Current Psychiatry

Anxiety in children during a new administration

Since the current administration took office, many children continue to grapple with the initial shock of the election results and the uncertainty of what the next 4 years will bring. In the days after the election, several patients sat in my office and spoke of intense feelings of sadness, anger, and worry. Their stress levels were elevated, and they searched desperately for refuge from the unknown. On the other side of the hospital, patients expressing suicidal ideation filed into the emergency room. A similar scene played out nationally when suicide prevention hotlines experienced a sharp increase in calls.

During this emotional time, it is critical to support our children. Some will be more affected than others. Children from immigrant backgrounds might be particularly fearful of what this means for them and their families. In the days after the election, a video surfaced from a middle school in Michigan featuring kids at lunch chanting, “Build the wall!”

Bullying also is a concern. Despite being a third-generation American, an 8-year-old boy woke up the day after the election confused and scared. One mother told me that a student confronted her 11-year-old son at school, yelling that the election outcome was a “good thing” and he should “go back to his country.” Like his mother, the 11-year-old was born in the United States.

Kids get their cues from the adults in their lives. Parents and teachers play an important role in modeling behavior and providing comfort. Adults need to support children and to do that properly they need make sure they have processed their own feelings. They do not need to be unrealistic or overly positive, but should offer hope and trust in our democratic system. With discussion, children should have ample opportunity to express how they feel. Psychiatrists can evaluate a child’s symptoms and presentation. Are current medications helping enough with the recent changes? Does a child need a medication adjustment or to be seen more often? Does he (she) need to be admitted to the hospital for evaluation of suicidal ideation? As a psychiatrist, do you need to revisit the list of resources in the community and give children a crisis hotline number? Also consider referring a child to a psychotherapist if needed. Some schools offered counseling after the election. It is worthwhile to contact school officials if a student is struggling or could benefit from additional support.

Although many unknowns remain, 1 thing is certain: children will have more questions and we must be ready to answer.

Balkozar S. Adam, MD
Associate Professor of Clinical Psychiatry Child and Adolescent Psychiatry
University of Missouri
Columbia, Missouri
Co-Editor
Missouri Psychiatry Newsletter
Jefferson City, Missouri

Two additional adjunctive therapies for mental health

I was excited to read Dr. Nasrallah’s editorial about adjunctive therapies for mental health disorders (Are you neuroprotecting your patients? 10 Adjunctive therapies to consider, Current Psychiatry. December 2016, p. 12-14). I am a psychiatric physician assistant and have incorporated the principles of integrative medicine into my practice over the past year. I was thrilled to see the editorial outline many of the holistic treatments I use with clients.

The article missed 2 important vitamins that play a crucial role in positive mental health treatment outcomes: folic acid and vitamin B₁₂. In my practice, I have found up to 50% of my patients with depression have a vitamin B₁₂ deficiency. After supplementation, these patients’ symptoms improve to the point that we often can reduce or eliminate medication. Folic acid deficiency has been found among individuals with depression and linked to poor response to treatment.¹ Higher serum levels of homocysteine—a consequence of low folic acid levels—are linked to increased risk of developing depression later in life, as well as higher risk of cardiovascular disease.^2,3 Folate also can be used for enhancing treatment response to antidepressants by increasing production of neurotransmitters.²

Another factor to consider is methylenetetrahydrofolate reductase (MTHFR) variants. Approximately 20% of the population cannot methylate B vitamins because of a variation on the MTHFR gene.^4,5 These patients are at increased risk for depression because they are unable to use B vitamins, which are essential in the synthesis of serotonin and dopamine. These patients do not respond to B₁₂ and folate supplements. For these individuals, I recommend methylated products, which can be purchased online.

I have found these practices, as well as many of those listed in the editorial, are effective in treating depression and anxiety.

Lara Kain, PA-C, MPAS
Psychiatric Physician Assistant
Tidewater Psychotherapy Services
Virginia Beach, Virginia

References
1. Kaner G, Soylu M, Yüksel N, et al. Evaluation of nutritional status of patients with depression. Biomed Res Int. 2015;2015:521481. doi: 10.1155/2015/521481.
2. Seppälä J, Koponen H, Kautiainen H, et al. Association between vitamin B12 and melancholic depressive symptoms: a Finnish population-based study. BMC Psychiatry. 2013;13:145. doi: 10.1186/1471-244X-13-145.
3. Petridou ET, Kousoulis AA, Michelakos T, et al. Folate and B12 serum levels in association with depression in the aged: a systemic review and meta-analysis. Aging Ment Health. 2016;20(9):965-973.
4. Lynch B. MTHFR mutations and the conditions they cause. MTHFR.Net. http://mthfr.net/mthfr-mutations-and-the-conditions-they-cause/2011/09/07. Accessed February 16, 2017.
5. Eszlari N, Kovacs D, Petschner P, et al. Distinct effects of folate pathway genes MTHFR and MTHFD1L on ruminative response style: a potential risk mechanism for depression. Transl Psychiatry. 2016;6(3):e745. doi: 10.1038/tp.2016.19.

An honest perspective on Cannabis in therapy

I enjoyed Dr. Nasrallah’s editorial “Maddening therapies: How hallucinogens morphed into novel treatments” (From the Editor, Current Psychiatry. January 2017, p. 19-21). In this world, physicians still regard “street” drugs as issues of morality and criminality rather than a health issue, so it is refreshing when respected physicians take fearless, evidence-based approaches to potential therapeutic use of such drugs. Dr. Nasrallah did not glorify or condemn their effects; he simply described them.

As a psychiatrist specializing in bipolar and psychotic disorders—as well as the founder and Board President of Doctors for Cannabis Regulation—I appreciate his reservations about the potential of Cannabis to trigger psychosis in vulnerable individuals. My reading of the literature is there is good evidence for marijuana as a trigger—not as a cause—of the disease. However, what is the evidence for hallucinogens?

Cannabis can have adverse effects on brain development, but it is not clear whether those effects are worse than those caused by alcohol. In the absence of any head-to-head studies, how can we proceed?

David L. Nathan, MD, DFAPA
Clinical Associate Professor
Rutgers Robert Wood Johnson Medical School
Director of Continuing Medical Education
Princeton HealthCare System
Princeton, New Jersey

Dr. Nasrallah responds

LSD can cause psychosis, paranoid delusions, and altered thinking in addition to vivid visual hallucinations in some individuals but not all, because vulnerability occurs on a spectrum. I postulate that the recently discovered inverse agonist of the serotonin 5-HT2A receptor, pimavanserin (FDA-approved for visual hallucinations and delusions of Parkinson’s disease psychosis), might be effective for LSD psychosis because this hallucinogen has a strong binding affinity to the serotonin 5-HT2A receptors.

Studies show that marijuana can induce apoptosis, which would adversely affect brain development. Patients with schizophrenia who abuse marijuana have a lower gray matter volume than those who do not abuse the drug, and both groups have lower gray matter volume than matched healthy controls. I strongly advise a pregnant woman against smoking marijuana because it could impair the fetus’s brain development.

Henry A. Nasrallah, MD
Professor and Chair
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

Self-administering LSD: Solution or abuse

Dr. Nasrallah’s editorial (From the Editor, Current Psychiatry. January 2017, p. 19-21) gave an interesting update about the potential therapeutic uses of LSD. However, he did not mention the growing self-prescribed usage of microdoses of LSD, which is said to reduce anxiety and depression with less risk than usual dosages.

H. Steven Moffic, MD
Retired Tenured Professor of Psychiatry
Medical College of Wisconsin
Milwaukee, Wisconsin

Dr. Nasrallah responds

I am not aware of any systematic data about self-prescribed use of microdoses of LSD to reduce anxiety and depression. Among persons with anxiety and depression who have not had access to psychiatric care, self-medicating with agents such as alcohol, stimulants, ketamine, or LSD is regarded as substance abuse. It also is questionable whether people can determine which microdose of LSD to use. Finally, most drugs of abuse are not “pure,” and many are laced with potentially harmful contaminants.

Henry A. Nasrallah, MD
Professor and Chair
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

Why medical psychiatry is vital for my patients

Dr. Paul Summergrad’s guest editorial “Medical psychiatry: The skill of integrating medical and psychiatric care” (Current Psychiatry. February 2017, p. 11-13) was enormously helpful and validating for those of us who treat the full array of biomedical causes of psychiatric symptoms. My specialty is treating persons with intellectual and developmental disabilities who do not communicate through speech, display serious symptoms such as severe aggression toward themselves or others, or have life-threatening failure to thrive. For my patients, the key is to accurately diagnose and treat the vast array of co-occurring biomedical conditions. This requires me to perform physical examinations that my colleagues have skipped in the 5-minute primary care visits they are allowed, make a lot of home visits, and order more blood tests and imaging studies than my fellow psychiatrists in other specialties do. Only in these ways, I am able to offer effective treatment options that improve the quality of life of these suffering individuals. I suspect there are many more psychiatrists who work the same way.

For me, the most inspiring sentence in Dr. Summergrad’s editorial was, “It is incumbent on us to pursue the medical differential of patients when we think it is needed, even if other physicians disagree.” I believe that this describes our job as physicians who specialize in psychiatry. To have a clinician of Dr. Summergrad’s stature write this was inspiring because it goes to the core of what more of us should do.

Ruth Myers, MD
Psychiatrist
The Community Circle PLLC
Burnsville, Minnesota

Anxiety in children during a new administration

Since the current administration took office, many children continue to grapple with the initial shock of the election results and the uncertainty of what the next 4 years will bring. In the days after the election, several patients sat in my office and spoke of intense feelings of sadness, anger, and worry. Their stress levels were elevated, and they searched desperately for refuge from the unknown. On the other side of the hospital, patients expressing suicidal ideation filed into the emergency room. A similar scene played out nationally when suicide prevention hotlines experienced a sharp increase in calls.

During this emotional time, it is critical to support our children. Some will be more affected than others. Children from immigrant backgrounds might be particularly fearful of what this means for them and their families. In the days after the election, a video surfaced from a middle school in Michigan featuring kids at lunch chanting, “Build the wall!”

Bullying also is a concern. Despite being a third-generation American, an 8-year-old boy woke up the day after the election confused and scared. One mother told me that a student confronted her 11-year-old son at school, yelling that the election outcome was a “good thing” and he should “go back to his country.” Like his mother, the 11-year-old was born in the United States.

Kids get their cues from the adults in their lives. Parents and teachers play an important role in modeling behavior and providing comfort. Adults need to support children and to do that properly they need make sure they have processed their own feelings. They do not need to be unrealistic or overly positive, but should offer hope and trust in our democratic system. With discussion, children should have ample opportunity to express how they feel. Psychiatrists can evaluate a child’s symptoms and presentation. Are current medications helping enough with the recent changes? Does a child need a medication adjustment or to be seen more often? Does he (she) need to be admitted to the hospital for evaluation of suicidal ideation? As a psychiatrist, do you need to revisit the list of resources in the community and give children a crisis hotline number? Also consider referring a child to a psychotherapist if needed. Some schools offered counseling after the election. It is worthwhile to contact school officials if a student is struggling or could benefit from additional support.

Although many unknowns remain, 1 thing is certain: children will have more questions and we must be ready to answer.

Balkozar S. Adam, MD
Associate Professor of Clinical Psychiatry Child and Adolescent Psychiatry
University of Missouri
Columbia, Missouri
Co-Editor
Missouri Psychiatry Newsletter
Jefferson City, Missouri

Two additional adjunctive therapies for mental health

I was excited to read Dr. Nasrallah’s editorial about adjunctive therapies for mental health disorders (Are you neuroprotecting your patients? 10 Adjunctive therapies to consider, Current Psychiatry. December 2016, p. 12-14). I am a psychiatric physician assistant and have incorporated the principles of integrative medicine into my practice over the past year. I was thrilled to see the editorial outline many of the holistic treatments I use with clients.

The article missed 2 important vitamins that play a crucial role in positive mental health treatment outcomes: folic acid and vitamin B₁₂. In my practice, I have found up to 50% of my patients with depression have a vitamin B₁₂ deficiency. After supplementation, these patients’ symptoms improve to the point that we often can reduce or eliminate medication. Folic acid deficiency has been found among individuals with depression and linked to poor response to treatment.¹ Higher serum levels of homocysteine—a consequence of low folic acid levels—are linked to increased risk of developing depression later in life, as well as higher risk of cardiovascular disease.^2,3 Folate also can be used for enhancing treatment response to antidepressants by increasing production of neurotransmitters.²

Another factor to consider is methylenetetrahydrofolate reductase (MTHFR) variants. Approximately 20% of the population cannot methylate B vitamins because of a variation on the MTHFR gene.^4,5 These patients are at increased risk for depression because they are unable to use B vitamins, which are essential in the synthesis of serotonin and dopamine. These patients do not respond to B₁₂ and folate supplements. For these individuals, I recommend methylated products, which can be purchased online.

I have found these practices, as well as many of those listed in the editorial, are effective in treating depression and anxiety.

Lara Kain, PA-C, MPAS
Psychiatric Physician Assistant
Tidewater Psychotherapy Services
Virginia Beach, Virginia

References
1. Kaner G, Soylu M, Yüksel N, et al. Evaluation of nutritional status of patients with depression. Biomed Res Int. 2015;2015:521481. doi: 10.1155/2015/521481.
2. Seppälä J, Koponen H, Kautiainen H, et al. Association between vitamin B12 and melancholic depressive symptoms: a Finnish population-based study. BMC Psychiatry. 2013;13:145. doi: 10.1186/1471-244X-13-145.
3. Petridou ET, Kousoulis AA, Michelakos T, et al. Folate and B12 serum levels in association with depression in the aged: a systemic review and meta-analysis. Aging Ment Health. 2016;20(9):965-973.
4. Lynch B. MTHFR mutations and the conditions they cause. MTHFR.Net. http://mthfr.net/mthfr-mutations-and-the-conditions-they-cause/2011/09/07. Accessed February 16, 2017.
5. Eszlari N, Kovacs D, Petschner P, et al. Distinct effects of folate pathway genes MTHFR and MTHFD1L on ruminative response style: a potential risk mechanism for depression. Transl Psychiatry. 2016;6(3):e745. doi: 10.1038/tp.2016.19.

An honest perspective on Cannabis in therapy

I enjoyed Dr. Nasrallah’s editorial “Maddening therapies: How hallucinogens morphed into novel treatments” (From the Editor, Current Psychiatry. January 2017, p. 19-21). In this world, physicians still regard “street” drugs as issues of morality and criminality rather than a health issue, so it is refreshing when respected physicians take fearless, evidence-based approaches to potential therapeutic use of such drugs. Dr. Nasrallah did not glorify or condemn their effects; he simply described them.

As a psychiatrist specializing in bipolar and psychotic disorders—as well as the founder and Board President of Doctors for Cannabis Regulation—I appreciate his reservations about the potential of Cannabis to trigger psychosis in vulnerable individuals. My reading of the literature is there is good evidence for marijuana as a trigger—not as a cause—of the disease. However, what is the evidence for hallucinogens?

Cannabis can have adverse effects on brain development, but it is not clear whether those effects are worse than those caused by alcohol. In the absence of any head-to-head studies, how can we proceed?

David L. Nathan, MD, DFAPA
Clinical Associate Professor
Rutgers Robert Wood Johnson Medical School
Director of Continuing Medical Education
Princeton HealthCare System
Princeton, New Jersey

Dr. Nasrallah responds

LSD can cause psychosis, paranoid delusions, and altered thinking in addition to vivid visual hallucinations in some individuals but not all, because vulnerability occurs on a spectrum. I postulate that the recently discovered inverse agonist of the serotonin 5-HT2A receptor, pimavanserin (FDA-approved for visual hallucinations and delusions of Parkinson’s disease psychosis), might be effective for LSD psychosis because this hallucinogen has a strong binding affinity to the serotonin 5-HT2A receptors.

Studies show that marijuana can induce apoptosis, which would adversely affect brain development. Patients with schizophrenia who abuse marijuana have a lower gray matter volume than those who do not abuse the drug, and both groups have lower gray matter volume than matched healthy controls. I strongly advise a pregnant woman against smoking marijuana because it could impair the fetus’s brain development.

Henry A. Nasrallah, MD
Professor and Chair
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

Self-administering LSD: Solution or abuse

Dr. Nasrallah’s editorial (From the Editor, Current Psychiatry. January 2017, p. 19-21) gave an interesting update about the potential therapeutic uses of LSD. However, he did not mention the growing self-prescribed usage of microdoses of LSD, which is said to reduce anxiety and depression with less risk than usual dosages.

H. Steven Moffic, MD
Retired Tenured Professor of Psychiatry
Medical College of Wisconsin
Milwaukee, Wisconsin

Dr. Nasrallah responds

I am not aware of any systematic data about self-prescribed use of microdoses of LSD to reduce anxiety and depression. Among persons with anxiety and depression who have not had access to psychiatric care, self-medicating with agents such as alcohol, stimulants, ketamine, or LSD is regarded as substance abuse. It also is questionable whether people can determine which microdose of LSD to use. Finally, most drugs of abuse are not “pure,” and many are laced with potentially harmful contaminants.

Henry A. Nasrallah, MD
Professor and Chair
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

Why medical psychiatry is vital for my patients

Dr. Paul Summergrad’s guest editorial “Medical psychiatry: The skill of integrating medical and psychiatric care” (Current Psychiatry. February 2017, p. 11-13) was enormously helpful and validating for those of us who treat the full array of biomedical causes of psychiatric symptoms. My specialty is treating persons with intellectual and developmental disabilities who do not communicate through speech, display serious symptoms such as severe aggression toward themselves or others, or have life-threatening failure to thrive. For my patients, the key is to accurately diagnose and treat the vast array of co-occurring biomedical conditions. This requires me to perform physical examinations that my colleagues have skipped in the 5-minute primary care visits they are allowed, make a lot of home visits, and order more blood tests and imaging studies than my fellow psychiatrists in other specialties do. Only in these ways, I am able to offer effective treatment options that improve the quality of life of these suffering individuals. I suspect there are many more psychiatrists who work the same way.

For me, the most inspiring sentence in Dr. Summergrad’s editorial was, “It is incumbent on us to pursue the medical differential of patients when we think it is needed, even if other physicians disagree.” I believe that this describes our job as physicians who specialize in psychiatry. To have a clinician of Dr. Summergrad’s stature write this was inspiring because it goes to the core of what more of us should do.

Ruth Myers, MD
Psychiatrist
The Community Circle PLLC
Burnsville, Minnesota

Anxiety in children during a new administration

Since the current administration took office, many children continue to grapple with the initial shock of the election results and the uncertainty of what the next 4 years will bring. In the days after the election, several patients sat in my office and spoke of intense feelings of sadness, anger, and worry. Their stress levels were elevated, and they searched desperately for refuge from the unknown. On the other side of the hospital, patients expressing suicidal ideation filed into the emergency room. A similar scene played out nationally when suicide prevention hotlines experienced a sharp increase in calls.

During this emotional time, it is critical to support our children. Some will be more affected than others. Children from immigrant backgrounds might be particularly fearful of what this means for them and their families. In the days after the election, a video surfaced from a middle school in Michigan featuring kids at lunch chanting, “Build the wall!”

Bullying also is a concern. Despite being a third-generation American, an 8-year-old boy woke up the day after the election confused and scared. One mother told me that a student confronted her 11-year-old son at school, yelling that the election outcome was a “good thing” and he should “go back to his country.” Like his mother, the 11-year-old was born in the United States.

Kids get their cues from the adults in their lives. Parents and teachers play an important role in modeling behavior and providing comfort. Adults need to support children and to do that properly they need make sure they have processed their own feelings. They do not need to be unrealistic or overly positive, but should offer hope and trust in our democratic system. With discussion, children should have ample opportunity to express how they feel. Psychiatrists can evaluate a child’s symptoms and presentation. Are current medications helping enough with the recent changes? Does a child need a medication adjustment or to be seen more often? Does he (she) need to be admitted to the hospital for evaluation of suicidal ideation? As a psychiatrist, do you need to revisit the list of resources in the community and give children a crisis hotline number? Also consider referring a child to a psychotherapist if needed. Some schools offered counseling after the election. It is worthwhile to contact school officials if a student is struggling or could benefit from additional support.

Although many unknowns remain, 1 thing is certain: children will have more questions and we must be ready to answer.

Balkozar S. Adam, MD
Associate Professor of Clinical Psychiatry Child and Adolescent Psychiatry
University of Missouri
Columbia, Missouri
Co-Editor
Missouri Psychiatry Newsletter
Jefferson City, Missouri

Two additional adjunctive therapies for mental health

I was excited to read Dr. Nasrallah’s editorial about adjunctive therapies for mental health disorders (Are you neuroprotecting your patients? 10 Adjunctive therapies to consider, Current Psychiatry. December 2016, p. 12-14). I am a psychiatric physician assistant and have incorporated the principles of integrative medicine into my practice over the past year. I was thrilled to see the editorial outline many of the holistic treatments I use with clients.

The article missed 2 important vitamins that play a crucial role in positive mental health treatment outcomes: folic acid and vitamin B₁₂. In my practice, I have found up to 50% of my patients with depression have a vitamin B₁₂ deficiency. After supplementation, these patients’ symptoms improve to the point that we often can reduce or eliminate medication. Folic acid deficiency has been found among individuals with depression and linked to poor response to treatment.¹ Higher serum levels of homocysteine—a consequence of low folic acid levels—are linked to increased risk of developing depression later in life, as well as higher risk of cardiovascular disease.^2,3 Folate also can be used for enhancing treatment response to antidepressants by increasing production of neurotransmitters.²

Another factor to consider is methylenetetrahydrofolate reductase (MTHFR) variants. Approximately 20% of the population cannot methylate B vitamins because of a variation on the MTHFR gene.^4,5 These patients are at increased risk for depression because they are unable to use B vitamins, which are essential in the synthesis of serotonin and dopamine. These patients do not respond to B₁₂ and folate supplements. For these individuals, I recommend methylated products, which can be purchased online.

I have found these practices, as well as many of those listed in the editorial, are effective in treating depression and anxiety.

Lara Kain, PA-C, MPAS
Psychiatric Physician Assistant
Tidewater Psychotherapy Services
Virginia Beach, Virginia

References
1. Kaner G, Soylu M, Yüksel N, et al. Evaluation of nutritional status of patients with depression. Biomed Res Int. 2015;2015:521481. doi: 10.1155/2015/521481.
2. Seppälä J, Koponen H, Kautiainen H, et al. Association between vitamin B12 and melancholic depressive symptoms: a Finnish population-based study. BMC Psychiatry. 2013;13:145. doi: 10.1186/1471-244X-13-145.
3. Petridou ET, Kousoulis AA, Michelakos T, et al. Folate and B12 serum levels in association with depression in the aged: a systemic review and meta-analysis. Aging Ment Health. 2016;20(9):965-973.
4. Lynch B. MTHFR mutations and the conditions they cause. MTHFR.Net. http://mthfr.net/mthfr-mutations-and-the-conditions-they-cause/2011/09/07. Accessed February 16, 2017.
5. Eszlari N, Kovacs D, Petschner P, et al. Distinct effects of folate pathway genes MTHFR and MTHFD1L on ruminative response style: a potential risk mechanism for depression. Transl Psychiatry. 2016;6(3):e745. doi: 10.1038/tp.2016.19.

An honest perspective on Cannabis in therapy

I enjoyed Dr. Nasrallah’s editorial “Maddening therapies: How hallucinogens morphed into novel treatments” (From the Editor, Current Psychiatry. January 2017, p. 19-21). In this world, physicians still regard “street” drugs as issues of morality and criminality rather than a health issue, so it is refreshing when respected physicians take fearless, evidence-based approaches to potential therapeutic use of such drugs. Dr. Nasrallah did not glorify or condemn their effects; he simply described them.

As a psychiatrist specializing in bipolar and psychotic disorders—as well as the founder and Board President of Doctors for Cannabis Regulation—I appreciate his reservations about the potential of Cannabis to trigger psychosis in vulnerable individuals. My reading of the literature is there is good evidence for marijuana as a trigger—not as a cause—of the disease. However, what is the evidence for hallucinogens?

Cannabis can have adverse effects on brain development, but it is not clear whether those effects are worse than those caused by alcohol. In the absence of any head-to-head studies, how can we proceed?

David L. Nathan, MD, DFAPA
Clinical Associate Professor
Rutgers Robert Wood Johnson Medical School
Director of Continuing Medical Education
Princeton HealthCare System
Princeton, New Jersey

Dr. Nasrallah responds

LSD can cause psychosis, paranoid delusions, and altered thinking in addition to vivid visual hallucinations in some individuals but not all, because vulnerability occurs on a spectrum. I postulate that the recently discovered inverse agonist of the serotonin 5-HT2A receptor, pimavanserin (FDA-approved for visual hallucinations and delusions of Parkinson’s disease psychosis), might be effective for LSD psychosis because this hallucinogen has a strong binding affinity to the serotonin 5-HT2A receptors.

Studies show that marijuana can induce apoptosis, which would adversely affect brain development. Patients with schizophrenia who abuse marijuana have a lower gray matter volume than those who do not abuse the drug, and both groups have lower gray matter volume than matched healthy controls. I strongly advise a pregnant woman against smoking marijuana because it could impair the fetus’s brain development.

Henry A. Nasrallah, MD
Professor and Chair
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

Self-administering LSD: Solution or abuse

Dr. Nasrallah’s editorial (From the Editor, Current Psychiatry. January 2017, p. 19-21) gave an interesting update about the potential therapeutic uses of LSD. However, he did not mention the growing self-prescribed usage of microdoses of LSD, which is said to reduce anxiety and depression with less risk than usual dosages.

H. Steven Moffic, MD
Retired Tenured Professor of Psychiatry
Medical College of Wisconsin
Milwaukee, Wisconsin

Dr. Nasrallah responds

I am not aware of any systematic data about self-prescribed use of microdoses of LSD to reduce anxiety and depression. Among persons with anxiety and depression who have not had access to psychiatric care, self-medicating with agents such as alcohol, stimulants, ketamine, or LSD is regarded as substance abuse. It also is questionable whether people can determine which microdose of LSD to use. Finally, most drugs of abuse are not “pure,” and many are laced with potentially harmful contaminants.

Henry A. Nasrallah, MD
Professor and Chair
Department of Psychiatry and Behavioral Neuroscience
Saint Louis University School of Medicine
St. Louis, Missouri

Why medical psychiatry is vital for my patients

Dr. Paul Summergrad’s guest editorial “Medical psychiatry: The skill of integrating medical and psychiatric care” (Current Psychiatry. February 2017, p. 11-13) was enormously helpful and validating for those of us who treat the full array of biomedical causes of psychiatric symptoms. My specialty is treating persons with intellectual and developmental disabilities who do not communicate through speech, display serious symptoms such as severe aggression toward themselves or others, or have life-threatening failure to thrive. For my patients, the key is to accurately diagnose and treat the vast array of co-occurring biomedical conditions. This requires me to perform physical examinations that my colleagues have skipped in the 5-minute primary care visits they are allowed, make a lot of home visits, and order more blood tests and imaging studies than my fellow psychiatrists in other specialties do. Only in these ways, I am able to offer effective treatment options that improve the quality of life of these suffering individuals. I suspect there are many more psychiatrists who work the same way.

For me, the most inspiring sentence in Dr. Summergrad’s editorial was, “It is incumbent on us to pursue the medical differential of patients when we think it is needed, even if other physicians disagree.” I believe that this describes our job as physicians who specialize in psychiatry. To have a clinician of Dr. Summergrad’s stature write this was inspiring because it goes to the core of what more of us should do.

Ruth Myers, MD
Psychiatrist
The Community Circle PLLC
Burnsville, Minnesota

The course of chronic psychiatric conditions, such as schizophrenia, differs from chronic medical conditions, such as diabetes. Some patients with chronic psychiatric conditions achieve remission and become symptom-free, while others continue to have lingering signs of disease for life.

Residual symptoms of schizophrenia are not fully defined in the literature, which poses a challenge because they are central in the overall treatment of schizophrenia spectrum disorders.¹ During this phase of schizophrenia, patients continue to have symptoms after psychosis has subsided. These patients might continue to have negative symptoms such as social and emotional withdrawal and low energy. Although frank psychotic behavior has disappeared, the patient might continue to hold strange beliefs. Pharmacotherapy is the primary treatment option for psychiatric conditions, but the psychosocial aspect may have greater importance when treating residual symptoms and patients with chronic psychiatric illness.²

A naturalistic study in Germany evaluated the occurrence and characteristics of residual symptoms in patients with schizophrenia.³ The authors used a Positive and Negative Syndrome Scale symptom severity score >1 for those purposes, which is possibly a stringent criterion to define residual symptoms. This multicenter study enrolled 399 individuals age 18 to 65 with a DSM-IV-TR diagnosis of schizophrenia, schizophreniform disorder, delusional disorder, or schizoaffective disorder.³ Of the 236 patients achieving remission at discharge, 94% had at least 1 residual symptom and 69% had at least 4 residual symptoms. Therefore, residual symptoms were highly prevalent in remitted patients. The most frequent residual symptoms were:

• blunted affect
• conceptual disorganization
• passive or apathetic social withdrawal
• emotional withdrawal
• lack of judgment and insight
• poor attention
• somatic concern
• difficulty with abstract thinking
• anxiety
• poor rapport.³

Of note, positive symptoms, such as delusions and hallucinatory behavior, were found in remitted patients at discharge (17% and 10%, respectively). The study concluded that the severity of residual symptoms was associated with relapse risk and had an overall negative impact on the outcome of patients with schizophrenia.³ The study noted that residual symptoms may be greater in number or volume than negative symptoms and questioned the origins of residual symptoms because most were present at baseline in more than two-third of patients.

Patients with residual symptoms of schizophrenia usually are older and therefore present specific management challenges for clinicians. Changes associated with aging, such as medical problems, cognitive deficits, and lack of social support, could create new care needs for this patient population. Although the biopsycho­social model used to treat chronic psychiatric conditions, especially schizophrenia, is preferred, older schizophrenia patients with residual symptoms often need more psychosocial interventions compared with young adults with schizophrenia.

Managing residual symptoms in schizophrenia

Few studies are devoted to pharmacological treatment of older adults with schizophrenia, likely because pharmacotherapy for older patients with schizophrenia can be challenging. Evidence-based treatment is based primarily on findings from younger patients who survived into later life. Clinicians often use the adage of geriatric psychiatry, “start low, go slow,” because older patients are susceptible to adverse effects associated with psychiatric medications, including cardiovascular, metabolic, anticholinergic, and extrapyramidal effects, orthostasis, sedation, falls, and neuroleptic malignant syndrome.

Older patients with schizophrenia are at an increased risk for extrapyramidal symptoms (EPS) and anticholinergic adverse effects, perhaps because of degeneration of dopaminergic and cholinergic neurons.⁴ Lowering the anticholinergic load by discontinuing or reducing the dosage of medications with anticholinergic properties, when possible, is a key principle when treating these patients. This tactic could help improve cognition and quality of life by decreasing the risk of other anticholinergic adverse effects, including delirium, constipation, urinary retention, and blurred vision.

Patients treated with typical antipsychotics are nearly twice as likely to develop tardive dyskinesia compared with those receiving atypical antipsychotics.⁵ Sedation, orthostatic hypotension, and anticholinergic effects can cause cognitive clouding, worsen cognitive impairment, and increase the risk of falls, especially in older patients.⁶ Clozapine and olanzapine have the strongest association with clinically significant weight gain and treatment-induced type 2 diabetes mellitus.⁷

The appropriate starting dosage of antipsychotics in older patients with schizophrenia is one-fourth of the starting adult dosage. Total daily maintenance dosages may be one-third to one-half of the adult dosage.⁶ Consensus guidelines for dosing atypical antipsychotics for older patients with schizophrenia are as shown in Table 1.⁸

Another point to consider when treating residual symptoms in patients with schizophrenia is to not discontinue antipsychotic medications. Relapse rates for these patients can occur up to 5 times higher than for those who continue treatment.¹⁰ A way to address this problem could be the use of depot antipsychotic medications, but there are no set recommendations for the use of long-acting injectable antipsychotics in older patients. These medications should be used with caution and at lowest effective dosages to offset potential adverse effects.

With the introduction of typical and atypical antipsychotics, the use of electroconvulsive therapy in older patients with schizophrenia has declined. In a 2009 meta-analysis of studies that included patients with refractory schizophrenia and repetitive transcranial magnetic stimulation (rTMS), results revealed a mixed effect size for controlled and uncontrolled studies. The authors stated the need for further controlled trials, assessing the efficacy of rTMS on negative and positive symptoms of schizophrenia.¹¹

Psychotherapy and psychosocial interventions

Patients with schizophrenia who have persistent psychotic symptoms while receiving adequate pharmacotherapy should be offered adjunctive cognitive, behaviorally oriented psychotherapy to reduce symptom severity. Cognitive-behavioral therapy (CBT) has been shown to help reduce relapse rates, reduce psychotic symptoms, and improve patients’ mental state.¹² Amotivation and lack of insight can be particularly troublesome, which CBT can help address.¹² Psychoeducation can:

• empower patients to understand their illness
• help them cope with their disease
• be aware of symptom relapse
• seek help sooner rather than later.

Also, counseling and supportive therapy are recommended by the American Psychiatric Association guidelines. Providers should involve family and loved ones in this discussion, so that they can help collaborate with care and provide a supportive and non-judgmental environment.

Older patients with residual symptoms of schizophrenia are less likely to have completed their education, pursued a career, or developed long-lasting relationships. Family members who were their support system earlier in life, such as parents, often are unable to provide care for them by the time patients with schizophrenia become older. These patients also are less likely to get married or have children, meaning that they are more likely to live alone. The advent of the interdisciplinary team, integration of several therapeutic modalities, the provision of case managers, and assertive community treatment (ACT) teams has provided help with social support, relapses, and hospitalizations, for older patients with schizophrenia.¹³ Key elements of ACT include:

• a multidisciplinary team, including a medication prescriber
• a shared caseload among team members
• direct service provision by team members
• frequent patient contact
• low patient to staff ratios
• outreach to patients in the community.

Medical care

Patients with schizophrenia are at higher risk for several comorbid medical conditions, such as diabetes, coronary artery disease, and digestive and liver disorders, compared with individuals without schizophrenia. This risk is associated with numerous factors, including sedentary lifestyle, high rates of lifetime cigarette use (70% to 80% of schizophrenia outpatients age <67 smoke), poor self-management skills, frequent homelessness, and unhealthy diet.

Although substantial attention is devoted to the psychiatric and behavioral management of patients with schizophrenia, many barriers impede the detection and treatment of their medical conditions. Patients with schizophrenia could experience delays in diagnosing a medical disorder, leading to more acute comorbidities at the time of diagnosis and premature mortality. Studies have confirmed that cardiovascular diseases are the leading cause of premature death among psychiatric patients in the United States.¹⁴ Key risk factors include smoking, obesity, hypertension, dyslipidemia, diabetes, and lack of physical activity, all of which are more common among patients with schizophrenia compared with the general population.¹⁵ In addition, antipsychotics are associated with adverse metabolic effects.¹⁶

What are realistic treatment goals to manage residual symptoms in schizophrenia?

We believe that because remission in schizophrenia has been defined consensually, the bar for treatment expectations is set higher than it was 20 years ago. There can be patient-, family-, and system-related variables affecting the feasibility of treating residual symptoms. Providers who treat patients with schizophrenia should consider the following treatment goals:

• Prevent relapse and acute psychiatric hospitalization
• Use evidence-based strategies to minimize or monitor adverse effects
• Monitor compliance and consider use of depot antipsychotics combined with patients’ preference
• Facilitate ongoing safety assessment, including suicide risk
• Monitor negative and cognitive symptoms in addition to positive symptoms, using evidence-based management
• Encourage collaboration of care with family, caretakers, and other members of the treatment team
• Empower patients by providing psycho­education and social skills training and assisting in their vocational rehabilitation 
• Educate the patient and family about healthy lifestyle interventions and medical comorbidities common with schizophrenia
• Perform baseline screening and follow-up for early detection and treatment of medical comorbidities in patients with schizophrenia
• Improve functional status and quality of life.

In addition to meeting these treatment goals, a measurement-based method can be implemented to monitor improvement and status of the independent treatment domains. A collection of rating instruments can be found in Table 2.^17-30

Summing up

The clinical presentation of patients with residual symptoms of schizophrenia differs from that of other patients with schizophrenia. Our understanding of residual symptoms in schizophrenia has come a long way in the last decade; however, we are still far from pinning the complex nature of these symptoms, let alone their management. Given the risk of morbidity and disability, there clearly is a need for further investigation and investment of time and resources to support developing novel pharmacological treatment options to manage residual symptoms in patients with schizophrenia.

Because patients with residual symptoms of schizophrenia usually are older, psychiatrists should be responsible for implementing necessary screening assessments and should closely collaborate with primary care practitioners and other specialists, and when necessary, treat comorbid medical conditions. The importance of educating patients, their families, and the treatment team cannot be overlooked. Further, psychiatric treatment facilities should offer and promote healthy lifestyle interventions.

The course of chronic psychiatric conditions, such as schizophrenia, differs from chronic medical conditions, such as diabetes. Some patients with chronic psychiatric conditions achieve remission and become symptom-free, while others continue to have lingering signs of disease for life.

Residual symptoms of schizophrenia are not fully defined in the literature, which poses a challenge because they are central in the overall treatment of schizophrenia spectrum disorders.¹ During this phase of schizophrenia, patients continue to have symptoms after psychosis has subsided. These patients might continue to have negative symptoms such as social and emotional withdrawal and low energy. Although frank psychotic behavior has disappeared, the patient might continue to hold strange beliefs. Pharmacotherapy is the primary treatment option for psychiatric conditions, but the psychosocial aspect may have greater importance when treating residual symptoms and patients with chronic psychiatric illness.²

A naturalistic study in Germany evaluated the occurrence and characteristics of residual symptoms in patients with schizophrenia.³ The authors used a Positive and Negative Syndrome Scale symptom severity score >1 for those purposes, which is possibly a stringent criterion to define residual symptoms. This multicenter study enrolled 399 individuals age 18 to 65 with a DSM-IV-TR diagnosis of schizophrenia, schizophreniform disorder, delusional disorder, or schizoaffective disorder.³ Of the 236 patients achieving remission at discharge, 94% had at least 1 residual symptom and 69% had at least 4 residual symptoms. Therefore, residual symptoms were highly prevalent in remitted patients. The most frequent residual symptoms were:

• blunted affect
• conceptual disorganization
• passive or apathetic social withdrawal
• emotional withdrawal
• lack of judgment and insight
• poor attention
• somatic concern
• difficulty with abstract thinking
• anxiety
• poor rapport.³

Of note, positive symptoms, such as delusions and hallucinatory behavior, were found in remitted patients at discharge (17% and 10%, respectively). The study concluded that the severity of residual symptoms was associated with relapse risk and had an overall negative impact on the outcome of patients with schizophrenia.³ The study noted that residual symptoms may be greater in number or volume than negative symptoms and questioned the origins of residual symptoms because most were present at baseline in more than two-third of patients.

Patients with residual symptoms of schizophrenia usually are older and therefore present specific management challenges for clinicians. Changes associated with aging, such as medical problems, cognitive deficits, and lack of social support, could create new care needs for this patient population. Although the biopsycho­social model used to treat chronic psychiatric conditions, especially schizophrenia, is preferred, older schizophrenia patients with residual symptoms often need more psychosocial interventions compared with young adults with schizophrenia.

Managing residual symptoms in schizophrenia

Few studies are devoted to pharmacological treatment of older adults with schizophrenia, likely because pharmacotherapy for older patients with schizophrenia can be challenging. Evidence-based treatment is based primarily on findings from younger patients who survived into later life. Clinicians often use the adage of geriatric psychiatry, “start low, go slow,” because older patients are susceptible to adverse effects associated with psychiatric medications, including cardiovascular, metabolic, anticholinergic, and extrapyramidal effects, orthostasis, sedation, falls, and neuroleptic malignant syndrome.

Older patients with schizophrenia are at an increased risk for extrapyramidal symptoms (EPS) and anticholinergic adverse effects, perhaps because of degeneration of dopaminergic and cholinergic neurons.⁴ Lowering the anticholinergic load by discontinuing or reducing the dosage of medications with anticholinergic properties, when possible, is a key principle when treating these patients. This tactic could help improve cognition and quality of life by decreasing the risk of other anticholinergic adverse effects, including delirium, constipation, urinary retention, and blurred vision.

Patients treated with typical antipsychotics are nearly twice as likely to develop tardive dyskinesia compared with those receiving atypical antipsychotics.⁵ Sedation, orthostatic hypotension, and anticholinergic effects can cause cognitive clouding, worsen cognitive impairment, and increase the risk of falls, especially in older patients.⁶ Clozapine and olanzapine have the strongest association with clinically significant weight gain and treatment-induced type 2 diabetes mellitus.⁷

The appropriate starting dosage of antipsychotics in older patients with schizophrenia is one-fourth of the starting adult dosage. Total daily maintenance dosages may be one-third to one-half of the adult dosage.⁶ Consensus guidelines for dosing atypical antipsychotics for older patients with schizophrenia are as shown in Table 1.⁸

Another point to consider when treating residual symptoms in patients with schizophrenia is to not discontinue antipsychotic medications. Relapse rates for these patients can occur up to 5 times higher than for those who continue treatment.¹⁰ A way to address this problem could be the use of depot antipsychotic medications, but there are no set recommendations for the use of long-acting injectable antipsychotics in older patients. These medications should be used with caution and at lowest effective dosages to offset potential adverse effects.

With the introduction of typical and atypical antipsychotics, the use of electroconvulsive therapy in older patients with schizophrenia has declined. In a 2009 meta-analysis of studies that included patients with refractory schizophrenia and repetitive transcranial magnetic stimulation (rTMS), results revealed a mixed effect size for controlled and uncontrolled studies. The authors stated the need for further controlled trials, assessing the efficacy of rTMS on negative and positive symptoms of schizophrenia.¹¹

Psychotherapy and psychosocial interventions

Patients with schizophrenia who have persistent psychotic symptoms while receiving adequate pharmacotherapy should be offered adjunctive cognitive, behaviorally oriented psychotherapy to reduce symptom severity. Cognitive-behavioral therapy (CBT) has been shown to help reduce relapse rates, reduce psychotic symptoms, and improve patients’ mental state.¹² Amotivation and lack of insight can be particularly troublesome, which CBT can help address.¹² Psychoeducation can:

• empower patients to understand their illness
• help them cope with their disease
• be aware of symptom relapse
• seek help sooner rather than later.

Also, counseling and supportive therapy are recommended by the American Psychiatric Association guidelines. Providers should involve family and loved ones in this discussion, so that they can help collaborate with care and provide a supportive and non-judgmental environment.

Older patients with residual symptoms of schizophrenia are less likely to have completed their education, pursued a career, or developed long-lasting relationships. Family members who were their support system earlier in life, such as parents, often are unable to provide care for them by the time patients with schizophrenia become older. These patients also are less likely to get married or have children, meaning that they are more likely to live alone. The advent of the interdisciplinary team, integration of several therapeutic modalities, the provision of case managers, and assertive community treatment (ACT) teams has provided help with social support, relapses, and hospitalizations, for older patients with schizophrenia.¹³ Key elements of ACT include:

• a multidisciplinary team, including a medication prescriber
• a shared caseload among team members
• direct service provision by team members
• frequent patient contact
• low patient to staff ratios
• outreach to patients in the community.

Medical care

Patients with schizophrenia are at higher risk for several comorbid medical conditions, such as diabetes, coronary artery disease, and digestive and liver disorders, compared with individuals without schizophrenia. This risk is associated with numerous factors, including sedentary lifestyle, high rates of lifetime cigarette use (70% to 80% of schizophrenia outpatients age <67 smoke), poor self-management skills, frequent homelessness, and unhealthy diet.

Although substantial attention is devoted to the psychiatric and behavioral management of patients with schizophrenia, many barriers impede the detection and treatment of their medical conditions. Patients with schizophrenia could experience delays in diagnosing a medical disorder, leading to more acute comorbidities at the time of diagnosis and premature mortality. Studies have confirmed that cardiovascular diseases are the leading cause of premature death among psychiatric patients in the United States.¹⁴ Key risk factors include smoking, obesity, hypertension, dyslipidemia, diabetes, and lack of physical activity, all of which are more common among patients with schizophrenia compared with the general population.¹⁵ In addition, antipsychotics are associated with adverse metabolic effects.¹⁶

What are realistic treatment goals to manage residual symptoms in schizophrenia?

We believe that because remission in schizophrenia has been defined consensually, the bar for treatment expectations is set higher than it was 20 years ago. There can be patient-, family-, and system-related variables affecting the feasibility of treating residual symptoms. Providers who treat patients with schizophrenia should consider the following treatment goals:

• Prevent relapse and acute psychiatric hospitalization
• Use evidence-based strategies to minimize or monitor adverse effects
• Monitor compliance and consider use of depot antipsychotics combined with patients’ preference
• Facilitate ongoing safety assessment, including suicide risk
• Monitor negative and cognitive symptoms in addition to positive symptoms, using evidence-based management
• Encourage collaboration of care with family, caretakers, and other members of the treatment team
• Empower patients by providing psycho­education and social skills training and assisting in their vocational rehabilitation 
• Educate the patient and family about healthy lifestyle interventions and medical comorbidities common with schizophrenia
• Perform baseline screening and follow-up for early detection and treatment of medical comorbidities in patients with schizophrenia
• Improve functional status and quality of life.

In addition to meeting these treatment goals, a measurement-based method can be implemented to monitor improvement and status of the independent treatment domains. A collection of rating instruments can be found in Table 2.^17-30

Summing up

The clinical presentation of patients with residual symptoms of schizophrenia differs from that of other patients with schizophrenia. Our understanding of residual symptoms in schizophrenia has come a long way in the last decade; however, we are still far from pinning the complex nature of these symptoms, let alone their management. Given the risk of morbidity and disability, there clearly is a need for further investigation and investment of time and resources to support developing novel pharmacological treatment options to manage residual symptoms in patients with schizophrenia.

Because patients with residual symptoms of schizophrenia usually are older, psychiatrists should be responsible for implementing necessary screening assessments and should closely collaborate with primary care practitioners and other specialists, and when necessary, treat comorbid medical conditions. The importance of educating patients, their families, and the treatment team cannot be overlooked. Further, psychiatric treatment facilities should offer and promote healthy lifestyle interventions.

The course of chronic psychiatric conditions, such as schizophrenia, differs from chronic medical conditions, such as diabetes. Some patients with chronic psychiatric conditions achieve remission and become symptom-free, while others continue to have lingering signs of disease for life.

Residual symptoms of schizophrenia are not fully defined in the literature, which poses a challenge because they are central in the overall treatment of schizophrenia spectrum disorders.¹ During this phase of schizophrenia, patients continue to have symptoms after psychosis has subsided. These patients might continue to have negative symptoms such as social and emotional withdrawal and low energy. Although frank psychotic behavior has disappeared, the patient might continue to hold strange beliefs. Pharmacotherapy is the primary treatment option for psychiatric conditions, but the psychosocial aspect may have greater importance when treating residual symptoms and patients with chronic psychiatric illness.²

A naturalistic study in Germany evaluated the occurrence and characteristics of residual symptoms in patients with schizophrenia.³ The authors used a Positive and Negative Syndrome Scale symptom severity score >1 for those purposes, which is possibly a stringent criterion to define residual symptoms. This multicenter study enrolled 399 individuals age 18 to 65 with a DSM-IV-TR diagnosis of schizophrenia, schizophreniform disorder, delusional disorder, or schizoaffective disorder.³ Of the 236 patients achieving remission at discharge, 94% had at least 1 residual symptom and 69% had at least 4 residual symptoms. Therefore, residual symptoms were highly prevalent in remitted patients. The most frequent residual symptoms were:

• blunted affect
• conceptual disorganization
• passive or apathetic social withdrawal
• emotional withdrawal
• lack of judgment and insight
• poor attention
• somatic concern
• difficulty with abstract thinking
• anxiety
• poor rapport.³

Of note, positive symptoms, such as delusions and hallucinatory behavior, were found in remitted patients at discharge (17% and 10%, respectively). The study concluded that the severity of residual symptoms was associated with relapse risk and had an overall negative impact on the outcome of patients with schizophrenia.³ The study noted that residual symptoms may be greater in number or volume than negative symptoms and questioned the origins of residual symptoms because most were present at baseline in more than two-third of patients.

Patients with residual symptoms of schizophrenia usually are older and therefore present specific management challenges for clinicians. Changes associated with aging, such as medical problems, cognitive deficits, and lack of social support, could create new care needs for this patient population. Although the biopsycho­social model used to treat chronic psychiatric conditions, especially schizophrenia, is preferred, older schizophrenia patients with residual symptoms often need more psychosocial interventions compared with young adults with schizophrenia.

Managing residual symptoms in schizophrenia

Few studies are devoted to pharmacological treatment of older adults with schizophrenia, likely because pharmacotherapy for older patients with schizophrenia can be challenging. Evidence-based treatment is based primarily on findings from younger patients who survived into later life. Clinicians often use the adage of geriatric psychiatry, “start low, go slow,” because older patients are susceptible to adverse effects associated with psychiatric medications, including cardiovascular, metabolic, anticholinergic, and extrapyramidal effects, orthostasis, sedation, falls, and neuroleptic malignant syndrome.

Older patients with schizophrenia are at an increased risk for extrapyramidal symptoms (EPS) and anticholinergic adverse effects, perhaps because of degeneration of dopaminergic and cholinergic neurons.⁴ Lowering the anticholinergic load by discontinuing or reducing the dosage of medications with anticholinergic properties, when possible, is a key principle when treating these patients. This tactic could help improve cognition and quality of life by decreasing the risk of other anticholinergic adverse effects, including delirium, constipation, urinary retention, and blurred vision.

Patients treated with typical antipsychotics are nearly twice as likely to develop tardive dyskinesia compared with those receiving atypical antipsychotics.⁵ Sedation, orthostatic hypotension, and anticholinergic effects can cause cognitive clouding, worsen cognitive impairment, and increase the risk of falls, especially in older patients.⁶ Clozapine and olanzapine have the strongest association with clinically significant weight gain and treatment-induced type 2 diabetes mellitus.⁷

The appropriate starting dosage of antipsychotics in older patients with schizophrenia is one-fourth of the starting adult dosage. Total daily maintenance dosages may be one-third to one-half of the adult dosage.⁶ Consensus guidelines for dosing atypical antipsychotics for older patients with schizophrenia are as shown in Table 1.⁸

Another point to consider when treating residual symptoms in patients with schizophrenia is to not discontinue antipsychotic medications. Relapse rates for these patients can occur up to 5 times higher than for those who continue treatment.¹⁰ A way to address this problem could be the use of depot antipsychotic medications, but there are no set recommendations for the use of long-acting injectable antipsychotics in older patients. These medications should be used with caution and at lowest effective dosages to offset potential adverse effects.

With the introduction of typical and atypical antipsychotics, the use of electroconvulsive therapy in older patients with schizophrenia has declined. In a 2009 meta-analysis of studies that included patients with refractory schizophrenia and repetitive transcranial magnetic stimulation (rTMS), results revealed a mixed effect size for controlled and uncontrolled studies. The authors stated the need for further controlled trials, assessing the efficacy of rTMS on negative and positive symptoms of schizophrenia.¹¹

Psychotherapy and psychosocial interventions

Patients with schizophrenia who have persistent psychotic symptoms while receiving adequate pharmacotherapy should be offered adjunctive cognitive, behaviorally oriented psychotherapy to reduce symptom severity. Cognitive-behavioral therapy (CBT) has been shown to help reduce relapse rates, reduce psychotic symptoms, and improve patients’ mental state.¹² Amotivation and lack of insight can be particularly troublesome, which CBT can help address.¹² Psychoeducation can:

• empower patients to understand their illness
• help them cope with their disease
• be aware of symptom relapse
• seek help sooner rather than later.

Also, counseling and supportive therapy are recommended by the American Psychiatric Association guidelines. Providers should involve family and loved ones in this discussion, so that they can help collaborate with care and provide a supportive and non-judgmental environment.

Older patients with residual symptoms of schizophrenia are less likely to have completed their education, pursued a career, or developed long-lasting relationships. Family members who were their support system earlier in life, such as parents, often are unable to provide care for them by the time patients with schizophrenia become older. These patients also are less likely to get married or have children, meaning that they are more likely to live alone. The advent of the interdisciplinary team, integration of several therapeutic modalities, the provision of case managers, and assertive community treatment (ACT) teams has provided help with social support, relapses, and hospitalizations, for older patients with schizophrenia.¹³ Key elements of ACT include:

• a multidisciplinary team, including a medication prescriber
• a shared caseload among team members
• direct service provision by team members
• frequent patient contact
• low patient to staff ratios
• outreach to patients in the community.

Medical care

Patients with schizophrenia are at higher risk for several comorbid medical conditions, such as diabetes, coronary artery disease, and digestive and liver disorders, compared with individuals without schizophrenia. This risk is associated with numerous factors, including sedentary lifestyle, high rates of lifetime cigarette use (70% to 80% of schizophrenia outpatients age <67 smoke), poor self-management skills, frequent homelessness, and unhealthy diet.

Although substantial attention is devoted to the psychiatric and behavioral management of patients with schizophrenia, many barriers impede the detection and treatment of their medical conditions. Patients with schizophrenia could experience delays in diagnosing a medical disorder, leading to more acute comorbidities at the time of diagnosis and premature mortality. Studies have confirmed that cardiovascular diseases are the leading cause of premature death among psychiatric patients in the United States.¹⁴ Key risk factors include smoking, obesity, hypertension, dyslipidemia, diabetes, and lack of physical activity, all of which are more common among patients with schizophrenia compared with the general population.¹⁵ In addition, antipsychotics are associated with adverse metabolic effects.¹⁶

What are realistic treatment goals to manage residual symptoms in schizophrenia?

We believe that because remission in schizophrenia has been defined consensually, the bar for treatment expectations is set higher than it was 20 years ago. There can be patient-, family-, and system-related variables affecting the feasibility of treating residual symptoms. Providers who treat patients with schizophrenia should consider the following treatment goals:

• Prevent relapse and acute psychiatric hospitalization
• Use evidence-based strategies to minimize or monitor adverse effects
• Monitor compliance and consider use of depot antipsychotics combined with patients’ preference
• Facilitate ongoing safety assessment, including suicide risk
• Monitor negative and cognitive symptoms in addition to positive symptoms, using evidence-based management
• Encourage collaboration of care with family, caretakers, and other members of the treatment team
• Empower patients by providing psycho­education and social skills training and assisting in their vocational rehabilitation 
• Educate the patient and family about healthy lifestyle interventions and medical comorbidities common with schizophrenia
• Perform baseline screening and follow-up for early detection and treatment of medical comorbidities in patients with schizophrenia
• Improve functional status and quality of life.

In addition to meeting these treatment goals, a measurement-based method can be implemented to monitor improvement and status of the independent treatment domains. A collection of rating instruments can be found in Table 2.^17-30

Summing up

The clinical presentation of patients with residual symptoms of schizophrenia differs from that of other patients with schizophrenia. Our understanding of residual symptoms in schizophrenia has come a long way in the last decade; however, we are still far from pinning the complex nature of these symptoms, let alone their management. Given the risk of morbidity and disability, there clearly is a need for further investigation and investment of time and resources to support developing novel pharmacological treatment options to manage residual symptoms in patients with schizophrenia.

Because patients with residual symptoms of schizophrenia usually are older, psychiatrists should be responsible for implementing necessary screening assessments and should closely collaborate with primary care practitioners and other specialists, and when necessary, treat comorbid medical conditions. The importance of educating patients, their families, and the treatment team cannot be overlooked. Further, psychiatric treatment facilities should offer and promote healthy lifestyle interventions.

Attention-deficit/hyperactivity disorder (ADHD) is common; it affects 5% to 7% of children^1,2 and 4% to 5% of all adults.^3,4 Pediatric ADHD often persists into adulthood, as 65% of individuals diagnosed as children retain impairing symptoms by age 25.⁴

The prevalence of ADHD in childhood is 2 to 3 times greater among boys than girls, but more comparable between the sexes in adulthood.² Symptoms could be more easily overlooked in women because of the greater prominence of hyperactivity and impulsivity-type symptoms in men.⁵

Untreated ADHD is associated with significant costs. Adults with ADHD have increased unemployment rates, poor work performance, and comparatively lower educational performance.^6,7 Compared with non-ADHD adults, those with ADHD have:

• more traffic violations and accidents and a higher rate of criminal convictions and incarcerations^8,9
• a mortality rate almost 2 times higher, with the greatest differences seen in deaths by suicide and accidents.^10,11

Adults with ADHD also are more likely to have a comorbid psychiatric disorder—in particular, substance use¹¹—and often are in treatment for other mental or substance use disorders. Among adults who meet diagnostic criteria for ADHD, approximately only 10% are receiving treatment for ADHD symptoms.^3,12

Changes in DSM-5

Revisions within DSM-5 simplify ADHD’s diagnosis—and make it more difficult to ignore in

DSM-5 also provides examples of behaviors more commonly found in adults, such as “feelings of restlessness,” compared with DSM-IV’s “often runs about or climbs excessively in situations in which it is inappropriate.” Finally, ADHD now may be diagnosed in a person with an autism spectrum disorder who meets diagnostic criteria for both disorders.^13,14

Identifying ADHD in adults

ADHD diagnosis in adults is made through careful clinical interviewing. For example, ask about what factors motivated an individual to seek evaluation for ADHD. Often, patients present after a change in responsibility at work or at home, such as a promotion or birth/adoption of a new child.

Consider incorporating a brief screen for adult ADHD in all new outpatient evaluations (Table 2).¹⁵ Screen for other psychiatric disorders as well; comorbidity with ADHD is high, and hyperactivity and inattention symptoms may result from anxiety, depression, or substance use.

Screen for learning disorders, which can present with ADHD symptoms (such as poor concentration) when the individual attempts difficult tasks. Evaluate for risk factors associated with ADHD medications, such as a history of cardiac problems, hypertension, or tachycardia. A family history of ADHD is found in approximately 80% of cases.^16,17 Determine the presence of ADHD symptoms in childhood. A careful review of the educational history often reveals long-term underachievement and struggles in school. Patients may report a chronic history of poor attention or feelings of restlessness in school. Sometimes problems do not become apparent until high school or college; some individuals, especially those with high intelligence, compensate for deficits and show fewer overt symptoms of impairment until later in their education.¹⁸Occupational history also may be revealing:

• How are they performing at work?
• Have they changed jobs multiple times in a short period?
• Do they have difficulty organizing tasks?

Subtle ADHD signs include time of arrival to appointments (eg, late or extremely early), missing data on intake paperwork, and a history of losing keys or phones.

Neuropsychological testing. Some clinicians routinely include neuropsychological testing in an adult ADHD evaluation, but these studies have shown inconsistent cognitive deficits in people with ADHD.^19,20 No distinct psychometric cognitive test or profile is diagnostic of ADHD or its subtypes.²¹

Treatment and follow-up care

Four general categories of medications are used to treat ADHD in children and adults:

After starting a patient on medication, at each follow-up appointment ask about new cardiac symptoms or diagnoses, new family history of cardiac problems, or new medications. Measure pulse and blood pressure every 1 to 3 months. Measure vital signs more frequently during titration and weaning periods.²³

Stimulant medications

Amphetamines have dual action: they block the reuptake of dopamine and noradrenaline by competitive inhibition of the transporters and promote the release of dopamine and noradrenaline by competitive inhibition of the intraneuronal vesicular monoamine transporter.²⁴

For most amphetamine products, including dextroamphetamine and amphetamine mixed salts, the target dosage is approximately 0.5 mg/kg. Start at a lower dosage, however, and rapidly titrate weekly so patients can adjust to the medication while not becoming frustrated with a lack of efficacy. Some patients may require short-acting forms with dosing 3 times per day, and twice daily dosing is not uncommon with extended-release (ER) formulations.

Metabolism of most amphetamine products—with the exception of lisdexamfetamine—involves the cytochrome P450 (CYP) enzyme CYP2D6, leading to the formation of the metabolite 4-hydroxyamphetamine.²⁵ The pharmacokinetics of lisdexamfetamine in slow or ultra-rapid CYP2D6 metabolizers has not been evaluated (Shire US Inc., written communication, July 2014).

Agents that alter urinary pH can affect blood levels of amphetamine. Acidifying agents decrease amphetamine blood levels, while alkalinizing agents increase amphetamine blood levels.²⁶

Lisdexamfetamine contains L-lysine, an essential amino acid, covalently bound to d-amphetamine via an amide linking group.²⁷ After absorption, lisdexamfetamine is metabolized by rate-limited, enzymatic hydrolysis to yield d-amphetamine and L-lysine.^24,28,29 A starting dose of 40 mg is advised; twice-daily dosing rarely is required.

A meta-analysis of 5 randomized, controlled trials in the treatment of adult ADHD showed a response rate of 70% for lisdexamfetamine compared with 37% for placebo. Trial duration ranged from 4 to 14 weeks, with dosages of 30 to 70 mg/d.³⁰ Another analysis of data from lisdexamfetamine trials predicted an effect size of 1.07 for European adults, which is larger than the 0.8 threshold for large effect sizes.³¹

Methylphenidate products. Methyl­phenidate’s main action is through enhancement of dopamine signaling by blockade of the dopamine transporter, leading to increases in extracellular dopamine as well as norepinephrine.^22,32 Optimized dosing is generally 1 mg/kg per day, and dosing up to 80 to 120 mg/d is not unusual.³³

Dexmethylphenidate is the more pharmacologically active enantiomer of racemic methylphenidate and is twice as potent.^34-36 Target dosing of dexmethylphenidate should be one-half as much (ie, 0.5 mg/kg per day) as other methylphenidate products.³⁷

Managing stimulants’ side effects

Amphetamines’ side effects may include insomnia, dry mouth, decreased appetite, weight loss, headaches, and anxiety. To help minimize sleep problems, advise patients to take a second immediate-release dose at noon, rather than later in the afternoon. The longer-acting formulation taken once per day in the morning may be offered as an alternative. Some patients may experience improved sleep because of diminished bedtime ruminations.

Oral rinses, such as Biotène, could help reduce discomfort associated with dry mouth. Pilocarpine, which stimulates saliva production, is another option if rinses are not effective. To address decreased appetite, advise patients to take their medication after they eat. Switching from an immediate-release amphetamine to a longer-acting formulation also may lessen symptoms. Lisdexamfetamine might be a good choice for adults with ADHD who have undergone bariatric surgeries because it is absorbed in the small bowel.³⁸

Methylphenidate has no interactions with CYP enzymes, making it an attractive option for patients taking CYP inhibiting or stimulating medications.³⁹ The most common side effects of methylphenidate products include appetite loss, insomnia, irritability, and tachycardia. Some side effects will abate after 1 to 2 weeks of treatment, but persistence of insomnia and appetite loss may require a decrease in dosage. In rare cases, methylphenidate may produce tics, exacerbate an existing tic disorder, or produce mania or psychosis.^40,41 Methylphenidate inhibits the metabolism of tricyclic antidepressants; use methylphenidate with caution in patients taking monoamine oxidase inhibitors.^42,43Cardiovascular risks. Possible cardiovascular risks associated with stimulant use have gained widespread attention, although research has not demonstrated an increased risk of serious cardiovascular events in young and middle-aged adults receiving stimulant medications for ADHD.⁴⁴ Nonetheless, obtain a thorough medical history in adult patients, including cardiac history, family history of cardiac disease, history of any cardiac symptoms, and a medication history. Baseline ECG is not required.⁴⁵

Screen for a family history of sudden death in a young person, sudden death during exercise, cardiac arrhythmia, cardiomyopathies (including hypertrophic cardiomyopathy, dilated cardiomyopathy, and right ventricular cardiomyopathy), prolonged QT interval, short QT syndrome, Brugada syndrome, Wolff-Parkinson-White syndrome, Marfan syndrome, and an event requiring resuscitation in a family member younger than 35, including syncope requiring rescuscitation.²³ If fainting spells, palpitations, chest pain, or other symptoms suggest preexisting cardiovascular disease, refer the patient promptly to a cardiologist.

Peripheral vasculopathy, including Raynaud’s phenomenon, is a lesser known side effect associated with stimulants.⁴⁶ Symptoms are usually mild, but in rare instances stimulants are associated with digital ulceration or soft tissue breakdown.⁴⁷ Advise patients to tell you if they experience any new symptoms of numbness, pain, skin color changes, or sensitivity to temperature in fingers and toes. Signs and symptoms generally improve after dosage reduction or discontinuation of the stimulant medication.⁴⁶ Referral to a rheumatologist might be appropriate if symptoms persist.

A noradrenergic medication

Atomoxetine is a potent, selective inhibitor of the presynaptic noradrenaline transporter that increases the availability of extracellular noradrenaline in the prefrontal cortex.^48,49 Atomoxetine may be a good alternative for adult patients with ADHD and comorbid anxiety.⁵⁰

For adults, the optimal starting dosage is 40 mg in the morning for 1 week, followed by an increase to 80 mg. Insufficient dosing is common with atomoxetine, and the dosage could be increased to 100 mg/d.⁵¹ Dosing twice per day may be associated with higher rates of insomnia.

Atomoxetine’s efficacy for managing ADHD in adults has been consistently demonstrated by 6 placebo-controlled trials of 10 to 16 weeks, 3 placebo-controlled 6-month trials, and a 1-year maintenance-of-response trial.⁵² Atomoxetine was found to have an effect size of 0.45 (medium) (number needed to treat [NNT] = 5).^53-55The most common adverse effects include nausea, dry mouth, insomnia, and erectile dysfunction. Small increases in heart rate and blood pressure have been reported, so use this medication with caution in patients for whom this might be problematic. Atomoxetine is metabolized by CYP2D6; 7% of white individuals have a genotype corresponding to a nonfunctional CYP2D6 enzyme.^56-58

Alpha-2 adrenergic agonists

Clonidine and guanfacine are antihypertensive drugs that induce peripheral sympathoinhibition via the stimulation of receptors. Clonidine binds equally to adrenergic receptor subtypes α-2A, α-2B, and α-2C (as well as to α-1 and β subtypes, histamine receptors, and possibly dopamine receptors).^59,60 Guanfacine binds preferentially to postsynaptic α-2A adrenoceptors in the prefrontal cortex, which have been implicated in attentional and organizational functions.^61,62

ER guanfacine and ER clonidine are FDA-approved as monotherapy for ADHD in children and adolescents.

Efficacy in adults. A small (N = 17), double-blind, placebo-controlled, crossover study comparing immediate-release guanfacine and dextroamphetamine found that both medications significantly reduced adult ADHD symptoms, as measured with the DSM-IV Adult Behavior Checklist for Adults.⁶³

No trials have been published regarding the efficacy of ER clonidine in adults with ADHD; adverse effects including sedation, bradycardia, and hypotension may limit its use. One study compared the supplemental use of ER guanfacine (1 to 6 mg/d) or a matching placebo in 26 adults with ADHD who had suboptimal response to stimulant-only treatment. After 10 weeks, both the guanfacine ER and placebo groups showed statistically significant improvements in ADHD symptoms and general functioning. The treatments did not differ in efficacy, safety, or tolerability.⁶⁴

Adverse events. Compared with clonidine, guanfacine has less CNS depressant and hypotensive activity.⁵⁸ A phase I trial of ER guanfacine in healthy adults found its single-dose pharmacokinetic properties in 1-, 2-, and 4-mg tablets appeared to be statistically linear. Somnolence—the most common treatment-emergent adverse effect—occurred in 33 of 52 participants (63.5%). All mean vital-sign measurements and ECG parameters remained within normal limits after dosing, and no marked changes from baseline measurements were noted.⁶⁵

Antidepressants

Antidepressants used in ADHD treatment include bupropion and tricyclic antidepressants.
Bupropion is a noradrenaline and dopamine reuptake inhibitor and is considered to be a mild psychostimulant because of its amphetamine-derived chemical structure.^66,67 It generally is considered a third-line medication when stimulants have not improved ADHD symptoms or are not tolerated.

A 2011 meta-analysis examined 5 randomized, controlled trials including 175 adults treated with bupropion for ADHD. Bupropion was found to be more effective than placebo (NNT = 5), although bupropion’s therapeutic benefits were not observed until weeks 5 and 6. Its effects were less pronounced than those of methylphenidate. Mean daily dosages were 362 mg for the bupropion SR trials and 393 mg for the bupropion XL trial.⁶⁸

Tricyclics. Desipramine and nortriptyline have been found to be efficacious in childhood ADHD,^69,70 although cardiovascular risk and toxicity in overdose limit their use.⁷¹

Attention-deficit/hyperactivity disorder (ADHD) is common; it affects 5% to 7% of children^1,2 and 4% to 5% of all adults.^3,4 Pediatric ADHD often persists into adulthood, as 65% of individuals diagnosed as children retain impairing symptoms by age 25.⁴

The prevalence of ADHD in childhood is 2 to 3 times greater among boys than girls, but more comparable between the sexes in adulthood.² Symptoms could be more easily overlooked in women because of the greater prominence of hyperactivity and impulsivity-type symptoms in men.⁵

Untreated ADHD is associated with significant costs. Adults with ADHD have increased unemployment rates, poor work performance, and comparatively lower educational performance.^6,7 Compared with non-ADHD adults, those with ADHD have:

• more traffic violations and accidents and a higher rate of criminal convictions and incarcerations^8,9
• a mortality rate almost 2 times higher, with the greatest differences seen in deaths by suicide and accidents.^10,11

Adults with ADHD also are more likely to have a comorbid psychiatric disorder—in particular, substance use¹¹—and often are in treatment for other mental or substance use disorders. Among adults who meet diagnostic criteria for ADHD, approximately only 10% are receiving treatment for ADHD symptoms.^3,12

Changes in DSM-5

Revisions within DSM-5 simplify ADHD’s diagnosis—and make it more difficult to ignore in

DSM-5 also provides examples of behaviors more commonly found in adults, such as “feelings of restlessness,” compared with DSM-IV’s “often runs about or climbs excessively in situations in which it is inappropriate.” Finally, ADHD now may be diagnosed in a person with an autism spectrum disorder who meets diagnostic criteria for both disorders.^13,14

Identifying ADHD in adults

ADHD diagnosis in adults is made through careful clinical interviewing. For example, ask about what factors motivated an individual to seek evaluation for ADHD. Often, patients present after a change in responsibility at work or at home, such as a promotion or birth/adoption of a new child.

Consider incorporating a brief screen for adult ADHD in all new outpatient evaluations (Table 2).¹⁵ Screen for other psychiatric disorders as well; comorbidity with ADHD is high, and hyperactivity and inattention symptoms may result from anxiety, depression, or substance use.

Screen for learning disorders, which can present with ADHD symptoms (such as poor concentration) when the individual attempts difficult tasks. Evaluate for risk factors associated with ADHD medications, such as a history of cardiac problems, hypertension, or tachycardia. A family history of ADHD is found in approximately 80% of cases.^16,17 Determine the presence of ADHD symptoms in childhood. A careful review of the educational history often reveals long-term underachievement and struggles in school. Patients may report a chronic history of poor attention or feelings of restlessness in school. Sometimes problems do not become apparent until high school or college; some individuals, especially those with high intelligence, compensate for deficits and show fewer overt symptoms of impairment until later in their education.¹⁸Occupational history also may be revealing:

• How are they performing at work?
• Have they changed jobs multiple times in a short period?
• Do they have difficulty organizing tasks?

Subtle ADHD signs include time of arrival to appointments (eg, late or extremely early), missing data on intake paperwork, and a history of losing keys or phones.

Neuropsychological testing. Some clinicians routinely include neuropsychological testing in an adult ADHD evaluation, but these studies have shown inconsistent cognitive deficits in people with ADHD.^19,20 No distinct psychometric cognitive test or profile is diagnostic of ADHD or its subtypes.²¹

Treatment and follow-up care

Four general categories of medications are used to treat ADHD in children and adults:

After starting a patient on medication, at each follow-up appointment ask about new cardiac symptoms or diagnoses, new family history of cardiac problems, or new medications. Measure pulse and blood pressure every 1 to 3 months. Measure vital signs more frequently during titration and weaning periods.²³

Stimulant medications

Amphetamines have dual action: they block the reuptake of dopamine and noradrenaline by competitive inhibition of the transporters and promote the release of dopamine and noradrenaline by competitive inhibition of the intraneuronal vesicular monoamine transporter.²⁴

For most amphetamine products, including dextroamphetamine and amphetamine mixed salts, the target dosage is approximately 0.5 mg/kg. Start at a lower dosage, however, and rapidly titrate weekly so patients can adjust to the medication while not becoming frustrated with a lack of efficacy. Some patients may require short-acting forms with dosing 3 times per day, and twice daily dosing is not uncommon with extended-release (ER) formulations.

Metabolism of most amphetamine products—with the exception of lisdexamfetamine—involves the cytochrome P450 (CYP) enzyme CYP2D6, leading to the formation of the metabolite 4-hydroxyamphetamine.²⁵ The pharmacokinetics of lisdexamfetamine in slow or ultra-rapid CYP2D6 metabolizers has not been evaluated (Shire US Inc., written communication, July 2014).

Agents that alter urinary pH can affect blood levels of amphetamine. Acidifying agents decrease amphetamine blood levels, while alkalinizing agents increase amphetamine blood levels.²⁶

Lisdexamfetamine contains L-lysine, an essential amino acid, covalently bound to d-amphetamine via an amide linking group.²⁷ After absorption, lisdexamfetamine is metabolized by rate-limited, enzymatic hydrolysis to yield d-amphetamine and L-lysine.^24,28,29 A starting dose of 40 mg is advised; twice-daily dosing rarely is required.

A meta-analysis of 5 randomized, controlled trials in the treatment of adult ADHD showed a response rate of 70% for lisdexamfetamine compared with 37% for placebo. Trial duration ranged from 4 to 14 weeks, with dosages of 30 to 70 mg/d.³⁰ Another analysis of data from lisdexamfetamine trials predicted an effect size of 1.07 for European adults, which is larger than the 0.8 threshold for large effect sizes.³¹

Methylphenidate products. Methyl­phenidate’s main action is through enhancement of dopamine signaling by blockade of the dopamine transporter, leading to increases in extracellular dopamine as well as norepinephrine.^22,32 Optimized dosing is generally 1 mg/kg per day, and dosing up to 80 to 120 mg/d is not unusual.³³

Dexmethylphenidate is the more pharmacologically active enantiomer of racemic methylphenidate and is twice as potent.^34-36 Target dosing of dexmethylphenidate should be one-half as much (ie, 0.5 mg/kg per day) as other methylphenidate products.³⁷

Managing stimulants’ side effects

Amphetamines’ side effects may include insomnia, dry mouth, decreased appetite, weight loss, headaches, and anxiety. To help minimize sleep problems, advise patients to take a second immediate-release dose at noon, rather than later in the afternoon. The longer-acting formulation taken once per day in the morning may be offered as an alternative. Some patients may experience improved sleep because of diminished bedtime ruminations.

Oral rinses, such as Biotène, could help reduce discomfort associated with dry mouth. Pilocarpine, which stimulates saliva production, is another option if rinses are not effective. To address decreased appetite, advise patients to take their medication after they eat. Switching from an immediate-release amphetamine to a longer-acting formulation also may lessen symptoms. Lisdexamfetamine might be a good choice for adults with ADHD who have undergone bariatric surgeries because it is absorbed in the small bowel.³⁸

Methylphenidate has no interactions with CYP enzymes, making it an attractive option for patients taking CYP inhibiting or stimulating medications.³⁹ The most common side effects of methylphenidate products include appetite loss, insomnia, irritability, and tachycardia. Some side effects will abate after 1 to 2 weeks of treatment, but persistence of insomnia and appetite loss may require a decrease in dosage. In rare cases, methylphenidate may produce tics, exacerbate an existing tic disorder, or produce mania or psychosis.^40,41 Methylphenidate inhibits the metabolism of tricyclic antidepressants; use methylphenidate with caution in patients taking monoamine oxidase inhibitors.^42,43Cardiovascular risks. Possible cardiovascular risks associated with stimulant use have gained widespread attention, although research has not demonstrated an increased risk of serious cardiovascular events in young and middle-aged adults receiving stimulant medications for ADHD.⁴⁴ Nonetheless, obtain a thorough medical history in adult patients, including cardiac history, family history of cardiac disease, history of any cardiac symptoms, and a medication history. Baseline ECG is not required.⁴⁵

Screen for a family history of sudden death in a young person, sudden death during exercise, cardiac arrhythmia, cardiomyopathies (including hypertrophic cardiomyopathy, dilated cardiomyopathy, and right ventricular cardiomyopathy), prolonged QT interval, short QT syndrome, Brugada syndrome, Wolff-Parkinson-White syndrome, Marfan syndrome, and an event requiring resuscitation in a family member younger than 35, including syncope requiring rescuscitation.²³ If fainting spells, palpitations, chest pain, or other symptoms suggest preexisting cardiovascular disease, refer the patient promptly to a cardiologist.

Peripheral vasculopathy, including Raynaud’s phenomenon, is a lesser known side effect associated with stimulants.⁴⁶ Symptoms are usually mild, but in rare instances stimulants are associated with digital ulceration or soft tissue breakdown.⁴⁷ Advise patients to tell you if they experience any new symptoms of numbness, pain, skin color changes, or sensitivity to temperature in fingers and toes. Signs and symptoms generally improve after dosage reduction or discontinuation of the stimulant medication.⁴⁶ Referral to a rheumatologist might be appropriate if symptoms persist.

A noradrenergic medication

Atomoxetine is a potent, selective inhibitor of the presynaptic noradrenaline transporter that increases the availability of extracellular noradrenaline in the prefrontal cortex.^48,49 Atomoxetine may be a good alternative for adult patients with ADHD and comorbid anxiety.⁵⁰

For adults, the optimal starting dosage is 40 mg in the morning for 1 week, followed by an increase to 80 mg. Insufficient dosing is common with atomoxetine, and the dosage could be increased to 100 mg/d.⁵¹ Dosing twice per day may be associated with higher rates of insomnia.

Atomoxetine’s efficacy for managing ADHD in adults has been consistently demonstrated by 6 placebo-controlled trials of 10 to 16 weeks, 3 placebo-controlled 6-month trials, and a 1-year maintenance-of-response trial.⁵² Atomoxetine was found to have an effect size of 0.45 (medium) (number needed to treat [NNT] = 5).^53-55The most common adverse effects include nausea, dry mouth, insomnia, and erectile dysfunction. Small increases in heart rate and blood pressure have been reported, so use this medication with caution in patients for whom this might be problematic. Atomoxetine is metabolized by CYP2D6; 7% of white individuals have a genotype corresponding to a nonfunctional CYP2D6 enzyme.^56-58

Alpha-2 adrenergic agonists

Clonidine and guanfacine are antihypertensive drugs that induce peripheral sympathoinhibition via the stimulation of receptors. Clonidine binds equally to adrenergic receptor subtypes α-2A, α-2B, and α-2C (as well as to α-1 and β subtypes, histamine receptors, and possibly dopamine receptors).^59,60 Guanfacine binds preferentially to postsynaptic α-2A adrenoceptors in the prefrontal cortex, which have been implicated in attentional and organizational functions.^61,62

ER guanfacine and ER clonidine are FDA-approved as monotherapy for ADHD in children and adolescents.

Efficacy in adults. A small (N = 17), double-blind, placebo-controlled, crossover study comparing immediate-release guanfacine and dextroamphetamine found that both medications significantly reduced adult ADHD symptoms, as measured with the DSM-IV Adult Behavior Checklist for Adults.⁶³

No trials have been published regarding the efficacy of ER clonidine in adults with ADHD; adverse effects including sedation, bradycardia, and hypotension may limit its use. One study compared the supplemental use of ER guanfacine (1 to 6 mg/d) or a matching placebo in 26 adults with ADHD who had suboptimal response to stimulant-only treatment. After 10 weeks, both the guanfacine ER and placebo groups showed statistically significant improvements in ADHD symptoms and general functioning. The treatments did not differ in efficacy, safety, or tolerability.⁶⁴

Adverse events. Compared with clonidine, guanfacine has less CNS depressant and hypotensive activity.⁵⁸ A phase I trial of ER guanfacine in healthy adults found its single-dose pharmacokinetic properties in 1-, 2-, and 4-mg tablets appeared to be statistically linear. Somnolence—the most common treatment-emergent adverse effect—occurred in 33 of 52 participants (63.5%). All mean vital-sign measurements and ECG parameters remained within normal limits after dosing, and no marked changes from baseline measurements were noted.⁶⁵

Antidepressants

Antidepressants used in ADHD treatment include bupropion and tricyclic antidepressants.
Bupropion is a noradrenaline and dopamine reuptake inhibitor and is considered to be a mild psychostimulant because of its amphetamine-derived chemical structure.^66,67 It generally is considered a third-line medication when stimulants have not improved ADHD symptoms or are not tolerated.

A 2011 meta-analysis examined 5 randomized, controlled trials including 175 adults treated with bupropion for ADHD. Bupropion was found to be more effective than placebo (NNT = 5), although bupropion’s therapeutic benefits were not observed until weeks 5 and 6. Its effects were less pronounced than those of methylphenidate. Mean daily dosages were 362 mg for the bupropion SR trials and 393 mg for the bupropion XL trial.⁶⁸

Tricyclics. Desipramine and nortriptyline have been found to be efficacious in childhood ADHD,^69,70 although cardiovascular risk and toxicity in overdose limit their use.⁷¹

Attention-deficit/hyperactivity disorder (ADHD) is common; it affects 5% to 7% of children^1,2 and 4% to 5% of all adults.^3,4 Pediatric ADHD often persists into adulthood, as 65% of individuals diagnosed as children retain impairing symptoms by age 25.⁴

The prevalence of ADHD in childhood is 2 to 3 times greater among boys than girls, but more comparable between the sexes in adulthood.² Symptoms could be more easily overlooked in women because of the greater prominence of hyperactivity and impulsivity-type symptoms in men.⁵

Untreated ADHD is associated with significant costs. Adults with ADHD have increased unemployment rates, poor work performance, and comparatively lower educational performance.^6,7 Compared with non-ADHD adults, those with ADHD have:

• more traffic violations and accidents and a higher rate of criminal convictions and incarcerations^8,9
• a mortality rate almost 2 times higher, with the greatest differences seen in deaths by suicide and accidents.^10,11

Adults with ADHD also are more likely to have a comorbid psychiatric disorder—in particular, substance use¹¹—and often are in treatment for other mental or substance use disorders. Among adults who meet diagnostic criteria for ADHD, approximately only 10% are receiving treatment for ADHD symptoms.^3,12

Changes in DSM-5

Revisions within DSM-5 simplify ADHD’s diagnosis—and make it more difficult to ignore in

DSM-5 also provides examples of behaviors more commonly found in adults, such as “feelings of restlessness,” compared with DSM-IV’s “often runs about or climbs excessively in situations in which it is inappropriate.” Finally, ADHD now may be diagnosed in a person with an autism spectrum disorder who meets diagnostic criteria for both disorders.^13,14

Identifying ADHD in adults

ADHD diagnosis in adults is made through careful clinical interviewing. For example, ask about what factors motivated an individual to seek evaluation for ADHD. Often, patients present after a change in responsibility at work or at home, such as a promotion or birth/adoption of a new child.

Consider incorporating a brief screen for adult ADHD in all new outpatient evaluations (Table 2).¹⁵ Screen for other psychiatric disorders as well; comorbidity with ADHD is high, and hyperactivity and inattention symptoms may result from anxiety, depression, or substance use.

Screen for learning disorders, which can present with ADHD symptoms (such as poor concentration) when the individual attempts difficult tasks. Evaluate for risk factors associated with ADHD medications, such as a history of cardiac problems, hypertension, or tachycardia. A family history of ADHD is found in approximately 80% of cases.^16,17 Determine the presence of ADHD symptoms in childhood. A careful review of the educational history often reveals long-term underachievement and struggles in school. Patients may report a chronic history of poor attention or feelings of restlessness in school. Sometimes problems do not become apparent until high school or college; some individuals, especially those with high intelligence, compensate for deficits and show fewer overt symptoms of impairment until later in their education.¹⁸Occupational history also may be revealing:

• How are they performing at work?
• Have they changed jobs multiple times in a short period?
• Do they have difficulty organizing tasks?

Subtle ADHD signs include time of arrival to appointments (eg, late or extremely early), missing data on intake paperwork, and a history of losing keys or phones.

Neuropsychological testing. Some clinicians routinely include neuropsychological testing in an adult ADHD evaluation, but these studies have shown inconsistent cognitive deficits in people with ADHD.^19,20 No distinct psychometric cognitive test or profile is diagnostic of ADHD or its subtypes.²¹

Treatment and follow-up care

Four general categories of medications are used to treat ADHD in children and adults:

After starting a patient on medication, at each follow-up appointment ask about new cardiac symptoms or diagnoses, new family history of cardiac problems, or new medications. Measure pulse and blood pressure every 1 to 3 months. Measure vital signs more frequently during titration and weaning periods.²³

Stimulant medications

Amphetamines have dual action: they block the reuptake of dopamine and noradrenaline by competitive inhibition of the transporters and promote the release of dopamine and noradrenaline by competitive inhibition of the intraneuronal vesicular monoamine transporter.²⁴

For most amphetamine products, including dextroamphetamine and amphetamine mixed salts, the target dosage is approximately 0.5 mg/kg. Start at a lower dosage, however, and rapidly titrate weekly so patients can adjust to the medication while not becoming frustrated with a lack of efficacy. Some patients may require short-acting forms with dosing 3 times per day, and twice daily dosing is not uncommon with extended-release (ER) formulations.

Metabolism of most amphetamine products—with the exception of lisdexamfetamine—involves the cytochrome P450 (CYP) enzyme CYP2D6, leading to the formation of the metabolite 4-hydroxyamphetamine.²⁵ The pharmacokinetics of lisdexamfetamine in slow or ultra-rapid CYP2D6 metabolizers has not been evaluated (Shire US Inc., written communication, July 2014).

Agents that alter urinary pH can affect blood levels of amphetamine. Acidifying agents decrease amphetamine blood levels, while alkalinizing agents increase amphetamine blood levels.²⁶

Lisdexamfetamine contains L-lysine, an essential amino acid, covalently bound to d-amphetamine via an amide linking group.²⁷ After absorption, lisdexamfetamine is metabolized by rate-limited, enzymatic hydrolysis to yield d-amphetamine and L-lysine.^24,28,29 A starting dose of 40 mg is advised; twice-daily dosing rarely is required.

A meta-analysis of 5 randomized, controlled trials in the treatment of adult ADHD showed a response rate of 70% for lisdexamfetamine compared with 37% for placebo. Trial duration ranged from 4 to 14 weeks, with dosages of 30 to 70 mg/d.³⁰ Another analysis of data from lisdexamfetamine trials predicted an effect size of 1.07 for European adults, which is larger than the 0.8 threshold for large effect sizes.³¹

Methylphenidate products. Methyl­phenidate’s main action is through enhancement of dopamine signaling by blockade of the dopamine transporter, leading to increases in extracellular dopamine as well as norepinephrine.^22,32 Optimized dosing is generally 1 mg/kg per day, and dosing up to 80 to 120 mg/d is not unusual.³³

Dexmethylphenidate is the more pharmacologically active enantiomer of racemic methylphenidate and is twice as potent.^34-36 Target dosing of dexmethylphenidate should be one-half as much (ie, 0.5 mg/kg per day) as other methylphenidate products.³⁷

Managing stimulants’ side effects

Amphetamines’ side effects may include insomnia, dry mouth, decreased appetite, weight loss, headaches, and anxiety. To help minimize sleep problems, advise patients to take a second immediate-release dose at noon, rather than later in the afternoon. The longer-acting formulation taken once per day in the morning may be offered as an alternative. Some patients may experience improved sleep because of diminished bedtime ruminations.

Oral rinses, such as Biotène, could help reduce discomfort associated with dry mouth. Pilocarpine, which stimulates saliva production, is another option if rinses are not effective. To address decreased appetite, advise patients to take their medication after they eat. Switching from an immediate-release amphetamine to a longer-acting formulation also may lessen symptoms. Lisdexamfetamine might be a good choice for adults with ADHD who have undergone bariatric surgeries because it is absorbed in the small bowel.³⁸

Methylphenidate has no interactions with CYP enzymes, making it an attractive option for patients taking CYP inhibiting or stimulating medications.³⁹ The most common side effects of methylphenidate products include appetite loss, insomnia, irritability, and tachycardia. Some side effects will abate after 1 to 2 weeks of treatment, but persistence of insomnia and appetite loss may require a decrease in dosage. In rare cases, methylphenidate may produce tics, exacerbate an existing tic disorder, or produce mania or psychosis.^40,41 Methylphenidate inhibits the metabolism of tricyclic antidepressants; use methylphenidate with caution in patients taking monoamine oxidase inhibitors.^42,43Cardiovascular risks. Possible cardiovascular risks associated with stimulant use have gained widespread attention, although research has not demonstrated an increased risk of serious cardiovascular events in young and middle-aged adults receiving stimulant medications for ADHD.⁴⁴ Nonetheless, obtain a thorough medical history in adult patients, including cardiac history, family history of cardiac disease, history of any cardiac symptoms, and a medication history. Baseline ECG is not required.⁴⁵

Screen for a family history of sudden death in a young person, sudden death during exercise, cardiac arrhythmia, cardiomyopathies (including hypertrophic cardiomyopathy, dilated cardiomyopathy, and right ventricular cardiomyopathy), prolonged QT interval, short QT syndrome, Brugada syndrome, Wolff-Parkinson-White syndrome, Marfan syndrome, and an event requiring resuscitation in a family member younger than 35, including syncope requiring rescuscitation.²³ If fainting spells, palpitations, chest pain, or other symptoms suggest preexisting cardiovascular disease, refer the patient promptly to a cardiologist.

Peripheral vasculopathy, including Raynaud’s phenomenon, is a lesser known side effect associated with stimulants.⁴⁶ Symptoms are usually mild, but in rare instances stimulants are associated with digital ulceration or soft tissue breakdown.⁴⁷ Advise patients to tell you if they experience any new symptoms of numbness, pain, skin color changes, or sensitivity to temperature in fingers and toes. Signs and symptoms generally improve after dosage reduction or discontinuation of the stimulant medication.⁴⁶ Referral to a rheumatologist might be appropriate if symptoms persist.

A noradrenergic medication

Atomoxetine is a potent, selective inhibitor of the presynaptic noradrenaline transporter that increases the availability of extracellular noradrenaline in the prefrontal cortex.^48,49 Atomoxetine may be a good alternative for adult patients with ADHD and comorbid anxiety.⁵⁰

For adults, the optimal starting dosage is 40 mg in the morning for 1 week, followed by an increase to 80 mg. Insufficient dosing is common with atomoxetine, and the dosage could be increased to 100 mg/d.⁵¹ Dosing twice per day may be associated with higher rates of insomnia.

Atomoxetine’s efficacy for managing ADHD in adults has been consistently demonstrated by 6 placebo-controlled trials of 10 to 16 weeks, 3 placebo-controlled 6-month trials, and a 1-year maintenance-of-response trial.⁵² Atomoxetine was found to have an effect size of 0.45 (medium) (number needed to treat [NNT] = 5).^53-55The most common adverse effects include nausea, dry mouth, insomnia, and erectile dysfunction. Small increases in heart rate and blood pressure have been reported, so use this medication with caution in patients for whom this might be problematic. Atomoxetine is metabolized by CYP2D6; 7% of white individuals have a genotype corresponding to a nonfunctional CYP2D6 enzyme.^56-58

Alpha-2 adrenergic agonists

Clonidine and guanfacine are antihypertensive drugs that induce peripheral sympathoinhibition via the stimulation of receptors. Clonidine binds equally to adrenergic receptor subtypes α-2A, α-2B, and α-2C (as well as to α-1 and β subtypes, histamine receptors, and possibly dopamine receptors).^59,60 Guanfacine binds preferentially to postsynaptic α-2A adrenoceptors in the prefrontal cortex, which have been implicated in attentional and organizational functions.^61,62

ER guanfacine and ER clonidine are FDA-approved as monotherapy for ADHD in children and adolescents.

Efficacy in adults. A small (N = 17), double-blind, placebo-controlled, crossover study comparing immediate-release guanfacine and dextroamphetamine found that both medications significantly reduced adult ADHD symptoms, as measured with the DSM-IV Adult Behavior Checklist for Adults.⁶³

No trials have been published regarding the efficacy of ER clonidine in adults with ADHD; adverse effects including sedation, bradycardia, and hypotension may limit its use. One study compared the supplemental use of ER guanfacine (1 to 6 mg/d) or a matching placebo in 26 adults with ADHD who had suboptimal response to stimulant-only treatment. After 10 weeks, both the guanfacine ER and placebo groups showed statistically significant improvements in ADHD symptoms and general functioning. The treatments did not differ in efficacy, safety, or tolerability.⁶⁴

Adverse events. Compared with clonidine, guanfacine has less CNS depressant and hypotensive activity.⁵⁸ A phase I trial of ER guanfacine in healthy adults found its single-dose pharmacokinetic properties in 1-, 2-, and 4-mg tablets appeared to be statistically linear. Somnolence—the most common treatment-emergent adverse effect—occurred in 33 of 52 participants (63.5%). All mean vital-sign measurements and ECG parameters remained within normal limits after dosing, and no marked changes from baseline measurements were noted.⁶⁵

Antidepressants

Antidepressants used in ADHD treatment include bupropion and tricyclic antidepressants.
Bupropion is a noradrenaline and dopamine reuptake inhibitor and is considered to be a mild psychostimulant because of its amphetamine-derived chemical structure.^66,67 It generally is considered a third-line medication when stimulants have not improved ADHD symptoms or are not tolerated.

A 2011 meta-analysis examined 5 randomized, controlled trials including 175 adults treated with bupropion for ADHD. Bupropion was found to be more effective than placebo (NNT = 5), although bupropion’s therapeutic benefits were not observed until weeks 5 and 6. Its effects were less pronounced than those of methylphenidate. Mean daily dosages were 362 mg for the bupropion SR trials and 393 mg for the bupropion XL trial.⁶⁸

Tricyclics. Desipramine and nortriptyline have been found to be efficacious in childhood ADHD,^69,70 although cardiovascular risk and toxicity in overdose limit their use.⁷¹

An individual’s identity is a learned response to social stimuli, modeling oneself to the expectations of others. Doctors are perceived to be benevolent, knowledgeable, and powerful in matters of life and death. However, a complex concept of reverse hierarchy and role disorientation can take place when a doctor becomes a patient. Because doctors dedicate much of their lives to ensuring the well-being of patients, they may have a skewed perception of their personal health risks and fail to acknowledge that they, too, can fall victim to illness. 

‘Them, not me’

Studies have found that doctors often do not advocate the same treatments for themselves than they would for their patients:

• Although most doctors recommend annual check-ups for their patients, 70% of physicians do not get one themselves.¹ 
• Doctors are more likely to recommend potentially life-saving treatment with severe side effects to their patients than for themselves.²

These studies highlight how objectivity may be absent when doctors make decisions about their own treatment, as well as the complexity associated with treating a doctor as a patient.

A doctor’s sense of identity often is strongest in a health care setting. However, becoming a patient precipitates a drastic change in authority, duty, privacy, and even attire. Earlier this year, a colleague was in the hospital for workup of a cluster of symptoms. On a personal level, she experienced a momentary loss of identity, increased anxiety, and loss of self-esteem, which reduced her ability to connect with those who, in her professional role as “doctor,” were her colleagues. Trust became a matter of contention, especially in the context of understanding the inner workings of the health care system—its limitations, risks, and the possibility of human error. Professionally, she thought some management procedures were objectionable, but quickly assumed the passive role to avoid being labeled as “difficult.”

My colleague relayed 2 interesting viewpoints. First, doctors’ detached communication style seemed to evaporate when she revealed that she also is a physician. Perhaps it was the feeling of pride or competition that comes with being responsible for a colleague’s welfare or the camaraderie that lessened the divide. Slowness to relay clinical information or disregard for transparency—sometimes seen in the inpatient setting—were not apparent during my colleague’s care. However, aspects considered trivial from a doctor’s point of view, such as pre-procedural fasting, lack of privacy, and room changes became acutely intrusive.

Second, my colleague observed that her treatment team was overly solicitous. They wanted her to be pain-free and organized “urgent” tests to minimize waiting time. She recognized that there was an overt obligation to procure excessive investigations and treatment compared with a usual patient, because there was wariness of her vigilance of when things go wrong or are overlooked.

This situation was a reminder that clinicians should be mindful of finding the middle ground between unnecessary treatment for a “doctor as patient” and uninformed treatment for a “standard patient.”

Seek to understand

Role reversal represents the fundamental skill of connecting with others through self-awareness, self-regulation, and empathy.³ Studies have found that doctors who have assumed the patient role show more empathy and possess better communication skills.⁴ The situation for the doctor who becomes a patient may be disconcerting, but the “do no harm” nature of medicine and the generally accepting demeanor of patients render the relationship between empathy and role reversal especially harmonious. Although it is comfortable and convenient to stay on one side of the relationship, grasping an emotional representation of the other side is essential. It is the process of overcoming egocentricity and perceiving the subjective experience of the other role that is rewarding. We all desire to be understood, but to be understood, we must first seek to understand.

An individual’s identity is a learned response to social stimuli, modeling oneself to the expectations of others. Doctors are perceived to be benevolent, knowledgeable, and powerful in matters of life and death. However, a complex concept of reverse hierarchy and role disorientation can take place when a doctor becomes a patient. Because doctors dedicate much of their lives to ensuring the well-being of patients, they may have a skewed perception of their personal health risks and fail to acknowledge that they, too, can fall victim to illness. 

‘Them, not me’

Studies have found that doctors often do not advocate the same treatments for themselves than they would for their patients:

• Although most doctors recommend annual check-ups for their patients, 70% of physicians do not get one themselves.¹ 
• Doctors are more likely to recommend potentially life-saving treatment with severe side effects to their patients than for themselves.²

These studies highlight how objectivity may be absent when doctors make decisions about their own treatment, as well as the complexity associated with treating a doctor as a patient.

A doctor’s sense of identity often is strongest in a health care setting. However, becoming a patient precipitates a drastic change in authority, duty, privacy, and even attire. Earlier this year, a colleague was in the hospital for workup of a cluster of symptoms. On a personal level, she experienced a momentary loss of identity, increased anxiety, and loss of self-esteem, which reduced her ability to connect with those who, in her professional role as “doctor,” were her colleagues. Trust became a matter of contention, especially in the context of understanding the inner workings of the health care system—its limitations, risks, and the possibility of human error. Professionally, she thought some management procedures were objectionable, but quickly assumed the passive role to avoid being labeled as “difficult.”

My colleague relayed 2 interesting viewpoints. First, doctors’ detached communication style seemed to evaporate when she revealed that she also is a physician. Perhaps it was the feeling of pride or competition that comes with being responsible for a colleague’s welfare or the camaraderie that lessened the divide. Slowness to relay clinical information or disregard for transparency—sometimes seen in the inpatient setting—were not apparent during my colleague’s care. However, aspects considered trivial from a doctor’s point of view, such as pre-procedural fasting, lack of privacy, and room changes became acutely intrusive.

Second, my colleague observed that her treatment team was overly solicitous. They wanted her to be pain-free and organized “urgent” tests to minimize waiting time. She recognized that there was an overt obligation to procure excessive investigations and treatment compared with a usual patient, because there was wariness of her vigilance of when things go wrong or are overlooked.

This situation was a reminder that clinicians should be mindful of finding the middle ground between unnecessary treatment for a “doctor as patient” and uninformed treatment for a “standard patient.”

Seek to understand

Role reversal represents the fundamental skill of connecting with others through self-awareness, self-regulation, and empathy.³ Studies have found that doctors who have assumed the patient role show more empathy and possess better communication skills.⁴ The situation for the doctor who becomes a patient may be disconcerting, but the “do no harm” nature of medicine and the generally accepting demeanor of patients render the relationship between empathy and role reversal especially harmonious. Although it is comfortable and convenient to stay on one side of the relationship, grasping an emotional representation of the other side is essential. It is the process of overcoming egocentricity and perceiving the subjective experience of the other role that is rewarding. We all desire to be understood, but to be understood, we must first seek to understand.

An individual’s identity is a learned response to social stimuli, modeling oneself to the expectations of others. Doctors are perceived to be benevolent, knowledgeable, and powerful in matters of life and death. However, a complex concept of reverse hierarchy and role disorientation can take place when a doctor becomes a patient. Because doctors dedicate much of their lives to ensuring the well-being of patients, they may have a skewed perception of their personal health risks and fail to acknowledge that they, too, can fall victim to illness. 

‘Them, not me’

Studies have found that doctors often do not advocate the same treatments for themselves than they would for their patients:

• Although most doctors recommend annual check-ups for their patients, 70% of physicians do not get one themselves.¹ 
• Doctors are more likely to recommend potentially life-saving treatment with severe side effects to their patients than for themselves.²

These studies highlight how objectivity may be absent when doctors make decisions about their own treatment, as well as the complexity associated with treating a doctor as a patient.

A doctor’s sense of identity often is strongest in a health care setting. However, becoming a patient precipitates a drastic change in authority, duty, privacy, and even attire. Earlier this year, a colleague was in the hospital for workup of a cluster of symptoms. On a personal level, she experienced a momentary loss of identity, increased anxiety, and loss of self-esteem, which reduced her ability to connect with those who, in her professional role as “doctor,” were her colleagues. Trust became a matter of contention, especially in the context of understanding the inner workings of the health care system—its limitations, risks, and the possibility of human error. Professionally, she thought some management procedures were objectionable, but quickly assumed the passive role to avoid being labeled as “difficult.”

My colleague relayed 2 interesting viewpoints. First, doctors’ detached communication style seemed to evaporate when she revealed that she also is a physician. Perhaps it was the feeling of pride or competition that comes with being responsible for a colleague’s welfare or the camaraderie that lessened the divide. Slowness to relay clinical information or disregard for transparency—sometimes seen in the inpatient setting—were not apparent during my colleague’s care. However, aspects considered trivial from a doctor’s point of view, such as pre-procedural fasting, lack of privacy, and room changes became acutely intrusive.

Second, my colleague observed that her treatment team was overly solicitous. They wanted her to be pain-free and organized “urgent” tests to minimize waiting time. She recognized that there was an overt obligation to procure excessive investigations and treatment compared with a usual patient, because there was wariness of her vigilance of when things go wrong or are overlooked.

This situation was a reminder that clinicians should be mindful of finding the middle ground between unnecessary treatment for a “doctor as patient” and uninformed treatment for a “standard patient.”

Seek to understand

Role reversal represents the fundamental skill of connecting with others through self-awareness, self-regulation, and empathy.³ Studies have found that doctors who have assumed the patient role show more empathy and possess better communication skills.⁴ The situation for the doctor who becomes a patient may be disconcerting, but the “do no harm” nature of medicine and the generally accepting demeanor of patients render the relationship between empathy and role reversal especially harmonious. Although it is comfortable and convenient to stay on one side of the relationship, grasping an emotional representation of the other side is essential. It is the process of overcoming egocentricity and perceiving the subjective experience of the other role that is rewarding. We all desire to be understood, but to be understood, we must first seek to understand.

Dosage windows could be difficult to understand pharmacologically, but for a partial agonist the presumed mechanism could be more evident. Clinicians should be aware that more is not always better, meaning that with partial agonist drugs a higher dosage might not lead to greater patient response. With brexpiprazole, a dopamine D2 partial agonist FDA-approved for schizophrenia and an adjunct for major depressive disorder (MDD),¹ moderation is best because of the drug’s known dosage window of efficacy in the treatment of MDD. It is important to note that studies examine populations and not individuals. Specific patients could have genetic variations or be taking agents that may alter metabolism of brexpiprazole, and therefore may benefit from lower or higher doses.

Recommended dosage

Two placebo-controlled studies^2,3 examined brexpiprazole dosages of 1, 2, and 3 mg/d. The recommended dosage of 2 mg/d for MDD was determined by changes in Montgomery-Åsburg Depression Rating Scale scores (Figure).⁴ Lower dosages of 1 mg/d did not reach statistical significance, and 3 mg/d were less effective than the intermediate dosage of 2 mg/d. This result suggests a window of efficacy for brexpiprazole for MDD. This therapeutic window likely applies to most patients; however, patient-specific variables could alter the optimum dosage.

Dosage window

Brexpiprazole has high affinity for dopamine D2, D3, serotonin 5-HT1A, 5-HT2A, norepinephrine α1B, and α2 Creceptors. At relatively low drug concentrations, brexpiprazole achieves high receptor occupancy. At receptors for which brexpiprazole is a partial agonist (5-HT1A, D2, D3) the drug blocks the receptor and stimulates it at a fraction of the endogenous neurotransmitter. With a very high affinity agent, the endogenous neuro­transmitter could be completely excluded from interacting with these receptors if brexpiprazole occupancy is high. At lower dosages, the drug occupies only a fraction of the receptors, allowing the endogenous neuro­transmitters to continue interacting with their receptors, thereby magnifying the signal of that receptor above baseline.

Dosage windows could be difficult to understand pharmacologically, but for a partial agonist the presumed mechanism could be more evident. Clinicians should be aware that more is not always better, meaning that with partial agonist drugs a higher dosage might not lead to greater patient response. With brexpiprazole, a dopamine D2 partial agonist FDA-approved for schizophrenia and an adjunct for major depressive disorder (MDD),¹ moderation is best because of the drug’s known dosage window of efficacy in the treatment of MDD. It is important to note that studies examine populations and not individuals. Specific patients could have genetic variations or be taking agents that may alter metabolism of brexpiprazole, and therefore may benefit from lower or higher doses.

Recommended dosage

Two placebo-controlled studies^2,3 examined brexpiprazole dosages of 1, 2, and 3 mg/d. The recommended dosage of 2 mg/d for MDD was determined by changes in Montgomery-Åsburg Depression Rating Scale scores (Figure).⁴ Lower dosages of 1 mg/d did not reach statistical significance, and 3 mg/d were less effective than the intermediate dosage of 2 mg/d. This result suggests a window of efficacy for brexpiprazole for MDD. This therapeutic window likely applies to most patients; however, patient-specific variables could alter the optimum dosage.

Dosage window

Brexpiprazole has high affinity for dopamine D2, D3, serotonin 5-HT1A, 5-HT2A, norepinephrine α1B, and α2 Creceptors. At relatively low drug concentrations, brexpiprazole achieves high receptor occupancy. At receptors for which brexpiprazole is a partial agonist (5-HT1A, D2, D3) the drug blocks the receptor and stimulates it at a fraction of the endogenous neurotransmitter. With a very high affinity agent, the endogenous neuro­transmitter could be completely excluded from interacting with these receptors if brexpiprazole occupancy is high. At lower dosages, the drug occupies only a fraction of the receptors, allowing the endogenous neuro­transmitters to continue interacting with their receptors, thereby magnifying the signal of that receptor above baseline.

Dosage windows could be difficult to understand pharmacologically, but for a partial agonist the presumed mechanism could be more evident. Clinicians should be aware that more is not always better, meaning that with partial agonist drugs a higher dosage might not lead to greater patient response. With brexpiprazole, a dopamine D2 partial agonist FDA-approved for schizophrenia and an adjunct for major depressive disorder (MDD),¹ moderation is best because of the drug’s known dosage window of efficacy in the treatment of MDD. It is important to note that studies examine populations and not individuals. Specific patients could have genetic variations or be taking agents that may alter metabolism of brexpiprazole, and therefore may benefit from lower or higher doses.

Recommended dosage

Two placebo-controlled studies^2,3 examined brexpiprazole dosages of 1, 2, and 3 mg/d. The recommended dosage of 2 mg/d for MDD was determined by changes in Montgomery-Åsburg Depression Rating Scale scores (Figure).⁴ Lower dosages of 1 mg/d did not reach statistical significance, and 3 mg/d were less effective than the intermediate dosage of 2 mg/d. This result suggests a window of efficacy for brexpiprazole for MDD. This therapeutic window likely applies to most patients; however, patient-specific variables could alter the optimum dosage.

Dosage window

Brexpiprazole has high affinity for dopamine D2, D3, serotonin 5-HT1A, 5-HT2A, norepinephrine α1B, and α2 Creceptors. At relatively low drug concentrations, brexpiprazole achieves high receptor occupancy. At receptors for which brexpiprazole is a partial agonist (5-HT1A, D2, D3) the drug blocks the receptor and stimulates it at a fraction of the endogenous neurotransmitter. With a very high affinity agent, the endogenous neuro­transmitter could be completely excluded from interacting with these receptors if brexpiprazole occupancy is high. At lower dosages, the drug occupies only a fraction of the receptors, allowing the endogenous neuro­transmitters to continue interacting with their receptors, thereby magnifying the signal of that receptor above baseline.

At approximately 3 to 4 million patients, hepatitis C virus (HCV) is the most common viral hepatitis in the United States. Patients with mental illness are disproportionately affected by HCV and the management of their disease poses particular challenges.

HCV is commonly transmitted via IV drug use and blood transfusions; transmission through sexual contact is rare. Most patients with HCV are asymptomatic, although some do develop symptoms of acute hepatitis. Most HCV infections become chronic, with a high incidence of liver failure requiring liver transplantation.

Hepatitis refers to inflammation of the liver, which could have various etiologies, including viral infections, alcohol abuse, or autoimmune disease. Viral hepatitis refers to infection from 5 distinct groups of virus, coined A through E.¹ This article will focus on chronic HCV (Table 1).

CASE Bipolar disorder, stress, history of IV drug use

Ms. S, age 48, has bipolar I disorder and has been hospitalized 4 times in the past, including once for a suicide attempt. She has 3 children and works as a cashier. Her psychiatric symptoms have been stable on lurasidone, 80 mg/d, and escitalopram, 10 mg/d. Recently, Ms. S has been under more stress at her job. Sometimes she misses doses of her medication, and then becomes more irritable and impulsive. Her husband, noting that she has used IV heroin in the past, comes with her today and is concerned that she is “not acting right.” What is Ms. S’s risk for HCV?

HCV in mental illness

Compared with the general population, HCV is more prevalent among chronically mentally ill persons. In one study, HCV occurred twice as often in men vs women with chronic mental illness.² Up to 50% of patients with HCV have a history of mental illness and nearly 90% have a history of substance use disorders.³ Among 668 chronically mentally ill patients at 4 public sector clinics, risk factors for HCV were common and included use of injection drugs (>20%), sharing needles (14%), and crack cocaine use (>20%).⁴ Higher rates of HCV were reported in hospitalized patients with schizophrenia and comorbid psychoactive substance abuse in Japan.⁵ Because of the high prevalence in this population, it is essential to assess for substance use disorders. Employing a non-judgmental approach with motivational interviewing techniques can be effective.⁶

Individuals with mental illness should be screened for HCV risk factors, such as unprotected intercourse with high-risk partners and sharing needles used for illicit drug use. Patients frequently underreport these activities. At-risk individuals should undergo laboratory testing for the HIV-1 antibody, hepatitis C antibodies, and hepatitis B antibodies. Mental health providers should counsel patients about risk reduction (eg, avoiding unprotected sexual intercourse and sharing of drug paraphernalia). Educating patients about complications of viral hepatitis, such as liver failure, could be motivation to change risky behaviors.

CASE continued

During your interview with Ms. S, she becomes irritable and tells you that you are asking too many questions. It is clear that she is not taking her medications consistently, but she agrees to do so because she does not want to lose custody of her children. She denies current use of heroin but her husband says, “I don’t know what she is doing.” In addition to advising her on reducing risk factors, you order appropriate screening tests, including hepatitis and HIV antibody tests.

Screening guidelines

The U.S. Preventive Services Task Force and the CDC both recommend a 1-time screening for HCV in asymptomatic or low-risk patients born between 1945 and 1965.^1,7 Furthermore, both organizations recommend screening for HCV in persons at high risk, including:

• those with a history of injection drug use
• persons with recognizable exposure, such as needlesticks
• persons who received blood transfusions before 1992
• medical conditions, such as long-term dialysis.

There is no vaccine for HCV; however, patients with HCV should receive vaccination against hepatitis B.

Diagnosis

Acute symptoms include fever, fatigue, headache, cough, nausea, and vomiting. Jaundice could develop, often accompanied by pain in the right upper quadrant. If there is suspicion of viral hepatitis, psychiatrists can initiate the laboratory evaluation. Chronic hepatitis, on the other hand, often is asymptomatic, although stigmata of chronic liver disease (eg, jaundice, ascites, peripheral edema) might be detected on physical exam.⁸ Elevated serum transaminases are seen with acute viral hepatitis, although levels could vary in chronic cases. Serologic detection of anti-HCV antibodies establishes a HCV diagnosis.

Treatment recommendations

All patients who test positive for HCV should be evaluated and treated by a hepatologist. Goals of therapy are to reduce complications from chronic viral hepatitis, including cirrhosis and hepatic failure. Duration and optimal regimen depends on the HCV genotype.⁸ Treatment outcomes are measured by virological parameters, including serum aminotransferases, HCV RNA levels, and histology. The most important parameter in treating chronic HCV is the sustained virological response (SVR), which is the absence of HCV RNA 12 weeks after completing therapy.⁹

Treatment is recommended for all persons with chronic HCV infection, according to current treatment guidelines, which are updated regularly by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.¹⁰ Until recently, treatment consisted of IV pegylated interferon (PEG-IFN) in combination with oral ribavirin. Success rates with this regimen are approximately 40% to 50%. The advent of direct-acting antivirals (DAAs) has revolutionized treatment of chronic HCV. These agents include simeprevir, sofosbuvir, ledipasvir, and the combination of ombitasvir-paritaprevir-ritonavir plus dasabuvir (brand name, Viekira Pak). Advantages of these agents are oral administration, high treatment success rates (>90%), shorter treatment duration (12 weeks vs up to 48 weeks with older regimens), and few serious adverse effects^9-11; drawbacks include the pricing of these regimens, which could cost upward of ≥$100,000 for a 12-week course, and a lack of coverage under some health insurance plans.¹² The manufacturers of 2 agents, telaprevir and boceprevir, removed them from the market because of decreased demand related to their unfavorable side-effect profile and the availability of better tolerated agents.

Treatment considerations for interferon in psychiatric patients

Various neuropsychiatric symptoms have been reported with the use of PEG-IFN. The range of reported symptoms include:

• depressed mood
• anxiety
• hostility
• slowness
• fatigue
• sleep disturbance
• lethargy
• irritability
• emotional lability
• social withdrawal
• poor concentration.^13,14

Depressive symptoms can present as early as 1 month after starting treatment, but typically occur at 8 to 12 weeks. A systematic review and meta-analysis of 26 observational studies found a cumulative 25% risk of interferon (IFN)-induced depression in the general HCV population.¹⁵ Risk factors for IFN-induced depression include:

• female sex
• history of major depression or other psychiatric disorder
• low educational level
• the presence of baseline subthreshold depressive symptoms.

Because of the risk of inducing depression, there was initial hesitation with providing IFN treatment to patients with psychiatric disorders. However, there is evidence that individuals with chronic psychiatric illness can be treated safely with IFN-based regimens and achieve results similar to non-psychiatric populations.^16,17 For example, patients with schizophrenia in a small Veterans Affairs database who received IFN for HCV did not experience higher rates of symptoms of schizophrenia, depression, or mania over 8 years of follow-up.¹⁸ Furthermore, those with schizophrenia were just as likely to reach SVR as patients without psychiatric illness.¹⁹ Other encouraging results have been reported in depressed patients. One study found similar rates of treatment completion and SVR in patients with a history of major depressive disorder compared with those without depression.²⁰ No difference in frequency of neuropsychiatric side effects was found between the groups.

Presence of a psychiatric disorder is no longer an absolute contraindication to IFN treatment for HCV. Optimal control of psychiatric symptoms should be attained in all patients before starting HCV treatment, and close clinical monitoring is warranted. A review of 9 studies showed benefit of antidepressants for HCV patients with elevated baseline depression or a history of IFN-induced depression.²¹ The largest body of evidence supports the safety and efficacy of selective serotonin reuptake inhibitors for treating IFN-induced depression. Although no antidepressants are FDA-approved for this indication, the best-studied agents include citalopram, escitalopram, sertraline, and paroxetine.

A review of 6 studies on using antidepressants to prevent IFN-induced depression concluded there was inadequate evidence to support this approach in all patients.²² Pretreatment primarily is indicated for those with elevated depressive symptoms at baseline or those with a history of IFN-induced depression. The prevailing approach to IFN-induced depression assessment, prevention, and treatment is summarized in Table 2.

CASE continued

Ms. S tests positive for the HCV antibody but negative for HIV and hepatitis B. She immediately receives the hepatitis B vaccine series. Her sister discourages her from receiving treatment for HCV, warning her, “it will make you crazy depressed.” As a result, Ms. S avoids following up with the hepatologist. Her psychiatrist, aware that she now was taking her psychotropic medication and seeing that her mood is stable, educates her about new treatment options for HCV that do not cause depression. Ms. S finally agrees to see a hepatologist to discuss her treatment options.

IFN-free regimens

With the arrival of the DAAs, the potential now exists to use IFN-free treatment regimens,¹⁰ which could eliminate concerns about IFN-induced depression.

Clinical trials of the DAAs and real-world use so far do not indicate an elevated risk for neuropsychiatric symptoms, including depression.¹¹ As a result, more patients with severe psychiatric illness likely will be eligible to receive treatment for HCV. However, as clinical experience builds with these new agents, it is important to monitor the experience of patients with psychiatric comorbidity. Current treatment guidelines for HCV genotype 1, which is most common in the United States, do not include IFN-based regimens.¹⁰ Treatment of genotype 3, which affects 6% of the U.S. population, still includes IFN. Therefore, the risk of IFN-induced depression still exists for some patients with HCV. Table 3¹⁰ describes current treatment regimens in use for HCV without cirrhosis (see Related Resources for treating HCV with cirrhosis).

Evolving role of the psychiatrist

The availability of shorter, better-tolerated regimens means that the psychiatric contraindications to HCV treatment will be eased. With the emergence of non-IFN treatment regimens, the role of mental health providers could shift toward assisting with treatment adherence, monitoring drug–drug interactions, and managing comorbid substance use disorders.¹⁰

The psychiatrist’s role might shift away from the psychosocial assessment of factors affecting treatment eligibility, such as IFN-associated depressive symptoms. Clinical focus will likely shift to supporting adherence to HCV treatment regimens.²³ Because depression and substance use disorders are risk factors for non-adherence, mental health providers may be called upon to optimize treatment of these conditions before beginning DAA regimens. A multi-dose regimen might be complicated for those with severe mental illness, and increased psychiatric and community support could be needed in these patients.²³ Furthermore, models of care that integrate an HCV specialist with psychiatric care have demonstrated benefits.^6,23 Long-term follow-up with a mental health provider will be key to provide ongoing psychiatric support, especially for those who do not achieve SVR.

Psychotropic drug–drug interactions with DAAs

Both sofosbuvir and ledipasvir are substrates of P-glycoprotein and not metabolized by cytochrome P450 (CYP) enzymes.²⁴ Therefore, there are no known contraindications with psychotropic medications. However, co-administration of P-glycoprotein inducers, such as St. John’s wort, could reduce sofosbuvir and ledipasvir levels leading to reduced therapeutic efficacy.

Because it has been used for many years as an HIV treatment, drug interactions with ritonavir have been well-described. This agent is a “pan-inhibitor” and inhibits the CYP3A4, 2D6, 2C9, and 2C19 enzymes and could increase levels of any psychotropic metabolized by these enzymes.²⁵ After several weeks of treatment, it also could induce CYP3A4, which could lead to reduced efficacy of oral contraceptives because ethinylestradiol is metabolized by CYP3A4. Ritonavir is primarily metabolized by CYP3A4 (and CYP2D6 to a smaller degree). Carbamazepine induces CYP3A4, which may lead to decreased levels of ritonavir.²³ This, in turn, could reduce the likelihood of attaining SVR and successful treatment of HCV.

Boceprevir, telaprevir, and simeprevir inhibit CYP3A4 to varying degrees and therefore could affect psychotropic medications metabolized by this enzyme.^23,26,27 These DAAs are metabolized by CYP3A4; therefore CYP3A4 inducers, such as carbamazepine, could lower DAA blood levels, increasing risk of HCV treatment failure and viral resistance.

Daclatasvir is a substrate of CYP3A4 and an inhibitor of P-glycoprotein.²⁸ Concomitant buprenorphine or buprenorphine/naloxone levels may be increased, although the manufacturer does not recommend dosage adjustment. Elbasvir and grazoprevir are metabolized by CYP3A4.²⁹ Drug–drug interactions therefore may result when administered with either CYP3A4 inducers or inhibitors.

CASE Conclusion

Ms. S sees her new hepatologist, Dr. Smith. She decides to try a 12-week course of ledipasvir/sofosbuvir. Dr. Smith collaborates frequently with Ms. S’s psychiatrist to discuss her case and to help monitor her psychiatric symptoms. She follows up closely with her psychiatrist for symptom monitoring and to help ensure treatment compliance. Ms. S does well with the IFN-free treatment regimen and experiences no worsening of her psychiatric symptoms during treatment.

At approximately 3 to 4 million patients, hepatitis C virus (HCV) is the most common viral hepatitis in the United States. Patients with mental illness are disproportionately affected by HCV and the management of their disease poses particular challenges.

HCV is commonly transmitted via IV drug use and blood transfusions; transmission through sexual contact is rare. Most patients with HCV are asymptomatic, although some do develop symptoms of acute hepatitis. Most HCV infections become chronic, with a high incidence of liver failure requiring liver transplantation.

Hepatitis refers to inflammation of the liver, which could have various etiologies, including viral infections, alcohol abuse, or autoimmune disease. Viral hepatitis refers to infection from 5 distinct groups of virus, coined A through E.¹ This article will focus on chronic HCV (Table 1).

CASE Bipolar disorder, stress, history of IV drug use

Ms. S, age 48, has bipolar I disorder and has been hospitalized 4 times in the past, including once for a suicide attempt. She has 3 children and works as a cashier. Her psychiatric symptoms have been stable on lurasidone, 80 mg/d, and escitalopram, 10 mg/d. Recently, Ms. S has been under more stress at her job. Sometimes she misses doses of her medication, and then becomes more irritable and impulsive. Her husband, noting that she has used IV heroin in the past, comes with her today and is concerned that she is “not acting right.” What is Ms. S’s risk for HCV?

HCV in mental illness

Compared with the general population, HCV is more prevalent among chronically mentally ill persons. In one study, HCV occurred twice as often in men vs women with chronic mental illness.² Up to 50% of patients with HCV have a history of mental illness and nearly 90% have a history of substance use disorders.³ Among 668 chronically mentally ill patients at 4 public sector clinics, risk factors for HCV were common and included use of injection drugs (>20%), sharing needles (14%), and crack cocaine use (>20%).⁴ Higher rates of HCV were reported in hospitalized patients with schizophrenia and comorbid psychoactive substance abuse in Japan.⁵ Because of the high prevalence in this population, it is essential to assess for substance use disorders. Employing a non-judgmental approach with motivational interviewing techniques can be effective.⁶

Individuals with mental illness should be screened for HCV risk factors, such as unprotected intercourse with high-risk partners and sharing needles used for illicit drug use. Patients frequently underreport these activities. At-risk individuals should undergo laboratory testing for the HIV-1 antibody, hepatitis C antibodies, and hepatitis B antibodies. Mental health providers should counsel patients about risk reduction (eg, avoiding unprotected sexual intercourse and sharing of drug paraphernalia). Educating patients about complications of viral hepatitis, such as liver failure, could be motivation to change risky behaviors.

CASE continued

During your interview with Ms. S, she becomes irritable and tells you that you are asking too many questions. It is clear that she is not taking her medications consistently, but she agrees to do so because she does not want to lose custody of her children. She denies current use of heroin but her husband says, “I don’t know what she is doing.” In addition to advising her on reducing risk factors, you order appropriate screening tests, including hepatitis and HIV antibody tests.

Screening guidelines

The U.S. Preventive Services Task Force and the CDC both recommend a 1-time screening for HCV in asymptomatic or low-risk patients born between 1945 and 1965.^1,7 Furthermore, both organizations recommend screening for HCV in persons at high risk, including:

• those with a history of injection drug use
• persons with recognizable exposure, such as needlesticks
• persons who received blood transfusions before 1992
• medical conditions, such as long-term dialysis.

There is no vaccine for HCV; however, patients with HCV should receive vaccination against hepatitis B.

Diagnosis

Acute symptoms include fever, fatigue, headache, cough, nausea, and vomiting. Jaundice could develop, often accompanied by pain in the right upper quadrant. If there is suspicion of viral hepatitis, psychiatrists can initiate the laboratory evaluation. Chronic hepatitis, on the other hand, often is asymptomatic, although stigmata of chronic liver disease (eg, jaundice, ascites, peripheral edema) might be detected on physical exam.⁸ Elevated serum transaminases are seen with acute viral hepatitis, although levels could vary in chronic cases. Serologic detection of anti-HCV antibodies establishes a HCV diagnosis.

Treatment recommendations

All patients who test positive for HCV should be evaluated and treated by a hepatologist. Goals of therapy are to reduce complications from chronic viral hepatitis, including cirrhosis and hepatic failure. Duration and optimal regimen depends on the HCV genotype.⁸ Treatment outcomes are measured by virological parameters, including serum aminotransferases, HCV RNA levels, and histology. The most important parameter in treating chronic HCV is the sustained virological response (SVR), which is the absence of HCV RNA 12 weeks after completing therapy.⁹

Treatment is recommended for all persons with chronic HCV infection, according to current treatment guidelines, which are updated regularly by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.¹⁰ Until recently, treatment consisted of IV pegylated interferon (PEG-IFN) in combination with oral ribavirin. Success rates with this regimen are approximately 40% to 50%. The advent of direct-acting antivirals (DAAs) has revolutionized treatment of chronic HCV. These agents include simeprevir, sofosbuvir, ledipasvir, and the combination of ombitasvir-paritaprevir-ritonavir plus dasabuvir (brand name, Viekira Pak). Advantages of these agents are oral administration, high treatment success rates (>90%), shorter treatment duration (12 weeks vs up to 48 weeks with older regimens), and few serious adverse effects^9-11; drawbacks include the pricing of these regimens, which could cost upward of ≥$100,000 for a 12-week course, and a lack of coverage under some health insurance plans.¹² The manufacturers of 2 agents, telaprevir and boceprevir, removed them from the market because of decreased demand related to their unfavorable side-effect profile and the availability of better tolerated agents.

Treatment considerations for interferon in psychiatric patients

Various neuropsychiatric symptoms have been reported with the use of PEG-IFN. The range of reported symptoms include:

• depressed mood
• anxiety
• hostility
• slowness
• fatigue
• sleep disturbance
• lethargy
• irritability
• emotional lability
• social withdrawal
• poor concentration.^13,14

Depressive symptoms can present as early as 1 month after starting treatment, but typically occur at 8 to 12 weeks. A systematic review and meta-analysis of 26 observational studies found a cumulative 25% risk of interferon (IFN)-induced depression in the general HCV population.¹⁵ Risk factors for IFN-induced depression include:

• female sex
• history of major depression or other psychiatric disorder
• low educational level
• the presence of baseline subthreshold depressive symptoms.

Because of the risk of inducing depression, there was initial hesitation with providing IFN treatment to patients with psychiatric disorders. However, there is evidence that individuals with chronic psychiatric illness can be treated safely with IFN-based regimens and achieve results similar to non-psychiatric populations.^16,17 For example, patients with schizophrenia in a small Veterans Affairs database who received IFN for HCV did not experience higher rates of symptoms of schizophrenia, depression, or mania over 8 years of follow-up.¹⁸ Furthermore, those with schizophrenia were just as likely to reach SVR as patients without psychiatric illness.¹⁹ Other encouraging results have been reported in depressed patients. One study found similar rates of treatment completion and SVR in patients with a history of major depressive disorder compared with those without depression.²⁰ No difference in frequency of neuropsychiatric side effects was found between the groups.

Presence of a psychiatric disorder is no longer an absolute contraindication to IFN treatment for HCV. Optimal control of psychiatric symptoms should be attained in all patients before starting HCV treatment, and close clinical monitoring is warranted. A review of 9 studies showed benefit of antidepressants for HCV patients with elevated baseline depression or a history of IFN-induced depression.²¹ The largest body of evidence supports the safety and efficacy of selective serotonin reuptake inhibitors for treating IFN-induced depression. Although no antidepressants are FDA-approved for this indication, the best-studied agents include citalopram, escitalopram, sertraline, and paroxetine.

A review of 6 studies on using antidepressants to prevent IFN-induced depression concluded there was inadequate evidence to support this approach in all patients.²² Pretreatment primarily is indicated for those with elevated depressive symptoms at baseline or those with a history of IFN-induced depression. The prevailing approach to IFN-induced depression assessment, prevention, and treatment is summarized in Table 2.

CASE continued

Ms. S tests positive for the HCV antibody but negative for HIV and hepatitis B. She immediately receives the hepatitis B vaccine series. Her sister discourages her from receiving treatment for HCV, warning her, “it will make you crazy depressed.” As a result, Ms. S avoids following up with the hepatologist. Her psychiatrist, aware that she now was taking her psychotropic medication and seeing that her mood is stable, educates her about new treatment options for HCV that do not cause depression. Ms. S finally agrees to see a hepatologist to discuss her treatment options.

IFN-free regimens

With the arrival of the DAAs, the potential now exists to use IFN-free treatment regimens,¹⁰ which could eliminate concerns about IFN-induced depression.

Clinical trials of the DAAs and real-world use so far do not indicate an elevated risk for neuropsychiatric symptoms, including depression.¹¹ As a result, more patients with severe psychiatric illness likely will be eligible to receive treatment for HCV. However, as clinical experience builds with these new agents, it is important to monitor the experience of patients with psychiatric comorbidity. Current treatment guidelines for HCV genotype 1, which is most common in the United States, do not include IFN-based regimens.¹⁰ Treatment of genotype 3, which affects 6% of the U.S. population, still includes IFN. Therefore, the risk of IFN-induced depression still exists for some patients with HCV. Table 3¹⁰ describes current treatment regimens in use for HCV without cirrhosis (see Related Resources for treating HCV with cirrhosis).

Evolving role of the psychiatrist

The availability of shorter, better-tolerated regimens means that the psychiatric contraindications to HCV treatment will be eased. With the emergence of non-IFN treatment regimens, the role of mental health providers could shift toward assisting with treatment adherence, monitoring drug–drug interactions, and managing comorbid substance use disorders.¹⁰

The psychiatrist’s role might shift away from the psychosocial assessment of factors affecting treatment eligibility, such as IFN-associated depressive symptoms. Clinical focus will likely shift to supporting adherence to HCV treatment regimens.²³ Because depression and substance use disorders are risk factors for non-adherence, mental health providers may be called upon to optimize treatment of these conditions before beginning DAA regimens. A multi-dose regimen might be complicated for those with severe mental illness, and increased psychiatric and community support could be needed in these patients.²³ Furthermore, models of care that integrate an HCV specialist with psychiatric care have demonstrated benefits.^6,23 Long-term follow-up with a mental health provider will be key to provide ongoing psychiatric support, especially for those who do not achieve SVR.

Psychotropic drug–drug interactions with DAAs

Both sofosbuvir and ledipasvir are substrates of P-glycoprotein and not metabolized by cytochrome P450 (CYP) enzymes.²⁴ Therefore, there are no known contraindications with psychotropic medications. However, co-administration of P-glycoprotein inducers, such as St. John’s wort, could reduce sofosbuvir and ledipasvir levels leading to reduced therapeutic efficacy.

Because it has been used for many years as an HIV treatment, drug interactions with ritonavir have been well-described. This agent is a “pan-inhibitor” and inhibits the CYP3A4, 2D6, 2C9, and 2C19 enzymes and could increase levels of any psychotropic metabolized by these enzymes.²⁵ After several weeks of treatment, it also could induce CYP3A4, which could lead to reduced efficacy of oral contraceptives because ethinylestradiol is metabolized by CYP3A4. Ritonavir is primarily metabolized by CYP3A4 (and CYP2D6 to a smaller degree). Carbamazepine induces CYP3A4, which may lead to decreased levels of ritonavir.²³ This, in turn, could reduce the likelihood of attaining SVR and successful treatment of HCV.

Boceprevir, telaprevir, and simeprevir inhibit CYP3A4 to varying degrees and therefore could affect psychotropic medications metabolized by this enzyme.^23,26,27 These DAAs are metabolized by CYP3A4; therefore CYP3A4 inducers, such as carbamazepine, could lower DAA blood levels, increasing risk of HCV treatment failure and viral resistance.

Daclatasvir is a substrate of CYP3A4 and an inhibitor of P-glycoprotein.²⁸ Concomitant buprenorphine or buprenorphine/naloxone levels may be increased, although the manufacturer does not recommend dosage adjustment. Elbasvir and grazoprevir are metabolized by CYP3A4.²⁹ Drug–drug interactions therefore may result when administered with either CYP3A4 inducers or inhibitors.

CASE Conclusion

Ms. S sees her new hepatologist, Dr. Smith. She decides to try a 12-week course of ledipasvir/sofosbuvir. Dr. Smith collaborates frequently with Ms. S’s psychiatrist to discuss her case and to help monitor her psychiatric symptoms. She follows up closely with her psychiatrist for symptom monitoring and to help ensure treatment compliance. Ms. S does well with the IFN-free treatment regimen and experiences no worsening of her psychiatric symptoms during treatment.

At approximately 3 to 4 million patients, hepatitis C virus (HCV) is the most common viral hepatitis in the United States. Patients with mental illness are disproportionately affected by HCV and the management of their disease poses particular challenges.

HCV is commonly transmitted via IV drug use and blood transfusions; transmission through sexual contact is rare. Most patients with HCV are asymptomatic, although some do develop symptoms of acute hepatitis. Most HCV infections become chronic, with a high incidence of liver failure requiring liver transplantation.

Hepatitis refers to inflammation of the liver, which could have various etiologies, including viral infections, alcohol abuse, or autoimmune disease. Viral hepatitis refers to infection from 5 distinct groups of virus, coined A through E.¹ This article will focus on chronic HCV (Table 1).

CASE Bipolar disorder, stress, history of IV drug use

Ms. S, age 48, has bipolar I disorder and has been hospitalized 4 times in the past, including once for a suicide attempt. She has 3 children and works as a cashier. Her psychiatric symptoms have been stable on lurasidone, 80 mg/d, and escitalopram, 10 mg/d. Recently, Ms. S has been under more stress at her job. Sometimes she misses doses of her medication, and then becomes more irritable and impulsive. Her husband, noting that she has used IV heroin in the past, comes with her today and is concerned that she is “not acting right.” What is Ms. S’s risk for HCV?

HCV in mental illness

Compared with the general population, HCV is more prevalent among chronically mentally ill persons. In one study, HCV occurred twice as often in men vs women with chronic mental illness.² Up to 50% of patients with HCV have a history of mental illness and nearly 90% have a history of substance use disorders.³ Among 668 chronically mentally ill patients at 4 public sector clinics, risk factors for HCV were common and included use of injection drugs (>20%), sharing needles (14%), and crack cocaine use (>20%).⁴ Higher rates of HCV were reported in hospitalized patients with schizophrenia and comorbid psychoactive substance abuse in Japan.⁵ Because of the high prevalence in this population, it is essential to assess for substance use disorders. Employing a non-judgmental approach with motivational interviewing techniques can be effective.⁶

Individuals with mental illness should be screened for HCV risk factors, such as unprotected intercourse with high-risk partners and sharing needles used for illicit drug use. Patients frequently underreport these activities. At-risk individuals should undergo laboratory testing for the HIV-1 antibody, hepatitis C antibodies, and hepatitis B antibodies. Mental health providers should counsel patients about risk reduction (eg, avoiding unprotected sexual intercourse and sharing of drug paraphernalia). Educating patients about complications of viral hepatitis, such as liver failure, could be motivation to change risky behaviors.

CASE continued

During your interview with Ms. S, she becomes irritable and tells you that you are asking too many questions. It is clear that she is not taking her medications consistently, but she agrees to do so because she does not want to lose custody of her children. She denies current use of heroin but her husband says, “I don’t know what she is doing.” In addition to advising her on reducing risk factors, you order appropriate screening tests, including hepatitis and HIV antibody tests.

Screening guidelines

The U.S. Preventive Services Task Force and the CDC both recommend a 1-time screening for HCV in asymptomatic or low-risk patients born between 1945 and 1965.^1,7 Furthermore, both organizations recommend screening for HCV in persons at high risk, including:

• those with a history of injection drug use
• persons with recognizable exposure, such as needlesticks
• persons who received blood transfusions before 1992
• medical conditions, such as long-term dialysis.

There is no vaccine for HCV; however, patients with HCV should receive vaccination against hepatitis B.

Diagnosis

Acute symptoms include fever, fatigue, headache, cough, nausea, and vomiting. Jaundice could develop, often accompanied by pain in the right upper quadrant. If there is suspicion of viral hepatitis, psychiatrists can initiate the laboratory evaluation. Chronic hepatitis, on the other hand, often is asymptomatic, although stigmata of chronic liver disease (eg, jaundice, ascites, peripheral edema) might be detected on physical exam.⁸ Elevated serum transaminases are seen with acute viral hepatitis, although levels could vary in chronic cases. Serologic detection of anti-HCV antibodies establishes a HCV diagnosis.

Treatment recommendations

All patients who test positive for HCV should be evaluated and treated by a hepatologist. Goals of therapy are to reduce complications from chronic viral hepatitis, including cirrhosis and hepatic failure. Duration and optimal regimen depends on the HCV genotype.⁸ Treatment outcomes are measured by virological parameters, including serum aminotransferases, HCV RNA levels, and histology. The most important parameter in treating chronic HCV is the sustained virological response (SVR), which is the absence of HCV RNA 12 weeks after completing therapy.⁹

Treatment is recommended for all persons with chronic HCV infection, according to current treatment guidelines, which are updated regularly by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America.¹⁰ Until recently, treatment consisted of IV pegylated interferon (PEG-IFN) in combination with oral ribavirin. Success rates with this regimen are approximately 40% to 50%. The advent of direct-acting antivirals (DAAs) has revolutionized treatment of chronic HCV. These agents include simeprevir, sofosbuvir, ledipasvir, and the combination of ombitasvir-paritaprevir-ritonavir plus dasabuvir (brand name, Viekira Pak). Advantages of these agents are oral administration, high treatment success rates (>90%), shorter treatment duration (12 weeks vs up to 48 weeks with older regimens), and few serious adverse effects^9-11; drawbacks include the pricing of these regimens, which could cost upward of ≥$100,000 for a 12-week course, and a lack of coverage under some health insurance plans.¹² The manufacturers of 2 agents, telaprevir and boceprevir, removed them from the market because of decreased demand related to their unfavorable side-effect profile and the availability of better tolerated agents.

Treatment considerations for interferon in psychiatric patients

Various neuropsychiatric symptoms have been reported with the use of PEG-IFN. The range of reported symptoms include:

• depressed mood
• anxiety
• hostility
• slowness
• fatigue
• sleep disturbance
• lethargy
• irritability
• emotional lability
• social withdrawal
• poor concentration.^13,14

Depressive symptoms can present as early as 1 month after starting treatment, but typically occur at 8 to 12 weeks. A systematic review and meta-analysis of 26 observational studies found a cumulative 25% risk of interferon (IFN)-induced depression in the general HCV population.¹⁵ Risk factors for IFN-induced depression include:

• female sex
• history of major depression or other psychiatric disorder
• low educational level
• the presence of baseline subthreshold depressive symptoms.

Because of the risk of inducing depression, there was initial hesitation with providing IFN treatment to patients with psychiatric disorders. However, there is evidence that individuals with chronic psychiatric illness can be treated safely with IFN-based regimens and achieve results similar to non-psychiatric populations.^16,17 For example, patients with schizophrenia in a small Veterans Affairs database who received IFN for HCV did not experience higher rates of symptoms of schizophrenia, depression, or mania over 8 years of follow-up.¹⁸ Furthermore, those with schizophrenia were just as likely to reach SVR as patients without psychiatric illness.¹⁹ Other encouraging results have been reported in depressed patients. One study found similar rates of treatment completion and SVR in patients with a history of major depressive disorder compared with those without depression.²⁰ No difference in frequency of neuropsychiatric side effects was found between the groups.

Presence of a psychiatric disorder is no longer an absolute contraindication to IFN treatment for HCV. Optimal control of psychiatric symptoms should be attained in all patients before starting HCV treatment, and close clinical monitoring is warranted. A review of 9 studies showed benefit of antidepressants for HCV patients with elevated baseline depression or a history of IFN-induced depression.²¹ The largest body of evidence supports the safety and efficacy of selective serotonin reuptake inhibitors for treating IFN-induced depression. Although no antidepressants are FDA-approved for this indication, the best-studied agents include citalopram, escitalopram, sertraline, and paroxetine.

A review of 6 studies on using antidepressants to prevent IFN-induced depression concluded there was inadequate evidence to support this approach in all patients.²² Pretreatment primarily is indicated for those with elevated depressive symptoms at baseline or those with a history of IFN-induced depression. The prevailing approach to IFN-induced depression assessment, prevention, and treatment is summarized in Table 2.

CASE continued

Ms. S tests positive for the HCV antibody but negative for HIV and hepatitis B. She immediately receives the hepatitis B vaccine series. Her sister discourages her from receiving treatment for HCV, warning her, “it will make you crazy depressed.” As a result, Ms. S avoids following up with the hepatologist. Her psychiatrist, aware that she now was taking her psychotropic medication and seeing that her mood is stable, educates her about new treatment options for HCV that do not cause depression. Ms. S finally agrees to see a hepatologist to discuss her treatment options.

IFN-free regimens

With the arrival of the DAAs, the potential now exists to use IFN-free treatment regimens,¹⁰ which could eliminate concerns about IFN-induced depression.

Clinical trials of the DAAs and real-world use so far do not indicate an elevated risk for neuropsychiatric symptoms, including depression.¹¹ As a result, more patients with severe psychiatric illness likely will be eligible to receive treatment for HCV. However, as clinical experience builds with these new agents, it is important to monitor the experience of patients with psychiatric comorbidity. Current treatment guidelines for HCV genotype 1, which is most common in the United States, do not include IFN-based regimens.¹⁰ Treatment of genotype 3, which affects 6% of the U.S. population, still includes IFN. Therefore, the risk of IFN-induced depression still exists for some patients with HCV. Table 3¹⁰ describes current treatment regimens in use for HCV without cirrhosis (see Related Resources for treating HCV with cirrhosis).

Evolving role of the psychiatrist

The availability of shorter, better-tolerated regimens means that the psychiatric contraindications to HCV treatment will be eased. With the emergence of non-IFN treatment regimens, the role of mental health providers could shift toward assisting with treatment adherence, monitoring drug–drug interactions, and managing comorbid substance use disorders.¹⁰

The psychiatrist’s role might shift away from the psychosocial assessment of factors affecting treatment eligibility, such as IFN-associated depressive symptoms. Clinical focus will likely shift to supporting adherence to HCV treatment regimens.²³ Because depression and substance use disorders are risk factors for non-adherence, mental health providers may be called upon to optimize treatment of these conditions before beginning DAA regimens. A multi-dose regimen might be complicated for those with severe mental illness, and increased psychiatric and community support could be needed in these patients.²³ Furthermore, models of care that integrate an HCV specialist with psychiatric care have demonstrated benefits.^6,23 Long-term follow-up with a mental health provider will be key to provide ongoing psychiatric support, especially for those who do not achieve SVR.

Psychotropic drug–drug interactions with DAAs

Both sofosbuvir and ledipasvir are substrates of P-glycoprotein and not metabolized by cytochrome P450 (CYP) enzymes.²⁴ Therefore, there are no known contraindications with psychotropic medications. However, co-administration of P-glycoprotein inducers, such as St. John’s wort, could reduce sofosbuvir and ledipasvir levels leading to reduced therapeutic efficacy.

Because it has been used for many years as an HIV treatment, drug interactions with ritonavir have been well-described. This agent is a “pan-inhibitor” and inhibits the CYP3A4, 2D6, 2C9, and 2C19 enzymes and could increase levels of any psychotropic metabolized by these enzymes.²⁵ After several weeks of treatment, it also could induce CYP3A4, which could lead to reduced efficacy of oral contraceptives because ethinylestradiol is metabolized by CYP3A4. Ritonavir is primarily metabolized by CYP3A4 (and CYP2D6 to a smaller degree). Carbamazepine induces CYP3A4, which may lead to decreased levels of ritonavir.²³ This, in turn, could reduce the likelihood of attaining SVR and successful treatment of HCV.

Boceprevir, telaprevir, and simeprevir inhibit CYP3A4 to varying degrees and therefore could affect psychotropic medications metabolized by this enzyme.^23,26,27 These DAAs are metabolized by CYP3A4; therefore CYP3A4 inducers, such as carbamazepine, could lower DAA blood levels, increasing risk of HCV treatment failure and viral resistance.

Daclatasvir is a substrate of CYP3A4 and an inhibitor of P-glycoprotein.²⁸ Concomitant buprenorphine or buprenorphine/naloxone levels may be increased, although the manufacturer does not recommend dosage adjustment. Elbasvir and grazoprevir are metabolized by CYP3A4.²⁹ Drug–drug interactions therefore may result when administered with either CYP3A4 inducers or inhibitors.

CASE Conclusion

Ms. S sees her new hepatologist, Dr. Smith. She decides to try a 12-week course of ledipasvir/sofosbuvir. Dr. Smith collaborates frequently with Ms. S’s psychiatrist to discuss her case and to help monitor her psychiatric symptoms. She follows up closely with her psychiatrist for symptom monitoring and to help ensure treatment compliance. Ms. S does well with the IFN-free treatment regimen and experiences no worsening of her psychiatric symptoms during treatment.

CASE Withdrawn and confused

Mr. J, age 54, is brought to the emergency department from a correctional treatment facility where he is reported to be displaying new, unusual behavior. He has a history of schizoaffective disorder, which has been stable with haloperidol, 10 mg/d, for more than a year.

Although previously Mr. J openly discussed his long-standing delusions about the FBI coming to release him from prison, he no longer mentions this or any other delusional beliefs, and has become less communicative with staff and peers. Mr. J no longer accompanies the other patients to the cafeteria for meals and eats in his room alone and appears to be losing weight. He says, “I do not feel good,” but otherwise does not communicate spontaneously. Intermittently, he is irritable, without known triggers. The staff notices that Mr. J often lays on his bed, sometimes in a fetal position. Over time, he becomes confused and is seen attempting to open his room door with a toothbrush. His personal hygiene is poor, and he often urinates through his clothes, on the floor, and in his bed. Recently, Mr. J’s eczema has worsened. His gait has become unsteady, and he has orthostasis.

What could be causing these new symptoms?

a) worsening schizoaffective disorder
b) illicit drug use in the prison
c) atypical dementia
d) cardiac etiology

The author’s observations

The differential diagnosis for Mr. J appeared to be wide and without specific etiology. Because of the complex types of symptoms that Mr. J was experiencing, the emergency department managed his care and specialty clinic referrals were ordered.

It was reported that Mr. J started complaining of lightheadedness a few months ago, which worsened (unsteady gait, near falls). In the context of Mr. J’s history of lightheadedness and orthostasis, the cardiology clinic ordered a tilt table test, which was within normal limits:

• 70º head-up tilt: blood pressure, 91/67 to 102/62 mm Hg, and pulse, 70 to 79 beats per minute (bpm)
• with isoproterenol, 1 μg/minute: blood pressure, 90/66 to 110/70 mm Hg, and pulse, 77 to 124 bpm
• with isoproterenol, 2 μg/minute: blood pressure, 98/58 to 111/66 mm Hg, and pulse, 121 to 134 bpm.

The neurologist’s diagnostic impression was atypical dementia; however, Mr. J showed no memory deficits. Parkinsonism also was considered, but Mr. J had no unilateral tremor, masked facies, or micrographia. Mr. J showed some restriction in his movement, but he was not bradykinetic. The team suspected haloperidol could be causing his stiff movement.

Although it was possible that Mr. J’s schizoaffective disorder was worsening and led to the new symptoms, Mr. J appeared to be less delusional because he was no longer talking to the staff about his delusions. There seemed to be no outward evidence of progression of psychotic symptoms.

Mr. J had a history of substance abuse, including alcohol, cocaine, and Cannabis. Although prison inmates have been known to manufacture and drink “hooch,” the new symptoms Mr. J was experiencing were severe enough that his social interactions with other inmates diminished substantially. Because Mr. J had not been communicating with the other inmates and had no recent visitors, the team felt that it was unlikely that drugs were causing these symptoms. Also, a urine drug screen for cocaine, amphetamines, benzodiazepines, Cannabis, and opioids was negative.

HISTORY Substance use, violence

Mr. J was diagnosed with bipolar disorder at age 18. After later hospitalizations, his diagnosis was changed to schizoaffective disorder as a matter of diagnostic clarification. He has a long history of non-compliance with treatment, homelessness, and drug abuse.

Mr. J is serving a 20-year sentence for first-degree reckless homicide. A year after he was incarcerated, Mr. J was sent to a specialized mental health facility for inmates whose illness cannot be managed in a typical correctional setting. While at the treatment facility, Mr. J was non-compliant with medications and because of concerns about dangerousness and psychosis, the court found probable cause for involuntary commitment.

His medication regimen is trihexyphenidyl, 2 mg/d, for extrapyramidal symptoms; haloperidol, 10 mg/d, for psychosis; trazodone, 150 mg/d, for insomnia; vitamin D₃, 2,000 IU/d; vitamin E, 400 IU/d, for symptoms of tardive dyskinesia; IM ziprasidone, 20 mg, because he refused oral haliperidol; and hydrocortisone cream 1% for eczema.

EVALUATION Additional tests

Mr. J’s blood pressure is 124/72 mm Hg, and pulse, 104 bpm, laying down; blood pressure, 110/84 mm Hg, and pulse, 112 bpm, sitting; and blood pressure, 108/82 mm Hg, and pulse, 129 bpm, standing. With repeated readings: blood pressure, 128/84 mm Hg, and pulse, 98 bpm, laying down; blood pressure, 125/86 mm Hg, and pulse, 113 bpm, sitting; and blood pressure, 105/76 mm Hg, and pulse, 130 bpm, standing.

Laboratory tests, including complete blood count, chemistry panel, thyroid-stimulating hormone, are within normal limits. The team feels that the investigation for an etiology for Mr. J’s symptoms needs to be more exhaustive and additional tests are ordered, including vitamin levels (C, B₁, B₁₂, B₆), rapid plasma reagin for syphilis, and arbovirus testing (eastern equine encephalitis virus, western equine encephalitis, West Nile virus, La Crosse encephalitis, St. Louis encephalitis), which are negative.

What’s the next best step in managing Mr. J’s care?

a) adjust his medication

b) eliminate a mediation

c) order further testing

The author’s observations

To determine if Mr. J’s new-onset symptoms might be related to the progression of his psychiatric illness, the haloperidol dosage was increased to 20 mg/d; however, we saw no positive response to this change. His tardive dyskinesia symptoms (bruxism and other oral buccal movements) worsened. Haloperidol was reduced to 10 mg/d.

Trihexyphenidyl then was suspected to contribute to Mr. J’s confusion. Unfortunately, lowering the dosage of trihexyphenidyl to 1 mg/d, did not affect Mr. J’s current symptoms and exacerbated extrapyramidal symptoms.

The treatment team then questioned if porphyria—known as the “little imitator”—might be considered because of the variety of symptoms without an etiology, despite extensive testing. A 24-hour urine collection was ordered.

What is the correct method of collecting a urine sample for porphyrins?

a) collect a small sample and expose it to light before testing

b) collect a 24-hour sample with the sample kept in ambient temperature and light

c) collect a 24-hour sample with the sample kept on ice in a light-blocking container and frozen when sent to the laboratory

EVALUATION Diagnosis revealed

The 24-hour urine collection is obtained. However, it needed to be collected twice, because the first sample was not a full sample. Interestingly, the first sample, which is exposed to light and not kept on ice, turned dark in color. The second sample is obtained properly and sent to the laboratory. When the laboratory results are returned (Figure 1), Mr. J is diagnosed with hereditary coproporphyria (HCP).

The author’s observations

There are several types of porphyria, each associated with a different step in the chain of enzymes associated with synthesis of a heme molecule in the mitochondria. A defect in any single enzyme step will create a build up of porphyrins—a precursor to heme molecules—in erythrocytes or hepatic cells.

It is important to differentiate hepatic from erythropoietic porphyrias. The acute porphyrias (acute intermittent porphyria [AIP], HCP, and variegate porphyria generally are hepatic in origin with neuropsychiatric and neurovisceral symptoms. Cutaneous porphyrias originate in bone marrow and therefore are erythropoietic. However, there are exceptions such as porphyria cutanea tarda (PCT), which is hepatic in origin but the manifestations mainly are cutaneous¹ (Figure 2).²

• muscle spasms (commonly abdominal, but can be any muscle group)
• confusion
• disorientation
• autonomic instability
• lightheadness
• disorientation
• diarrhea
• light sensitivity
• dermatologic conditions
• weakness (particularly peripheral weakness)
• hypesthesia
• allodynia
• severe nausea and vomiting
• emotional lability
• psychosis as well as general malaise.

The attack could result in death.

Mr. J had many differing symptoms and was evaluated by several specialty providers. He had a chronic dermatologic condition; he was confused, disoriented, and complained of nausea, weakness, orthostasis, and loose stools. With the variety of possible symptoms that patients such as Mr. J could experience, one can see why it would lead to many different providers being involved in the diagnosis. It is not uncommon for psychiatrists to be the last providers to care for such patients who could have been evaluated by hematology, cardiology, gastroenterology, dermatology, and/or neurology.

Hereditary coproporphyria

The team considered hepatic porphyias because of new-onset symptoms of mood lability, confusion, orthostasis, unsteady gait, weakness, dermatologic conditions on hands not responsive to treatment, and general malaise. Mr. J was diagnosed with HCP, a type of porphyria caused by a defect in coproporphyrinogen oxidase that leads to an accumulation of coproporphyrinogen III. This precursor, as are many porphyrin precursors, is neurotoxic, leading to neurovisceral or neuropsychiatric effects. Although in Mr. J’s case the coproporphyrinogen III value from the 24-hour drug screen was only modestly elevated, it has been noted that levels of excreted prophyrins do not necessarily correlate with symptom severity.³

In the past, porphyria testing was performed using the Watson-Schwartz test, which used Ehrlich’s reagent to precipitate porphyrins in a urine sample,⁴ and was used as a “bedside” test. Interestingly, porphyrins—not the iron found in the heme molecule—are precipitated in this test and cause the reddish-purple coloration of the urine sample. When quantitative testing was developed, a 24-hour sample of urine—kept on ice and away from ambient light, later to be frozen when sent to the laboratory—became the standard tool for testing for porphyrins. Now DNA testing can be used to diagnose HCP.

OUTCOME Symptoms resolve

Mr. J is started on loxapine, 20 mg at bedtime, and his symptoms resolve within 2 weeks. He maintains some baseline delusional ideation consistent with his history of schizoaffective disorder, but he is more social, his personal hygiene improves, he attends groups, eats in the cafeteria with his peers, and is no longer confused.

The author’s observations

In the 1950s, chlorpromazine was used to treat AIP.⁵ Mr. J received loxapine, a mid-potency first-generation antipsychotic, although it has been this author’s observation that high-potency first-generation antipsychotics are not effective for treating porphyria.

CASE Withdrawn and confused

Mr. J, age 54, is brought to the emergency department from a correctional treatment facility where he is reported to be displaying new, unusual behavior. He has a history of schizoaffective disorder, which has been stable with haloperidol, 10 mg/d, for more than a year.

Although previously Mr. J openly discussed his long-standing delusions about the FBI coming to release him from prison, he no longer mentions this or any other delusional beliefs, and has become less communicative with staff and peers. Mr. J no longer accompanies the other patients to the cafeteria for meals and eats in his room alone and appears to be losing weight. He says, “I do not feel good,” but otherwise does not communicate spontaneously. Intermittently, he is irritable, without known triggers. The staff notices that Mr. J often lays on his bed, sometimes in a fetal position. Over time, he becomes confused and is seen attempting to open his room door with a toothbrush. His personal hygiene is poor, and he often urinates through his clothes, on the floor, and in his bed. Recently, Mr. J’s eczema has worsened. His gait has become unsteady, and he has orthostasis.

What could be causing these new symptoms?

a) worsening schizoaffective disorder
b) illicit drug use in the prison
c) atypical dementia
d) cardiac etiology

The author’s observations

The differential diagnosis for Mr. J appeared to be wide and without specific etiology. Because of the complex types of symptoms that Mr. J was experiencing, the emergency department managed his care and specialty clinic referrals were ordered.

It was reported that Mr. J started complaining of lightheadedness a few months ago, which worsened (unsteady gait, near falls). In the context of Mr. J’s history of lightheadedness and orthostasis, the cardiology clinic ordered a tilt table test, which was within normal limits:

• 70º head-up tilt: blood pressure, 91/67 to 102/62 mm Hg, and pulse, 70 to 79 beats per minute (bpm)
• with isoproterenol, 1 μg/minute: blood pressure, 90/66 to 110/70 mm Hg, and pulse, 77 to 124 bpm
• with isoproterenol, 2 μg/minute: blood pressure, 98/58 to 111/66 mm Hg, and pulse, 121 to 134 bpm.

The neurologist’s diagnostic impression was atypical dementia; however, Mr. J showed no memory deficits. Parkinsonism also was considered, but Mr. J had no unilateral tremor, masked facies, or micrographia. Mr. J showed some restriction in his movement, but he was not bradykinetic. The team suspected haloperidol could be causing his stiff movement.

Although it was possible that Mr. J’s schizoaffective disorder was worsening and led to the new symptoms, Mr. J appeared to be less delusional because he was no longer talking to the staff about his delusions. There seemed to be no outward evidence of progression of psychotic symptoms.

Mr. J had a history of substance abuse, including alcohol, cocaine, and Cannabis. Although prison inmates have been known to manufacture and drink “hooch,” the new symptoms Mr. J was experiencing were severe enough that his social interactions with other inmates diminished substantially. Because Mr. J had not been communicating with the other inmates and had no recent visitors, the team felt that it was unlikely that drugs were causing these symptoms. Also, a urine drug screen for cocaine, amphetamines, benzodiazepines, Cannabis, and opioids was negative.

HISTORY Substance use, violence

Mr. J was diagnosed with bipolar disorder at age 18. After later hospitalizations, his diagnosis was changed to schizoaffective disorder as a matter of diagnostic clarification. He has a long history of non-compliance with treatment, homelessness, and drug abuse.

Mr. J is serving a 20-year sentence for first-degree reckless homicide. A year after he was incarcerated, Mr. J was sent to a specialized mental health facility for inmates whose illness cannot be managed in a typical correctional setting. While at the treatment facility, Mr. J was non-compliant with medications and because of concerns about dangerousness and psychosis, the court found probable cause for involuntary commitment.

His medication regimen is trihexyphenidyl, 2 mg/d, for extrapyramidal symptoms; haloperidol, 10 mg/d, for psychosis; trazodone, 150 mg/d, for insomnia; vitamin D₃, 2,000 IU/d; vitamin E, 400 IU/d, for symptoms of tardive dyskinesia; IM ziprasidone, 20 mg, because he refused oral haliperidol; and hydrocortisone cream 1% for eczema.

EVALUATION Additional tests

Mr. J’s blood pressure is 124/72 mm Hg, and pulse, 104 bpm, laying down; blood pressure, 110/84 mm Hg, and pulse, 112 bpm, sitting; and blood pressure, 108/82 mm Hg, and pulse, 129 bpm, standing. With repeated readings: blood pressure, 128/84 mm Hg, and pulse, 98 bpm, laying down; blood pressure, 125/86 mm Hg, and pulse, 113 bpm, sitting; and blood pressure, 105/76 mm Hg, and pulse, 130 bpm, standing.

Laboratory tests, including complete blood count, chemistry panel, thyroid-stimulating hormone, are within normal limits. The team feels that the investigation for an etiology for Mr. J’s symptoms needs to be more exhaustive and additional tests are ordered, including vitamin levels (C, B₁, B₁₂, B₆), rapid plasma reagin for syphilis, and arbovirus testing (eastern equine encephalitis virus, western equine encephalitis, West Nile virus, La Crosse encephalitis, St. Louis encephalitis), which are negative.

What’s the next best step in managing Mr. J’s care?

a) adjust his medication

b) eliminate a mediation

c) order further testing

The author’s observations

To determine if Mr. J’s new-onset symptoms might be related to the progression of his psychiatric illness, the haloperidol dosage was increased to 20 mg/d; however, we saw no positive response to this change. His tardive dyskinesia symptoms (bruxism and other oral buccal movements) worsened. Haloperidol was reduced to 10 mg/d.

Trihexyphenidyl then was suspected to contribute to Mr. J’s confusion. Unfortunately, lowering the dosage of trihexyphenidyl to 1 mg/d, did not affect Mr. J’s current symptoms and exacerbated extrapyramidal symptoms.

The treatment team then questioned if porphyria—known as the “little imitator”—might be considered because of the variety of symptoms without an etiology, despite extensive testing. A 24-hour urine collection was ordered.

What is the correct method of collecting a urine sample for porphyrins?

a) collect a small sample and expose it to light before testing

b) collect a 24-hour sample with the sample kept in ambient temperature and light

c) collect a 24-hour sample with the sample kept on ice in a light-blocking container and frozen when sent to the laboratory

EVALUATION Diagnosis revealed

The 24-hour urine collection is obtained. However, it needed to be collected twice, because the first sample was not a full sample. Interestingly, the first sample, which is exposed to light and not kept on ice, turned dark in color. The second sample is obtained properly and sent to the laboratory. When the laboratory results are returned (Figure 1), Mr. J is diagnosed with hereditary coproporphyria (HCP).

The author’s observations

There are several types of porphyria, each associated with a different step in the chain of enzymes associated with synthesis of a heme molecule in the mitochondria. A defect in any single enzyme step will create a build up of porphyrins—a precursor to heme molecules—in erythrocytes or hepatic cells.

It is important to differentiate hepatic from erythropoietic porphyrias. The acute porphyrias (acute intermittent porphyria [AIP], HCP, and variegate porphyria generally are hepatic in origin with neuropsychiatric and neurovisceral symptoms. Cutaneous porphyrias originate in bone marrow and therefore are erythropoietic. However, there are exceptions such as porphyria cutanea tarda (PCT), which is hepatic in origin but the manifestations mainly are cutaneous¹ (Figure 2).²

• muscle spasms (commonly abdominal, but can be any muscle group)
• confusion
• disorientation
• autonomic instability
• lightheadness
• disorientation
• diarrhea
• light sensitivity
• dermatologic conditions
• weakness (particularly peripheral weakness)
• hypesthesia
• allodynia
• severe nausea and vomiting
• emotional lability
• psychosis as well as general malaise.

The attack could result in death.

Mr. J had many differing symptoms and was evaluated by several specialty providers. He had a chronic dermatologic condition; he was confused, disoriented, and complained of nausea, weakness, orthostasis, and loose stools. With the variety of possible symptoms that patients such as Mr. J could experience, one can see why it would lead to many different providers being involved in the diagnosis. It is not uncommon for psychiatrists to be the last providers to care for such patients who could have been evaluated by hematology, cardiology, gastroenterology, dermatology, and/or neurology.

Hereditary coproporphyria

The team considered hepatic porphyias because of new-onset symptoms of mood lability, confusion, orthostasis, unsteady gait, weakness, dermatologic conditions on hands not responsive to treatment, and general malaise. Mr. J was diagnosed with HCP, a type of porphyria caused by a defect in coproporphyrinogen oxidase that leads to an accumulation of coproporphyrinogen III. This precursor, as are many porphyrin precursors, is neurotoxic, leading to neurovisceral or neuropsychiatric effects. Although in Mr. J’s case the coproporphyrinogen III value from the 24-hour drug screen was only modestly elevated, it has been noted that levels of excreted prophyrins do not necessarily correlate with symptom severity.³

In the past, porphyria testing was performed using the Watson-Schwartz test, which used Ehrlich’s reagent to precipitate porphyrins in a urine sample,⁴ and was used as a “bedside” test. Interestingly, porphyrins—not the iron found in the heme molecule—are precipitated in this test and cause the reddish-purple coloration of the urine sample. When quantitative testing was developed, a 24-hour sample of urine—kept on ice and away from ambient light, later to be frozen when sent to the laboratory—became the standard tool for testing for porphyrins. Now DNA testing can be used to diagnose HCP.

OUTCOME Symptoms resolve

Mr. J is started on loxapine, 20 mg at bedtime, and his symptoms resolve within 2 weeks. He maintains some baseline delusional ideation consistent with his history of schizoaffective disorder, but he is more social, his personal hygiene improves, he attends groups, eats in the cafeteria with his peers, and is no longer confused.

The author’s observations

In the 1950s, chlorpromazine was used to treat AIP.⁵ Mr. J received loxapine, a mid-potency first-generation antipsychotic, although it has been this author’s observation that high-potency first-generation antipsychotics are not effective for treating porphyria.

CASE Withdrawn and confused

Mr. J, age 54, is brought to the emergency department from a correctional treatment facility where he is reported to be displaying new, unusual behavior. He has a history of schizoaffective disorder, which has been stable with haloperidol, 10 mg/d, for more than a year.

Although previously Mr. J openly discussed his long-standing delusions about the FBI coming to release him from prison, he no longer mentions this or any other delusional beliefs, and has become less communicative with staff and peers. Mr. J no longer accompanies the other patients to the cafeteria for meals and eats in his room alone and appears to be losing weight. He says, “I do not feel good,” but otherwise does not communicate spontaneously. Intermittently, he is irritable, without known triggers. The staff notices that Mr. J often lays on his bed, sometimes in a fetal position. Over time, he becomes confused and is seen attempting to open his room door with a toothbrush. His personal hygiene is poor, and he often urinates through his clothes, on the floor, and in his bed. Recently, Mr. J’s eczema has worsened. His gait has become unsteady, and he has orthostasis.

What could be causing these new symptoms?

a) worsening schizoaffective disorder
b) illicit drug use in the prison
c) atypical dementia
d) cardiac etiology

The author’s observations

The differential diagnosis for Mr. J appeared to be wide and without specific etiology. Because of the complex types of symptoms that Mr. J was experiencing, the emergency department managed his care and specialty clinic referrals were ordered.

It was reported that Mr. J started complaining of lightheadedness a few months ago, which worsened (unsteady gait, near falls). In the context of Mr. J’s history of lightheadedness and orthostasis, the cardiology clinic ordered a tilt table test, which was within normal limits:

• 70º head-up tilt: blood pressure, 91/67 to 102/62 mm Hg, and pulse, 70 to 79 beats per minute (bpm)
• with isoproterenol, 1 μg/minute: blood pressure, 90/66 to 110/70 mm Hg, and pulse, 77 to 124 bpm
• with isoproterenol, 2 μg/minute: blood pressure, 98/58 to 111/66 mm Hg, and pulse, 121 to 134 bpm.

The neurologist’s diagnostic impression was atypical dementia; however, Mr. J showed no memory deficits. Parkinsonism also was considered, but Mr. J had no unilateral tremor, masked facies, or micrographia. Mr. J showed some restriction in his movement, but he was not bradykinetic. The team suspected haloperidol could be causing his stiff movement.

Although it was possible that Mr. J’s schizoaffective disorder was worsening and led to the new symptoms, Mr. J appeared to be less delusional because he was no longer talking to the staff about his delusions. There seemed to be no outward evidence of progression of psychotic symptoms.

Mr. J had a history of substance abuse, including alcohol, cocaine, and Cannabis. Although prison inmates have been known to manufacture and drink “hooch,” the new symptoms Mr. J was experiencing were severe enough that his social interactions with other inmates diminished substantially. Because Mr. J had not been communicating with the other inmates and had no recent visitors, the team felt that it was unlikely that drugs were causing these symptoms. Also, a urine drug screen for cocaine, amphetamines, benzodiazepines, Cannabis, and opioids was negative.

HISTORY Substance use, violence

Mr. J was diagnosed with bipolar disorder at age 18. After later hospitalizations, his diagnosis was changed to schizoaffective disorder as a matter of diagnostic clarification. He has a long history of non-compliance with treatment, homelessness, and drug abuse.

Mr. J is serving a 20-year sentence for first-degree reckless homicide. A year after he was incarcerated, Mr. J was sent to a specialized mental health facility for inmates whose illness cannot be managed in a typical correctional setting. While at the treatment facility, Mr. J was non-compliant with medications and because of concerns about dangerousness and psychosis, the court found probable cause for involuntary commitment.

His medication regimen is trihexyphenidyl, 2 mg/d, for extrapyramidal symptoms; haloperidol, 10 mg/d, for psychosis; trazodone, 150 mg/d, for insomnia; vitamin D₃, 2,000 IU/d; vitamin E, 400 IU/d, for symptoms of tardive dyskinesia; IM ziprasidone, 20 mg, because he refused oral haliperidol; and hydrocortisone cream 1% for eczema.

EVALUATION Additional tests

Mr. J’s blood pressure is 124/72 mm Hg, and pulse, 104 bpm, laying down; blood pressure, 110/84 mm Hg, and pulse, 112 bpm, sitting; and blood pressure, 108/82 mm Hg, and pulse, 129 bpm, standing. With repeated readings: blood pressure, 128/84 mm Hg, and pulse, 98 bpm, laying down; blood pressure, 125/86 mm Hg, and pulse, 113 bpm, sitting; and blood pressure, 105/76 mm Hg, and pulse, 130 bpm, standing.

Laboratory tests, including complete blood count, chemistry panel, thyroid-stimulating hormone, are within normal limits. The team feels that the investigation for an etiology for Mr. J’s symptoms needs to be more exhaustive and additional tests are ordered, including vitamin levels (C, B₁, B₁₂, B₆), rapid plasma reagin for syphilis, and arbovirus testing (eastern equine encephalitis virus, western equine encephalitis, West Nile virus, La Crosse encephalitis, St. Louis encephalitis), which are negative.

What’s the next best step in managing Mr. J’s care?

a) adjust his medication

b) eliminate a mediation

c) order further testing

The author’s observations

To determine if Mr. J’s new-onset symptoms might be related to the progression of his psychiatric illness, the haloperidol dosage was increased to 20 mg/d; however, we saw no positive response to this change. His tardive dyskinesia symptoms (bruxism and other oral buccal movements) worsened. Haloperidol was reduced to 10 mg/d.

Trihexyphenidyl then was suspected to contribute to Mr. J’s confusion. Unfortunately, lowering the dosage of trihexyphenidyl to 1 mg/d, did not affect Mr. J’s current symptoms and exacerbated extrapyramidal symptoms.

The treatment team then questioned if porphyria—known as the “little imitator”—might be considered because of the variety of symptoms without an etiology, despite extensive testing. A 24-hour urine collection was ordered.

What is the correct method of collecting a urine sample for porphyrins?

a) collect a small sample and expose it to light before testing

b) collect a 24-hour sample with the sample kept in ambient temperature and light

c) collect a 24-hour sample with the sample kept on ice in a light-blocking container and frozen when sent to the laboratory

EVALUATION Diagnosis revealed

The 24-hour urine collection is obtained. However, it needed to be collected twice, because the first sample was not a full sample. Interestingly, the first sample, which is exposed to light and not kept on ice, turned dark in color. The second sample is obtained properly and sent to the laboratory. When the laboratory results are returned (Figure 1), Mr. J is diagnosed with hereditary coproporphyria (HCP).

The author’s observations

There are several types of porphyria, each associated with a different step in the chain of enzymes associated with synthesis of a heme molecule in the mitochondria. A defect in any single enzyme step will create a build up of porphyrins—a precursor to heme molecules—in erythrocytes or hepatic cells.

It is important to differentiate hepatic from erythropoietic porphyrias. The acute porphyrias (acute intermittent porphyria [AIP], HCP, and variegate porphyria generally are hepatic in origin with neuropsychiatric and neurovisceral symptoms. Cutaneous porphyrias originate in bone marrow and therefore are erythropoietic. However, there are exceptions such as porphyria cutanea tarda (PCT), which is hepatic in origin but the manifestations mainly are cutaneous¹ (Figure 2).²

• muscle spasms (commonly abdominal, but can be any muscle group)
• confusion
• disorientation
• autonomic instability
• lightheadness
• disorientation
• diarrhea
• light sensitivity
• dermatologic conditions
• weakness (particularly peripheral weakness)
• hypesthesia
• allodynia
• severe nausea and vomiting
• emotional lability
• psychosis as well as general malaise.

The attack could result in death.

Mr. J had many differing symptoms and was evaluated by several specialty providers. He had a chronic dermatologic condition; he was confused, disoriented, and complained of nausea, weakness, orthostasis, and loose stools. With the variety of possible symptoms that patients such as Mr. J could experience, one can see why it would lead to many different providers being involved in the diagnosis. It is not uncommon for psychiatrists to be the last providers to care for such patients who could have been evaluated by hematology, cardiology, gastroenterology, dermatology, and/or neurology.

Hereditary coproporphyria

The team considered hepatic porphyias because of new-onset symptoms of mood lability, confusion, orthostasis, unsteady gait, weakness, dermatologic conditions on hands not responsive to treatment, and general malaise. Mr. J was diagnosed with HCP, a type of porphyria caused by a defect in coproporphyrinogen oxidase that leads to an accumulation of coproporphyrinogen III. This precursor, as are many porphyrin precursors, is neurotoxic, leading to neurovisceral or neuropsychiatric effects. Although in Mr. J’s case the coproporphyrinogen III value from the 24-hour drug screen was only modestly elevated, it has been noted that levels of excreted prophyrins do not necessarily correlate with symptom severity.³

In the past, porphyria testing was performed using the Watson-Schwartz test, which used Ehrlich’s reagent to precipitate porphyrins in a urine sample,⁴ and was used as a “bedside” test. Interestingly, porphyrins—not the iron found in the heme molecule—are precipitated in this test and cause the reddish-purple coloration of the urine sample. When quantitative testing was developed, a 24-hour sample of urine—kept on ice and away from ambient light, later to be frozen when sent to the laboratory—became the standard tool for testing for porphyrins. Now DNA testing can be used to diagnose HCP.

OUTCOME Symptoms resolve

Mr. J is started on loxapine, 20 mg at bedtime, and his symptoms resolve within 2 weeks. He maintains some baseline delusional ideation consistent with his history of schizoaffective disorder, but he is more social, his personal hygiene improves, he attends groups, eats in the cafeteria with his peers, and is no longer confused.

The author’s observations

In the 1950s, chlorpromazine was used to treat AIP.⁵ Mr. J received loxapine, a mid-potency first-generation antipsychotic, although it has been this author’s observation that high-potency first-generation antipsychotics are not effective for treating porphyria.