medications as first-line options. The Texas Medication Algorithm Project (TMAP) Algorithm for MDD,⁵ which closely focuses on treatment of MDD with psychotic features, can be used for treatment decisions (see Related Resources).

Electroconvulsive therapy is known to be efficacious in treating patients with MDD with psychotic features and should be considered as a treatment option. However, medication therapy is often chosen as the initial treatment due to the limitations of ECT, including accessibility, cost, and patient preference. However, in certain cases, ECT is the preferred option because it can provide rapid and significant improvement in patients with severe psychosis, suicidality, or risk of imminent harm.

Continue to: Pharmacotherapy

Pharmacotherapy for the treatment of MDD with psychotic features should consist of a combination of an antidepressant and antipsychotic medication. This combination has been shown to be more effective than either agent alone. Some combinations have been studied specifically for MDD with psychosis. The Study of the Pharmacotherapy of Psychotic Depression (STOP-PD), a 12-week, double-blind, randomized controlled trial, found that the combination of sertraline and olanzapine was efficacious and superior to monotherapy with olanzapine in an acute setting.⁶ In another study, the combination of olanzapine and fluoxetine was also found to be superior to olanzapine monotherapy in reducing Hamilton Depression Rating Scale (HAM-D) scores.⁷Quetiapine, when used in combination with venlafaxine, was found to be superior to venlafaxine monotherapy in response.⁸ Lastly, amitriptyline in combination with either haloperidol or perphenazine has been shown to be superior to monotherapy.^9,10 However, no medications are specifically FDA-approved for the indication of depression with psychotic features. Because none of these agents have been compared in head-to-head trials, any combination of antidepressant and antipsychotic medication can be used. Due to the greater risk of adverse effects with first-generation antipsychotics (FGAs), such as extrapyramidal symptoms (EPS), second-generation antipsychotics (SGAs) should be trialed first.

How long should treatment last?

The optimal timeline for treating patients with MDD with psychotic features is unknown. According to the TMAP algorithm and expert opinion, the continuation phase of pharmacotherapy should include treatment for at least 4 months with an antipsychotic medication and at least 2 years to lifetime treatment with an antidepressant.⁵ The STOP-PD II study, which was a continuation of the 12-week STOP-PD study, examined antipsychotic duration to determine the effects of continuing olanzapine once an episode of psychotic depression had responded to olanzapine and sertraline.¹¹ Patients who had achieved remission after receiving olanzapine and sertraline were randomized to continue to receive this combination or to receive sertraline plus placebo for 36 weeks. The primary outcome was relapse, which was broadly defined as 1 of the following¹¹:

• a Structured Clinical Interview for the DSM (SCID)-rated assessment that revealed the patient had enough symptoms to meet criteria for a DSM-IV major depressive episode
• a 17-item HAM-D scoren of ≥18
• SCID-rated psychosis
• other significant clinical worsening, defined as having a suicide plan or attempting suicide, developing SCID-rated symptoms of mania or hypomania, or being hospitalized in a psychiatric unit.

Compared with sertraline plus placebo, continuing sertraline plus olanzapine reduced the risk of relapse over 36 weeks (hazard ratio, 0.25; 95% confidence interval, 0.13 to 0.48; P < .001).¹¹ However, as expected, the incidence of adverse effects such as weight gain and parkinsonism was higher in the olanzapine group. Therefore, it is important to consider the potential long-term adverse effects of continuing antipsychotic medications. The STOP-PD II trial showed benefit in continuing antipsychotic therapy over 36 weeks, but did not answer the question of how long to continue antipsychotic therapy.

Weighing the evidence

Electroconvulsive therapy is considered a first-line treatment option for MDD with psychotic features; however, because of limitations associated with this approach, antidepressants plus antipsychotics are often utilized as an initial treatment. Essentially, any antipsychotic agent can be prescribed in conjunction with an antidepressant, but due to the greater risk of adverse effects associated with FGAs, SGAs should be trialed first. The results of the STOP-PD⁶ and STOP-PD II¹¹ studies have shown that once a patient responds to an antidepressant and antipsychotic, combination therapy needs to continue for at least 9 months to reduce the risk of relapse. Thereafter, reducing the dose of the antipsychotic can be considered after 1 year of treatment; however, no data exist about which agent and tapering schedule to consider. Because no optimal duration has been fully established, consider a slow and gradual taper when stopping antipsychotic therapy to allow for assessment of recurring symptoms.

Continue to: CASE

Based on the results of the STOP-PD and STOP-PD II trials, Mrs. C should be continued on sertraline plus olanzapine for at least another 3 to 6 months before an olanzapine taper should be considered. At that time, the risks and benefits of a taper vs continuing therapy should be considered. Given her history of MDD and the severity of this most recent episode, sertraline therapy should be continued for at least 2 years, and possibly indefinitely.

Related Resources

• Texas Medication Algorithm Project. Algorithm for the treatment of major depressive disorder with psychotic features. https://chsciowa.org/sites/chsciowa.org/files/resource/files/9_-_depression_med_algorithm_supplement.pdf
• Dold M, Bartova L, Kautzky A, et al. Psychotic features in patients with major depressive disorder: a report from the European Group for the Study of Resistant Depression. J Clin Psychiatry. 2019;80(1):17m12090. doi: 10.4088/ JCP.17m12090
• Flint AJ, Meyers BS, Rothschild AJ, et al. Effect of continuing olanzapine vs placebo on relapse among patients with psychotic depression in remission: the STOP-PD II randomized clinical trial. JAMA. 2019;322(7): 622-631.

Drug Brand Names

Amitriptyline • Elavil, Endep
Fluoxetine • Prozac
Haloperidol • Haldol
Olanzapine • Zyprexa
Quetiapine • Seroquel
Sertraline • Zoloft
Venlafaxine • Effexor

Mrs. C, age 56, has a history of major depressive disorder (MDD). She has been stable for 5 years without medication. Six months ago, she presented to you, along with her son, seeking help. She reported that she had been experiencing insomnia, fatigue, and was not engaging in hobbies. Her son told you that his mother had lost weight and had been avoiding family dinners. Mrs. C reported recurrent thoughts of dying and heard voices vividly telling her that she was a burden and that her family would be better off without her. However, there was no imminent danger of self-harm. At that appointment, you initiated sertraline, 50 mg/d titrated to 100 mg/d, and olanzapine, 5 mg/d.

Since that time, Mrs. C has followed up with you monthly with good response to the medications. Currently, she states her depression is much improved, and she denies hearing voices for approximately 5 months.

Based on her presentation and response, what do the data suggest about her length of treatment, and when should you consider tapering the antipsychotic medication?

In DSM-5, MDD with psychotic features is a severe subtype of MDD that is defined as a major depressive episode characterized by delusions and/or hallucinations.¹ In the general population, the lifetime prevalence of this disorder varies from 0.35% to 1%, and the rate is higher in older patients.² Risk factors include female gender, family history, and concomitant bipolar disorder.²

Epidemiologic studies have shown that psychotic features can occur in 15% to 20% of patients with MDD. The psychotic features that occur during these episodes are delusions and hallucinations.¹ These features can be either mood-congruent (related to the depressive themes of worthlessness or guilt) or mood-incongruent (ie, unrelated to depressive themes).¹

Treatment options: ECT or pharmacotherapy

Guidelines from the American Psychiatric Association³ and the National Institute for Clinical Excellence⁴ recommend treating depression with psychosis with electroconvulsive therapy (ECT) or with combined antidepressant and antipsychotic medications as first-line options. The Texas Medication Algorithm Project (TMAP) Algorithm for MDD,⁵ which closely focuses on treatment of MDD with psychotic features, can be used for treatment decisions (see Related Resources).

Electroconvulsive therapy is known to be efficacious in treating patients with MDD with psychotic features and should be considered as a treatment option. However, medication therapy is often chosen as the initial treatment due to the limitations of ECT, including accessibility, cost, and patient preference. However, in certain cases, ECT is the preferred option because it can provide rapid and significant improvement in patients with severe psychosis, suicidality, or risk of imminent harm.

Continue to: Pharmacotherapy

Pharmacotherapy for the treatment of MDD with psychotic features should consist of a combination of an antidepressant and antipsychotic medication. This combination has been shown to be more effective than either agent alone. Some combinations have been studied specifically for MDD with psychosis. The Study of the Pharmacotherapy of Psychotic Depression (STOP-PD), a 12-week, double-blind, randomized controlled trial, found that the combination of sertraline and olanzapine was efficacious and superior to monotherapy with olanzapine in an acute setting.⁶ In another study, the combination of olanzapine and fluoxetine was also found to be superior to olanzapine monotherapy in reducing Hamilton Depression Rating Scale (HAM-D) scores.⁷Quetiapine, when used in combination with venlafaxine, was found to be superior to venlafaxine monotherapy in response.⁸ Lastly, amitriptyline in combination with either haloperidol or perphenazine has been shown to be superior to monotherapy.^9,10 However, no medications are specifically FDA-approved for the indication of depression with psychotic features. Because none of these agents have been compared in head-to-head trials, any combination of antidepressant and antipsychotic medication can be used. Due to the greater risk of adverse effects with first-generation antipsychotics (FGAs), such as extrapyramidal symptoms (EPS), second-generation antipsychotics (SGAs) should be trialed first.

How long should treatment last?

The optimal timeline for treating patients with MDD with psychotic features is unknown. According to the TMAP algorithm and expert opinion, the continuation phase of pharmacotherapy should include treatment for at least 4 months with an antipsychotic medication and at least 2 years to lifetime treatment with an antidepressant.⁵ The STOP-PD II study, which was a continuation of the 12-week STOP-PD study, examined antipsychotic duration to determine the effects of continuing olanzapine once an episode of psychotic depression had responded to olanzapine and sertraline.¹¹ Patients who had achieved remission after receiving olanzapine and sertraline were randomized to continue to receive this combination or to receive sertraline plus placebo for 36 weeks. The primary outcome was relapse, which was broadly defined as 1 of the following¹¹:

• a Structured Clinical Interview for the DSM (SCID)-rated assessment that revealed the patient had enough symptoms to meet criteria for a DSM-IV major depressive episode
• a 17-item HAM-D scoren of ≥18
• SCID-rated psychosis
• other significant clinical worsening, defined as having a suicide plan or attempting suicide, developing SCID-rated symptoms of mania or hypomania, or being hospitalized in a psychiatric unit.

Compared with sertraline plus placebo, continuing sertraline plus olanzapine reduced the risk of relapse over 36 weeks (hazard ratio, 0.25; 95% confidence interval, 0.13 to 0.48; P < .001).¹¹ However, as expected, the incidence of adverse effects such as weight gain and parkinsonism was higher in the olanzapine group. Therefore, it is important to consider the potential long-term adverse effects of continuing antipsychotic medications. The STOP-PD II trial showed benefit in continuing antipsychotic therapy over 36 weeks, but did not answer the question of how long to continue antipsychotic therapy.

Weighing the evidence

Electroconvulsive therapy is considered a first-line treatment option for MDD with psychotic features; however, because of limitations associated with this approach, antidepressants plus antipsychotics are often utilized as an initial treatment. Essentially, any antipsychotic agent can be prescribed in conjunction with an antidepressant, but due to the greater risk of adverse effects associated with FGAs, SGAs should be trialed first. The results of the STOP-PD⁶ and STOP-PD II¹¹ studies have shown that once a patient responds to an antidepressant and antipsychotic, combination therapy needs to continue for at least 9 months to reduce the risk of relapse. Thereafter, reducing the dose of the antipsychotic can be considered after 1 year of treatment; however, no data exist about which agent and tapering schedule to consider. Because no optimal duration has been fully established, consider a slow and gradual taper when stopping antipsychotic therapy to allow for assessment of recurring symptoms.

Continue to: CASE

Based on the results of the STOP-PD and STOP-PD II trials, Mrs. C should be continued on sertraline plus olanzapine for at least another 3 to 6 months before an olanzapine taper should be considered. At that time, the risks and benefits of a taper vs continuing therapy should be considered. Given her history of MDD and the severity of this most recent episode, sertraline therapy should be continued for at least 2 years, and possibly indefinitely.

Related Resources

• Texas Medication Algorithm Project. Algorithm for the treatment of major depressive disorder with psychotic features. https://chsciowa.org/sites/chsciowa.org/files/resource/files/9_-_depression_med_algorithm_supplement.pdf
• Dold M, Bartova L, Kautzky A, et al. Psychotic features in patients with major depressive disorder: a report from the European Group for the Study of Resistant Depression. J Clin Psychiatry. 2019;80(1):17m12090. doi: 10.4088/ JCP.17m12090
• Flint AJ, Meyers BS, Rothschild AJ, et al. Effect of continuing olanzapine vs placebo on relapse among patients with psychotic depression in remission: the STOP-PD II randomized clinical trial. JAMA. 2019;322(7): 622-631.

Drug Brand Names

Amitriptyline • Elavil, Endep
Fluoxetine • Prozac
Haloperidol • Haldol
Olanzapine • Zyprexa
Quetiapine • Seroquel
Sertraline • Zoloft
Venlafaxine • Effexor

The coronavirus disease 2019 (COVID-19) pandemic has fundamentally changed our way of life. It has affected everything from how we go to the grocery store, attend school, worship, and spend time with our loved ones. As vaccinations are becoming available, there’s hope for a time when we can all enjoy a mask-free life again. Despite this, many of us are beginning to sense that the precautions and technology employed in response to COVID-19, and some of the lessons learned as a result, are likely to stay in place long after the virus has been controlled.

Victor Rendon, DO, MPA

Working remotely through audio and visual synchronous communication is now becoming the norm throughout the American workplace and educational system. Hospitals and graduate medical education programs are not exempt from this trend. For at least the foreseeable future, gone are the days of “unsocially distanced” bedside rounds in which 5 to 10 residents and medical students gather around with their attending as a case is presented in front of an agreeable patient.

My experience with ‘virtual’ supervision

Telemedicine has played a key role in the practice of health care during this pandemic, but little has been written about “telesupervision” of residents in the hospital setting. An unprecedented virtual approach to supervising emergency medicine residents was trialed at the University of Alabama a few months prior to my experience with it. This was found to be quite effective and well-received by all involved parties.¹

I am a PGY-2 psychiatry resident at ChristianaCare, a large multisite hospital system with more than 1,200 beds that serves the health care needs of Delaware and the surrounding areas. I recently had a novel educational experience working on a busy addiction medicine consult service. On the first day of this rotation, I met with my attending, Dr. Terry Horton, to discuss how the month would proceed. Together we developed a strategy for him to supervise me virtually.

Our arrangement was efficient and simple: I began each day by donning my surgical mask and protective eyewear and reviewing patients that had been placed on the consult list. Dr. Horton and I would have a conversation via telephone early in the morning to discuss the tasks that needed to be completed for the day. I would see and evaluate patients in the standard face-to-face way. After developing a treatment strategy, I contacted Dr. Horton on the phone, presented the patient, shared my plan, and gained information from his experienced perspective.

Then we saw the patient “together.” We used an iPad and Microsoft Teams video conferencing software. The information shared was protected using Microsoft Teams accounts, which were secured with profiles created by our institutional accounts. The iPad was placed on a rolling tripod, and the patient was able to converse with Dr. Horton as though he was physically in the room. I was there to facilitate the call, address any technical issues, and conduct any aspects of a physical exam that could only be done in person. After discussing any other changes to the treatment plan, I placed all medication orders, shared relevant details with nursing staff and other clinicians, wrote my progress note, and rolled my “attending on a stick” over to the next patient. Meanwhile, Dr. Horton was free to respond to pages or any other issues while I worked.

This description of my workflow is not very different from life before the virus. Based on informal feedback gathered from patients, the experience was overall positive. A physician is present; patients feel well cared for, and they look forward to visits and a virtual presence. This virtual approach not only spared unnecessary physical contact, reducing the risk of COVID-19 exposure, it also promoted efficiency.

Continue to: Fortunately, our hospital...

Certain psychosocial implications of the pandemic, including (but not limited to)social isolation and financial hardship, are often associated with increased substance use, and early data support the hypothesis that substance use has increased during this period.² Delaware seems to be included in the national trend. As such, our already-busy service is being stretched even further. Dr. Horton receives calls and is providing critical recommendations continuously throughout the day for multiple hospitals as well as for his outpatient practice. He used to spend a great deal of time traveling between different sites. With increasing need for his expertise, this model became increasingly difficult to practice. Our new model of attending supervision is welcomed in some settings because the attending can virtually be in multiple places at the same time.

For me, this experience has been positive. For a physician in training, virtual rounding can provide a critical balance of autonomy and support. I felt free on the rotation to make my own decisions, but I also did not feel like I was left to care for complicated cases on my own. Furthermore, my education did not suffer. In actuality, the experience enabled me to excel in my training. An attending physician was there for the important steps of plan formulation, but solo problem-solving opportunities were more readily available without his physical presence.

Aside from the medical lessons learned, I believe the participation has given me a glimpse of the future of medical training, health care delivery, and life in the increasingly digital post−COVID-19 world.

Hopefully, my experience will be helpful for other hospital systems as they continue to provide high-quality care to patients and education/training to their resident physicians in the face of the pandemic and the changing landscape of health care.

Acknowledgment

The author thanks Mustafa Mufti, MD, ChristianaCare Psychiatry Residency Program Director; Rachel Bronsther, MD, ChristianaCare Psychiatry Residency Associate Program Director; and Terry Horton, MD, ChristianaCare Addiction Medicine, for their assistance with this article.

The coronavirus disease 2019 (COVID-19) pandemic has fundamentally changed our way of life. It has affected everything from how we go to the grocery store, attend school, worship, and spend time with our loved ones. As vaccinations are becoming available, there’s hope for a time when we can all enjoy a mask-free life again. Despite this, many of us are beginning to sense that the precautions and technology employed in response to COVID-19, and some of the lessons learned as a result, are likely to stay in place long after the virus has been controlled.

Victor Rendon, DO, MPA

Working remotely through audio and visual synchronous communication is now becoming the norm throughout the American workplace and educational system. Hospitals and graduate medical education programs are not exempt from this trend. For at least the foreseeable future, gone are the days of “unsocially distanced” bedside rounds in which 5 to 10 residents and medical students gather around with their attending as a case is presented in front of an agreeable patient.

My experience with ‘virtual’ supervision

Telemedicine has played a key role in the practice of health care during this pandemic, but little has been written about “telesupervision” of residents in the hospital setting. An unprecedented virtual approach to supervising emergency medicine residents was trialed at the University of Alabama a few months prior to my experience with it. This was found to be quite effective and well-received by all involved parties.¹

I am a PGY-2 psychiatry resident at ChristianaCare, a large multisite hospital system with more than 1,200 beds that serves the health care needs of Delaware and the surrounding areas. I recently had a novel educational experience working on a busy addiction medicine consult service. On the first day of this rotation, I met with my attending, Dr. Terry Horton, to discuss how the month would proceed. Together we developed a strategy for him to supervise me virtually.

Our arrangement was efficient and simple: I began each day by donning my surgical mask and protective eyewear and reviewing patients that had been placed on the consult list. Dr. Horton and I would have a conversation via telephone early in the morning to discuss the tasks that needed to be completed for the day. I would see and evaluate patients in the standard face-to-face way. After developing a treatment strategy, I contacted Dr. Horton on the phone, presented the patient, shared my plan, and gained information from his experienced perspective.

Then we saw the patient “together.” We used an iPad and Microsoft Teams video conferencing software. The information shared was protected using Microsoft Teams accounts, which were secured with profiles created by our institutional accounts. The iPad was placed on a rolling tripod, and the patient was able to converse with Dr. Horton as though he was physically in the room. I was there to facilitate the call, address any technical issues, and conduct any aspects of a physical exam that could only be done in person. After discussing any other changes to the treatment plan, I placed all medication orders, shared relevant details with nursing staff and other clinicians, wrote my progress note, and rolled my “attending on a stick” over to the next patient. Meanwhile, Dr. Horton was free to respond to pages or any other issues while I worked.

This description of my workflow is not very different from life before the virus. Based on informal feedback gathered from patients, the experience was overall positive. A physician is present; patients feel well cared for, and they look forward to visits and a virtual presence. This virtual approach not only spared unnecessary physical contact, reducing the risk of COVID-19 exposure, it also promoted efficiency.

Continue to: Fortunately, our hospital...

Certain psychosocial implications of the pandemic, including (but not limited to)social isolation and financial hardship, are often associated with increased substance use, and early data support the hypothesis that substance use has increased during this period.² Delaware seems to be included in the national trend. As such, our already-busy service is being stretched even further. Dr. Horton receives calls and is providing critical recommendations continuously throughout the day for multiple hospitals as well as for his outpatient practice. He used to spend a great deal of time traveling between different sites. With increasing need for his expertise, this model became increasingly difficult to practice. Our new model of attending supervision is welcomed in some settings because the attending can virtually be in multiple places at the same time.

For me, this experience has been positive. For a physician in training, virtual rounding can provide a critical balance of autonomy and support. I felt free on the rotation to make my own decisions, but I also did not feel like I was left to care for complicated cases on my own. Furthermore, my education did not suffer. In actuality, the experience enabled me to excel in my training. An attending physician was there for the important steps of plan formulation, but solo problem-solving opportunities were more readily available without his physical presence.

Aside from the medical lessons learned, I believe the participation has given me a glimpse of the future of medical training, health care delivery, and life in the increasingly digital post−COVID-19 world.

Hopefully, my experience will be helpful for other hospital systems as they continue to provide high-quality care to patients and education/training to their resident physicians in the face of the pandemic and the changing landscape of health care.

Acknowledgment

The author thanks Mustafa Mufti, MD, ChristianaCare Psychiatry Residency Program Director; Rachel Bronsther, MD, ChristianaCare Psychiatry Residency Associate Program Director; and Terry Horton, MD, ChristianaCare Addiction Medicine, for their assistance with this article.

The coronavirus disease 2019 (COVID-19) pandemic has fundamentally changed our way of life. It has affected everything from how we go to the grocery store, attend school, worship, and spend time with our loved ones. As vaccinations are becoming available, there’s hope for a time when we can all enjoy a mask-free life again. Despite this, many of us are beginning to sense that the precautions and technology employed in response to COVID-19, and some of the lessons learned as a result, are likely to stay in place long after the virus has been controlled.

Victor Rendon, DO, MPA

Working remotely through audio and visual synchronous communication is now becoming the norm throughout the American workplace and educational system. Hospitals and graduate medical education programs are not exempt from this trend. For at least the foreseeable future, gone are the days of “unsocially distanced” bedside rounds in which 5 to 10 residents and medical students gather around with their attending as a case is presented in front of an agreeable patient.

My experience with ‘virtual’ supervision

Telemedicine has played a key role in the practice of health care during this pandemic, but little has been written about “telesupervision” of residents in the hospital setting. An unprecedented virtual approach to supervising emergency medicine residents was trialed at the University of Alabama a few months prior to my experience with it. This was found to be quite effective and well-received by all involved parties.¹

I am a PGY-2 psychiatry resident at ChristianaCare, a large multisite hospital system with more than 1,200 beds that serves the health care needs of Delaware and the surrounding areas. I recently had a novel educational experience working on a busy addiction medicine consult service. On the first day of this rotation, I met with my attending, Dr. Terry Horton, to discuss how the month would proceed. Together we developed a strategy for him to supervise me virtually.

Our arrangement was efficient and simple: I began each day by donning my surgical mask and protective eyewear and reviewing patients that had been placed on the consult list. Dr. Horton and I would have a conversation via telephone early in the morning to discuss the tasks that needed to be completed for the day. I would see and evaluate patients in the standard face-to-face way. After developing a treatment strategy, I contacted Dr. Horton on the phone, presented the patient, shared my plan, and gained information from his experienced perspective.

Then we saw the patient “together.” We used an iPad and Microsoft Teams video conferencing software. The information shared was protected using Microsoft Teams accounts, which were secured with profiles created by our institutional accounts. The iPad was placed on a rolling tripod, and the patient was able to converse with Dr. Horton as though he was physically in the room. I was there to facilitate the call, address any technical issues, and conduct any aspects of a physical exam that could only be done in person. After discussing any other changes to the treatment plan, I placed all medication orders, shared relevant details with nursing staff and other clinicians, wrote my progress note, and rolled my “attending on a stick” over to the next patient. Meanwhile, Dr. Horton was free to respond to pages or any other issues while I worked.

This description of my workflow is not very different from life before the virus. Based on informal feedback gathered from patients, the experience was overall positive. A physician is present; patients feel well cared for, and they look forward to visits and a virtual presence. This virtual approach not only spared unnecessary physical contact, reducing the risk of COVID-19 exposure, it also promoted efficiency.

Continue to: Fortunately, our hospital...

Certain psychosocial implications of the pandemic, including (but not limited to)social isolation and financial hardship, are often associated with increased substance use, and early data support the hypothesis that substance use has increased during this period.² Delaware seems to be included in the national trend. As such, our already-busy service is being stretched even further. Dr. Horton receives calls and is providing critical recommendations continuously throughout the day for multiple hospitals as well as for his outpatient practice. He used to spend a great deal of time traveling between different sites. With increasing need for his expertise, this model became increasingly difficult to practice. Our new model of attending supervision is welcomed in some settings because the attending can virtually be in multiple places at the same time.

For me, this experience has been positive. For a physician in training, virtual rounding can provide a critical balance of autonomy and support. I felt free on the rotation to make my own decisions, but I also did not feel like I was left to care for complicated cases on my own. Furthermore, my education did not suffer. In actuality, the experience enabled me to excel in my training. An attending physician was there for the important steps of plan formulation, but solo problem-solving opportunities were more readily available without his physical presence.

Aside from the medical lessons learned, I believe the participation has given me a glimpse of the future of medical training, health care delivery, and life in the increasingly digital post−COVID-19 world.

Hopefully, my experience will be helpful for other hospital systems as they continue to provide high-quality care to patients and education/training to their resident physicians in the face of the pandemic and the changing landscape of health care.

Acknowledgment

The author thanks Mustafa Mufti, MD, ChristianaCare Psychiatry Residency Program Director; Rachel Bronsther, MD, ChristianaCare Psychiatry Residency Associate Program Director; and Terry Horton, MD, ChristianaCare Addiction Medicine, for their assistance with this article.

On my third day as a PGY-4 junior attending on the inpatient psychiatric ward, 2 new PGY-1 residents, 2 medical students, and I stood in the wee hours of the morning, preparing to meet with our attending to begin rounds. I took the opportunity to discuss potential antipsychotic selection for one of our patients. I questioned the students to gauge their level of knowledge on antipsychotics in general, and did some “thinking out loud” about what our possible options could be. We discussed which antipsychotics are considered “weight-neutral” and which ones require caloric intake for adequate absorption. We discussed what other laboratory tests we should consider upon initiating the hypothetical medication. While discussing these things, I was suddenly taken aback to see that every member of my team was diligently taking notes and hanging on my every word!

Lessons from my teaching experiences

Taking on the role of junior attending has made me reflect on a few things about the transition that I will undergo at the end of this year, from resident to attending. First, teaching makes me keen to really sharpen my own knowledge, so that I can provide accurate information with confidence and ease. Making valid clinical decisions is a basic attending skill, but eloquently explaining clinical decisions to trainees with varying levels of background knowledge is a unique teaching attending necessity.

Second, I had this amazing feeling of helping patients beyond those currently in my care, since disseminating useful clinical information will allow trainees to better prepare to treat their own patients later. Random hypothetical situations presented by my attendings through the years may have seemed tangentially related to rounds at the time, but were meant to prepare me for actual future decisions (for example, “What would you change if this patient’s renal impairment were more severe?”). These teaching moments strengthen problem-solving skills and help us get as much benefit as possible from each case. The service to future patients extends to students who aren’t pursuing careers in psychiatry, because the skills they learn during a psychiatry rotation will help them connect with patients in any setting.

Third, I realized that teaching has the power to actively shape the future of medicine. What my attendings have taught me through the years is echoed and amplified in my teaching, and supplemented with my own readings and practice patterns.

Fourth, I noted what a privilege it is to be in a field with such attentive and eager trainees; as teachers in medicine, we truly get to work with the cream of the crop, which is a joy and a great responsibility. Working with such highly motivated and attentive students can be intimidating, but as I realized later in the morning, when asked about the complete indications for gabapentin, I realized I’m comfortable saying, “I don’t know, let’s look it up together!”

My fifth and final realization from this exciting teaching experience was that as an attending, I will need to help manage the wellness and growth of my trainees. Attendings must strike a balance between pushing learners to gain mastery while protecting them from excessive stress. I am so grateful for the perceptiveness of my attendings and their ability to adapt to the demands of a clinical environment while maintaining a strong focus on teaching. I have often told PGY-1 residents, when they face feelings of inadequacy for early mistakes, “You have 4 whole years to learn how to do this job!”

These are the moments that make me appreciate the fulfillment that can come from teaching residents and medical students, and really put into perspective how far I’ve come as a trainee. Not long ago, I was one of those medical students scribbling notes while my attending effortlessly spouted medical knowledge, and I was worried I’d never learn the difference between clonidine and clozapine.

On my third day as a PGY-4 junior attending on the inpatient psychiatric ward, 2 new PGY-1 residents, 2 medical students, and I stood in the wee hours of the morning, preparing to meet with our attending to begin rounds. I took the opportunity to discuss potential antipsychotic selection for one of our patients. I questioned the students to gauge their level of knowledge on antipsychotics in general, and did some “thinking out loud” about what our possible options could be. We discussed which antipsychotics are considered “weight-neutral” and which ones require caloric intake for adequate absorption. We discussed what other laboratory tests we should consider upon initiating the hypothetical medication. While discussing these things, I was suddenly taken aback to see that every member of my team was diligently taking notes and hanging on my every word!

Lessons from my teaching experiences

Taking on the role of junior attending has made me reflect on a few things about the transition that I will undergo at the end of this year, from resident to attending. First, teaching makes me keen to really sharpen my own knowledge, so that I can provide accurate information with confidence and ease. Making valid clinical decisions is a basic attending skill, but eloquently explaining clinical decisions to trainees with varying levels of background knowledge is a unique teaching attending necessity.

Second, I had this amazing feeling of helping patients beyond those currently in my care, since disseminating useful clinical information will allow trainees to better prepare to treat their own patients later. Random hypothetical situations presented by my attendings through the years may have seemed tangentially related to rounds at the time, but were meant to prepare me for actual future decisions (for example, “What would you change if this patient’s renal impairment were more severe?”). These teaching moments strengthen problem-solving skills and help us get as much benefit as possible from each case. The service to future patients extends to students who aren’t pursuing careers in psychiatry, because the skills they learn during a psychiatry rotation will help them connect with patients in any setting.

Third, I realized that teaching has the power to actively shape the future of medicine. What my attendings have taught me through the years is echoed and amplified in my teaching, and supplemented with my own readings and practice patterns.

Fourth, I noted what a privilege it is to be in a field with such attentive and eager trainees; as teachers in medicine, we truly get to work with the cream of the crop, which is a joy and a great responsibility. Working with such highly motivated and attentive students can be intimidating, but as I realized later in the morning, when asked about the complete indications for gabapentin, I realized I’m comfortable saying, “I don’t know, let’s look it up together!”

My fifth and final realization from this exciting teaching experience was that as an attending, I will need to help manage the wellness and growth of my trainees. Attendings must strike a balance between pushing learners to gain mastery while protecting them from excessive stress. I am so grateful for the perceptiveness of my attendings and their ability to adapt to the demands of a clinical environment while maintaining a strong focus on teaching. I have often told PGY-1 residents, when they face feelings of inadequacy for early mistakes, “You have 4 whole years to learn how to do this job!”

These are the moments that make me appreciate the fulfillment that can come from teaching residents and medical students, and really put into perspective how far I’ve come as a trainee. Not long ago, I was one of those medical students scribbling notes while my attending effortlessly spouted medical knowledge, and I was worried I’d never learn the difference between clonidine and clozapine.

On my third day as a PGY-4 junior attending on the inpatient psychiatric ward, 2 new PGY-1 residents, 2 medical students, and I stood in the wee hours of the morning, preparing to meet with our attending to begin rounds. I took the opportunity to discuss potential antipsychotic selection for one of our patients. I questioned the students to gauge their level of knowledge on antipsychotics in general, and did some “thinking out loud” about what our possible options could be. We discussed which antipsychotics are considered “weight-neutral” and which ones require caloric intake for adequate absorption. We discussed what other laboratory tests we should consider upon initiating the hypothetical medication. While discussing these things, I was suddenly taken aback to see that every member of my team was diligently taking notes and hanging on my every word!

Lessons from my teaching experiences

Taking on the role of junior attending has made me reflect on a few things about the transition that I will undergo at the end of this year, from resident to attending. First, teaching makes me keen to really sharpen my own knowledge, so that I can provide accurate information with confidence and ease. Making valid clinical decisions is a basic attending skill, but eloquently explaining clinical decisions to trainees with varying levels of background knowledge is a unique teaching attending necessity.

Second, I had this amazing feeling of helping patients beyond those currently in my care, since disseminating useful clinical information will allow trainees to better prepare to treat their own patients later. Random hypothetical situations presented by my attendings through the years may have seemed tangentially related to rounds at the time, but were meant to prepare me for actual future decisions (for example, “What would you change if this patient’s renal impairment were more severe?”). These teaching moments strengthen problem-solving skills and help us get as much benefit as possible from each case. The service to future patients extends to students who aren’t pursuing careers in psychiatry, because the skills they learn during a psychiatry rotation will help them connect with patients in any setting.

Third, I realized that teaching has the power to actively shape the future of medicine. What my attendings have taught me through the years is echoed and amplified in my teaching, and supplemented with my own readings and practice patterns.

Fourth, I noted what a privilege it is to be in a field with such attentive and eager trainees; as teachers in medicine, we truly get to work with the cream of the crop, which is a joy and a great responsibility. Working with such highly motivated and attentive students can be intimidating, but as I realized later in the morning, when asked about the complete indications for gabapentin, I realized I’m comfortable saying, “I don’t know, let’s look it up together!”

My fifth and final realization from this exciting teaching experience was that as an attending, I will need to help manage the wellness and growth of my trainees. Attendings must strike a balance between pushing learners to gain mastery while protecting them from excessive stress. I am so grateful for the perceptiveness of my attendings and their ability to adapt to the demands of a clinical environment while maintaining a strong focus on teaching. I have often told PGY-1 residents, when they face feelings of inadequacy for early mistakes, “You have 4 whole years to learn how to do this job!”

These are the moments that make me appreciate the fulfillment that can come from teaching residents and medical students, and really put into perspective how far I’ve come as a trainee. Not long ago, I was one of those medical students scribbling notes while my attending effortlessly spouted medical knowledge, and I was worried I’d never learn the difference between clonidine and clozapine.

Approved by the FDA on October 11, 2019, asenapine transdermal system (Secuado, manufactured by Hisamitsu Pharmaceutical Co., Inc. and distributed by Noven Therapeutics) is the first “patch” approved by the FDA for the treatment of adults with schizophrenia (Table 1).^1-3 Asenapine is a second-generation antipsychotic that was previously available only as a sublingual formulation (Saphris, Allergan [now AbbVie] under license from Merck Sharp & Dohme B.V.).^4-7 Asenapine’s reformulation potentially simplifies using this antipsychotic by reducing the dosing frequency from twice daily (recommended for the sublingual tablet) to once daily (recommended for the patch). The food and drink restrictions posed by the sublingual formulation are eliminated. Also avoided are dysgeusia (bad taste) and hypoesthesia of the tongue (numbing). Asenapine transdermal system offers a different method to manage schizophrenia, and this novel method of administration through the skin is worth considering.⁸

The asenapine transdermal system is available in 3 patch sizes: 20, 30, and 40 cm², which deliver 3.8, 5.7, and 7.6 mg/24 hours of asenapine, respectively.³ Based on the average exposure (area under the plasma concentration curve [AUC]) of asenapine, 3.8 mg/24 hours corresponds to 5 mg twice daily of sublingual asenapine, and 7.6 mg/24 hours corresponds to 10 mg twice daily of sublingual asenapine.³ The “in-between” dose strength of 5.7 mg/24 hours would correspond to exposure to a total of 15 mg/d of sublingual asenapine. The recommended starting dose for asenapine transdermal system is 3.8 mg/24 hours. The dosage may be increased to 5.7 mg/24 hours or 7.6 mg/24 hours, as needed, after 1 week. The safety of doses above 7.6 mg/24 hours has not been evaluated in clinical studies. Asenapine transdermal system is applied once daily and should be worn for 24 hours only, with only 1 patch at any time. Application sites include the upper arm, upper back, abdomen, and hip. A different application site of clean, dry, intact skin should be selected each time a new patch is applied. Although showering is permitted, the use of asenapine transdermal system during swimming or taking a bath has not been evaluated. Of note, prolonged application of heat over an asenapine transdermal system increases plasma concentrations of asenapine, and thus application of external heat sources (eg, heating pads) over the patch should be avoided.

How it works

Product labeling notes that asenapine is an atypical antipsychotic, and that its efficacy in schizophrenia could be mediated through a combination of antagonist activity at dopamine D2 and serotonin 5-HT2A receptors.³ The pharmacodynamic profile of asenapine is complex⁵ and receptor-binding assays performed using cloned human serotonin, norepinephrine, dopamine, histamine, and muscarinic receptors demonstrated picomolar affinity (extremely high) for 5-HT2C and 5-HT2A receptors, subnanomolar affinity (very high) for 5-HT7, 5-HT2B, 5-HT6, and D3 receptors, and nanomolar affinity (high) for D2 receptors, as well as histamine H1, D4, a1-adrenergic, a2-adrenergic, D1, 5-HT5, 5-HT1A, 5-HT1B, and histamine H2 receptors. Activity of asenapine is that of antagonism at these receptors. Asenapine has no appreciable affinity for muscarinic cholinergic receptors.

The asenapine receptor-binding “fingerprint” differs from that of other antipsychotics. Some of these receptor affinities are of special interest in terms of potential efficacy for pro-cognitive effects and amelioration of abnormal mood.^5,9 In terms of tolerability, a relative absence of affinity to muscarinic receptors would predict a low risk for anticholinergic adverse effects, but antagonism at histamine H1 and at a1-adrenergic receptors, either alone or in combination, may cause sedation, and blockade of H1 receptors would also predict weight gain.⁹ Antagonism of a1-adrenergic receptors can be associated with orthostatic hypotension and neurally mediated reflex bradycardia.⁹

Clinical pharmacokinetics

Three open-label, randomized, phase 1 studies were conducted to assess the relative bioavailability of asenapine transdermal system vs sublingual asenapine.¹⁰ These included single- and multiple-dose studies and clinical trials that examined the effects of different application sites and ethnic groups, and the effect of external heat on medication absorption. Studies were conducted in healthy individuals, except for the multiple-dose study, which was performed in adults with schizophrenia. The AUC for asenapine transdermal system was within the range of that of equivalent doses of sublingual asenapine, but peak exposure (maximum concentration) was significantly lower. As already noted, the AUC of the asenapine patch for 3.8 mg/24 hours and 7.6 mg/24 hours corresponds to sublingual asenapine 5 mg and 10 mg twice daily, respectively. Maximum asenapine concentrations are typically reached between 12 and 24 hours, with sustained concentrations during the 24-hour wear time.³ On average, approximately 60% of the available asenapine is released from the transdermal system over 24 hours. Steady-state plasma concentrations for asenapine transdermal system were achieved approximately 72 hours after the first application and, in contrast to sublingual asenapine, the peak-trough fluctuations were small (peak-to-trough ratio is 1.5 for asenapine transdermal system compared with >3 for sublingual asenapine). Dose-proportionality at steady state was evident for asenapine transdermal system. This is in contrast to sublingual asenapine, where exposure increases 1.7-fold with a 2-fold increase in dose.^4,5 Following patch removal, the apparent elimination half-life is approximately 30 hours.³ The pharmacokinetics of the patch did not vary with regards to the application site (upper arm, upper back, abdomen, or hip area), and the pharmacokinetic profile was similar across the ethnic groups that participated in the study. Direct exposure to external heat did increase both the rate and extent of absorption, so external heat sources should be avoided.³

Efficacy

The efficacy profile for asenapine transdermal system would be expected to mirror that for sublingual asenapine.^6,7 In addition to data supporting the use of asenapine as administered sublingually, a phase 3 study specifically assessed efficacy and safety of asenapine transdermal system in adults with schizophrenia.^11,12 This study was conducted in the United States and 4 other countries at a total of 59 study sites, and 616 patients with acutely exacerbated schizophrenia were enrolled. After a 3- to 14-day screening/single-blind run-in washout period, participants entered a 6-week inpatient double-blind period. Randomization was 1:1:1 to asenapine transdermal system 3.8 mg/24 hours, 7.6 mg/24 hours, or a placebo patch. Each of the patch doses demonstrated significant improvement vs placebo at Week 6 for the primary (change in Positive and Negative Syndrome Scale [PANSS] total score) and key secondary (change in Clinical Global Impression-Severity of Illness) endpoints. Response at endpoint, as defined by a ≥30% improvement from baseline PANSS total score, or by a Clinical Global Impression–Improvement score of 1 (very much improved) or 2 (much improved), was also assessed. For either definition of response, both doses of asenapine transdermal system were superior to placebo, with number needed to treat (NNT) (Box) values <10 for the 3.8 mg/24 hours dose (Table 2). These effect sizes are similar to what is known about sublingual asenapine as determined in a meta-analysis performed by the manufacturer and using individual patient data.¹³

Box

Overall tolerability and safety

The systemic safety and tolerability profile for asenapine transdermal system would be expected to be similar to that for sublingual asenapine, unless there are adverse events that are related to high peak plasma concentrations or large differences between peak and trough plasma concentrations.⁶ Nonsystemic local application site adverse events would, of course, differ between sublingual vs transdermal administration.

Continue to: Use of asenapine transdermal system...

Use of asenapine transdermal system avoids the dysgeusia and oral hypoesthesia that can be observed with sublingual asenapine^4,6; however, dermal effects need to be considered (see Dermal safety). The most commonly observed adverse reactions (incidence ≥5% and at least twice that for placebo) for asenapine transdermal system are extrapyramidal disorder, application site reaction, and weight gain.³ For sublingual asenapine for adults with schizophrenia, the list includes akathisia, oral hypoesthesia, and somnolence.⁴ These adverse events can be further described using the metric of number needed to harm (NNH) as shown in Table 3.^3,4,11,12,14 Of note, extrapyramidal disorder and weight gain appear to be dose-related for asenapine transdermal system. Akathisia appears to be dose-related for sublingual asenapine but not for asenapine transdermal system. Somnolence appears to be associated with sublingual asenapine but not necessarily with asenapine transdermal system.

For sublingual asenapine, the additional indications (bipolar I disorder as acute monotherapy treatment of manic or mixed episodes in adults and pediatric patients age 10 to 17, adjunctive treatment to lithium or valproate in adults, and maintenance monotherapy treatment in adults) have varying commonly encountered adverse reactions.⁴ Both transdermal asenapine system and sublingual asenapine are contraindicated in patients with severe hepatic impairment (Child-Pugh C) and those with known hypersensitivity to asenapine or to any components in the formulation. Both formulations carry similar warnings in their prescribing information regarding increased mortality in older patients with dementia-related psychosis, cerebrovascular adverse reactions in older patients with dementia-related psychosis, neuroleptic malignant syndrome, tardive dyskinesia, metabolic changes, orthostatic hypotension, leukopenia (and neutropenia and agranulocytosis), QT prolongation, seizures, and potential for cognitive and motor impairment.

Adverse events leading to discontinuation of study treatment in the asenapine transdermal system pivotal trial occurred in 4.9%, 7.8%, and 6.8% of participants in the 3.8 mg/24 hour, 7.6 mg/24 hour, and placebo groups, respectively.¹¹

Dermal safety

In the pivotal efficacy study,¹¹ the incidence of adverse events at patch application sites was higher in the active groups vs placebo (Table 3^3,4,11,12,14). The most frequently reported patch application site reactions were erythema and pruritus, occurring in approximately 10% and 4% in the active treatment arms vs 1.5% and 1.9% for placebo, respectively. With the exception of 1 adverse event of severe application site erythema during Week 2 (participant received 7.6 mg/24 hour, erythema resolved without intervention, and the patient continued the study), all other patch application site events were mild or moderate in severity. Rates of discontinuation due to application site reactions or skin disorders were ≤0.5% across all groups. In the pharmacokinetic studies,¹⁰ no patches were removed because of unacceptable irritation.

Why Rx?

Asenapine transdermal system is the first antipsychotic “patch” FDA-approved for the treatment of adults with schizophrenia. Asenapine has been available since 2009 as a sublingual formulation administered twice daily. The pharmacokinetic profile of the once-daily transdermal system demonstrates dose-proportional kinetics and sustained delivery of asenapine with a low peak-to-trough plasma level ratio. Three dosage strengths (3.8, 5.7, and 7.6 mg/24 hours) are available, corresponding to blood levels attained with sublingual asenapine exposures of 10, 15, and 20 mg/d, respectively. Application sites are rotated daily and include the upper arms, upper back, abdomen, or hip. Dysgeusia and hypoesthesia of the tongue are avoided with the use of the patch, and there are no food or drink restrictions. Attention will be needed in case of dermal reactions, similar to that observed with other medication patches.

The asenapine transdermal drug delivery system appears to be efficacious and reasonably well tolerated. The treatment of schizophrenia is complex and requires individualized choices in order to optimize outcomes. A patch may be the preferred formulation for selected patients, and caregivers will have the ability to visually check if the medication is being used.

Related Resource

• Hisamitsu Pharmaceutical Co., Inc. SECUADO® (asenapine) transdermal system prescribing information. October 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212268s000lbl.pdf

Drug Brand Names

Asenapine sublingual • Saphris
Asenapine transdermal system • Secuado
Lithium • Eskalith, Lithobid
Valproate • Depakote

Approved by the FDA on October 11, 2019, asenapine transdermal system (Secuado, manufactured by Hisamitsu Pharmaceutical Co., Inc. and distributed by Noven Therapeutics) is the first “patch” approved by the FDA for the treatment of adults with schizophrenia (Table 1).^1-3 Asenapine is a second-generation antipsychotic that was previously available only as a sublingual formulation (Saphris, Allergan [now AbbVie] under license from Merck Sharp & Dohme B.V.).^4-7 Asenapine’s reformulation potentially simplifies using this antipsychotic by reducing the dosing frequency from twice daily (recommended for the sublingual tablet) to once daily (recommended for the patch). The food and drink restrictions posed by the sublingual formulation are eliminated. Also avoided are dysgeusia (bad taste) and hypoesthesia of the tongue (numbing). Asenapine transdermal system offers a different method to manage schizophrenia, and this novel method of administration through the skin is worth considering.⁸

The asenapine transdermal system is available in 3 patch sizes: 20, 30, and 40 cm², which deliver 3.8, 5.7, and 7.6 mg/24 hours of asenapine, respectively.³ Based on the average exposure (area under the plasma concentration curve [AUC]) of asenapine, 3.8 mg/24 hours corresponds to 5 mg twice daily of sublingual asenapine, and 7.6 mg/24 hours corresponds to 10 mg twice daily of sublingual asenapine.³ The “in-between” dose strength of 5.7 mg/24 hours would correspond to exposure to a total of 15 mg/d of sublingual asenapine. The recommended starting dose for asenapine transdermal system is 3.8 mg/24 hours. The dosage may be increased to 5.7 mg/24 hours or 7.6 mg/24 hours, as needed, after 1 week. The safety of doses above 7.6 mg/24 hours has not been evaluated in clinical studies. Asenapine transdermal system is applied once daily and should be worn for 24 hours only, with only 1 patch at any time. Application sites include the upper arm, upper back, abdomen, and hip. A different application site of clean, dry, intact skin should be selected each time a new patch is applied. Although showering is permitted, the use of asenapine transdermal system during swimming or taking a bath has not been evaluated. Of note, prolonged application of heat over an asenapine transdermal system increases plasma concentrations of asenapine, and thus application of external heat sources (eg, heating pads) over the patch should be avoided.

How it works

Product labeling notes that asenapine is an atypical antipsychotic, and that its efficacy in schizophrenia could be mediated through a combination of antagonist activity at dopamine D2 and serotonin 5-HT2A receptors.³ The pharmacodynamic profile of asenapine is complex⁵ and receptor-binding assays performed using cloned human serotonin, norepinephrine, dopamine, histamine, and muscarinic receptors demonstrated picomolar affinity (extremely high) for 5-HT2C and 5-HT2A receptors, subnanomolar affinity (very high) for 5-HT7, 5-HT2B, 5-HT6, and D3 receptors, and nanomolar affinity (high) for D2 receptors, as well as histamine H1, D4, a1-adrenergic, a2-adrenergic, D1, 5-HT5, 5-HT1A, 5-HT1B, and histamine H2 receptors. Activity of asenapine is that of antagonism at these receptors. Asenapine has no appreciable affinity for muscarinic cholinergic receptors.

The asenapine receptor-binding “fingerprint” differs from that of other antipsychotics. Some of these receptor affinities are of special interest in terms of potential efficacy for pro-cognitive effects and amelioration of abnormal mood.^5,9 In terms of tolerability, a relative absence of affinity to muscarinic receptors would predict a low risk for anticholinergic adverse effects, but antagonism at histamine H1 and at a1-adrenergic receptors, either alone or in combination, may cause sedation, and blockade of H1 receptors would also predict weight gain.⁹ Antagonism of a1-adrenergic receptors can be associated with orthostatic hypotension and neurally mediated reflex bradycardia.⁹

Clinical pharmacokinetics

Three open-label, randomized, phase 1 studies were conducted to assess the relative bioavailability of asenapine transdermal system vs sublingual asenapine.¹⁰ These included single- and multiple-dose studies and clinical trials that examined the effects of different application sites and ethnic groups, and the effect of external heat on medication absorption. Studies were conducted in healthy individuals, except for the multiple-dose study, which was performed in adults with schizophrenia. The AUC for asenapine transdermal system was within the range of that of equivalent doses of sublingual asenapine, but peak exposure (maximum concentration) was significantly lower. As already noted, the AUC of the asenapine patch for 3.8 mg/24 hours and 7.6 mg/24 hours corresponds to sublingual asenapine 5 mg and 10 mg twice daily, respectively. Maximum asenapine concentrations are typically reached between 12 and 24 hours, with sustained concentrations during the 24-hour wear time.³ On average, approximately 60% of the available asenapine is released from the transdermal system over 24 hours. Steady-state plasma concentrations for asenapine transdermal system were achieved approximately 72 hours after the first application and, in contrast to sublingual asenapine, the peak-trough fluctuations were small (peak-to-trough ratio is 1.5 for asenapine transdermal system compared with >3 for sublingual asenapine). Dose-proportionality at steady state was evident for asenapine transdermal system. This is in contrast to sublingual asenapine, where exposure increases 1.7-fold with a 2-fold increase in dose.^4,5 Following patch removal, the apparent elimination half-life is approximately 30 hours.³ The pharmacokinetics of the patch did not vary with regards to the application site (upper arm, upper back, abdomen, or hip area), and the pharmacokinetic profile was similar across the ethnic groups that participated in the study. Direct exposure to external heat did increase both the rate and extent of absorption, so external heat sources should be avoided.³

Efficacy

The efficacy profile for asenapine transdermal system would be expected to mirror that for sublingual asenapine.^6,7 In addition to data supporting the use of asenapine as administered sublingually, a phase 3 study specifically assessed efficacy and safety of asenapine transdermal system in adults with schizophrenia.^11,12 This study was conducted in the United States and 4 other countries at a total of 59 study sites, and 616 patients with acutely exacerbated schizophrenia were enrolled. After a 3- to 14-day screening/single-blind run-in washout period, participants entered a 6-week inpatient double-blind period. Randomization was 1:1:1 to asenapine transdermal system 3.8 mg/24 hours, 7.6 mg/24 hours, or a placebo patch. Each of the patch doses demonstrated significant improvement vs placebo at Week 6 for the primary (change in Positive and Negative Syndrome Scale [PANSS] total score) and key secondary (change in Clinical Global Impression-Severity of Illness) endpoints. Response at endpoint, as defined by a ≥30% improvement from baseline PANSS total score, or by a Clinical Global Impression–Improvement score of 1 (very much improved) or 2 (much improved), was also assessed. For either definition of response, both doses of asenapine transdermal system were superior to placebo, with number needed to treat (NNT) (Box) values <10 for the 3.8 mg/24 hours dose (Table 2). These effect sizes are similar to what is known about sublingual asenapine as determined in a meta-analysis performed by the manufacturer and using individual patient data.¹³

Box

Overall tolerability and safety

The systemic safety and tolerability profile for asenapine transdermal system would be expected to be similar to that for sublingual asenapine, unless there are adverse events that are related to high peak plasma concentrations or large differences between peak and trough plasma concentrations.⁶ Nonsystemic local application site adverse events would, of course, differ between sublingual vs transdermal administration.

Continue to: Use of asenapine transdermal system...

Use of asenapine transdermal system avoids the dysgeusia and oral hypoesthesia that can be observed with sublingual asenapine^4,6; however, dermal effects need to be considered (see Dermal safety). The most commonly observed adverse reactions (incidence ≥5% and at least twice that for placebo) for asenapine transdermal system are extrapyramidal disorder, application site reaction, and weight gain.³ For sublingual asenapine for adults with schizophrenia, the list includes akathisia, oral hypoesthesia, and somnolence.⁴ These adverse events can be further described using the metric of number needed to harm (NNH) as shown in Table 3.^3,4,11,12,14 Of note, extrapyramidal disorder and weight gain appear to be dose-related for asenapine transdermal system. Akathisia appears to be dose-related for sublingual asenapine but not for asenapine transdermal system. Somnolence appears to be associated with sublingual asenapine but not necessarily with asenapine transdermal system.

For sublingual asenapine, the additional indications (bipolar I disorder as acute monotherapy treatment of manic or mixed episodes in adults and pediatric patients age 10 to 17, adjunctive treatment to lithium or valproate in adults, and maintenance monotherapy treatment in adults) have varying commonly encountered adverse reactions.⁴ Both transdermal asenapine system and sublingual asenapine are contraindicated in patients with severe hepatic impairment (Child-Pugh C) and those with known hypersensitivity to asenapine or to any components in the formulation. Both formulations carry similar warnings in their prescribing information regarding increased mortality in older patients with dementia-related psychosis, cerebrovascular adverse reactions in older patients with dementia-related psychosis, neuroleptic malignant syndrome, tardive dyskinesia, metabolic changes, orthostatic hypotension, leukopenia (and neutropenia and agranulocytosis), QT prolongation, seizures, and potential for cognitive and motor impairment.

Adverse events leading to discontinuation of study treatment in the asenapine transdermal system pivotal trial occurred in 4.9%, 7.8%, and 6.8% of participants in the 3.8 mg/24 hour, 7.6 mg/24 hour, and placebo groups, respectively.¹¹

Dermal safety

In the pivotal efficacy study,¹¹ the incidence of adverse events at patch application sites was higher in the active groups vs placebo (Table 3^3,4,11,12,14). The most frequently reported patch application site reactions were erythema and pruritus, occurring in approximately 10% and 4% in the active treatment arms vs 1.5% and 1.9% for placebo, respectively. With the exception of 1 adverse event of severe application site erythema during Week 2 (participant received 7.6 mg/24 hour, erythema resolved without intervention, and the patient continued the study), all other patch application site events were mild or moderate in severity. Rates of discontinuation due to application site reactions or skin disorders were ≤0.5% across all groups. In the pharmacokinetic studies,¹⁰ no patches were removed because of unacceptable irritation.

Why Rx?

Asenapine transdermal system is the first antipsychotic “patch” FDA-approved for the treatment of adults with schizophrenia. Asenapine has been available since 2009 as a sublingual formulation administered twice daily. The pharmacokinetic profile of the once-daily transdermal system demonstrates dose-proportional kinetics and sustained delivery of asenapine with a low peak-to-trough plasma level ratio. Three dosage strengths (3.8, 5.7, and 7.6 mg/24 hours) are available, corresponding to blood levels attained with sublingual asenapine exposures of 10, 15, and 20 mg/d, respectively. Application sites are rotated daily and include the upper arms, upper back, abdomen, or hip. Dysgeusia and hypoesthesia of the tongue are avoided with the use of the patch, and there are no food or drink restrictions. Attention will be needed in case of dermal reactions, similar to that observed with other medication patches.

The asenapine transdermal drug delivery system appears to be efficacious and reasonably well tolerated. The treatment of schizophrenia is complex and requires individualized choices in order to optimize outcomes. A patch may be the preferred formulation for selected patients, and caregivers will have the ability to visually check if the medication is being used.

Related Resource

• Hisamitsu Pharmaceutical Co., Inc. SECUADO® (asenapine) transdermal system prescribing information. October 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212268s000lbl.pdf

Drug Brand Names

Asenapine sublingual • Saphris
Asenapine transdermal system • Secuado
Lithium • Eskalith, Lithobid
Valproate • Depakote

Approved by the FDA on October 11, 2019, asenapine transdermal system (Secuado, manufactured by Hisamitsu Pharmaceutical Co., Inc. and distributed by Noven Therapeutics) is the first “patch” approved by the FDA for the treatment of adults with schizophrenia (Table 1).^1-3 Asenapine is a second-generation antipsychotic that was previously available only as a sublingual formulation (Saphris, Allergan [now AbbVie] under license from Merck Sharp & Dohme B.V.).^4-7 Asenapine’s reformulation potentially simplifies using this antipsychotic by reducing the dosing frequency from twice daily (recommended for the sublingual tablet) to once daily (recommended for the patch). The food and drink restrictions posed by the sublingual formulation are eliminated. Also avoided are dysgeusia (bad taste) and hypoesthesia of the tongue (numbing). Asenapine transdermal system offers a different method to manage schizophrenia, and this novel method of administration through the skin is worth considering.⁸

The asenapine transdermal system is available in 3 patch sizes: 20, 30, and 40 cm², which deliver 3.8, 5.7, and 7.6 mg/24 hours of asenapine, respectively.³ Based on the average exposure (area under the plasma concentration curve [AUC]) of asenapine, 3.8 mg/24 hours corresponds to 5 mg twice daily of sublingual asenapine, and 7.6 mg/24 hours corresponds to 10 mg twice daily of sublingual asenapine.³ The “in-between” dose strength of 5.7 mg/24 hours would correspond to exposure to a total of 15 mg/d of sublingual asenapine. The recommended starting dose for asenapine transdermal system is 3.8 mg/24 hours. The dosage may be increased to 5.7 mg/24 hours or 7.6 mg/24 hours, as needed, after 1 week. The safety of doses above 7.6 mg/24 hours has not been evaluated in clinical studies. Asenapine transdermal system is applied once daily and should be worn for 24 hours only, with only 1 patch at any time. Application sites include the upper arm, upper back, abdomen, and hip. A different application site of clean, dry, intact skin should be selected each time a new patch is applied. Although showering is permitted, the use of asenapine transdermal system during swimming or taking a bath has not been evaluated. Of note, prolonged application of heat over an asenapine transdermal system increases plasma concentrations of asenapine, and thus application of external heat sources (eg, heating pads) over the patch should be avoided.

How it works

Product labeling notes that asenapine is an atypical antipsychotic, and that its efficacy in schizophrenia could be mediated through a combination of antagonist activity at dopamine D2 and serotonin 5-HT2A receptors.³ The pharmacodynamic profile of asenapine is complex⁵ and receptor-binding assays performed using cloned human serotonin, norepinephrine, dopamine, histamine, and muscarinic receptors demonstrated picomolar affinity (extremely high) for 5-HT2C and 5-HT2A receptors, subnanomolar affinity (very high) for 5-HT7, 5-HT2B, 5-HT6, and D3 receptors, and nanomolar affinity (high) for D2 receptors, as well as histamine H1, D4, a1-adrenergic, a2-adrenergic, D1, 5-HT5, 5-HT1A, 5-HT1B, and histamine H2 receptors. Activity of asenapine is that of antagonism at these receptors. Asenapine has no appreciable affinity for muscarinic cholinergic receptors.

The asenapine receptor-binding “fingerprint” differs from that of other antipsychotics. Some of these receptor affinities are of special interest in terms of potential efficacy for pro-cognitive effects and amelioration of abnormal mood.^5,9 In terms of tolerability, a relative absence of affinity to muscarinic receptors would predict a low risk for anticholinergic adverse effects, but antagonism at histamine H1 and at a1-adrenergic receptors, either alone or in combination, may cause sedation, and blockade of H1 receptors would also predict weight gain.⁹ Antagonism of a1-adrenergic receptors can be associated with orthostatic hypotension and neurally mediated reflex bradycardia.⁹

Clinical pharmacokinetics

Three open-label, randomized, phase 1 studies were conducted to assess the relative bioavailability of asenapine transdermal system vs sublingual asenapine.¹⁰ These included single- and multiple-dose studies and clinical trials that examined the effects of different application sites and ethnic groups, and the effect of external heat on medication absorption. Studies were conducted in healthy individuals, except for the multiple-dose study, which was performed in adults with schizophrenia. The AUC for asenapine transdermal system was within the range of that of equivalent doses of sublingual asenapine, but peak exposure (maximum concentration) was significantly lower. As already noted, the AUC of the asenapine patch for 3.8 mg/24 hours and 7.6 mg/24 hours corresponds to sublingual asenapine 5 mg and 10 mg twice daily, respectively. Maximum asenapine concentrations are typically reached between 12 and 24 hours, with sustained concentrations during the 24-hour wear time.³ On average, approximately 60% of the available asenapine is released from the transdermal system over 24 hours. Steady-state plasma concentrations for asenapine transdermal system were achieved approximately 72 hours after the first application and, in contrast to sublingual asenapine, the peak-trough fluctuations were small (peak-to-trough ratio is 1.5 for asenapine transdermal system compared with >3 for sublingual asenapine). Dose-proportionality at steady state was evident for asenapine transdermal system. This is in contrast to sublingual asenapine, where exposure increases 1.7-fold with a 2-fold increase in dose.^4,5 Following patch removal, the apparent elimination half-life is approximately 30 hours.³ The pharmacokinetics of the patch did not vary with regards to the application site (upper arm, upper back, abdomen, or hip area), and the pharmacokinetic profile was similar across the ethnic groups that participated in the study. Direct exposure to external heat did increase both the rate and extent of absorption, so external heat sources should be avoided.³

Efficacy

The efficacy profile for asenapine transdermal system would be expected to mirror that for sublingual asenapine.^6,7 In addition to data supporting the use of asenapine as administered sublingually, a phase 3 study specifically assessed efficacy and safety of asenapine transdermal system in adults with schizophrenia.^11,12 This study was conducted in the United States and 4 other countries at a total of 59 study sites, and 616 patients with acutely exacerbated schizophrenia were enrolled. After a 3- to 14-day screening/single-blind run-in washout period, participants entered a 6-week inpatient double-blind period. Randomization was 1:1:1 to asenapine transdermal system 3.8 mg/24 hours, 7.6 mg/24 hours, or a placebo patch. Each of the patch doses demonstrated significant improvement vs placebo at Week 6 for the primary (change in Positive and Negative Syndrome Scale [PANSS] total score) and key secondary (change in Clinical Global Impression-Severity of Illness) endpoints. Response at endpoint, as defined by a ≥30% improvement from baseline PANSS total score, or by a Clinical Global Impression–Improvement score of 1 (very much improved) or 2 (much improved), was also assessed. For either definition of response, both doses of asenapine transdermal system were superior to placebo, with number needed to treat (NNT) (Box) values <10 for the 3.8 mg/24 hours dose (Table 2). These effect sizes are similar to what is known about sublingual asenapine as determined in a meta-analysis performed by the manufacturer and using individual patient data.¹³

Box

Overall tolerability and safety

The systemic safety and tolerability profile for asenapine transdermal system would be expected to be similar to that for sublingual asenapine, unless there are adverse events that are related to high peak plasma concentrations or large differences between peak and trough plasma concentrations.⁶ Nonsystemic local application site adverse events would, of course, differ between sublingual vs transdermal administration.

Continue to: Use of asenapine transdermal system...

Use of asenapine transdermal system avoids the dysgeusia and oral hypoesthesia that can be observed with sublingual asenapine^4,6; however, dermal effects need to be considered (see Dermal safety). The most commonly observed adverse reactions (incidence ≥5% and at least twice that for placebo) for asenapine transdermal system are extrapyramidal disorder, application site reaction, and weight gain.³ For sublingual asenapine for adults with schizophrenia, the list includes akathisia, oral hypoesthesia, and somnolence.⁴ These adverse events can be further described using the metric of number needed to harm (NNH) as shown in Table 3.^3,4,11,12,14 Of note, extrapyramidal disorder and weight gain appear to be dose-related for asenapine transdermal system. Akathisia appears to be dose-related for sublingual asenapine but not for asenapine transdermal system. Somnolence appears to be associated with sublingual asenapine but not necessarily with asenapine transdermal system.

For sublingual asenapine, the additional indications (bipolar I disorder as acute monotherapy treatment of manic or mixed episodes in adults and pediatric patients age 10 to 17, adjunctive treatment to lithium or valproate in adults, and maintenance monotherapy treatment in adults) have varying commonly encountered adverse reactions.⁴ Both transdermal asenapine system and sublingual asenapine are contraindicated in patients with severe hepatic impairment (Child-Pugh C) and those with known hypersensitivity to asenapine or to any components in the formulation. Both formulations carry similar warnings in their prescribing information regarding increased mortality in older patients with dementia-related psychosis, cerebrovascular adverse reactions in older patients with dementia-related psychosis, neuroleptic malignant syndrome, tardive dyskinesia, metabolic changes, orthostatic hypotension, leukopenia (and neutropenia and agranulocytosis), QT prolongation, seizures, and potential for cognitive and motor impairment.

Adverse events leading to discontinuation of study treatment in the asenapine transdermal system pivotal trial occurred in 4.9%, 7.8%, and 6.8% of participants in the 3.8 mg/24 hour, 7.6 mg/24 hour, and placebo groups, respectively.¹¹

Dermal safety

In the pivotal efficacy study,¹¹ the incidence of adverse events at patch application sites was higher in the active groups vs placebo (Table 3^3,4,11,12,14). The most frequently reported patch application site reactions were erythema and pruritus, occurring in approximately 10% and 4% in the active treatment arms vs 1.5% and 1.9% for placebo, respectively. With the exception of 1 adverse event of severe application site erythema during Week 2 (participant received 7.6 mg/24 hour, erythema resolved without intervention, and the patient continued the study), all other patch application site events were mild or moderate in severity. Rates of discontinuation due to application site reactions or skin disorders were ≤0.5% across all groups. In the pharmacokinetic studies,¹⁰ no patches were removed because of unacceptable irritation.

Why Rx?

Asenapine transdermal system is the first antipsychotic “patch” FDA-approved for the treatment of adults with schizophrenia. Asenapine has been available since 2009 as a sublingual formulation administered twice daily. The pharmacokinetic profile of the once-daily transdermal system demonstrates dose-proportional kinetics and sustained delivery of asenapine with a low peak-to-trough plasma level ratio. Three dosage strengths (3.8, 5.7, and 7.6 mg/24 hours) are available, corresponding to blood levels attained with sublingual asenapine exposures of 10, 15, and 20 mg/d, respectively. Application sites are rotated daily and include the upper arms, upper back, abdomen, or hip. Dysgeusia and hypoesthesia of the tongue are avoided with the use of the patch, and there are no food or drink restrictions. Attention will be needed in case of dermal reactions, similar to that observed with other medication patches.

The asenapine transdermal drug delivery system appears to be efficacious and reasonably well tolerated. The treatment of schizophrenia is complex and requires individualized choices in order to optimize outcomes. A patch may be the preferred formulation for selected patients, and caregivers will have the ability to visually check if the medication is being used.

Related Resource

• Hisamitsu Pharmaceutical Co., Inc. SECUADO® (asenapine) transdermal system prescribing information. October 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212268s000lbl.pdf

Drug Brand Names

Asenapine sublingual • Saphris
Asenapine transdermal system • Secuado
Lithium • Eskalith, Lithobid
Valproate • Depakote

CASE Visual, auditory, and tactile hallucinations

Mr. B, age 93, is brought to the emergency department by his son after experiencing hallucinations where he reportedly saw and heard individuals in his home. In frustration, Mr. B wielded a knife because he “wanted them to go away.”

Mr. B and his son report that the hallucinations had begun 2 years ago, without prior trauma, medication changes, changes in social situation, or other apparent precipitating events. The hallucinations “come and go,” without preceding symptoms, but have recurring content involving a friendly man named “Harry,” people coming out of the television, 2 children playing, and water covering the floor. Mr. B acknowledges these are hallucinations and had not felt threatened by them until recently, when he wielded the knife. He often tries to talk to them, but they do not reply.

Mr. B also reports intermittent auditory hallucinations including voices at home (non-command) and papers rustling. He also describes tactile hallucinations, where he says he can feel Harry and others prodding him, knocking things out of his hands, or splashing him with water.

Mr. B is admitted to the hospital because he is a danger to himself and others. While on the inpatient unit, Mr. B is pleasant with staff, and eats and sleeps normally; however, he continues to have hallucinations of Harry. Mr. B reports seeing Harry in the hall, and says that Harry pulls out Mr. B’s earpiece and steals his fork. Mr. B also reports hearing a sound “like a bee buzzing.” Mr. B is started on risperidone, 1 mg nightly, for a presumed psychotic disorder.

HISTORY Independent and in good health

Mr. B lives alone and is independent in his activities of daily living. He spends his days at home, often visited by his children, who bring him groceries and other necessities.

Mr. B takes no medications, and has no history of psychiatric treatment; psychotic, manic, or depressive episodes; posttraumatic stress disorder; obsessive-compulsive disorder; or recent emotional stress. His medical history includes chronic progressive hearing loss, which is managed with hearing aids; macular degeneration; and prior bilateral cataract surgeries.

EVALUATION Mental status exam and objective findings

During his evaluation, Mr. B appears well-nourished, and wears glasses and hearing aids. During the interview, he is euthymic with appropriately reactive affect. He is talkative but redirectable, with a goal-directed thought process. Mr. B does not appear to be internally preoccupied. His hearing is impaired, and he often requires questions to be repeated loudly. He is oriented to person, place, and time. There are no signs of delusions, paranoia, thought blocking, thought broadcasting/insertion, or referential thinking. He denies depressed mood, anhedonia, fatigue, sleep changes, or manic symptoms. He denies the occurrence of auditory or visual hallucinations during the evaluation.

Continue to: A neurologic exam shows...

A neurologic exam shows impaired hearing bilaterally and impaired visual acuity. Even with glasses, both eyes have acuity only to finger counting. All other cranial nerves are normal, and Mr. B’s strength, sensation, and cerebellar function are all intact, without rigidity, numbness, or tingling. His gait is steady without a walker, with symmetric arm swing and slight dragging of his feet. His vitals are stable, with normal orthostatic pressures.

Other objective data include a score of 24/30 on the Mini-Mental State Examination, notable for deficits in visuospatial orientation, attention, and calculation, with language and copying limited by poor vision. Mr. B scores 16/22 on the Montreal Cognitive Assessment (MoCA)-Blind (adapted version of MoCA), which is equivalent to a 22/30 on the MoCA, indicating some mild cognitive impairment; however, this modified test is still limited by his poor hearing. His serum and urine laboratory workup show no liver, kidney, metabolic, or electrolyte abnormalities, no sign of infection, negative urine drug screen, and normal B12 and thyroid-stimulating hormone levels. He undergoes a brain MRI, which shows chronic microvascular ischemic change, without mass lesions, infarction, or other pathology.

[polldaddy:10729178]

The authors’ observations

Given Mr. B’s presentation, we ruled out a primary psychotic disorder. He had no psychiatric history, with organized thought, a reactive affect, and no delusions, paranoia, or other psychotic symptoms, all pointing against psychosis. His brain MRI showed no malignancy or other lesions. He had no substance use history to suggest intoxication/withdrawal. His intact attention and orientation did not suggest delirium, and his serum and urine studies were all negative. Although his blaming Harry for knocking things out of his hands could suggest confabulation, Mr. B had no other signs of Korsakoff syndrome, such as ataxia, general confusion, or malnourishment.

We also considered early dementia. There was suspicion for Lewy body dementia given Mr. B’s prominent fluctuating visual hallucinations; however, he displayed no other signs of the disorder, such as parkinsonism, dysautonomia, or sensitivity to the antipsychotic (risperidone 1 mg nightly) started on admission. The presence of 1 core feature of Lewy body dementia—visual hallucinations—indicated a possible, but not probable, diagnosis. Additionally, Mr. B did not have the characteristic features of other types of dementia, such as the stepwise progression of vascular dementia, the behavioral disinhibition of frontotemporal dementia, or the insidious forgetfulness, confusion, language problems, or paranoia that may appear in Alzheimer’s disease. Remarkably, he had a relatively normal brain MRI for his age, given chronic microvascular ischemic changes, and cognitive testing that indicated only mild impairment further pointed against a dementia process.

Charles Bonnet syndrome

Based on Mr. B’s severe vision loss and history of ocular surgeries, we diagnosed him with CBS, described as visual hallucinations in the presence of impaired vision. Charles Bonnet syndrome has been observed in several disorders that affect vision, most commonly macular degeneration, diabetic retinopathy, and glaucoma, with an estimated prevalence of 11% to 39% in older patients with ocular disease.^1,2 Visual hallucinations in CBS occur due to ocular disease, likely resulting from changes in afferent sensory input to visual cortical regions of the brain. Table 1³ outlines the features of visual hallucinations in patients with CBS. The subsequent disinhibition and spontaneous firing of the visual association cortices leads to the “release hallucinations” of the syndrome.⁴ The disorder is thought to be significantly underdiagnosed—in a survey of patients with CBS, only 15% had reported their visual hallucinations to a physician.⁵

Continue to: Mr. B's symptoms...

Mr. B’s symptoms are atypical for CBS, but they fit the diagnosis when considering the entire clinical picture. While hallucinations in CBS are more often simple shapes, complex hallucinations including people and scenes have been noted in several instances.⁶

Similar to Mr. B’s case, patients with CBS can have recurring figures in their hallucinations, and the images may even move across the visual field.¹ Patients with CBS also frequently recognize that their hallucinations are not real, and may or may not be distressed by them.⁴ Patients with CBS often have hallucinations multiple times daily, lasting from a few seconds to many minutes,⁷ consistent with Mr. B’s temporary symptoms.

Although auditory and tactile hallucinations are typically not included in CBS, they can also be explained by Mr. B’s significant sensory impairment. Severe hearing impairment in geriatric adults has been associated with auditory hallucinations⁸; in 1 survey, half of these hallucinations consisted of voices.⁹ In contrast, tactile hallucinations are not described in sensory deprivation literature. However, in the context of Mr. B’s severe comorbid hearing and vision loss, we propose that these hallucinations reflect his interpretation of sensory events around him, and their integration into his extensive hallucination framework. In other words, Harry poking him and causing him to drop things may be Mr. B’s way of rationalizing events that he has trouble perceiving entirely, or his mild forgetfulness. Mr. B’s social isolation is another factor that may worsen his sensory deprivation and contribute to his extensive hallucinations.¹⁰ Additionally, his mild cognitive deficits on testing with chronic microvascular changes on the MRI may suggest a mild vascular-related dementia process, which could also exacerbate his hallucinations. While classic CBS occurs without cognitive impairment, dementia can often co-occur with CBS.¹¹

TREATMENT No significant improvement with medications

During his inpatient stay, Mr. B is treated with risperidone, 1 mg nightly, and is also started on donepezil, 5 mg/d, to treat a possible comorbid dementia. However, he continues to hallucinate without significant improvement.

[polldaddy:10729181]

The authors’ observations

There is no definitive treatment for CBS, and while the hallucinations may spontaneously resolve, per case reports, this typically occurs only as visual loss progresses to total blindness.¹² However, many patients can have the hallucinations remit after the underlying ocular etiology is corrected, such as through ocular surgery.¹³ Other optical interventions, such as special glasses or contact lenses, may help maximize remaining vision.⁸ In patients without this option, such as Mr. B, there are limited data on beneficial medications for CBS.

Continue to: Evidence for treatment of CBS...

Evidence for treatment of CBS with antipsychotic medications is mixed. Some case studies have found them to be ineffective, while others have found agents such as olanzapine or risperidone to be partially helpful in reducing symptoms.¹⁴ There are also data from case reports that may support the use of cholinesterase inhibitors such as donepezil, antiepileptics (carbamazepine, valproate, gabapentin, and clonazepam), and certain antidepressants (escitalopram, venlafaxine) (Table 2^8,11).³

Addressing loneliness and social isolation

With minimal definitive evidence for pharmacologic management, the most important intervention for treating CBS may be changing the patient’s sensory environment. Specifically, loneliness and social isolation are major exacerbating factors of CBS, and many clinicians advocate for the consistent presence of a sympathetic professional. Reassurance that hallucinations are from ocular disease rather than a primary mental disorder may be extremely relieving for patients.¹¹ A psychoeducation or support group may also be beneficial, not only for giving patients more social contact, but also for teaching them coping skills or strategies to reduce hallucinations, such as distraction, turning on more lights, or even certain eye/blinking movements.¹¹ Table 2^8,11 (page 49) outlines behavioral interventions for CBS.

Regardless of etiology, Mr. B’s hallucinations significantly affected his quality of life. During his inpatient stay, he was treated with risperidone, 1 mg nightly, because it was determined that the benefits of treatment with an antipsychotic medication outweigh the risks. He was also started on donepezil, 5 mg/d, to treat a possible comorbid dementia. However, his hallucinations continued without significant improvement.

OUTCOME Home care and family involvement

After discussion with Mr. B and his family about the risks and benefits of medication, the risperidone and donepezil are discontinued. Ultimately, it is determined that Mr. B requires a higher level of home care, both for his safety and to improve his social contact. Mr. B returns home with a combination of a professional home health aide and increased family involvement.

Bottom Line

When evaluating visual hallucinations in older adults, Charles Bonnet syndrome (CBS) should be considered. Sensory deprivation and social isolation are significant risk factors for CBS. While evidence is inconclusive for medical treatment, reassurance and behavioral interventions can often improve symptoms.

Continue to: Related Resources

• Charles Bonnet Syndrome Foundation. http://www.charlesbonnetsyndrome.org
• Schultz G, Melzack R. The Charles Bonnet syndrome: ‘phantom visual images’. Perception. 1991;20:809-825.
• Menon GJ, Rahman I, Menon SJ, et al. Complex visual hallucinations in the visually impaired: the Charles Bonnet syndrome. Surv Ophthalmol. 2003;48(1):58-72.

Drug Brand Names

Carbamazepine • Tegretol
Clonazepam • Klonopin
Donepezil • Aricept
Escitalopram • Lexapro
Gabapentin • Neurontin
Olanzapine • Zyprexa
Risperidone • Risperdal
Valproate • Depakote
Venlafaxine • Effexor

CASE Visual, auditory, and tactile hallucinations

Mr. B, age 93, is brought to the emergency department by his son after experiencing hallucinations where he reportedly saw and heard individuals in his home. In frustration, Mr. B wielded a knife because he “wanted them to go away.”

Mr. B and his son report that the hallucinations had begun 2 years ago, without prior trauma, medication changes, changes in social situation, or other apparent precipitating events. The hallucinations “come and go,” without preceding symptoms, but have recurring content involving a friendly man named “Harry,” people coming out of the television, 2 children playing, and water covering the floor. Mr. B acknowledges these are hallucinations and had not felt threatened by them until recently, when he wielded the knife. He often tries to talk to them, but they do not reply.

Mr. B also reports intermittent auditory hallucinations including voices at home (non-command) and papers rustling. He also describes tactile hallucinations, where he says he can feel Harry and others prodding him, knocking things out of his hands, or splashing him with water.

Mr. B is admitted to the hospital because he is a danger to himself and others. While on the inpatient unit, Mr. B is pleasant with staff, and eats and sleeps normally; however, he continues to have hallucinations of Harry. Mr. B reports seeing Harry in the hall, and says that Harry pulls out Mr. B’s earpiece and steals his fork. Mr. B also reports hearing a sound “like a bee buzzing.” Mr. B is started on risperidone, 1 mg nightly, for a presumed psychotic disorder.

HISTORY Independent and in good health

Mr. B lives alone and is independent in his activities of daily living. He spends his days at home, often visited by his children, who bring him groceries and other necessities.

Mr. B takes no medications, and has no history of psychiatric treatment; psychotic, manic, or depressive episodes; posttraumatic stress disorder; obsessive-compulsive disorder; or recent emotional stress. His medical history includes chronic progressive hearing loss, which is managed with hearing aids; macular degeneration; and prior bilateral cataract surgeries.

EVALUATION Mental status exam and objective findings

During his evaluation, Mr. B appears well-nourished, and wears glasses and hearing aids. During the interview, he is euthymic with appropriately reactive affect. He is talkative but redirectable, with a goal-directed thought process. Mr. B does not appear to be internally preoccupied. His hearing is impaired, and he often requires questions to be repeated loudly. He is oriented to person, place, and time. There are no signs of delusions, paranoia, thought blocking, thought broadcasting/insertion, or referential thinking. He denies depressed mood, anhedonia, fatigue, sleep changes, or manic symptoms. He denies the occurrence of auditory or visual hallucinations during the evaluation.

Continue to: A neurologic exam shows...

A neurologic exam shows impaired hearing bilaterally and impaired visual acuity. Even with glasses, both eyes have acuity only to finger counting. All other cranial nerves are normal, and Mr. B’s strength, sensation, and cerebellar function are all intact, without rigidity, numbness, or tingling. His gait is steady without a walker, with symmetric arm swing and slight dragging of his feet. His vitals are stable, with normal orthostatic pressures.

Other objective data include a score of 24/30 on the Mini-Mental State Examination, notable for deficits in visuospatial orientation, attention, and calculation, with language and copying limited by poor vision. Mr. B scores 16/22 on the Montreal Cognitive Assessment (MoCA)-Blind (adapted version of MoCA), which is equivalent to a 22/30 on the MoCA, indicating some mild cognitive impairment; however, this modified test is still limited by his poor hearing. His serum and urine laboratory workup show no liver, kidney, metabolic, or electrolyte abnormalities, no sign of infection, negative urine drug screen, and normal B12 and thyroid-stimulating hormone levels. He undergoes a brain MRI, which shows chronic microvascular ischemic change, without mass lesions, infarction, or other pathology.

[polldaddy:10729178]

The authors’ observations

Given Mr. B’s presentation, we ruled out a primary psychotic disorder. He had no psychiatric history, with organized thought, a reactive affect, and no delusions, paranoia, or other psychotic symptoms, all pointing against psychosis. His brain MRI showed no malignancy or other lesions. He had no substance use history to suggest intoxication/withdrawal. His intact attention and orientation did not suggest delirium, and his serum and urine studies were all negative. Although his blaming Harry for knocking things out of his hands could suggest confabulation, Mr. B had no other signs of Korsakoff syndrome, such as ataxia, general confusion, or malnourishment.

We also considered early dementia. There was suspicion for Lewy body dementia given Mr. B’s prominent fluctuating visual hallucinations; however, he displayed no other signs of the disorder, such as parkinsonism, dysautonomia, or sensitivity to the antipsychotic (risperidone 1 mg nightly) started on admission. The presence of 1 core feature of Lewy body dementia—visual hallucinations—indicated a possible, but not probable, diagnosis. Additionally, Mr. B did not have the characteristic features of other types of dementia, such as the stepwise progression of vascular dementia, the behavioral disinhibition of frontotemporal dementia, or the insidious forgetfulness, confusion, language problems, or paranoia that may appear in Alzheimer’s disease. Remarkably, he had a relatively normal brain MRI for his age, given chronic microvascular ischemic changes, and cognitive testing that indicated only mild impairment further pointed against a dementia process.

Charles Bonnet syndrome

Based on Mr. B’s severe vision loss and history of ocular surgeries, we diagnosed him with CBS, described as visual hallucinations in the presence of impaired vision. Charles Bonnet syndrome has been observed in several disorders that affect vision, most commonly macular degeneration, diabetic retinopathy, and glaucoma, with an estimated prevalence of 11% to 39% in older patients with ocular disease.^1,2 Visual hallucinations in CBS occur due to ocular disease, likely resulting from changes in afferent sensory input to visual cortical regions of the brain. Table 1³ outlines the features of visual hallucinations in patients with CBS. The subsequent disinhibition and spontaneous firing of the visual association cortices leads to the “release hallucinations” of the syndrome.⁴ The disorder is thought to be significantly underdiagnosed—in a survey of patients with CBS, only 15% had reported their visual hallucinations to a physician.⁵

Continue to: Mr. B's symptoms...

Mr. B’s symptoms are atypical for CBS, but they fit the diagnosis when considering the entire clinical picture. While hallucinations in CBS are more often simple shapes, complex hallucinations including people and scenes have been noted in several instances.⁶

Similar to Mr. B’s case, patients with CBS can have recurring figures in their hallucinations, and the images may even move across the visual field.¹ Patients with CBS also frequently recognize that their hallucinations are not real, and may or may not be distressed by them.⁴ Patients with CBS often have hallucinations multiple times daily, lasting from a few seconds to many minutes,⁷ consistent with Mr. B’s temporary symptoms.

Although auditory and tactile hallucinations are typically not included in CBS, they can also be explained by Mr. B’s significant sensory impairment. Severe hearing impairment in geriatric adults has been associated with auditory hallucinations⁸; in 1 survey, half of these hallucinations consisted of voices.⁹ In contrast, tactile hallucinations are not described in sensory deprivation literature. However, in the context of Mr. B’s severe comorbid hearing and vision loss, we propose that these hallucinations reflect his interpretation of sensory events around him, and their integration into his extensive hallucination framework. In other words, Harry poking him and causing him to drop things may be Mr. B’s way of rationalizing events that he has trouble perceiving entirely, or his mild forgetfulness. Mr. B’s social isolation is another factor that may worsen his sensory deprivation and contribute to his extensive hallucinations.¹⁰ Additionally, his mild cognitive deficits on testing with chronic microvascular changes on the MRI may suggest a mild vascular-related dementia process, which could also exacerbate his hallucinations. While classic CBS occurs without cognitive impairment, dementia can often co-occur with CBS.¹¹

TREATMENT No significant improvement with medications

During his inpatient stay, Mr. B is treated with risperidone, 1 mg nightly, and is also started on donepezil, 5 mg/d, to treat a possible comorbid dementia. However, he continues to hallucinate without significant improvement.

[polldaddy:10729181]

The authors’ observations

There is no definitive treatment for CBS, and while the hallucinations may spontaneously resolve, per case reports, this typically occurs only as visual loss progresses to total blindness.¹² However, many patients can have the hallucinations remit after the underlying ocular etiology is corrected, such as through ocular surgery.¹³ Other optical interventions, such as special glasses or contact lenses, may help maximize remaining vision.⁸ In patients without this option, such as Mr. B, there are limited data on beneficial medications for CBS.

Continue to: Evidence for treatment of CBS...

Evidence for treatment of CBS with antipsychotic medications is mixed. Some case studies have found them to be ineffective, while others have found agents such as olanzapine or risperidone to be partially helpful in reducing symptoms.¹⁴ There are also data from case reports that may support the use of cholinesterase inhibitors such as donepezil, antiepileptics (carbamazepine, valproate, gabapentin, and clonazepam), and certain antidepressants (escitalopram, venlafaxine) (Table 2^8,11).³

Addressing loneliness and social isolation

With minimal definitive evidence for pharmacologic management, the most important intervention for treating CBS may be changing the patient’s sensory environment. Specifically, loneliness and social isolation are major exacerbating factors of CBS, and many clinicians advocate for the consistent presence of a sympathetic professional. Reassurance that hallucinations are from ocular disease rather than a primary mental disorder may be extremely relieving for patients.¹¹ A psychoeducation or support group may also be beneficial, not only for giving patients more social contact, but also for teaching them coping skills or strategies to reduce hallucinations, such as distraction, turning on more lights, or even certain eye/blinking movements.¹¹ Table 2^8,11 (page 49) outlines behavioral interventions for CBS.

Regardless of etiology, Mr. B’s hallucinations significantly affected his quality of life. During his inpatient stay, he was treated with risperidone, 1 mg nightly, because it was determined that the benefits of treatment with an antipsychotic medication outweigh the risks. He was also started on donepezil, 5 mg/d, to treat a possible comorbid dementia. However, his hallucinations continued without significant improvement.

OUTCOME Home care and family involvement

After discussion with Mr. B and his family about the risks and benefits of medication, the risperidone and donepezil are discontinued. Ultimately, it is determined that Mr. B requires a higher level of home care, both for his safety and to improve his social contact. Mr. B returns home with a combination of a professional home health aide and increased family involvement.

Bottom Line

When evaluating visual hallucinations in older adults, Charles Bonnet syndrome (CBS) should be considered. Sensory deprivation and social isolation are significant risk factors for CBS. While evidence is inconclusive for medical treatment, reassurance and behavioral interventions can often improve symptoms.

Continue to: Related Resources

• Charles Bonnet Syndrome Foundation. http://www.charlesbonnetsyndrome.org
• Schultz G, Melzack R. The Charles Bonnet syndrome: ‘phantom visual images’. Perception. 1991;20:809-825.
• Menon GJ, Rahman I, Menon SJ, et al. Complex visual hallucinations in the visually impaired: the Charles Bonnet syndrome. Surv Ophthalmol. 2003;48(1):58-72.

Drug Brand Names

Carbamazepine • Tegretol
Clonazepam • Klonopin
Donepezil • Aricept
Escitalopram • Lexapro
Gabapentin • Neurontin
Olanzapine • Zyprexa
Risperidone • Risperdal
Valproate • Depakote
Venlafaxine • Effexor

CASE Visual, auditory, and tactile hallucinations

Mr. B, age 93, is brought to the emergency department by his son after experiencing hallucinations where he reportedly saw and heard individuals in his home. In frustration, Mr. B wielded a knife because he “wanted them to go away.”

Mr. B and his son report that the hallucinations had begun 2 years ago, without prior trauma, medication changes, changes in social situation, or other apparent precipitating events. The hallucinations “come and go,” without preceding symptoms, but have recurring content involving a friendly man named “Harry,” people coming out of the television, 2 children playing, and water covering the floor. Mr. B acknowledges these are hallucinations and had not felt threatened by them until recently, when he wielded the knife. He often tries to talk to them, but they do not reply.

Mr. B also reports intermittent auditory hallucinations including voices at home (non-command) and papers rustling. He also describes tactile hallucinations, where he says he can feel Harry and others prodding him, knocking things out of his hands, or splashing him with water.

Mr. B is admitted to the hospital because he is a danger to himself and others. While on the inpatient unit, Mr. B is pleasant with staff, and eats and sleeps normally; however, he continues to have hallucinations of Harry. Mr. B reports seeing Harry in the hall, and says that Harry pulls out Mr. B’s earpiece and steals his fork. Mr. B also reports hearing a sound “like a bee buzzing.” Mr. B is started on risperidone, 1 mg nightly, for a presumed psychotic disorder.

HISTORY Independent and in good health

Mr. B lives alone and is independent in his activities of daily living. He spends his days at home, often visited by his children, who bring him groceries and other necessities.

Mr. B takes no medications, and has no history of psychiatric treatment; psychotic, manic, or depressive episodes; posttraumatic stress disorder; obsessive-compulsive disorder; or recent emotional stress. His medical history includes chronic progressive hearing loss, which is managed with hearing aids; macular degeneration; and prior bilateral cataract surgeries.

EVALUATION Mental status exam and objective findings

During his evaluation, Mr. B appears well-nourished, and wears glasses and hearing aids. During the interview, he is euthymic with appropriately reactive affect. He is talkative but redirectable, with a goal-directed thought process. Mr. B does not appear to be internally preoccupied. His hearing is impaired, and he often requires questions to be repeated loudly. He is oriented to person, place, and time. There are no signs of delusions, paranoia, thought blocking, thought broadcasting/insertion, or referential thinking. He denies depressed mood, anhedonia, fatigue, sleep changes, or manic symptoms. He denies the occurrence of auditory or visual hallucinations during the evaluation.

Continue to: A neurologic exam shows...

A neurologic exam shows impaired hearing bilaterally and impaired visual acuity. Even with glasses, both eyes have acuity only to finger counting. All other cranial nerves are normal, and Mr. B’s strength, sensation, and cerebellar function are all intact, without rigidity, numbness, or tingling. His gait is steady without a walker, with symmetric arm swing and slight dragging of his feet. His vitals are stable, with normal orthostatic pressures.

Other objective data include a score of 24/30 on the Mini-Mental State Examination, notable for deficits in visuospatial orientation, attention, and calculation, with language and copying limited by poor vision. Mr. B scores 16/22 on the Montreal Cognitive Assessment (MoCA)-Blind (adapted version of MoCA), which is equivalent to a 22/30 on the MoCA, indicating some mild cognitive impairment; however, this modified test is still limited by his poor hearing. His serum and urine laboratory workup show no liver, kidney, metabolic, or electrolyte abnormalities, no sign of infection, negative urine drug screen, and normal B12 and thyroid-stimulating hormone levels. He undergoes a brain MRI, which shows chronic microvascular ischemic change, without mass lesions, infarction, or other pathology.

[polldaddy:10729178]

The authors’ observations

Given Mr. B’s presentation, we ruled out a primary psychotic disorder. He had no psychiatric history, with organized thought, a reactive affect, and no delusions, paranoia, or other psychotic symptoms, all pointing against psychosis. His brain MRI showed no malignancy or other lesions. He had no substance use history to suggest intoxication/withdrawal. His intact attention and orientation did not suggest delirium, and his serum and urine studies were all negative. Although his blaming Harry for knocking things out of his hands could suggest confabulation, Mr. B had no other signs of Korsakoff syndrome, such as ataxia, general confusion, or malnourishment.

We also considered early dementia. There was suspicion for Lewy body dementia given Mr. B’s prominent fluctuating visual hallucinations; however, he displayed no other signs of the disorder, such as parkinsonism, dysautonomia, or sensitivity to the antipsychotic (risperidone 1 mg nightly) started on admission. The presence of 1 core feature of Lewy body dementia—visual hallucinations—indicated a possible, but not probable, diagnosis. Additionally, Mr. B did not have the characteristic features of other types of dementia, such as the stepwise progression of vascular dementia, the behavioral disinhibition of frontotemporal dementia, or the insidious forgetfulness, confusion, language problems, or paranoia that may appear in Alzheimer’s disease. Remarkably, he had a relatively normal brain MRI for his age, given chronic microvascular ischemic changes, and cognitive testing that indicated only mild impairment further pointed against a dementia process.

Charles Bonnet syndrome

Based on Mr. B’s severe vision loss and history of ocular surgeries, we diagnosed him with CBS, described as visual hallucinations in the presence of impaired vision. Charles Bonnet syndrome has been observed in several disorders that affect vision, most commonly macular degeneration, diabetic retinopathy, and glaucoma, with an estimated prevalence of 11% to 39% in older patients with ocular disease.^1,2 Visual hallucinations in CBS occur due to ocular disease, likely resulting from changes in afferent sensory input to visual cortical regions of the brain. Table 1³ outlines the features of visual hallucinations in patients with CBS. The subsequent disinhibition and spontaneous firing of the visual association cortices leads to the “release hallucinations” of the syndrome.⁴ The disorder is thought to be significantly underdiagnosed—in a survey of patients with CBS, only 15% had reported their visual hallucinations to a physician.⁵

Continue to: Mr. B's symptoms...

Mr. B’s symptoms are atypical for CBS, but they fit the diagnosis when considering the entire clinical picture. While hallucinations in CBS are more often simple shapes, complex hallucinations including people and scenes have been noted in several instances.⁶

Similar to Mr. B’s case, patients with CBS can have recurring figures in their hallucinations, and the images may even move across the visual field.¹ Patients with CBS also frequently recognize that their hallucinations are not real, and may or may not be distressed by them.⁴ Patients with CBS often have hallucinations multiple times daily, lasting from a few seconds to many minutes,⁷ consistent with Mr. B’s temporary symptoms.

Although auditory and tactile hallucinations are typically not included in CBS, they can also be explained by Mr. B’s significant sensory impairment. Severe hearing impairment in geriatric adults has been associated with auditory hallucinations⁸; in 1 survey, half of these hallucinations consisted of voices.⁹ In contrast, tactile hallucinations are not described in sensory deprivation literature. However, in the context of Mr. B’s severe comorbid hearing and vision loss, we propose that these hallucinations reflect his interpretation of sensory events around him, and their integration into his extensive hallucination framework. In other words, Harry poking him and causing him to drop things may be Mr. B’s way of rationalizing events that he has trouble perceiving entirely, or his mild forgetfulness. Mr. B’s social isolation is another factor that may worsen his sensory deprivation and contribute to his extensive hallucinations.¹⁰ Additionally, his mild cognitive deficits on testing with chronic microvascular changes on the MRI may suggest a mild vascular-related dementia process, which could also exacerbate his hallucinations. While classic CBS occurs without cognitive impairment, dementia can often co-occur with CBS.¹¹

TREATMENT No significant improvement with medications

During his inpatient stay, Mr. B is treated with risperidone, 1 mg nightly, and is also started on donepezil, 5 mg/d, to treat a possible comorbid dementia. However, he continues to hallucinate without significant improvement.

[polldaddy:10729181]

The authors’ observations

There is no definitive treatment for CBS, and while the hallucinations may spontaneously resolve, per case reports, this typically occurs only as visual loss progresses to total blindness.¹² However, many patients can have the hallucinations remit after the underlying ocular etiology is corrected, such as through ocular surgery.¹³ Other optical interventions, such as special glasses or contact lenses, may help maximize remaining vision.⁸ In patients without this option, such as Mr. B, there are limited data on beneficial medications for CBS.

Continue to: Evidence for treatment of CBS...

Evidence for treatment of CBS with antipsychotic medications is mixed. Some case studies have found them to be ineffective, while others have found agents such as olanzapine or risperidone to be partially helpful in reducing symptoms.¹⁴ There are also data from case reports that may support the use of cholinesterase inhibitors such as donepezil, antiepileptics (carbamazepine, valproate, gabapentin, and clonazepam), and certain antidepressants (escitalopram, venlafaxine) (Table 2^8,11).³

Addressing loneliness and social isolation

With minimal definitive evidence for pharmacologic management, the most important intervention for treating CBS may be changing the patient’s sensory environment. Specifically, loneliness and social isolation are major exacerbating factors of CBS, and many clinicians advocate for the consistent presence of a sympathetic professional. Reassurance that hallucinations are from ocular disease rather than a primary mental disorder may be extremely relieving for patients.¹¹ A psychoeducation or support group may also be beneficial, not only for giving patients more social contact, but also for teaching them coping skills or strategies to reduce hallucinations, such as distraction, turning on more lights, or even certain eye/blinking movements.¹¹ Table 2^8,11 (page 49) outlines behavioral interventions for CBS.

Regardless of etiology, Mr. B’s hallucinations significantly affected his quality of life. During his inpatient stay, he was treated with risperidone, 1 mg nightly, because it was determined that the benefits of treatment with an antipsychotic medication outweigh the risks. He was also started on donepezil, 5 mg/d, to treat a possible comorbid dementia. However, his hallucinations continued without significant improvement.

OUTCOME Home care and family involvement

After discussion with Mr. B and his family about the risks and benefits of medication, the risperidone and donepezil are discontinued. Ultimately, it is determined that Mr. B requires a higher level of home care, both for his safety and to improve his social contact. Mr. B returns home with a combination of a professional home health aide and increased family involvement.

Bottom Line

When evaluating visual hallucinations in older adults, Charles Bonnet syndrome (CBS) should be considered. Sensory deprivation and social isolation are significant risk factors for CBS. While evidence is inconclusive for medical treatment, reassurance and behavioral interventions can often improve symptoms.

Continue to: Related Resources

• Charles Bonnet Syndrome Foundation. http://www.charlesbonnetsyndrome.org
• Schultz G, Melzack R. The Charles Bonnet syndrome: ‘phantom visual images’. Perception. 1991;20:809-825.
• Menon GJ, Rahman I, Menon SJ, et al. Complex visual hallucinations in the visually impaired: the Charles Bonnet syndrome. Surv Ophthalmol. 2003;48(1):58-72.

Drug Brand Names

Carbamazepine • Tegretol
Clonazepam • Klonopin
Donepezil • Aricept
Escitalopram • Lexapro
Gabapentin • Neurontin
Olanzapine • Zyprexa
Risperidone • Risperdal
Valproate • Depakote
Venlafaxine • Effexor

Delirium is characterized by a disturbance of consciousness or cognition that typically has a rapid onset and fluctuating course.¹ Up to 42% of hospitalized geriatric patients experience delirium.¹ Approximately 10% to 31% of these patients have the condition upon admission, and the remainder develop it during their hospitalization.¹ Unfortunately, options for preventing or treating delirium are limited. Benzodiazepines and antipsychotic medications have been used to treat problematic behaviors associated with delirium, but they do not effectively reduce the occurrence, duration, or severity of this condition.^2,3

Recent evidence suggests that suvorexant, which is FDA-approved for insomnia, may be useful for preventing delirium. Suvorexant—a dual orexin receptor (OX1R, OX2R) antagonist—promotes sleep onset and maintenance, and is associated with normal measures of sleep activity such as rapid eye movement (REM) sleep, non-REM sleep, and sleep stage–specific electroencephalographic profiles.⁴ Here we review 3 studies that evaluated suvorexant for preventing delirium.

Hatta et al.⁵ In this randomized, placebo-controlled, blinded, multicenter study, 72 patients (age 65 to 89) newly admitted to an ICU were randomized to suvorexant, 15 mg/d, (n = 36) or placebo (n = 36) for 3 days.⁵ None of the patients taking suvorexant developed delirium, whereas 17% (6 patients) in the placebo group did (P = .025).⁵

Azuma et al.⁶ In this 7-day, blinded, randomized study of 70 adult patients (age ≥20) admitted to an ICU, 34 participants received suvorexant (15 mg nightly for age <65, 20 mg nightly for age ≥65) and the rest received treatment as usual (TAU). Suvorexant was associated with a lower incidence of delirium symptoms (n = 6, 17.6%) compared with TAU (n = 17, 47.2%) (P = .011).⁶ The onset of delirium was earlier in the TAU group (P < .05).⁶

Hatta et al.⁷ In this large prospective, observational study of adults (age >65), 526 patients with significant risk factors for delirium were prescribed suvorexant and/or ramelteon. Approximately 16% of the patients who received either or both of these medications met DSM-5 criteria for delirium, compared with 24% who did not receive these medications (P = .005).⁷

Acknowledgment

The authors thank Jakob Evans, BS, for compiling much of the research for this article.

Delirium is characterized by a disturbance of consciousness or cognition that typically has a rapid onset and fluctuating course.¹ Up to 42% of hospitalized geriatric patients experience delirium.¹ Approximately 10% to 31% of these patients have the condition upon admission, and the remainder develop it during their hospitalization.¹ Unfortunately, options for preventing or treating delirium are limited. Benzodiazepines and antipsychotic medications have been used to treat problematic behaviors associated with delirium, but they do not effectively reduce the occurrence, duration, or severity of this condition.^2,3

Recent evidence suggests that suvorexant, which is FDA-approved for insomnia, may be useful for preventing delirium. Suvorexant—a dual orexin receptor (OX1R, OX2R) antagonist—promotes sleep onset and maintenance, and is associated with normal measures of sleep activity such as rapid eye movement (REM) sleep, non-REM sleep, and sleep stage–specific electroencephalographic profiles.⁴ Here we review 3 studies that evaluated suvorexant for preventing delirium.

Hatta et al.⁵ In this randomized, placebo-controlled, blinded, multicenter study, 72 patients (age 65 to 89) newly admitted to an ICU were randomized to suvorexant, 15 mg/d, (n = 36) or placebo (n = 36) for 3 days.⁵ None of the patients taking suvorexant developed delirium, whereas 17% (6 patients) in the placebo group did (P = .025).⁵

Azuma et al.⁶ In this 7-day, blinded, randomized study of 70 adult patients (age ≥20) admitted to an ICU, 34 participants received suvorexant (15 mg nightly for age <65, 20 mg nightly for age ≥65) and the rest received treatment as usual (TAU). Suvorexant was associated with a lower incidence of delirium symptoms (n = 6, 17.6%) compared with TAU (n = 17, 47.2%) (P = .011).⁶ The onset of delirium was earlier in the TAU group (P < .05).⁶

Hatta et al.⁷ In this large prospective, observational study of adults (age >65), 526 patients with significant risk factors for delirium were prescribed suvorexant and/or ramelteon. Approximately 16% of the patients who received either or both of these medications met DSM-5 criteria for delirium, compared with 24% who did not receive these medications (P = .005).⁷

Acknowledgment

The authors thank Jakob Evans, BS, for compiling much of the research for this article.

Delirium is characterized by a disturbance of consciousness or cognition that typically has a rapid onset and fluctuating course.¹ Up to 42% of hospitalized geriatric patients experience delirium.¹ Approximately 10% to 31% of these patients have the condition upon admission, and the remainder develop it during their hospitalization.¹ Unfortunately, options for preventing or treating delirium are limited. Benzodiazepines and antipsychotic medications have been used to treat problematic behaviors associated with delirium, but they do not effectively reduce the occurrence, duration, or severity of this condition.^2,3

Recent evidence suggests that suvorexant, which is FDA-approved for insomnia, may be useful for preventing delirium. Suvorexant—a dual orexin receptor (OX1R, OX2R) antagonist—promotes sleep onset and maintenance, and is associated with normal measures of sleep activity such as rapid eye movement (REM) sleep, non-REM sleep, and sleep stage–specific electroencephalographic profiles.⁴ Here we review 3 studies that evaluated suvorexant for preventing delirium.

Hatta et al.⁵ In this randomized, placebo-controlled, blinded, multicenter study, 72 patients (age 65 to 89) newly admitted to an ICU were randomized to suvorexant, 15 mg/d, (n = 36) or placebo (n = 36) for 3 days.⁵ None of the patients taking suvorexant developed delirium, whereas 17% (6 patients) in the placebo group did (P = .025).⁵

Azuma et al.⁶ In this 7-day, blinded, randomized study of 70 adult patients (age ≥20) admitted to an ICU, 34 participants received suvorexant (15 mg nightly for age <65, 20 mg nightly for age ≥65) and the rest received treatment as usual (TAU). Suvorexant was associated with a lower incidence of delirium symptoms (n = 6, 17.6%) compared with TAU (n = 17, 47.2%) (P = .011).⁶ The onset of delirium was earlier in the TAU group (P < .05).⁶

Hatta et al.⁷ In this large prospective, observational study of adults (age >65), 526 patients with significant risk factors for delirium were prescribed suvorexant and/or ramelteon. Approximately 16% of the patients who received either or both of these medications met DSM-5 criteria for delirium, compared with 24% who did not receive these medications (P = .005).⁷

Acknowledgment

The authors thank Jakob Evans, BS, for compiling much of the research for this article.

The Mission Act—signed into law in 2018—recognizes that the health care needs of patients who are veterans can no longer be fully served by the Veterans Health Administration.¹ This act allows some veterans who are enrolled in the Veterans Affairs (VA) health care system or otherwise entitled to VA care to access treatment outside of VA facilities.¹ As a result, psychiatrists may treat veterans more frequently.

During such patients’ initial visit, obtaining a detailed history of their military service can reveal vital clinical information and establish a therapeutic alliance that can help foster positive treatment outcomes. Here we offer an A-to-L list of important questions to ask veterans about their military service, and explanations of why these questions are valuable.

Attained rank. What rank did you attain during your military service? Did you retire from the military? How many years did you serve?

Asking about your patient’s rank, retirement status, and time in service is vital to understanding their military experience. By military law, only individuals who retired from the military can use their rank as an identifier after they leave the military, although some veterans may not wish to be called by their rank in a clinical setting.

Branch. Which branch of the military did you serve? Were you in Active Duty, the Reserves, or the National Guard?

Military members often take great pride in service of their specific branch. Each branch has its own language, culture, values, and exposures. If your patient has served in a combination of Active Duty, Reserves, and/or National Guard, ask how much time they spent in each.

Culture. What part of the military culture was positive or negative for you?

Continue to: There is a clear culture...

There is a clear culture within the military. Some veterans may feel lost without the military structure, and even devalued without the respect of rank. Others may feel jaded and spiteful about the strict military culture, procedures, and expectations.

Discharge. When, why, and under what circumstances were you discharged? What type of discharge did you receive?

There are 6 types of discharge: Honorable, General, Other than Honorable (OTH), Entry Level Separation, Bad Conduct, and Dishonorable. The type of discharge a veteran received may impact what resources are available to them. It also can influence a veteran’s perception of their military career.

Exposures. Were you exposed to combat, death, explosive blasts, or hazardous chemicals?

Do not ask a veteran if they have killed anyone. This question is both disrespectful and highly presumptuous because most veterans have not killed anyone. Be respectful of their experiences. Depending on the veteran’s mission, they may have unique exposures (Agent Orange, burn pits, detainee camps, etc.). Consider asking follow-up questions to learn the details of these exposures.

Continue to: Family impact

Family impact. How has your military service impacted your family?

A veteran’s military service often affects family members. Deployments can cause strain on marital relationships, children’s birthdays and special events may be missed, and extended family may have negative reactions to military service. Understanding the impact on the veteran’s family members can help uncover potential stressful relationships as well as help enhance any positive support systems that are available at home.

Go. Where were you stationed? Were you deployed?

Training location, geography of combat theater, peace-keeping locations, and area of station can all profoundly impact a veteran’s military experience. Ask follow-up questions about their duty stations, deployment locations, and experiences with these locations.

Hot water. Did you ever get into “trouble” while serving the military (eg, lose rank, get arrested, etc.)? How did you respond to the military’s method of discipline?

Continue to: Although it may be difficult...

Although it may be difficult or uncomfortable to ask your patient if they experienced any disciplinary action, this information may prove useful. It can help provide context when you discuss the veteran’s ease of assimilation into civilian life and other important information regarding the type of discharge.

Injuries. Have you experienced any moral, physical, sexual, emotional, or concussive injuries?

Moral injury, guilt, and regret are common for veterans. Not all injuries are from combat. Your patient may have experienced sexual assault, hazing rituals, pranks, etc.

Job. What was your job in the military? What kind of security clearance did you have?

Note that not all veterans’ “jobs” in the military accurately reflect the duties and tasks that they actually performed. Security clearance will often influence the duties and tasks they were required to perform.

Continue to: Keeping it inside

Keeping it inside. Do you have anyone to talk with about your military experiences?

Many veterans feel uncomfortable discussing their experiences with others. Some veterans may be concerned that others will not understand what they went through. Some might perceive that disclosing their experiences could burden other people, or they may be concerned that explaining their experiences may be too shocking. Asking this question may present an opportunity for you to suggest psychotherapy for your patient.

Life as a civilian. How is your life different as a civilian? How have you adjusted to civilian life?

During the process of assimilation into civilian life, veterans may experience symptoms of depression, posttraumatic stress disorder, anxiety, or other disorders. These symptoms may emerge and/or become exacerbated during their transition to civilian life.

The Mission Act—signed into law in 2018—recognizes that the health care needs of patients who are veterans can no longer be fully served by the Veterans Health Administration.¹ This act allows some veterans who are enrolled in the Veterans Affairs (VA) health care system or otherwise entitled to VA care to access treatment outside of VA facilities.¹ As a result, psychiatrists may treat veterans more frequently.

During such patients’ initial visit, obtaining a detailed history of their military service can reveal vital clinical information and establish a therapeutic alliance that can help foster positive treatment outcomes. Here we offer an A-to-L list of important questions to ask veterans about their military service, and explanations of why these questions are valuable.

Attained rank. What rank did you attain during your military service? Did you retire from the military? How many years did you serve?

Asking about your patient’s rank, retirement status, and time in service is vital to understanding their military experience. By military law, only individuals who retired from the military can use their rank as an identifier after they leave the military, although some veterans may not wish to be called by their rank in a clinical setting.

Branch. Which branch of the military did you serve? Were you in Active Duty, the Reserves, or the National Guard?

Military members often take great pride in service of their specific branch. Each branch has its own language, culture, values, and exposures. If your patient has served in a combination of Active Duty, Reserves, and/or National Guard, ask how much time they spent in each.

Culture. What part of the military culture was positive or negative for you?

Continue to: There is a clear culture...

There is a clear culture within the military. Some veterans may feel lost without the military structure, and even devalued without the respect of rank. Others may feel jaded and spiteful about the strict military culture, procedures, and expectations.

Discharge. When, why, and under what circumstances were you discharged? What type of discharge did you receive?

There are 6 types of discharge: Honorable, General, Other than Honorable (OTH), Entry Level Separation, Bad Conduct, and Dishonorable. The type of discharge a veteran received may impact what resources are available to them. It also can influence a veteran’s perception of their military career.

Exposures. Were you exposed to combat, death, explosive blasts, or hazardous chemicals?

Do not ask a veteran if they have killed anyone. This question is both disrespectful and highly presumptuous because most veterans have not killed anyone. Be respectful of their experiences. Depending on the veteran’s mission, they may have unique exposures (Agent Orange, burn pits, detainee camps, etc.). Consider asking follow-up questions to learn the details of these exposures.

Continue to: Family impact

Family impact. How has your military service impacted your family?

A veteran’s military service often affects family members. Deployments can cause strain on marital relationships, children’s birthdays and special events may be missed, and extended family may have negative reactions to military service. Understanding the impact on the veteran’s family members can help uncover potential stressful relationships as well as help enhance any positive support systems that are available at home.

Go. Where were you stationed? Were you deployed?

Training location, geography of combat theater, peace-keeping locations, and area of station can all profoundly impact a veteran’s military experience. Ask follow-up questions about their duty stations, deployment locations, and experiences with these locations.

Hot water. Did you ever get into “trouble” while serving the military (eg, lose rank, get arrested, etc.)? How did you respond to the military’s method of discipline?

Continue to: Although it may be difficult...

Although it may be difficult or uncomfortable to ask your patient if they experienced any disciplinary action, this information may prove useful. It can help provide context when you discuss the veteran’s ease of assimilation into civilian life and other important information regarding the type of discharge.

Injuries. Have you experienced any moral, physical, sexual, emotional, or concussive injuries?

Moral injury, guilt, and regret are common for veterans. Not all injuries are from combat. Your patient may have experienced sexual assault, hazing rituals, pranks, etc.

Job. What was your job in the military? What kind of security clearance did you have?

Note that not all veterans’ “jobs” in the military accurately reflect the duties and tasks that they actually performed. Security clearance will often influence the duties and tasks they were required to perform.

Continue to: Keeping it inside

Keeping it inside. Do you have anyone to talk with about your military experiences?

Many veterans feel uncomfortable discussing their experiences with others. Some veterans may be concerned that others will not understand what they went through. Some might perceive that disclosing their experiences could burden other people, or they may be concerned that explaining their experiences may be too shocking. Asking this question may present an opportunity for you to suggest psychotherapy for your patient.

Life as a civilian. How is your life different as a civilian? How have you adjusted to civilian life?

During the process of assimilation into civilian life, veterans may experience symptoms of depression, posttraumatic stress disorder, anxiety, or other disorders. These symptoms may emerge and/or become exacerbated during their transition to civilian life.

The Mission Act—signed into law in 2018—recognizes that the health care needs of patients who are veterans can no longer be fully served by the Veterans Health Administration.¹ This act allows some veterans who are enrolled in the Veterans Affairs (VA) health care system or otherwise entitled to VA care to access treatment outside of VA facilities.¹ As a result, psychiatrists may treat veterans more frequently.

During such patients’ initial visit, obtaining a detailed history of their military service can reveal vital clinical information and establish a therapeutic alliance that can help foster positive treatment outcomes. Here we offer an A-to-L list of important questions to ask veterans about their military service, and explanations of why these questions are valuable.

Attained rank. What rank did you attain during your military service? Did you retire from the military? How many years did you serve?

Asking about your patient’s rank, retirement status, and time in service is vital to understanding their military experience. By military law, only individuals who retired from the military can use their rank as an identifier after they leave the military, although some veterans may not wish to be called by their rank in a clinical setting.

Branch. Which branch of the military did you serve? Were you in Active Duty, the Reserves, or the National Guard?

Military members often take great pride in service of their specific branch. Each branch has its own language, culture, values, and exposures. If your patient has served in a combination of Active Duty, Reserves, and/or National Guard, ask how much time they spent in each.

Culture. What part of the military culture was positive or negative for you?

Continue to: There is a clear culture...

There is a clear culture within the military. Some veterans may feel lost without the military structure, and even devalued without the respect of rank. Others may feel jaded and spiteful about the strict military culture, procedures, and expectations.

Discharge. When, why, and under what circumstances were you discharged? What type of discharge did you receive?

There are 6 types of discharge: Honorable, General, Other than Honorable (OTH), Entry Level Separation, Bad Conduct, and Dishonorable. The type of discharge a veteran received may impact what resources are available to them. It also can influence a veteran’s perception of their military career.

Exposures. Were you exposed to combat, death, explosive blasts, or hazardous chemicals?

Do not ask a veteran if they have killed anyone. This question is both disrespectful and highly presumptuous because most veterans have not killed anyone. Be respectful of their experiences. Depending on the veteran’s mission, they may have unique exposures (Agent Orange, burn pits, detainee camps, etc.). Consider asking follow-up questions to learn the details of these exposures.

Continue to: Family impact

Family impact. How has your military service impacted your family?

A veteran’s military service often affects family members. Deployments can cause strain on marital relationships, children’s birthdays and special events may be missed, and extended family may have negative reactions to military service. Understanding the impact on the veteran’s family members can help uncover potential stressful relationships as well as help enhance any positive support systems that are available at home.

Go. Where were you stationed? Were you deployed?

Training location, geography of combat theater, peace-keeping locations, and area of station can all profoundly impact a veteran’s military experience. Ask follow-up questions about their duty stations, deployment locations, and experiences with these locations.

Hot water. Did you ever get into “trouble” while serving the military (eg, lose rank, get arrested, etc.)? How did you respond to the military’s method of discipline?

Continue to: Although it may be difficult...

Although it may be difficult or uncomfortable to ask your patient if they experienced any disciplinary action, this information may prove useful. It can help provide context when you discuss the veteran’s ease of assimilation into civilian life and other important information regarding the type of discharge.

Injuries. Have you experienced any moral, physical, sexual, emotional, or concussive injuries?

Moral injury, guilt, and regret are common for veterans. Not all injuries are from combat. Your patient may have experienced sexual assault, hazing rituals, pranks, etc.

Job. What was your job in the military? What kind of security clearance did you have?

Note that not all veterans’ “jobs” in the military accurately reflect the duties and tasks that they actually performed. Security clearance will often influence the duties and tasks they were required to perform.

Continue to: Keeping it inside

Keeping it inside. Do you have anyone to talk with about your military experiences?

Many veterans feel uncomfortable discussing their experiences with others. Some veterans may be concerned that others will not understand what they went through. Some might perceive that disclosing their experiences could burden other people, or they may be concerned that explaining their experiences may be too shocking. Asking this question may present an opportunity for you to suggest psychotherapy for your patient.

Life as a civilian. How is your life different as a civilian? How have you adjusted to civilian life?

During the process of assimilation into civilian life, veterans may experience symptoms of depression, posttraumatic stress disorder, anxiety, or other disorders. These symptoms may emerge and/or become exacerbated during their transition to civilian life.

Human trafficking (HT) is a secretive, multibillion dollar criminal industry involving the use of coercion, threats, and fraud to force individuals to engage in labor or commercial sex acts. In 2017, the International Labour Organization estimated that 24.9 million people worldwide were victims of forced labor (ie, working under threat or coercion).¹ Risk factors for individuals who are vulnerable to HT include recent migration, substance use, housing insecurity, runaway youth, and mental illness. Traffickers continue the cycle of HT through isolation and emotional, physical, financial, and verbal abuse.

Survivors of HT may avoid seeking health care due to cultural reasons or feelings of guilt, isolation, distrust, or fear of criminal sanctions. There can be missed opportunities for victims to obtain help through health care services, law enforcement, child welfare services, or even family or friends. In a study of 173 survivors of HT in the United States, 68% of those who were currently trafficked visited with a health care professional at least once and were not identified as being trafficked.² Psychiatrists rarely receive education on HT, which can lead to missed opportunities for identifying victims. Table 1 lists screening questions psychiatrists can ask patients they suspect may be trafficked.

The psychiatric sequelae of trafficking

Survivors of HT commonly experience psychiatric illness, substance use, pain, sexually transmitted diseases, and unplanned pregnancies.³ Here we discuss some of the psychiatric conditions that are common among HT survivors, and outline a multidisciplinary approach to their care.

PTSD, mood disorders, and anxiety disorders. Studies suggest survivors of HT who seek care have a high prevalence of depression, anxiety, and posttraumatic stress disorder (PTSD).³ Survivors may have experienced multiple repetitive trauma, such as physical and sexual abuse.³ Compared with survivors of forced labor trafficking, survivors of sex trafficking have higher rates of childhood abuse, violence during trafficking, severe symptoms of PTSD, and comorbid depression and PTSD.⁴ For survivors with PTSD, consider psychosocial interventions that address social support, coping strategies, and community reintegration.⁵ Survivors can also benefit from trauma-informed care that focuses on the cognitive aspect of the trauma, such as cognitive processing therapy, which involves cognitive restructuring without a written account of the trauma.⁶

Substance use disorders. Some individuals who are trafficked may be forced to use drugs of abuse or alcohol, while others may use substances to help cope while they are being trafficked or afterwards.³ For these patients, motivational interviewing may be beneficial. Also, consider referring them to detoxification or rehabilitation programs.

Suicide and self-harm. In a study of 98 HT survivors in England, 33% reported a history of self-harm before receiving care and 25% engaged in self-harm during care.⁷ After engaging in self-harm, survivors of HT were more likely to be admitted to psychiatric inpatient units than were patients who had not been trafficked.⁷ It is crucial to conduct a suicide risk assessment as part of the trauma-informed care of these patients.

Other conditions. In addition to psychiatric illness, survivors of HT may experience physical symptoms such as headache, back pain, stomach pain, fatigue, dizziness, memory problems, and weight loss.³ Referral to other specialties may be necessary for addressing any of the patient’s other conditions.

Continue to: Use a multidisciplinary approach

Use a multidisciplinary approach

Treatment for survivors of HT should be tailored to their specific mental health needs by including psychopharmacology; individual, group, or family psychotherapy; and peer advocate support. Rehabilitation, social services, and case management should also be considered. The care of survivors of HT benefits from a multidisciplinary, culturally-sensitive, and trauma-informed approach. Table 2⁸ describes the PEARR Tool (Provide privacy, Educate, Ask, Respect, and Respond), which offers physicians 4 steps for addressing abuse, neglect, or violence with their patients. Also, the National Human Trafficking Hotline (1-888-373-7888) is available 24/7 for trafficked persons, survivors, and health care professionals to provide guidance on reporting laws and finding additional resources such as housing and legal services.

Human trafficking (HT) is a secretive, multibillion dollar criminal industry involving the use of coercion, threats, and fraud to force individuals to engage in labor or commercial sex acts. In 2017, the International Labour Organization estimated that 24.9 million people worldwide were victims of forced labor (ie, working under threat or coercion).¹ Risk factors for individuals who are vulnerable to HT include recent migration, substance use, housing insecurity, runaway youth, and mental illness. Traffickers continue the cycle of HT through isolation and emotional, physical, financial, and verbal abuse.

Survivors of HT may avoid seeking health care due to cultural reasons or feelings of guilt, isolation, distrust, or fear of criminal sanctions. There can be missed opportunities for victims to obtain help through health care services, law enforcement, child welfare services, or even family or friends. In a study of 173 survivors of HT in the United States, 68% of those who were currently trafficked visited with a health care professional at least once and were not identified as being trafficked.² Psychiatrists rarely receive education on HT, which can lead to missed opportunities for identifying victims. Table 1 lists screening questions psychiatrists can ask patients they suspect may be trafficked.

The psychiatric sequelae of trafficking

Survivors of HT commonly experience psychiatric illness, substance use, pain, sexually transmitted diseases, and unplanned pregnancies.³ Here we discuss some of the psychiatric conditions that are common among HT survivors, and outline a multidisciplinary approach to their care.

PTSD, mood disorders, and anxiety disorders. Studies suggest survivors of HT who seek care have a high prevalence of depression, anxiety, and posttraumatic stress disorder (PTSD).³ Survivors may have experienced multiple repetitive trauma, such as physical and sexual abuse.³ Compared with survivors of forced labor trafficking, survivors of sex trafficking have higher rates of childhood abuse, violence during trafficking, severe symptoms of PTSD, and comorbid depression and PTSD.⁴ For survivors with PTSD, consider psychosocial interventions that address social support, coping strategies, and community reintegration.⁵ Survivors can also benefit from trauma-informed care that focuses on the cognitive aspect of the trauma, such as cognitive processing therapy, which involves cognitive restructuring without a written account of the trauma.⁶

Substance use disorders. Some individuals who are trafficked may be forced to use drugs of abuse or alcohol, while others may use substances to help cope while they are being trafficked or afterwards.³ For these patients, motivational interviewing may be beneficial. Also, consider referring them to detoxification or rehabilitation programs.

Suicide and self-harm. In a study of 98 HT survivors in England, 33% reported a history of self-harm before receiving care and 25% engaged in self-harm during care.⁷ After engaging in self-harm, survivors of HT were more likely to be admitted to psychiatric inpatient units than were patients who had not been trafficked.⁷ It is crucial to conduct a suicide risk assessment as part of the trauma-informed care of these patients.

Other conditions. In addition to psychiatric illness, survivors of HT may experience physical symptoms such as headache, back pain, stomach pain, fatigue, dizziness, memory problems, and weight loss.³ Referral to other specialties may be necessary for addressing any of the patient’s other conditions.

Continue to: Use a multidisciplinary approach

Use a multidisciplinary approach

Treatment for survivors of HT should be tailored to their specific mental health needs by including psychopharmacology; individual, group, or family psychotherapy; and peer advocate support. Rehabilitation, social services, and case management should also be considered. The care of survivors of HT benefits from a multidisciplinary, culturally-sensitive, and trauma-informed approach. Table 2⁸ describes the PEARR Tool (Provide privacy, Educate, Ask, Respect, and Respond), which offers physicians 4 steps for addressing abuse, neglect, or violence with their patients. Also, the National Human Trafficking Hotline (1-888-373-7888) is available 24/7 for trafficked persons, survivors, and health care professionals to provide guidance on reporting laws and finding additional resources such as housing and legal services.

Human trafficking (HT) is a secretive, multibillion dollar criminal industry involving the use of coercion, threats, and fraud to force individuals to engage in labor or commercial sex acts. In 2017, the International Labour Organization estimated that 24.9 million people worldwide were victims of forced labor (ie, working under threat or coercion).¹ Risk factors for individuals who are vulnerable to HT include recent migration, substance use, housing insecurity, runaway youth, and mental illness. Traffickers continue the cycle of HT through isolation and emotional, physical, financial, and verbal abuse.

Survivors of HT may avoid seeking health care due to cultural reasons or feelings of guilt, isolation, distrust, or fear of criminal sanctions. There can be missed opportunities for victims to obtain help through health care services, law enforcement, child welfare services, or even family or friends. In a study of 173 survivors of HT in the United States, 68% of those who were currently trafficked visited with a health care professional at least once and were not identified as being trafficked.² Psychiatrists rarely receive education on HT, which can lead to missed opportunities for identifying victims. Table 1 lists screening questions psychiatrists can ask patients they suspect may be trafficked.

The psychiatric sequelae of trafficking

Survivors of HT commonly experience psychiatric illness, substance use, pain, sexually transmitted diseases, and unplanned pregnancies.³ Here we discuss some of the psychiatric conditions that are common among HT survivors, and outline a multidisciplinary approach to their care.

PTSD, mood disorders, and anxiety disorders. Studies suggest survivors of HT who seek care have a high prevalence of depression, anxiety, and posttraumatic stress disorder (PTSD).³ Survivors may have experienced multiple repetitive trauma, such as physical and sexual abuse.³ Compared with survivors of forced labor trafficking, survivors of sex trafficking have higher rates of childhood abuse, violence during trafficking, severe symptoms of PTSD, and comorbid depression and PTSD.⁴ For survivors with PTSD, consider psychosocial interventions that address social support, coping strategies, and community reintegration.⁵ Survivors can also benefit from trauma-informed care that focuses on the cognitive aspect of the trauma, such as cognitive processing therapy, which involves cognitive restructuring without a written account of the trauma.⁶

Substance use disorders. Some individuals who are trafficked may be forced to use drugs of abuse or alcohol, while others may use substances to help cope while they are being trafficked or afterwards.³ For these patients, motivational interviewing may be beneficial. Also, consider referring them to detoxification or rehabilitation programs.

Suicide and self-harm. In a study of 98 HT survivors in England, 33% reported a history of self-harm before receiving care and 25% engaged in self-harm during care.⁷ After engaging in self-harm, survivors of HT were more likely to be admitted to psychiatric inpatient units than were patients who had not been trafficked.⁷ It is crucial to conduct a suicide risk assessment as part of the trauma-informed care of these patients.

Other conditions. In addition to psychiatric illness, survivors of HT may experience physical symptoms such as headache, back pain, stomach pain, fatigue, dizziness, memory problems, and weight loss.³ Referral to other specialties may be necessary for addressing any of the patient’s other conditions.

Continue to: Use a multidisciplinary approach

Use a multidisciplinary approach

Treatment for survivors of HT should be tailored to their specific mental health needs by including psychopharmacology; individual, group, or family psychotherapy; and peer advocate support. Rehabilitation, social services, and case management should also be considered. The care of survivors of HT benefits from a multidisciplinary, culturally-sensitive, and trauma-informed approach. Table 2⁸ describes the PEARR Tool (Provide privacy, Educate, Ask, Respect, and Respond), which offers physicians 4 steps for addressing abuse, neglect, or violence with their patients. Also, the National Human Trafficking Hotline (1-888-373-7888) is available 24/7 for trafficked persons, survivors, and health care professionals to provide guidance on reporting laws and finding additional resources such as housing and legal services.

We are committed to using our platform at the Journal of Hospital Medicine (JHM) to address inequities in healthcare delivery, policy, and research. Race was conceived as a mechanism of social division, leading to the false belief, propagated over time, of race as a biological variable.¹ As a result, racism has contributed to the medical abuse and exploitation of Black and Brown communities and inequities in health status among racialized groups. We must abandon practices that perpetuate inequities and champion practices that resolve them. Racial health equity—the absence of unjust and avoidable health disparities among racialized groups—is unattainable if we continue to simply identify inequities without naming racism as a determinant of health. As a journal, our responsibility is to disseminate evidence-based manuscripts that reflect an understanding of race, racism, and health.

We have modified our author guidelines. First, we now require authors to clearly define race and provide justification for its inclusion in clinical case descriptions and study analyses. We aim to contribute to the necessary course correction as well as promote self-reflection on study design choices that propagate false notions of race as a biological concept and conclusions that reinforce race-based rather than race-conscious practices in medicine.² Second, we expect authors to explicitly name racism and make a concerted effort to explore its role, identify its specific forms, and examine mutually reinforcing mechanisms of inequity that potentially contributed to study findings. Finally, we instruct authors to avoid the use of phrases like “patient mistrust,” which places blame for inequities on patients and their families and decouples mistrust from the fraught history of racism in medicine.

We must also acknowledge and reflect on our previous contributions to such inequity as authors, reviewers, and editors in order to learn and grow. Among the more than 2,000 articles published in JHM since its inception, only four included the term “racism.” Three of these articles are perspectives published in June 2020 and beyond. The only original research manuscript that directly addressed racism was a qualitative study of adults with sickle cell disease.³ The authors described study participants’ perspectives: “In contrast, the hospital experience during adulthood was often punctuated by bitter relationships with staff, and distrust over possible excessive use of opioids. Moreover, participants raised the possibility of racism in their interactions with hospital staff.” In this example, patients called out racism and its impact on their experience. We know JHM is not alone in falling woefully short in advancing our understanding of racism and racial health inequities. Each of us should identify missed opportunities to call out racism as a driver of racial health disparities in our own publications. We must act on these lessons regarding the ways in which racism infiltrates scientific publishing. We must use this awareness, along with our influence, voice, and collective power, to enact change for the betterment of our patients, their families, and the medical community.

We at JHM will contribute to uncovering and disseminating solutions to health inequities that result from racism. We are grateful to Boyd et al for their call to action and for providing a blueprint for improvement to those of us who write, review, and publish scholarly work.⁴

We are committed to using our platform at the Journal of Hospital Medicine (JHM) to address inequities in healthcare delivery, policy, and research. Race was conceived as a mechanism of social division, leading to the false belief, propagated over time, of race as a biological variable.¹ As a result, racism has contributed to the medical abuse and exploitation of Black and Brown communities and inequities in health status among racialized groups. We must abandon practices that perpetuate inequities and champion practices that resolve them. Racial health equity—the absence of unjust and avoidable health disparities among racialized groups—is unattainable if we continue to simply identify inequities without naming racism as a determinant of health. As a journal, our responsibility is to disseminate evidence-based manuscripts that reflect an understanding of race, racism, and health.

We have modified our author guidelines. First, we now require authors to clearly define race and provide justification for its inclusion in clinical case descriptions and study analyses. We aim to contribute to the necessary course correction as well as promote self-reflection on study design choices that propagate false notions of race as a biological concept and conclusions that reinforce race-based rather than race-conscious practices in medicine.² Second, we expect authors to explicitly name racism and make a concerted effort to explore its role, identify its specific forms, and examine mutually reinforcing mechanisms of inequity that potentially contributed to study findings. Finally, we instruct authors to avoid the use of phrases like “patient mistrust,” which places blame for inequities on patients and their families and decouples mistrust from the fraught history of racism in medicine.

We must also acknowledge and reflect on our previous contributions to such inequity as authors, reviewers, and editors in order to learn and grow. Among the more than 2,000 articles published in JHM since its inception, only four included the term “racism.” Three of these articles are perspectives published in June 2020 and beyond. The only original research manuscript that directly addressed racism was a qualitative study of adults with sickle cell disease.³ The authors described study participants’ perspectives: “In contrast, the hospital experience during adulthood was often punctuated by bitter relationships with staff, and distrust over possible excessive use of opioids. Moreover, participants raised the possibility of racism in their interactions with hospital staff.” In this example, patients called out racism and its impact on their experience. We know JHM is not alone in falling woefully short in advancing our understanding of racism and racial health inequities. Each of us should identify missed opportunities to call out racism as a driver of racial health disparities in our own publications. We must act on these lessons regarding the ways in which racism infiltrates scientific publishing. We must use this awareness, along with our influence, voice, and collective power, to enact change for the betterment of our patients, their families, and the medical community.

We at JHM will contribute to uncovering and disseminating solutions to health inequities that result from racism. We are grateful to Boyd et al for their call to action and for providing a blueprint for improvement to those of us who write, review, and publish scholarly work.⁴

We are committed to using our platform at the Journal of Hospital Medicine (JHM) to address inequities in healthcare delivery, policy, and research. Race was conceived as a mechanism of social division, leading to the false belief, propagated over time, of race as a biological variable.¹ As a result, racism has contributed to the medical abuse and exploitation of Black and Brown communities and inequities in health status among racialized groups. We must abandon practices that perpetuate inequities and champion practices that resolve them. Racial health equity—the absence of unjust and avoidable health disparities among racialized groups—is unattainable if we continue to simply identify inequities without naming racism as a determinant of health. As a journal, our responsibility is to disseminate evidence-based manuscripts that reflect an understanding of race, racism, and health.

We have modified our author guidelines. First, we now require authors to clearly define race and provide justification for its inclusion in clinical case descriptions and study analyses. We aim to contribute to the necessary course correction as well as promote self-reflection on study design choices that propagate false notions of race as a biological concept and conclusions that reinforce race-based rather than race-conscious practices in medicine.² Second, we expect authors to explicitly name racism and make a concerted effort to explore its role, identify its specific forms, and examine mutually reinforcing mechanisms of inequity that potentially contributed to study findings. Finally, we instruct authors to avoid the use of phrases like “patient mistrust,” which places blame for inequities on patients and their families and decouples mistrust from the fraught history of racism in medicine.

We must also acknowledge and reflect on our previous contributions to such inequity as authors, reviewers, and editors in order to learn and grow. Among the more than 2,000 articles published in JHM since its inception, only four included the term “racism.” Three of these articles are perspectives published in June 2020 and beyond. The only original research manuscript that directly addressed racism was a qualitative study of adults with sickle cell disease.³ The authors described study participants’ perspectives: “In contrast, the hospital experience during adulthood was often punctuated by bitter relationships with staff, and distrust over possible excessive use of opioids. Moreover, participants raised the possibility of racism in their interactions with hospital staff.” In this example, patients called out racism and its impact on their experience. We know JHM is not alone in falling woefully short in advancing our understanding of racism and racial health inequities. Each of us should identify missed opportunities to call out racism as a driver of racial health disparities in our own publications. We must act on these lessons regarding the ways in which racism infiltrates scientific publishing. We must use this awareness, along with our influence, voice, and collective power, to enact change for the betterment of our patients, their families, and the medical community.

We at JHM will contribute to uncovering and disseminating solutions to health inequities that result from racism. We are grateful to Boyd et al for their call to action and for providing a blueprint for improvement to those of us who write, review, and publish scholarly work.⁴