CASE Sudden personality change
Ms. L, age 38, is brought to the university hospital’s emergency department (ED) under police escort after she awoke in the middle of the night screaming, “I found it out! I’m a lie! Life is a lie!” and began threatening suicide. This prompted her spouse to call emergency services because of concerns about her safety.

Over the preceding 9 days—and, most precipitously, over the last 24 hours—Ms. L has experienced a dramatic “change in her personality,” according to her spouse. In the ED, she is oriented to person, place, and time. Her vital signs are within normal limits, other than a mild tachycardia. Complete blood count and complete metabolic profile are unremarkable and a urine drug screen is positive only for benzodiazepines (she recently was prescribed alprazolam). Ms. L smiles inappropriately at the ED physicians and confides that she is hearing music by The Lumineers, despite silence in her room.

The psychiatry service is consulted after she is seen making threats of harm to her family members.

EVALUATION Confusion
Over past several weeks, Ms. L has experienced rapid onset of neurovegetative symptoms, with poor oral intake, increased somnolence, neglect of hygiene, excessive time spent in bed, and weight loss of 15 to 20 lb, according to her spouse. She also has been complaining of foggy mentation, weakening handgrip, and tinnitus. She has no previous psychiatric history.

She recently established care with an outpatient neurologist and infectious disease specialist to address these symptoms. Outpatient EEG and sexually transmitted infection (STI) tests were scheduled but not yet obtained. Ms. L’s spouse observes that her drastic “personality change” over the preceding 24 hours coincided with her feeling upset and offended by a physician’s recommendation to obtain STI tests (it is unclear why the physician recommended these tests).

Ms. L had presented to another local ED 4 times over several weeks for various complaints, and had been prescribed alprazolam, 0.5 mg, 3 times a day as needed, and buspirone, 15 mg/d, for anxiety. She also had received a short course of doxycycline, 200 mg/d, which she did not finish, for treatment of presumed Lyme disease. According to her spouse, Ms. L had completed a course of doxycycline for Lyme disease 1 year earlier, but the medical records are not available for review.

During the interview, Ms. L is fairly well groomed but appears confused; she asks her spouse if she is “real” and states that she feels “crazy.” She seems uncomfortable and is guarded, with a minimally reactive, anxious affect. She has general psychomotor slowing and her speech is soft and monotonous, with prominent latency. She reports passive suicidal ideations as well as active auditory hallucinations of a musical quality.

The Mini-Mental State Examination (MMSE) score is 19/30, indicating moderate cognitive impairment, and she is unable to complete attention, executive function, 3-stage command, and delayed word recall tasks. She reports fatigue, diarrhea, and decreased appetite. Her physical examination is notable for an overweight white woman without focal neurologic deficits. Her family psychiatric history reveals bipolar disorder in 2 distant relatives.

In the ED, Ms. L is given 3 provisional diagnoses:

• adjustment disorder, because of her reaction to the proposed STI testing
• psychotic disorder not otherwise specified, because of her obvious psychosis of unknown cause
• rule out delirium due to a general medical condition, because of her sudden onset of attention, perception, and memory difficulties.

As Ms. L sits in her room, her abnormal behaviors become more apparent. She starts to endorse active suicidal ideations and becomes aggressive, trying to choke her spouse, shouting, jumping on her bed, and attempting to strike herself. For her safety, she is physically restrained and given IM haloperidol, 10 mg, and IM lorazepam, 2 mg.

What would you do next to treat Ms. L?
   a) Admit her to the psychiatric unit for monitoring and treatment of psychosis and consider additional antipsychotics for agitation
   b) Perform a bedside lumbar puncture to assess for findings suggestive of a CNS infection or anomaly
   c) Sedate her with IM ketamine, intubate her, and admit her to the intensive care unit (ICU) for further medical workup
   d) Begin IV antibiotic therapy with ceftriaxone for early-disseminated Lyme disease with CNS involvement

The authors’ observations
Clearly, Ms. L was psychotic. However, psychosis is a nonspecific term used to describe a heterogeneous group of phenomena in which one experiences an impaired sense of reality. Although commonly caused by psychiatric disorders, psychosis can arise from a variety of causes.¹ Ms. L’s initial physical examination and laboratory studies were within the normal range, but her mental status exam and MMSE were abnormal. At this point, selecting the appropriate setting for further observation, workup, and treatment became important.

TREATMENT The right setting
Given the abrupt onset of Ms. L’s symptoms, the treatment team is concerned about active neurologic or infectious disease. However, no acute laboratory or physical examination findings support this hypothesis, and the ED physicians conclude that no further emergent workup is indicated. Because Ms. L is threatening harm to herself and others, she cannot be safely discharged. The treatment team decides the safest option is to admit Ms. L to the inpatient psychiatric unit for observation, further non-emergent workup, and consultation with the neurology service.

At admission. Ms. L is cooperative and calm, lying in bed comfortably. She obeys simple commands; a brief neurologic examination is remarkable for a sedated female without focal motor or sensory deficits. Although her answers to questions are brief, they are appropriate. She sleeps without incident for approximately 10 hours.

The next morning. Ms. L does not awaken to verbal or gentle physical stimuli. Upon sternal rub, she awakens and forcefully squeezes the examiner’s arm, after which she closes her eyes and does not answer further questions (but does resist passive eye opening). After several minutes, she begins exhibiting verbigeration, shouting repeated phrases such as “The birds are in my ears” and “No, I am not okay.”

An emergent EEG is ordered because the team is concerned about nonconvulsive status epilepticus and the neurology service is consulted about the need for an urgent lumbar puncture. Without any obvious abnormal physical examination findings, however, the neurology team’s initial assessment attributes Ms. L’s presentation to a primary psychiatric illness and does not recommend a lumbar puncture or EEG.

That day and night, Ms. L has several episodes of agitation with a disorganized thought process and perseverative speech. She appears distraught and exhibits menacing behaviors. She is poorly redirectable and physically hostile toward staff, requiring several emergent doses of IM haloperidol and IM lorazepam, to which she responds minimally. Ms. L is placed on constant observation, requiring frequent redirection from the rooms of other patients and intermittent seclusion because of her violent, destructive behavior.

The next day. Ms. L remains grossly agitated and psychotic. Although an EEG is ordered, it is not performed because the technicians are concerned about their safety. With her unclear history of Lyme disease and concern for an infectious encephalopathy, Ms. L’s history and symptoms are discussed with the infectious disease service. Given her abrupt onset of symptoms, including auditory hallucinations, they express concern for herpes simplex encephalitis and recommend emergent treatment with IV acyclovir and ceftriaxone.

This recommendation, however, causes a practical conundrum. Because of state laws and differences in staff training, the treatment team believes that the inpatient psychiatric unit is not the appropriate setting to administer these IV treatments. At the same time, hospital security, nursing staff, and the receiving medical team are concerned about transporting Ms. L to the general medical floor.

In the ICU. After discussion, the teams decide that the safest and least traumatic option is to transport Ms. L to the ICU after she is sedated and intubated. In the ICU, she undergoes empirical treatment for herpes simplex encephalitis and further medical workup.

An EEG reveals findings suggestive of severe encephalopathy. A lumbar puncture shows lymphocytic pleocytosis with an opening pressure of 28 cm H₂O and normal protein and glucose levels. Her serum C-reactive protein is slightly elevated at 1.4 mg/dL. She also is found to have an elevated herpes simplex virus (HSV)-2 IgG antibody.

Subsequent hospital stay. Ms. L has 2 episodes of seizure-like activity, for which she is treated with levetiracetam, 2,000 mg/d, increased to 3,000 mg/d. She is sedated for several days to allow broad treatment with antiviral and antibiotic medications. Although she experiences intermittent fevers and tachycardia, cultures of blood, urine, and cerebrospinal fluid (CSF) show no growth. Similarly, a test of serum HSV IgM antibodies is negative.

CT of the chest, abdomen, and pelvis reveals no findings suggestive of malignancy but does show a solid-appearing 6-mm nodule in her right lung. Magnetic resonance angiography of the head and neck shows no evidence of abnormalities other than atrophy of the superior cerebellar vermis and a subtle focus of T2/FLAIR signal abnormality in the medial portion of the left occipital lobe.

The following weeks. Ms. L’s cognitive status improves markedly. Extensive studies—including serum ammonia, thyroid-stimulating hormone, Lyme disease antibody, vitamin B₁₂, folate, beta-hCG, HIV, hepatitis B and C, Varicella zoster, syphilis, Lyme disease serology, CSF Eastern equine encephalitis, St. Louis encephalitis virus, West Nile virus, Ehrlichia chaffeensis, Babesia microti, Rocky Mountain spotted fever, John Cunningham virus, typhus fever, cryptococcal antigen, rabies, 2 serum tests for anti-N-methyl-D-aspartate (NMDA) receptor antibodies, and serum ceruloplasmin—are normal.

At discharge, Ms. L’s clinical presentation is thought to be most consistent with viral encephalitis, because of her CSF lymphocytic pleocytosis, fever, and improvement with supportive care. Because she improves, the team does not find it necessary to wait for results of pending studies, including a paraneoplastic autoantibody panel and a CSF anti-NMDA receptor antibody, before discharging her.

Readmission. Although the results of the paraneoplastic autoantibody panel are unremarkable, several weeks after discharge Ms. L’s CSF anti-NMDA receptor antibodies return positive, despite 2 earlier negative serum studies. She is readmitted to the neurology service for treatment with immunomodulators.

A positron-emission tomography scan is negative for malignancy. She is treated on an ongoing basis with immunomodulators; cognition improves such that she is able to start working again with good overall functioning. Despite this improvement, she experiences residual sequelae, including noise sensitivity, amnesia of the events surrounding her hospitalization, mild short-term memory deficits, and persistent affective blunting.

The authors’ observations
Psychosis is not exclusive to psychiatric syndromes and frequently is a symptom of an underlying neurologic, immunologic, metabolic, infectious, or oncologic abnormality.¹ Anti-NMDA receptor encephalitis is an autoimmune disease in which antibodies attack NMDA-type glutamate receptors at central neuronal synapses and can produce psychosis, as seen with Ms. L² (Table 1^2,3). The etiology of the disease is not fully understood. Determining the appropriate setting to perform a complete medical workup in a severely agitated patient after an initial negative medical workup can be challenging.

What’s the most appropriate treatment setting?
This case illustrates the importance, with any new-onset psychosis, of weighing heavily a carefully obtained psychiatric history, even in the absence of focal physical examination and initial laboratory abnormalities. It also highlights the challenge of determining the most appropriate initial setting for performing the important task of a complete medical workup for first-episode psychosis.

Ms. L initially was treated in the inpatient psychiatric unit because of safety concerns and practical limitations, but was later found to have a disease that could not be managed in that setting. She proved to be too agitated to obtain a full medical workup on the inpatient psychiatric or general medical floors and required transfer to the ICU. Despite her normal basic laboratory tests, her EEG and CSF studies did demonstrate abnormalities, suggesting these can be useful to the basic workup for psychosis of unknown cause (Table 2^1,2).

This case also demonstrates that negative serum anti-NMDA receptor antibody tests do not rule out the disease; one study found that only 85% of patients with CSF anti-NMDA receptor antibodies also had detectable antibodies in their serum and that detectability changed during the course of the disease.⁴ This supports the utility of a lumbar puncture as part of a basic initial workup for some cases of new-onset psychosis. Because clinical outcomes often correlate with early treatment, as with anti-NMDA receptor encephalitis, a timely diagnostic workup of psychosis often can be important.^3,5 The ICU can be considered an appropriate setting for working up some patients who develop new, rapid-onset psychosis and severe agitation, even in the absence of initial laboratory or physical examination findings.

Ms. L’s case also illustrates the importance of completing a thorough medical workup for patients with new-onset psychosis before transferring them to an independent psychiatric hospital. Initially, the university’s psychiatric unit was at capacity and a bed was sought at outside psychiatric hospitals while Ms. L waited in the ED. Had Ms. L not been admitted to a large academic medical center, she may not have had access to the multidisciplinary collaboration that proved necessary for the appropriate diagnosis and treatment of her anti-NMDA receptor encephalitis (Table 3^5,6).

What prodromal symptoms occur as long as 2 weeks as an initial presentation in many patients with anti-NMDA receptor encephalitis?
   a) Flu-like symptoms of lethargy, headache, gastrointestinal symptoms, myalgias, fevers, and upper respiratory symptoms
   b) Delusions, hallucinations, disorganized behaviors and thoughts, behavioral outbursts, hypersexuality, mood lability, personality change, paranoia, echolalia, mutism, anxiety, agitation, aggression, hyperactivity, sleep dysfunction, and blunted affect
   c) Dyskinesias, autonomic instability, central hypoventilation, and seizures

The authors’ observations
Lab results, vital signs, and physical examination should not supplant a careful history when determining an appropriate clinical course of action. As experts in the cognitive sciences, psychiatrists may be the most qualified in determining whether a patient with new-onset psychosis should undergo further medical testing before a condition is deemed to be solely of a psychiatric cause. As a neurologic disease of immunologic origin with psychiatric manifestations, anti-NMDA receptor encephalitis is a complex condition requiring collaboration among several specialists for appropriate management.

CASE Sudden personality change
Ms. L, age 38, is brought to the university hospital’s emergency department (ED) under police escort after she awoke in the middle of the night screaming, “I found it out! I’m a lie! Life is a lie!” and began threatening suicide. This prompted her spouse to call emergency services because of concerns about her safety.

Over the preceding 9 days—and, most precipitously, over the last 24 hours—Ms. L has experienced a dramatic “change in her personality,” according to her spouse. In the ED, she is oriented to person, place, and time. Her vital signs are within normal limits, other than a mild tachycardia. Complete blood count and complete metabolic profile are unremarkable and a urine drug screen is positive only for benzodiazepines (she recently was prescribed alprazolam). Ms. L smiles inappropriately at the ED physicians and confides that she is hearing music by The Lumineers, despite silence in her room.

The psychiatry service is consulted after she is seen making threats of harm to her family members.

EVALUATION Confusion
Over past several weeks, Ms. L has experienced rapid onset of neurovegetative symptoms, with poor oral intake, increased somnolence, neglect of hygiene, excessive time spent in bed, and weight loss of 15 to 20 lb, according to her spouse. She also has been complaining of foggy mentation, weakening handgrip, and tinnitus. She has no previous psychiatric history.

She recently established care with an outpatient neurologist and infectious disease specialist to address these symptoms. Outpatient EEG and sexually transmitted infection (STI) tests were scheduled but not yet obtained. Ms. L’s spouse observes that her drastic “personality change” over the preceding 24 hours coincided with her feeling upset and offended by a physician’s recommendation to obtain STI tests (it is unclear why the physician recommended these tests).

Ms. L had presented to another local ED 4 times over several weeks for various complaints, and had been prescribed alprazolam, 0.5 mg, 3 times a day as needed, and buspirone, 15 mg/d, for anxiety. She also had received a short course of doxycycline, 200 mg/d, which she did not finish, for treatment of presumed Lyme disease. According to her spouse, Ms. L had completed a course of doxycycline for Lyme disease 1 year earlier, but the medical records are not available for review.

During the interview, Ms. L is fairly well groomed but appears confused; she asks her spouse if she is “real” and states that she feels “crazy.” She seems uncomfortable and is guarded, with a minimally reactive, anxious affect. She has general psychomotor slowing and her speech is soft and monotonous, with prominent latency. She reports passive suicidal ideations as well as active auditory hallucinations of a musical quality.

The Mini-Mental State Examination (MMSE) score is 19/30, indicating moderate cognitive impairment, and she is unable to complete attention, executive function, 3-stage command, and delayed word recall tasks. She reports fatigue, diarrhea, and decreased appetite. Her physical examination is notable for an overweight white woman without focal neurologic deficits. Her family psychiatric history reveals bipolar disorder in 2 distant relatives.

In the ED, Ms. L is given 3 provisional diagnoses:

• adjustment disorder, because of her reaction to the proposed STI testing
• psychotic disorder not otherwise specified, because of her obvious psychosis of unknown cause
• rule out delirium due to a general medical condition, because of her sudden onset of attention, perception, and memory difficulties.

As Ms. L sits in her room, her abnormal behaviors become more apparent. She starts to endorse active suicidal ideations and becomes aggressive, trying to choke her spouse, shouting, jumping on her bed, and attempting to strike herself. For her safety, she is physically restrained and given IM haloperidol, 10 mg, and IM lorazepam, 2 mg.

What would you do next to treat Ms. L?
   a) Admit her to the psychiatric unit for monitoring and treatment of psychosis and consider additional antipsychotics for agitation
   b) Perform a bedside lumbar puncture to assess for findings suggestive of a CNS infection or anomaly
   c) Sedate her with IM ketamine, intubate her, and admit her to the intensive care unit (ICU) for further medical workup
   d) Begin IV antibiotic therapy with ceftriaxone for early-disseminated Lyme disease with CNS involvement

The authors’ observations
Clearly, Ms. L was psychotic. However, psychosis is a nonspecific term used to describe a heterogeneous group of phenomena in which one experiences an impaired sense of reality. Although commonly caused by psychiatric disorders, psychosis can arise from a variety of causes.¹ Ms. L’s initial physical examination and laboratory studies were within the normal range, but her mental status exam and MMSE were abnormal. At this point, selecting the appropriate setting for further observation, workup, and treatment became important.

TREATMENT The right setting
Given the abrupt onset of Ms. L’s symptoms, the treatment team is concerned about active neurologic or infectious disease. However, no acute laboratory or physical examination findings support this hypothesis, and the ED physicians conclude that no further emergent workup is indicated. Because Ms. L is threatening harm to herself and others, she cannot be safely discharged. The treatment team decides the safest option is to admit Ms. L to the inpatient psychiatric unit for observation, further non-emergent workup, and consultation with the neurology service.

At admission. Ms. L is cooperative and calm, lying in bed comfortably. She obeys simple commands; a brief neurologic examination is remarkable for a sedated female without focal motor or sensory deficits. Although her answers to questions are brief, they are appropriate. She sleeps without incident for approximately 10 hours.

The next morning. Ms. L does not awaken to verbal or gentle physical stimuli. Upon sternal rub, she awakens and forcefully squeezes the examiner’s arm, after which she closes her eyes and does not answer further questions (but does resist passive eye opening). After several minutes, she begins exhibiting verbigeration, shouting repeated phrases such as “The birds are in my ears” and “No, I am not okay.”

An emergent EEG is ordered because the team is concerned about nonconvulsive status epilepticus and the neurology service is consulted about the need for an urgent lumbar puncture. Without any obvious abnormal physical examination findings, however, the neurology team’s initial assessment attributes Ms. L’s presentation to a primary psychiatric illness and does not recommend a lumbar puncture or EEG.

That day and night, Ms. L has several episodes of agitation with a disorganized thought process and perseverative speech. She appears distraught and exhibits menacing behaviors. She is poorly redirectable and physically hostile toward staff, requiring several emergent doses of IM haloperidol and IM lorazepam, to which she responds minimally. Ms. L is placed on constant observation, requiring frequent redirection from the rooms of other patients and intermittent seclusion because of her violent, destructive behavior.

The next day. Ms. L remains grossly agitated and psychotic. Although an EEG is ordered, it is not performed because the technicians are concerned about their safety. With her unclear history of Lyme disease and concern for an infectious encephalopathy, Ms. L’s history and symptoms are discussed with the infectious disease service. Given her abrupt onset of symptoms, including auditory hallucinations, they express concern for herpes simplex encephalitis and recommend emergent treatment with IV acyclovir and ceftriaxone.

This recommendation, however, causes a practical conundrum. Because of state laws and differences in staff training, the treatment team believes that the inpatient psychiatric unit is not the appropriate setting to administer these IV treatments. At the same time, hospital security, nursing staff, and the receiving medical team are concerned about transporting Ms. L to the general medical floor.

In the ICU. After discussion, the teams decide that the safest and least traumatic option is to transport Ms. L to the ICU after she is sedated and intubated. In the ICU, she undergoes empirical treatment for herpes simplex encephalitis and further medical workup.

An EEG reveals findings suggestive of severe encephalopathy. A lumbar puncture shows lymphocytic pleocytosis with an opening pressure of 28 cm H₂O and normal protein and glucose levels. Her serum C-reactive protein is slightly elevated at 1.4 mg/dL. She also is found to have an elevated herpes simplex virus (HSV)-2 IgG antibody.

Subsequent hospital stay. Ms. L has 2 episodes of seizure-like activity, for which she is treated with levetiracetam, 2,000 mg/d, increased to 3,000 mg/d. She is sedated for several days to allow broad treatment with antiviral and antibiotic medications. Although she experiences intermittent fevers and tachycardia, cultures of blood, urine, and cerebrospinal fluid (CSF) show no growth. Similarly, a test of serum HSV IgM antibodies is negative.

CT of the chest, abdomen, and pelvis reveals no findings suggestive of malignancy but does show a solid-appearing 6-mm nodule in her right lung. Magnetic resonance angiography of the head and neck shows no evidence of abnormalities other than atrophy of the superior cerebellar vermis and a subtle focus of T2/FLAIR signal abnormality in the medial portion of the left occipital lobe.

The following weeks. Ms. L’s cognitive status improves markedly. Extensive studies—including serum ammonia, thyroid-stimulating hormone, Lyme disease antibody, vitamin B₁₂, folate, beta-hCG, HIV, hepatitis B and C, Varicella zoster, syphilis, Lyme disease serology, CSF Eastern equine encephalitis, St. Louis encephalitis virus, West Nile virus, Ehrlichia chaffeensis, Babesia microti, Rocky Mountain spotted fever, John Cunningham virus, typhus fever, cryptococcal antigen, rabies, 2 serum tests for anti-N-methyl-D-aspartate (NMDA) receptor antibodies, and serum ceruloplasmin—are normal.

At discharge, Ms. L’s clinical presentation is thought to be most consistent with viral encephalitis, because of her CSF lymphocytic pleocytosis, fever, and improvement with supportive care. Because she improves, the team does not find it necessary to wait for results of pending studies, including a paraneoplastic autoantibody panel and a CSF anti-NMDA receptor antibody, before discharging her.

Readmission. Although the results of the paraneoplastic autoantibody panel are unremarkable, several weeks after discharge Ms. L’s CSF anti-NMDA receptor antibodies return positive, despite 2 earlier negative serum studies. She is readmitted to the neurology service for treatment with immunomodulators.

A positron-emission tomography scan is negative for malignancy. She is treated on an ongoing basis with immunomodulators; cognition improves such that she is able to start working again with good overall functioning. Despite this improvement, she experiences residual sequelae, including noise sensitivity, amnesia of the events surrounding her hospitalization, mild short-term memory deficits, and persistent affective blunting.

The authors’ observations
Psychosis is not exclusive to psychiatric syndromes and frequently is a symptom of an underlying neurologic, immunologic, metabolic, infectious, or oncologic abnormality.¹ Anti-NMDA receptor encephalitis is an autoimmune disease in which antibodies attack NMDA-type glutamate receptors at central neuronal synapses and can produce psychosis, as seen with Ms. L² (Table 1^2,3). The etiology of the disease is not fully understood. Determining the appropriate setting to perform a complete medical workup in a severely agitated patient after an initial negative medical workup can be challenging.

What’s the most appropriate treatment setting?
This case illustrates the importance, with any new-onset psychosis, of weighing heavily a carefully obtained psychiatric history, even in the absence of focal physical examination and initial laboratory abnormalities. It also highlights the challenge of determining the most appropriate initial setting for performing the important task of a complete medical workup for first-episode psychosis.

Ms. L initially was treated in the inpatient psychiatric unit because of safety concerns and practical limitations, but was later found to have a disease that could not be managed in that setting. She proved to be too agitated to obtain a full medical workup on the inpatient psychiatric or general medical floors and required transfer to the ICU. Despite her normal basic laboratory tests, her EEG and CSF studies did demonstrate abnormalities, suggesting these can be useful to the basic workup for psychosis of unknown cause (Table 2^1,2).

This case also demonstrates that negative serum anti-NMDA receptor antibody tests do not rule out the disease; one study found that only 85% of patients with CSF anti-NMDA receptor antibodies also had detectable antibodies in their serum and that detectability changed during the course of the disease.⁴ This supports the utility of a lumbar puncture as part of a basic initial workup for some cases of new-onset psychosis. Because clinical outcomes often correlate with early treatment, as with anti-NMDA receptor encephalitis, a timely diagnostic workup of psychosis often can be important.^3,5 The ICU can be considered an appropriate setting for working up some patients who develop new, rapid-onset psychosis and severe agitation, even in the absence of initial laboratory or physical examination findings.

Ms. L’s case also illustrates the importance of completing a thorough medical workup for patients with new-onset psychosis before transferring them to an independent psychiatric hospital. Initially, the university’s psychiatric unit was at capacity and a bed was sought at outside psychiatric hospitals while Ms. L waited in the ED. Had Ms. L not been admitted to a large academic medical center, she may not have had access to the multidisciplinary collaboration that proved necessary for the appropriate diagnosis and treatment of her anti-NMDA receptor encephalitis (Table 3^5,6).

What prodromal symptoms occur as long as 2 weeks as an initial presentation in many patients with anti-NMDA receptor encephalitis?
   a) Flu-like symptoms of lethargy, headache, gastrointestinal symptoms, myalgias, fevers, and upper respiratory symptoms
   b) Delusions, hallucinations, disorganized behaviors and thoughts, behavioral outbursts, hypersexuality, mood lability, personality change, paranoia, echolalia, mutism, anxiety, agitation, aggression, hyperactivity, sleep dysfunction, and blunted affect
   c) Dyskinesias, autonomic instability, central hypoventilation, and seizures

The authors’ observations
Lab results, vital signs, and physical examination should not supplant a careful history when determining an appropriate clinical course of action. As experts in the cognitive sciences, psychiatrists may be the most qualified in determining whether a patient with new-onset psychosis should undergo further medical testing before a condition is deemed to be solely of a psychiatric cause. As a neurologic disease of immunologic origin with psychiatric manifestations, anti-NMDA receptor encephalitis is a complex condition requiring collaboration among several specialists for appropriate management.

CASE Sudden personality change
Ms. L, age 38, is brought to the university hospital’s emergency department (ED) under police escort after she awoke in the middle of the night screaming, “I found it out! I’m a lie! Life is a lie!” and began threatening suicide. This prompted her spouse to call emergency services because of concerns about her safety.

Over the preceding 9 days—and, most precipitously, over the last 24 hours—Ms. L has experienced a dramatic “change in her personality,” according to her spouse. In the ED, she is oriented to person, place, and time. Her vital signs are within normal limits, other than a mild tachycardia. Complete blood count and complete metabolic profile are unremarkable and a urine drug screen is positive only for benzodiazepines (she recently was prescribed alprazolam). Ms. L smiles inappropriately at the ED physicians and confides that she is hearing music by The Lumineers, despite silence in her room.

The psychiatry service is consulted after she is seen making threats of harm to her family members.

EVALUATION Confusion
Over past several weeks, Ms. L has experienced rapid onset of neurovegetative symptoms, with poor oral intake, increased somnolence, neglect of hygiene, excessive time spent in bed, and weight loss of 15 to 20 lb, according to her spouse. She also has been complaining of foggy mentation, weakening handgrip, and tinnitus. She has no previous psychiatric history.

She recently established care with an outpatient neurologist and infectious disease specialist to address these symptoms. Outpatient EEG and sexually transmitted infection (STI) tests were scheduled but not yet obtained. Ms. L’s spouse observes that her drastic “personality change” over the preceding 24 hours coincided with her feeling upset and offended by a physician’s recommendation to obtain STI tests (it is unclear why the physician recommended these tests).

Ms. L had presented to another local ED 4 times over several weeks for various complaints, and had been prescribed alprazolam, 0.5 mg, 3 times a day as needed, and buspirone, 15 mg/d, for anxiety. She also had received a short course of doxycycline, 200 mg/d, which she did not finish, for treatment of presumed Lyme disease. According to her spouse, Ms. L had completed a course of doxycycline for Lyme disease 1 year earlier, but the medical records are not available for review.

During the interview, Ms. L is fairly well groomed but appears confused; she asks her spouse if she is “real” and states that she feels “crazy.” She seems uncomfortable and is guarded, with a minimally reactive, anxious affect. She has general psychomotor slowing and her speech is soft and monotonous, with prominent latency. She reports passive suicidal ideations as well as active auditory hallucinations of a musical quality.

The Mini-Mental State Examination (MMSE) score is 19/30, indicating moderate cognitive impairment, and she is unable to complete attention, executive function, 3-stage command, and delayed word recall tasks. She reports fatigue, diarrhea, and decreased appetite. Her physical examination is notable for an overweight white woman without focal neurologic deficits. Her family psychiatric history reveals bipolar disorder in 2 distant relatives.

In the ED, Ms. L is given 3 provisional diagnoses:

• adjustment disorder, because of her reaction to the proposed STI testing
• psychotic disorder not otherwise specified, because of her obvious psychosis of unknown cause
• rule out delirium due to a general medical condition, because of her sudden onset of attention, perception, and memory difficulties.

As Ms. L sits in her room, her abnormal behaviors become more apparent. She starts to endorse active suicidal ideations and becomes aggressive, trying to choke her spouse, shouting, jumping on her bed, and attempting to strike herself. For her safety, she is physically restrained and given IM haloperidol, 10 mg, and IM lorazepam, 2 mg.

What would you do next to treat Ms. L?
   a) Admit her to the psychiatric unit for monitoring and treatment of psychosis and consider additional antipsychotics for agitation
   b) Perform a bedside lumbar puncture to assess for findings suggestive of a CNS infection or anomaly
   c) Sedate her with IM ketamine, intubate her, and admit her to the intensive care unit (ICU) for further medical workup
   d) Begin IV antibiotic therapy with ceftriaxone for early-disseminated Lyme disease with CNS involvement

The authors’ observations
Clearly, Ms. L was psychotic. However, psychosis is a nonspecific term used to describe a heterogeneous group of phenomena in which one experiences an impaired sense of reality. Although commonly caused by psychiatric disorders, psychosis can arise from a variety of causes.¹ Ms. L’s initial physical examination and laboratory studies were within the normal range, but her mental status exam and MMSE were abnormal. At this point, selecting the appropriate setting for further observation, workup, and treatment became important.

TREATMENT The right setting
Given the abrupt onset of Ms. L’s symptoms, the treatment team is concerned about active neurologic or infectious disease. However, no acute laboratory or physical examination findings support this hypothesis, and the ED physicians conclude that no further emergent workup is indicated. Because Ms. L is threatening harm to herself and others, she cannot be safely discharged. The treatment team decides the safest option is to admit Ms. L to the inpatient psychiatric unit for observation, further non-emergent workup, and consultation with the neurology service.

At admission. Ms. L is cooperative and calm, lying in bed comfortably. She obeys simple commands; a brief neurologic examination is remarkable for a sedated female without focal motor or sensory deficits. Although her answers to questions are brief, they are appropriate. She sleeps without incident for approximately 10 hours.

The next morning. Ms. L does not awaken to verbal or gentle physical stimuli. Upon sternal rub, she awakens and forcefully squeezes the examiner’s arm, after which she closes her eyes and does not answer further questions (but does resist passive eye opening). After several minutes, she begins exhibiting verbigeration, shouting repeated phrases such as “The birds are in my ears” and “No, I am not okay.”

An emergent EEG is ordered because the team is concerned about nonconvulsive status epilepticus and the neurology service is consulted about the need for an urgent lumbar puncture. Without any obvious abnormal physical examination findings, however, the neurology team’s initial assessment attributes Ms. L’s presentation to a primary psychiatric illness and does not recommend a lumbar puncture or EEG.

That day and night, Ms. L has several episodes of agitation with a disorganized thought process and perseverative speech. She appears distraught and exhibits menacing behaviors. She is poorly redirectable and physically hostile toward staff, requiring several emergent doses of IM haloperidol and IM lorazepam, to which she responds minimally. Ms. L is placed on constant observation, requiring frequent redirection from the rooms of other patients and intermittent seclusion because of her violent, destructive behavior.

The next day. Ms. L remains grossly agitated and psychotic. Although an EEG is ordered, it is not performed because the technicians are concerned about their safety. With her unclear history of Lyme disease and concern for an infectious encephalopathy, Ms. L’s history and symptoms are discussed with the infectious disease service. Given her abrupt onset of symptoms, including auditory hallucinations, they express concern for herpes simplex encephalitis and recommend emergent treatment with IV acyclovir and ceftriaxone.

This recommendation, however, causes a practical conundrum. Because of state laws and differences in staff training, the treatment team believes that the inpatient psychiatric unit is not the appropriate setting to administer these IV treatments. At the same time, hospital security, nursing staff, and the receiving medical team are concerned about transporting Ms. L to the general medical floor.

In the ICU. After discussion, the teams decide that the safest and least traumatic option is to transport Ms. L to the ICU after she is sedated and intubated. In the ICU, she undergoes empirical treatment for herpes simplex encephalitis and further medical workup.

An EEG reveals findings suggestive of severe encephalopathy. A lumbar puncture shows lymphocytic pleocytosis with an opening pressure of 28 cm H₂O and normal protein and glucose levels. Her serum C-reactive protein is slightly elevated at 1.4 mg/dL. She also is found to have an elevated herpes simplex virus (HSV)-2 IgG antibody.

Subsequent hospital stay. Ms. L has 2 episodes of seizure-like activity, for which she is treated with levetiracetam, 2,000 mg/d, increased to 3,000 mg/d. She is sedated for several days to allow broad treatment with antiviral and antibiotic medications. Although she experiences intermittent fevers and tachycardia, cultures of blood, urine, and cerebrospinal fluid (CSF) show no growth. Similarly, a test of serum HSV IgM antibodies is negative.

CT of the chest, abdomen, and pelvis reveals no findings suggestive of malignancy but does show a solid-appearing 6-mm nodule in her right lung. Magnetic resonance angiography of the head and neck shows no evidence of abnormalities other than atrophy of the superior cerebellar vermis and a subtle focus of T2/FLAIR signal abnormality in the medial portion of the left occipital lobe.

The following weeks. Ms. L’s cognitive status improves markedly. Extensive studies—including serum ammonia, thyroid-stimulating hormone, Lyme disease antibody, vitamin B₁₂, folate, beta-hCG, HIV, hepatitis B and C, Varicella zoster, syphilis, Lyme disease serology, CSF Eastern equine encephalitis, St. Louis encephalitis virus, West Nile virus, Ehrlichia chaffeensis, Babesia microti, Rocky Mountain spotted fever, John Cunningham virus, typhus fever, cryptococcal antigen, rabies, 2 serum tests for anti-N-methyl-D-aspartate (NMDA) receptor antibodies, and serum ceruloplasmin—are normal.

At discharge, Ms. L’s clinical presentation is thought to be most consistent with viral encephalitis, because of her CSF lymphocytic pleocytosis, fever, and improvement with supportive care. Because she improves, the team does not find it necessary to wait for results of pending studies, including a paraneoplastic autoantibody panel and a CSF anti-NMDA receptor antibody, before discharging her.

Readmission. Although the results of the paraneoplastic autoantibody panel are unremarkable, several weeks after discharge Ms. L’s CSF anti-NMDA receptor antibodies return positive, despite 2 earlier negative serum studies. She is readmitted to the neurology service for treatment with immunomodulators.

A positron-emission tomography scan is negative for malignancy. She is treated on an ongoing basis with immunomodulators; cognition improves such that she is able to start working again with good overall functioning. Despite this improvement, she experiences residual sequelae, including noise sensitivity, amnesia of the events surrounding her hospitalization, mild short-term memory deficits, and persistent affective blunting.

The authors’ observations
Psychosis is not exclusive to psychiatric syndromes and frequently is a symptom of an underlying neurologic, immunologic, metabolic, infectious, or oncologic abnormality.¹ Anti-NMDA receptor encephalitis is an autoimmune disease in which antibodies attack NMDA-type glutamate receptors at central neuronal synapses and can produce psychosis, as seen with Ms. L² (Table 1^2,3). The etiology of the disease is not fully understood. Determining the appropriate setting to perform a complete medical workup in a severely agitated patient after an initial negative medical workup can be challenging.

What’s the most appropriate treatment setting?
This case illustrates the importance, with any new-onset psychosis, of weighing heavily a carefully obtained psychiatric history, even in the absence of focal physical examination and initial laboratory abnormalities. It also highlights the challenge of determining the most appropriate initial setting for performing the important task of a complete medical workup for first-episode psychosis.

Ms. L initially was treated in the inpatient psychiatric unit because of safety concerns and practical limitations, but was later found to have a disease that could not be managed in that setting. She proved to be too agitated to obtain a full medical workup on the inpatient psychiatric or general medical floors and required transfer to the ICU. Despite her normal basic laboratory tests, her EEG and CSF studies did demonstrate abnormalities, suggesting these can be useful to the basic workup for psychosis of unknown cause (Table 2^1,2).

This case also demonstrates that negative serum anti-NMDA receptor antibody tests do not rule out the disease; one study found that only 85% of patients with CSF anti-NMDA receptor antibodies also had detectable antibodies in their serum and that detectability changed during the course of the disease.⁴ This supports the utility of a lumbar puncture as part of a basic initial workup for some cases of new-onset psychosis. Because clinical outcomes often correlate with early treatment, as with anti-NMDA receptor encephalitis, a timely diagnostic workup of psychosis often can be important.^3,5 The ICU can be considered an appropriate setting for working up some patients who develop new, rapid-onset psychosis and severe agitation, even in the absence of initial laboratory or physical examination findings.

Ms. L’s case also illustrates the importance of completing a thorough medical workup for patients with new-onset psychosis before transferring them to an independent psychiatric hospital. Initially, the university’s psychiatric unit was at capacity and a bed was sought at outside psychiatric hospitals while Ms. L waited in the ED. Had Ms. L not been admitted to a large academic medical center, she may not have had access to the multidisciplinary collaboration that proved necessary for the appropriate diagnosis and treatment of her anti-NMDA receptor encephalitis (Table 3^5,6).

What prodromal symptoms occur as long as 2 weeks as an initial presentation in many patients with anti-NMDA receptor encephalitis?
   a) Flu-like symptoms of lethargy, headache, gastrointestinal symptoms, myalgias, fevers, and upper respiratory symptoms
   b) Delusions, hallucinations, disorganized behaviors and thoughts, behavioral outbursts, hypersexuality, mood lability, personality change, paranoia, echolalia, mutism, anxiety, agitation, aggression, hyperactivity, sleep dysfunction, and blunted affect
   c) Dyskinesias, autonomic instability, central hypoventilation, and seizures

The authors’ observations
Lab results, vital signs, and physical examination should not supplant a careful history when determining an appropriate clinical course of action. As experts in the cognitive sciences, psychiatrists may be the most qualified in determining whether a patient with new-onset psychosis should undergo further medical testing before a condition is deemed to be solely of a psychiatric cause. As a neurologic disease of immunologic origin with psychiatric manifestations, anti-NMDA receptor encephalitis is a complex condition requiring collaboration among several specialists for appropriate management.

Ms. B, age 31, experienced her first depressive episode at age 24 during her second year of law school. These episodes are characterized by insomnia, sadness, guilt, suicidal ideation, and impaired concentration that affect her ability to function at work and interfere with her ability to maintain relationships. She has no history of mania, hypomania, or psychosis.

Ms. B has approximately 2 severe episodes a year, lasting 8 to 10 weeks. She has failed adequate (≥6 week) trials of sertraline, 200 mg/d; venlafaxine XR, 300 mg/d; bupropion XL, 450 mg/d; and vortioxetine, 20 mg/d. Adjunctive treatments were not well tolerated; lithium caused severe nausea and aripiprazole lead to intolerable akathisia. Psychotherapy was ineffective. A trial of electroconvulsive therapy relieved her depression but resulted in significant memory impairment.

Is ketamine a treatment option for Ms. B?

Ketamine, an N-methyl-D aspartate antagonist, was approved by the FDA in 1970.

as a dissociative anesthetic. It proved useful in military battlefield situations. The drug then became popular as a “club drug” and is used recreationally as a dissociative agent. It recently has been used clinically for treating post-operative pain and treatment-resistant depression (TRD). It has shown efficacy for several specific symptom clusters in depression, including anhedonia and suicidality.

Several small randomized, double-blind, placebo-controlled trials of ketamine—some of which studied TRD—have reported antidepressant effects after a single IV dose of 0.5 mg/kg in depressed patients.^1,2 The response rate, defined as a 50% reduction in symptoms, is reported to be as high as 50% to 71% twenty-four hours after infusion, with significant improvements noted in some patients after just 40 minutes.¹ These effects, peaking at 24 hours, last ≥72 hours in approximately 50% of patients, but gradually return to baseline over 1 to 2 weeks (Figure¹). The most common post-infusion adverse effects include:

• dissociation
• dizziness
• blurred vision
• poor concentration
• nausea.

Transient sedation and psychotomimetic symptoms, such as hallucinations, abnormal sensations, and confusion, also have been noted, as well as a small but significant increase in blood pressure shortly after infusion.¹

Use of repeated doses of ketamine also has been studied, although larger and extended-duration studies are lacking. Two groups^3,4 examined thrice weekly infusions (N = 24) and 1 group⁵ studied twice weekly infusions of 0.5 mg/kg for 2 weeks (6 and 4 doses, respectively) (N = 10). With thrice weekly dosing, 79% to 90% of patients showed symptomatic response overall and 25% to 100% of patients saw improvement after the first dose.^3,4 Of the 20 patients who responded, 65% were still reporting improved symptoms 2 weeks after the last infusion and 40% showed response for >28 days.^3,4 With twice weekly dosing,⁵ the response rate was 80% in 10 patients, while 5 patients (50%) achieved remission, lasting at least 28 days in 2 patients.

The authors of a recent Cochrane review⁶ evaluated ketamine for treating depression and concluded that, although there is evidence for ketamine’s efficacy early in treatment, effects are less certain after 2 weeks post-treatment. The Canadian Agency for Drugs and Technologies in Health also conducted an appraisal⁷ of ketamine for treating a variety of mental illnesses and similarly noted that, despite evidence in acute studies, (1) the role of the drug in clinical practice is unclear and (2) further comparative studies, as well as longer-term studies, are needed.

Last, the American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatments¹ conducted a systematic review and meta-analysis, whose authors concluded that ketamine produces a rapid and robust antidepressant effect that appears to be transient. They warn that, although results are promising, “enthusiasm should be tempered” and suggest that “its use in the clinical setting warrants caution.”

Should you consider treating depression with ketamine?
Although evidence for using ketamine as a rapid treatment of TRD is promising and non-IV forms of ketamine are being researched (eg, intranasal esketamine), there are factors that limit clinical application:

• The short duration of effect noted in studies highlights the need for research on maintenance strategies to assess longer-term efficacy as well as safety. For example, long-term ketamine abuse has been associated with cases of ulcerative or hemorrhagic cystitis causing severe and persistent pain, requiring a partial cystectomy.^8,9 Further, long-term ketamine use for pain has been associated with a transaminitis. Lastly, ketamine self-treatment for depression with escalating doses has also been associated with severe ketamine addiction and sequelae.¹⁰ The incidence and severity of these adverse effects at dosages and administration frequencies that might be required for maintenance treatment of depression is unclear and requires further investigation.
• Psychotomimetic and cardiovascular adverse effects of ketamine warrant monitoring in an acute clinical setting, until longer term safety and monitoring protocols are developed. Of note, the dosing regimen used in most studies requires anesthesia monitoring in many health care systems. Although acute adverse effects in studies to date are infrequent, both cardiovascular and gastrointestinal (vomiting) events requiring IV intervention have been reported,⁴ underscoring the importance of anesthesiologist involvement.
• Tolerance. It is unknown if patients develop tolerance to ketamine with recurring dosages and may present additional safety concerns with repeated, higher dosages. Lastly, patients on extended ketamine therapy could encounter drug interactions with agents commonly used to treat depression.

Although some authors^1,6 advise caution with widespread ketamine use, patients with TRD want effective treatments and may discount these warnings. Even though longer-term studies are needed, ketamine “infusion clinics” are already being established. Before referring patients to such clinics, it is important to understand the current clinical and safety limitations and requirements for ketamine in TRD and to consider and discuss the risks and benefits carefully.

CASE CONTINUED
Because Ms. B has tried several antidepressants and adjunctive therapies without success, and her depression is severe enough to affect her functioning in several domains, it might be reasonable to discuss a trial of ketamine. However, Ms. B also should be presented non-ketamine alternatives, such as other adjunctive strategies (liothyronine, buspirone, cognitive-behavioral therapy) or a trial of nortriptyline or a monoamine oxidase inhibitor.

If ketamine is thought to be the best option for Ms. B, her provider needs to establish a clear expectation that the effects likely will be temporary. Monitoring should include applying a rating scale to assess depressive symptoms, suicidality, and psychotomimetic symptoms. During and shortly after infusion, anesthesia support should be provided and blood pressure and other vital signs should be monitored. Additional monitoring, such as telemetry, might be indicated.

Ms. B, age 31, experienced her first depressive episode at age 24 during her second year of law school. These episodes are characterized by insomnia, sadness, guilt, suicidal ideation, and impaired concentration that affect her ability to function at work and interfere with her ability to maintain relationships. She has no history of mania, hypomania, or psychosis.

Ms. B has approximately 2 severe episodes a year, lasting 8 to 10 weeks. She has failed adequate (≥6 week) trials of sertraline, 200 mg/d; venlafaxine XR, 300 mg/d; bupropion XL, 450 mg/d; and vortioxetine, 20 mg/d. Adjunctive treatments were not well tolerated; lithium caused severe nausea and aripiprazole lead to intolerable akathisia. Psychotherapy was ineffective. A trial of electroconvulsive therapy relieved her depression but resulted in significant memory impairment.

Is ketamine a treatment option for Ms. B?

Ketamine, an N-methyl-D aspartate antagonist, was approved by the FDA in 1970.

as a dissociative anesthetic. It proved useful in military battlefield situations. The drug then became popular as a “club drug” and is used recreationally as a dissociative agent. It recently has been used clinically for treating post-operative pain and treatment-resistant depression (TRD). It has shown efficacy for several specific symptom clusters in depression, including anhedonia and suicidality.

Several small randomized, double-blind, placebo-controlled trials of ketamine—some of which studied TRD—have reported antidepressant effects after a single IV dose of 0.5 mg/kg in depressed patients.^1,2 The response rate, defined as a 50% reduction in symptoms, is reported to be as high as 50% to 71% twenty-four hours after infusion, with significant improvements noted in some patients after just 40 minutes.¹ These effects, peaking at 24 hours, last ≥72 hours in approximately 50% of patients, but gradually return to baseline over 1 to 2 weeks (Figure¹). The most common post-infusion adverse effects include:

• dissociation
• dizziness
• blurred vision
• poor concentration
• nausea.

Transient sedation and psychotomimetic symptoms, such as hallucinations, abnormal sensations, and confusion, also have been noted, as well as a small but significant increase in blood pressure shortly after infusion.¹

Use of repeated doses of ketamine also has been studied, although larger and extended-duration studies are lacking. Two groups^3,4 examined thrice weekly infusions (N = 24) and 1 group⁵ studied twice weekly infusions of 0.5 mg/kg for 2 weeks (6 and 4 doses, respectively) (N = 10). With thrice weekly dosing, 79% to 90% of patients showed symptomatic response overall and 25% to 100% of patients saw improvement after the first dose.^3,4 Of the 20 patients who responded, 65% were still reporting improved symptoms 2 weeks after the last infusion and 40% showed response for >28 days.^3,4 With twice weekly dosing,⁵ the response rate was 80% in 10 patients, while 5 patients (50%) achieved remission, lasting at least 28 days in 2 patients.

The authors of a recent Cochrane review⁶ evaluated ketamine for treating depression and concluded that, although there is evidence for ketamine’s efficacy early in treatment, effects are less certain after 2 weeks post-treatment. The Canadian Agency for Drugs and Technologies in Health also conducted an appraisal⁷ of ketamine for treating a variety of mental illnesses and similarly noted that, despite evidence in acute studies, (1) the role of the drug in clinical practice is unclear and (2) further comparative studies, as well as longer-term studies, are needed.

Last, the American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatments¹ conducted a systematic review and meta-analysis, whose authors concluded that ketamine produces a rapid and robust antidepressant effect that appears to be transient. They warn that, although results are promising, “enthusiasm should be tempered” and suggest that “its use in the clinical setting warrants caution.”

Should you consider treating depression with ketamine?
Although evidence for using ketamine as a rapid treatment of TRD is promising and non-IV forms of ketamine are being researched (eg, intranasal esketamine), there are factors that limit clinical application:

• The short duration of effect noted in studies highlights the need for research on maintenance strategies to assess longer-term efficacy as well as safety. For example, long-term ketamine abuse has been associated with cases of ulcerative or hemorrhagic cystitis causing severe and persistent pain, requiring a partial cystectomy.^8,9 Further, long-term ketamine use for pain has been associated with a transaminitis. Lastly, ketamine self-treatment for depression with escalating doses has also been associated with severe ketamine addiction and sequelae.¹⁰ The incidence and severity of these adverse effects at dosages and administration frequencies that might be required for maintenance treatment of depression is unclear and requires further investigation.
• Psychotomimetic and cardiovascular adverse effects of ketamine warrant monitoring in an acute clinical setting, until longer term safety and monitoring protocols are developed. Of note, the dosing regimen used in most studies requires anesthesia monitoring in many health care systems. Although acute adverse effects in studies to date are infrequent, both cardiovascular and gastrointestinal (vomiting) events requiring IV intervention have been reported,⁴ underscoring the importance of anesthesiologist involvement.
• Tolerance. It is unknown if patients develop tolerance to ketamine with recurring dosages and may present additional safety concerns with repeated, higher dosages. Lastly, patients on extended ketamine therapy could encounter drug interactions with agents commonly used to treat depression.

Although some authors^1,6 advise caution with widespread ketamine use, patients with TRD want effective treatments and may discount these warnings. Even though longer-term studies are needed, ketamine “infusion clinics” are already being established. Before referring patients to such clinics, it is important to understand the current clinical and safety limitations and requirements for ketamine in TRD and to consider and discuss the risks and benefits carefully.

CASE CONTINUED
Because Ms. B has tried several antidepressants and adjunctive therapies without success, and her depression is severe enough to affect her functioning in several domains, it might be reasonable to discuss a trial of ketamine. However, Ms. B also should be presented non-ketamine alternatives, such as other adjunctive strategies (liothyronine, buspirone, cognitive-behavioral therapy) or a trial of nortriptyline or a monoamine oxidase inhibitor.

If ketamine is thought to be the best option for Ms. B, her provider needs to establish a clear expectation that the effects likely will be temporary. Monitoring should include applying a rating scale to assess depressive symptoms, suicidality, and psychotomimetic symptoms. During and shortly after infusion, anesthesia support should be provided and blood pressure and other vital signs should be monitored. Additional monitoring, such as telemetry, might be indicated.

Ms. B, age 31, experienced her first depressive episode at age 24 during her second year of law school. These episodes are characterized by insomnia, sadness, guilt, suicidal ideation, and impaired concentration that affect her ability to function at work and interfere with her ability to maintain relationships. She has no history of mania, hypomania, or psychosis.

Ms. B has approximately 2 severe episodes a year, lasting 8 to 10 weeks. She has failed adequate (≥6 week) trials of sertraline, 200 mg/d; venlafaxine XR, 300 mg/d; bupropion XL, 450 mg/d; and vortioxetine, 20 mg/d. Adjunctive treatments were not well tolerated; lithium caused severe nausea and aripiprazole lead to intolerable akathisia. Psychotherapy was ineffective. A trial of electroconvulsive therapy relieved her depression but resulted in significant memory impairment.

Is ketamine a treatment option for Ms. B?

Ketamine, an N-methyl-D aspartate antagonist, was approved by the FDA in 1970.

as a dissociative anesthetic. It proved useful in military battlefield situations. The drug then became popular as a “club drug” and is used recreationally as a dissociative agent. It recently has been used clinically for treating post-operative pain and treatment-resistant depression (TRD). It has shown efficacy for several specific symptom clusters in depression, including anhedonia and suicidality.

Several small randomized, double-blind, placebo-controlled trials of ketamine—some of which studied TRD—have reported antidepressant effects after a single IV dose of 0.5 mg/kg in depressed patients.^1,2 The response rate, defined as a 50% reduction in symptoms, is reported to be as high as 50% to 71% twenty-four hours after infusion, with significant improvements noted in some patients after just 40 minutes.¹ These effects, peaking at 24 hours, last ≥72 hours in approximately 50% of patients, but gradually return to baseline over 1 to 2 weeks (Figure¹). The most common post-infusion adverse effects include:

• dissociation
• dizziness
• blurred vision
• poor concentration
• nausea.

Transient sedation and psychotomimetic symptoms, such as hallucinations, abnormal sensations, and confusion, also have been noted, as well as a small but significant increase in blood pressure shortly after infusion.¹

Use of repeated doses of ketamine also has been studied, although larger and extended-duration studies are lacking. Two groups^3,4 examined thrice weekly infusions (N = 24) and 1 group⁵ studied twice weekly infusions of 0.5 mg/kg for 2 weeks (6 and 4 doses, respectively) (N = 10). With thrice weekly dosing, 79% to 90% of patients showed symptomatic response overall and 25% to 100% of patients saw improvement after the first dose.^3,4 Of the 20 patients who responded, 65% were still reporting improved symptoms 2 weeks after the last infusion and 40% showed response for >28 days.^3,4 With twice weekly dosing,⁵ the response rate was 80% in 10 patients, while 5 patients (50%) achieved remission, lasting at least 28 days in 2 patients.

The authors of a recent Cochrane review⁶ evaluated ketamine for treating depression and concluded that, although there is evidence for ketamine’s efficacy early in treatment, effects are less certain after 2 weeks post-treatment. The Canadian Agency for Drugs and Technologies in Health also conducted an appraisal⁷ of ketamine for treating a variety of mental illnesses and similarly noted that, despite evidence in acute studies, (1) the role of the drug in clinical practice is unclear and (2) further comparative studies, as well as longer-term studies, are needed.

Last, the American Psychiatric Association Council of Research Task Force on Novel Biomarkers and Treatments¹ conducted a systematic review and meta-analysis, whose authors concluded that ketamine produces a rapid and robust antidepressant effect that appears to be transient. They warn that, although results are promising, “enthusiasm should be tempered” and suggest that “its use in the clinical setting warrants caution.”

Should you consider treating depression with ketamine?
Although evidence for using ketamine as a rapid treatment of TRD is promising and non-IV forms of ketamine are being researched (eg, intranasal esketamine), there are factors that limit clinical application:

• The short duration of effect noted in studies highlights the need for research on maintenance strategies to assess longer-term efficacy as well as safety. For example, long-term ketamine abuse has been associated with cases of ulcerative or hemorrhagic cystitis causing severe and persistent pain, requiring a partial cystectomy.^8,9 Further, long-term ketamine use for pain has been associated with a transaminitis. Lastly, ketamine self-treatment for depression with escalating doses has also been associated with severe ketamine addiction and sequelae.¹⁰ The incidence and severity of these adverse effects at dosages and administration frequencies that might be required for maintenance treatment of depression is unclear and requires further investigation.
• Psychotomimetic and cardiovascular adverse effects of ketamine warrant monitoring in an acute clinical setting, until longer term safety and monitoring protocols are developed. Of note, the dosing regimen used in most studies requires anesthesia monitoring in many health care systems. Although acute adverse effects in studies to date are infrequent, both cardiovascular and gastrointestinal (vomiting) events requiring IV intervention have been reported,⁴ underscoring the importance of anesthesiologist involvement.
• Tolerance. It is unknown if patients develop tolerance to ketamine with recurring dosages and may present additional safety concerns with repeated, higher dosages. Lastly, patients on extended ketamine therapy could encounter drug interactions with agents commonly used to treat depression.

Although some authors^1,6 advise caution with widespread ketamine use, patients with TRD want effective treatments and may discount these warnings. Even though longer-term studies are needed, ketamine “infusion clinics” are already being established. Before referring patients to such clinics, it is important to understand the current clinical and safety limitations and requirements for ketamine in TRD and to consider and discuss the risks and benefits carefully.

CASE CONTINUED
Because Ms. B has tried several antidepressants and adjunctive therapies without success, and her depression is severe enough to affect her functioning in several domains, it might be reasonable to discuss a trial of ketamine. However, Ms. B also should be presented non-ketamine alternatives, such as other adjunctive strategies (liothyronine, buspirone, cognitive-behavioral therapy) or a trial of nortriptyline or a monoamine oxidase inhibitor.

If ketamine is thought to be the best option for Ms. B, her provider needs to establish a clear expectation that the effects likely will be temporary. Monitoring should include applying a rating scale to assess depressive symptoms, suicidality, and psychotomimetic symptoms. During and shortly after infusion, anesthesia support should be provided and blood pressure and other vital signs should be monitored. Additional monitoring, such as telemetry, might be indicated.

The doctor is sick.

Her feet are swollen, as if her heart is failing. But it is strong and beating faster than usual, as she runs her fingers through her hair. Her vision gets blurry sometimes, and she has to hold onto something when she stands up or she will fall down. The doctor is sick because she is taking medicine to make her well. Lithium, Seroquel, Depakote. Mood stabilizer, antipsychotic, mood stabilizer. Two pills, 4 pills, 3 pills. Plus a multivitamin because Depakote can cause her hair to fall out. Skinny and fat bottles, next to her bed so she won’t forget. As if she would forget.

The doctor is sick because 3 weeks ago tomorrow she made a concrete plan to take her life. She wrote 5 letters, the longest to her sweet and supportive husband. She put some pills and some alcohol and the letters in her backpack and made it to the front stoop before she sat down, her heart breaking, and called her best friend.

The doctor is sick. Sicker now that she is home. As a patient in the psychiatric hospital, she was the doctor, and she held “office hours” (24 hours a day) to answer questions about GERD, schizophrenia, and stomachaches. This made her feel a lot less sick. Everyone said she was clever. She is only a medical student and offers a disclaimer with her advice (along with the suggestion to see a “real doctor”). But to most of the patients she is a doctor. And she feels the calling to be a doctor. Deep down inside herself she feels she was born to be a doctor.

In the psychiatric hospital, she felt alive when she gave advice. It made her feel she was helping people. She lives for people. And it distinguished her from the rest of them. They were her friends and she shared illness with them, but somehow she was different. Sometimes, this gave her comfort. Other times she held onto them as anchors in the madness they were swimming through together. Those times she found comfort in being the same as them. Exactly the same.

The doctor is sick. On the discharge sheet, 18 days after admission, her acceptance of this fact (“judgment and insight”) was judged “fair.” This is because the doctor does not believe in her diagnosis. She does not want to be sick. She wants to be the person she was before—minus those highs and lows. She would trade in the agitated anxious state that caused her to drop out of her pediatric rotation. She would trade in the days spent in bed in college, while everyone seemed to be having fun. She would trade in the Google searches of “suicide methods.” She would trade in the panic that caused her to stop her rotation, and therefore caused her to stop playing with the pediatric patients in the playroom at night, after her clinical duties were finished. In the playroom she was not a doctor or a medical student. She was just someone’s playmate. She held the little hand of her little patient and she felt like she was exactly where she was supposed to be. She knew she belonged when she helped her patients forget they were sick.

The doctor is sick. She is drinking hard lemonade, even though it makes the dizziness worse. The doctor has a swollen face and swollen fingers and her wedding ring does not fit anymore. She has gained 10, no, 15 lb because of the medicine, and she knows her husband has noticed. The doctor knows that she has enough pills beside her bed to end her life, but she also knows she is calm now. She is calm in a way she has not felt for as long as she can remember. She thinks back on college, on that 2-month period when she slept until 2 PM, and got out of bed only to smoke marijuana and change the CD on her stereo. She thinks back on the way she pulled the blanket over her head and she remembers that she wanted to be dead.

The doctor remembers writing her treatises later that year on the meaning of life, of the world, of peace and joy and love, on her desktop computer. She wrote and wrote and wrote, as she often did, and sleep did not seem very necessary or desired. She felt she was more connected to the world than anyone else on the planet. She felt more intensely than anyone else on the planet. She ran 5 miles a day, 15 miles on Saturdays. Tears streamed down her face as she bicycled back from her volunteer work with the elderly. She felt so much love and she felt so different from everyone else. Tears came again when she read literature; she felt alive with politics and meaning and urgency. Her heart pounded and she felt words run through her mind that told her to keep working, harder, and that she was capable of more efficient, more emotive, more effective, more productive work than anyone else on the planet. She had more insight than anyone else on the planet. But all of this was directed to help other people, and so she was connected to the whole world.

The doctor feels sick now as she recalls those events. Now she fears her past is part of this illness. Those thoughts and actions that were her proudest moments, the organizations that offered her awards and accolades, the papers that got high marks—those were just the consequence of neurotransmitters being sucked in and spat out in the wrong ratios. It is that simple. Something we can fix with around 10 pills a day, pills that will make the doctor better but will make the doctor sick. What about the doctor’s sense of humor? What about her energy? What about her wild dancing and her disinhibition? What about her ability to be the life of a party even when she is stone cold sober and everyone else has had 4 or 5 drinks? What about her accomplishments and her intensity? What about her ever-present belief that the world’s people are all connected, and she is to play a small but important, even vital, role in bringing them together? Sick, sick, all sick.

As a patient in the psychiatric hospital, the doctor would dance sometimes. She would be dancing, twirling, laughing, making others laugh. Then, on the same day, she would burst into tears and sit in her room, blanket over head, turning over the possibilities for a painless but sure death. She didn’t have much time to think on it because soon it would be time to line up for medicine.

Next … it’s time for her office hours, to reassure other patients, to pretend she is a doctor. But soon enough … the shrink beckons her for the daily session, and she is reminded of his infinite wisdom and her relative ignorance. She nods and agrees with some of what he says, believes it even when she is talking to him in his little room, but not later, when she is back in bed, nighttime, waiting for nightmares. The psychiatrist says that her frantic sleepless days before Christmas, the ones where her friends couldn’t understand why she couldn’t even sit down for lunch (“You’re going to have a stroke!” a less tactful one declared), the ones where she feigned listening to someone talking while in her head she entertained a disorganized, discordant symphony of thoughts trying to hammer out a requiem, a death march … those days were a “mixed state.” Mumbo jumbo. Nonsense. She tells herself she is just moody. At least now there are moments of heady delicious delight, no matter if they are brief.

So the doctor is improving! And she has reason to doubt their boxes and their labels, as she reads on this illness in rare moments when her mind is still, and she finds there is controversy surrounding every diagnosis and delineation. And so that is fuel for her disapproving, disbelieving fire. All of this is just an expression of eccentricity, she tells herself, and these lousy doctors don’t appreciate someone “as brilliant and beautiful as me.” But later, watching the nurses as they fill out their assessments of the day, she wonders how sick they think she really is, and she hates herself and this lunatic frenzy and she is embarrassed and ashamed.

If she does not believe she is sick, then she has to blame herself, and that hurts. But she can handle that pain and that bleeding, for she alone can suffer pain and bleeding like no others, and that is part of what makes her beautiful. But she is not sick …. According to them, the doctor is sick every day and so she stays in the hospital. She retorts, “Of course that is what they say. Isn’t that their job, to call me crazy?” And then, “If I was not crazy, wouldn’t that put them out of business?”

Nightmares have tormented the doctor since she was a child. But lately they are more twisted. They pull her out of the safety of the day such that she plunges, screaming, down, head-first, into black night, afraid. Some of her medicines exacerbate nightmares. In one awful dream, she is a patient, then a doctor, then a patient again, and she keeps waking up inside the dream to be transformed into doctor or patient, one then the other; it never stops. So first she is giving medicines, then she is being intubated, then she is finishing rounds, then she is enduring electroconvulsive therapy. Finally she drops out of the dream as if from the sky, and she is shivering and afraid.

Now, as she dozes, she awakens to every noise, and the shadows look like people, and she knows the nightmares wait for her again, so she fights sleep. Paxil made her hear voices (the psychiatrists proclaimed this “classic” for her illness; she shrugged her shoulders in response) and so now she listens carefully, holding her breath, in bed, trying to hear voices. She thought she heard something. Of course, now she is hypersensitive. Now it is hard not to describe everything as “classic” for the illness. If she thinks about it, from junior high school onwards she was “classic.” What nonsense! Her vision is 20/20 in hindsight. Who wouldn’t find madness in their past if they looked hard enough?

The doctor is sick. The night lasts forever. Somebody opens the door because, at this hospital, they check every 15 minutes, 24 hours per day, to make sure the doctor has not slit her wrists or hanged herself or found another way to end her sick life. For this reason, they have confiscated her shoelaces, and she has to floss at the nurses’ station. She startles as they open the door, and screams out loud. They reassure her they are just checking on her, and now they are gone, and the doctor is left to imagine them walking down the corridor to the nurses’ station, shaking their heads, saying, “That doctor sure is sick!”.

Yes, the doctor is sick. Who is she anyway? She is not even a doctor! She is just a third-year medical student who is fighting, fists up, her descent into madness. Has she won? She is trying to find a way to accept what she is. Does that mean she is a winner or a loser? It is chronic, but manageable, bipolar madness. There are lots of other people like her. But it is still overwhelming, and she is not even sure she wants to join anybody else. She never defined herself as part of any group before. Now she tries to get back to normal—but what can that mean now, after all this time, after release from a mental hospital, after taking a leave from school, after swallowing 10 pills a day (every day, for the rest of her life?), after finding out she is so sick? It is time for her meds. She hasn’t told most of her classmates or her parents because she doesn’t want them to find out that the doctor is sick. She doesn’t want to know if the doctor is sick. She doesn’t want to ponder if the doctor can ever get well.

The doctor misses seeing her patients. Tears are in her eyes and she swallows her sadness as best as she can. She aims to keep a brave face, but she is sad for what she has lost. She tries to shake that off, but it keeps returning. Like a virus, it sneaks up on her and she is shivering, feverish with grief. She hears stories from her friends as they continue to round, heal, cut and sew, take histories, stay up all night, get yelled at by senior physicians, and she wants so much to be there. She is in nowhere land. To some, a few, those who know the twisted tale of the last few months, she is sick. To those who know nothing of it, she is her usual slightly eccentric self, but well. But really she knows she is a liar and a fraud. Because somewhere in the middle she exists alone.

Well, no, she is not alone. Her husband stands by her and he is wonderful. He holds her and laughs with her and tells her she is beautiful and amazing. But she misses seeing lots of people; she thrives on people. Doesn’t anyone understand that she needs people to be alive? Is that so wrong? Is that so sick? She feels sorry for herself, sorry for what she must give up, sorry that she must graduate a year later, sorry that she cannot be with people, sorry that she feels so sorry so much of the time. And then she gets angry with herself for feeling so sorry and being so sick.

Every now and then, the doctor sees another side of things. She surfs the Internet and reads books and she finds out about lots of smart and creative and beautiful people who were sick like she is. These people have twisted, wonderful abilities but so many of them plunged to their death or swallowed pills or died so young. They wrote books or composed symphonies or made people laugh or created works of art but then they died. And so she is left feeling strong and beautiful sometimes, but also lonely and sad that all those souls have deserted her. She is sad that they have left her in this madness, and she must fight to stay alive all by herself. Then, every now and then, there are flickers of wisdom and insight and she knows she will stay alive and she will create beautiful things too, one day.

The doctor is sick. Getting sick stinks. She admits, “Nobody, especially not me, counted on the doctor getting sick. Please! Enough!”

She concedes: “I won’t forget this. I promise. OK, I have learned my lesson now. Please, enough of this!”

She pleads: “I need the doctor to get well. I am afraid of being the doctor that is sick, so afraid.”

She ponders: “Does this mean I will never be free? Does this mean I will never be well? Does this mean I will never be a mother? Oh, God, does this mean I will never be a doctor?”

Then there is silence because she asks these questions of herself, and she has no answers, and no office hours today.

Somebody better call a doctor.

Acknowledgment
The author is grateful for the support of her medical school and residency program during training.

The doctor is sick.

Her feet are swollen, as if her heart is failing. But it is strong and beating faster than usual, as she runs her fingers through her hair. Her vision gets blurry sometimes, and she has to hold onto something when she stands up or she will fall down. The doctor is sick because she is taking medicine to make her well. Lithium, Seroquel, Depakote. Mood stabilizer, antipsychotic, mood stabilizer. Two pills, 4 pills, 3 pills. Plus a multivitamin because Depakote can cause her hair to fall out. Skinny and fat bottles, next to her bed so she won’t forget. As if she would forget.

The doctor is sick because 3 weeks ago tomorrow she made a concrete plan to take her life. She wrote 5 letters, the longest to her sweet and supportive husband. She put some pills and some alcohol and the letters in her backpack and made it to the front stoop before she sat down, her heart breaking, and called her best friend.

The doctor is sick. Sicker now that she is home. As a patient in the psychiatric hospital, she was the doctor, and she held “office hours” (24 hours a day) to answer questions about GERD, schizophrenia, and stomachaches. This made her feel a lot less sick. Everyone said she was clever. She is only a medical student and offers a disclaimer with her advice (along with the suggestion to see a “real doctor”). But to most of the patients she is a doctor. And she feels the calling to be a doctor. Deep down inside herself she feels she was born to be a doctor.

In the psychiatric hospital, she felt alive when she gave advice. It made her feel she was helping people. She lives for people. And it distinguished her from the rest of them. They were her friends and she shared illness with them, but somehow she was different. Sometimes, this gave her comfort. Other times she held onto them as anchors in the madness they were swimming through together. Those times she found comfort in being the same as them. Exactly the same.

The doctor is sick. On the discharge sheet, 18 days after admission, her acceptance of this fact (“judgment and insight”) was judged “fair.” This is because the doctor does not believe in her diagnosis. She does not want to be sick. She wants to be the person she was before—minus those highs and lows. She would trade in the agitated anxious state that caused her to drop out of her pediatric rotation. She would trade in the days spent in bed in college, while everyone seemed to be having fun. She would trade in the Google searches of “suicide methods.” She would trade in the panic that caused her to stop her rotation, and therefore caused her to stop playing with the pediatric patients in the playroom at night, after her clinical duties were finished. In the playroom she was not a doctor or a medical student. She was just someone’s playmate. She held the little hand of her little patient and she felt like she was exactly where she was supposed to be. She knew she belonged when she helped her patients forget they were sick.

The doctor is sick. She is drinking hard lemonade, even though it makes the dizziness worse. The doctor has a swollen face and swollen fingers and her wedding ring does not fit anymore. She has gained 10, no, 15 lb because of the medicine, and she knows her husband has noticed. The doctor knows that she has enough pills beside her bed to end her life, but she also knows she is calm now. She is calm in a way she has not felt for as long as she can remember. She thinks back on college, on that 2-month period when she slept until 2 PM, and got out of bed only to smoke marijuana and change the CD on her stereo. She thinks back on the way she pulled the blanket over her head and she remembers that she wanted to be dead.

The doctor remembers writing her treatises later that year on the meaning of life, of the world, of peace and joy and love, on her desktop computer. She wrote and wrote and wrote, as she often did, and sleep did not seem very necessary or desired. She felt she was more connected to the world than anyone else on the planet. She felt more intensely than anyone else on the planet. She ran 5 miles a day, 15 miles on Saturdays. Tears streamed down her face as she bicycled back from her volunteer work with the elderly. She felt so much love and she felt so different from everyone else. Tears came again when she read literature; she felt alive with politics and meaning and urgency. Her heart pounded and she felt words run through her mind that told her to keep working, harder, and that she was capable of more efficient, more emotive, more effective, more productive work than anyone else on the planet. She had more insight than anyone else on the planet. But all of this was directed to help other people, and so she was connected to the whole world.

The doctor feels sick now as she recalls those events. Now she fears her past is part of this illness. Those thoughts and actions that were her proudest moments, the organizations that offered her awards and accolades, the papers that got high marks—those were just the consequence of neurotransmitters being sucked in and spat out in the wrong ratios. It is that simple. Something we can fix with around 10 pills a day, pills that will make the doctor better but will make the doctor sick. What about the doctor’s sense of humor? What about her energy? What about her wild dancing and her disinhibition? What about her ability to be the life of a party even when she is stone cold sober and everyone else has had 4 or 5 drinks? What about her accomplishments and her intensity? What about her ever-present belief that the world’s people are all connected, and she is to play a small but important, even vital, role in bringing them together? Sick, sick, all sick.

As a patient in the psychiatric hospital, the doctor would dance sometimes. She would be dancing, twirling, laughing, making others laugh. Then, on the same day, she would burst into tears and sit in her room, blanket over head, turning over the possibilities for a painless but sure death. She didn’t have much time to think on it because soon it would be time to line up for medicine.

Next … it’s time for her office hours, to reassure other patients, to pretend she is a doctor. But soon enough … the shrink beckons her for the daily session, and she is reminded of his infinite wisdom and her relative ignorance. She nods and agrees with some of what he says, believes it even when she is talking to him in his little room, but not later, when she is back in bed, nighttime, waiting for nightmares. The psychiatrist says that her frantic sleepless days before Christmas, the ones where her friends couldn’t understand why she couldn’t even sit down for lunch (“You’re going to have a stroke!” a less tactful one declared), the ones where she feigned listening to someone talking while in her head she entertained a disorganized, discordant symphony of thoughts trying to hammer out a requiem, a death march … those days were a “mixed state.” Mumbo jumbo. Nonsense. She tells herself she is just moody. At least now there are moments of heady delicious delight, no matter if they are brief.

So the doctor is improving! And she has reason to doubt their boxes and their labels, as she reads on this illness in rare moments when her mind is still, and she finds there is controversy surrounding every diagnosis and delineation. And so that is fuel for her disapproving, disbelieving fire. All of this is just an expression of eccentricity, she tells herself, and these lousy doctors don’t appreciate someone “as brilliant and beautiful as me.” But later, watching the nurses as they fill out their assessments of the day, she wonders how sick they think she really is, and she hates herself and this lunatic frenzy and she is embarrassed and ashamed.

If she does not believe she is sick, then she has to blame herself, and that hurts. But she can handle that pain and that bleeding, for she alone can suffer pain and bleeding like no others, and that is part of what makes her beautiful. But she is not sick …. According to them, the doctor is sick every day and so she stays in the hospital. She retorts, “Of course that is what they say. Isn’t that their job, to call me crazy?” And then, “If I was not crazy, wouldn’t that put them out of business?”

Nightmares have tormented the doctor since she was a child. But lately they are more twisted. They pull her out of the safety of the day such that she plunges, screaming, down, head-first, into black night, afraid. Some of her medicines exacerbate nightmares. In one awful dream, she is a patient, then a doctor, then a patient again, and she keeps waking up inside the dream to be transformed into doctor or patient, one then the other; it never stops. So first she is giving medicines, then she is being intubated, then she is finishing rounds, then she is enduring electroconvulsive therapy. Finally she drops out of the dream as if from the sky, and she is shivering and afraid.

Now, as she dozes, she awakens to every noise, and the shadows look like people, and she knows the nightmares wait for her again, so she fights sleep. Paxil made her hear voices (the psychiatrists proclaimed this “classic” for her illness; she shrugged her shoulders in response) and so now she listens carefully, holding her breath, in bed, trying to hear voices. She thought she heard something. Of course, now she is hypersensitive. Now it is hard not to describe everything as “classic” for the illness. If she thinks about it, from junior high school onwards she was “classic.” What nonsense! Her vision is 20/20 in hindsight. Who wouldn’t find madness in their past if they looked hard enough?

The doctor is sick. The night lasts forever. Somebody opens the door because, at this hospital, they check every 15 minutes, 24 hours per day, to make sure the doctor has not slit her wrists or hanged herself or found another way to end her sick life. For this reason, they have confiscated her shoelaces, and she has to floss at the nurses’ station. She startles as they open the door, and screams out loud. They reassure her they are just checking on her, and now they are gone, and the doctor is left to imagine them walking down the corridor to the nurses’ station, shaking their heads, saying, “That doctor sure is sick!”.

Yes, the doctor is sick. Who is she anyway? She is not even a doctor! She is just a third-year medical student who is fighting, fists up, her descent into madness. Has she won? She is trying to find a way to accept what she is. Does that mean she is a winner or a loser? It is chronic, but manageable, bipolar madness. There are lots of other people like her. But it is still overwhelming, and she is not even sure she wants to join anybody else. She never defined herself as part of any group before. Now she tries to get back to normal—but what can that mean now, after all this time, after release from a mental hospital, after taking a leave from school, after swallowing 10 pills a day (every day, for the rest of her life?), after finding out she is so sick? It is time for her meds. She hasn’t told most of her classmates or her parents because she doesn’t want them to find out that the doctor is sick. She doesn’t want to know if the doctor is sick. She doesn’t want to ponder if the doctor can ever get well.

The doctor misses seeing her patients. Tears are in her eyes and she swallows her sadness as best as she can. She aims to keep a brave face, but she is sad for what she has lost. She tries to shake that off, but it keeps returning. Like a virus, it sneaks up on her and she is shivering, feverish with grief. She hears stories from her friends as they continue to round, heal, cut and sew, take histories, stay up all night, get yelled at by senior physicians, and she wants so much to be there. She is in nowhere land. To some, a few, those who know the twisted tale of the last few months, she is sick. To those who know nothing of it, she is her usual slightly eccentric self, but well. But really she knows she is a liar and a fraud. Because somewhere in the middle she exists alone.

Well, no, she is not alone. Her husband stands by her and he is wonderful. He holds her and laughs with her and tells her she is beautiful and amazing. But she misses seeing lots of people; she thrives on people. Doesn’t anyone understand that she needs people to be alive? Is that so wrong? Is that so sick? She feels sorry for herself, sorry for what she must give up, sorry that she must graduate a year later, sorry that she cannot be with people, sorry that she feels so sorry so much of the time. And then she gets angry with herself for feeling so sorry and being so sick.

Every now and then, the doctor sees another side of things. She surfs the Internet and reads books and she finds out about lots of smart and creative and beautiful people who were sick like she is. These people have twisted, wonderful abilities but so many of them plunged to their death or swallowed pills or died so young. They wrote books or composed symphonies or made people laugh or created works of art but then they died. And so she is left feeling strong and beautiful sometimes, but also lonely and sad that all those souls have deserted her. She is sad that they have left her in this madness, and she must fight to stay alive all by herself. Then, every now and then, there are flickers of wisdom and insight and she knows she will stay alive and she will create beautiful things too, one day.

The doctor is sick. Getting sick stinks. She admits, “Nobody, especially not me, counted on the doctor getting sick. Please! Enough!”

She concedes: “I won’t forget this. I promise. OK, I have learned my lesson now. Please, enough of this!”

She pleads: “I need the doctor to get well. I am afraid of being the doctor that is sick, so afraid.”

She ponders: “Does this mean I will never be free? Does this mean I will never be well? Does this mean I will never be a mother? Oh, God, does this mean I will never be a doctor?”

Then there is silence because she asks these questions of herself, and she has no answers, and no office hours today.

Somebody better call a doctor.

Acknowledgment
The author is grateful for the support of her medical school and residency program during training.

The doctor is sick.

Her feet are swollen, as if her heart is failing. But it is strong and beating faster than usual, as she runs her fingers through her hair. Her vision gets blurry sometimes, and she has to hold onto something when she stands up or she will fall down. The doctor is sick because she is taking medicine to make her well. Lithium, Seroquel, Depakote. Mood stabilizer, antipsychotic, mood stabilizer. Two pills, 4 pills, 3 pills. Plus a multivitamin because Depakote can cause her hair to fall out. Skinny and fat bottles, next to her bed so she won’t forget. As if she would forget.

The doctor is sick because 3 weeks ago tomorrow she made a concrete plan to take her life. She wrote 5 letters, the longest to her sweet and supportive husband. She put some pills and some alcohol and the letters in her backpack and made it to the front stoop before she sat down, her heart breaking, and called her best friend.

The doctor is sick. Sicker now that she is home. As a patient in the psychiatric hospital, she was the doctor, and she held “office hours” (24 hours a day) to answer questions about GERD, schizophrenia, and stomachaches. This made her feel a lot less sick. Everyone said she was clever. She is only a medical student and offers a disclaimer with her advice (along with the suggestion to see a “real doctor”). But to most of the patients she is a doctor. And she feels the calling to be a doctor. Deep down inside herself she feels she was born to be a doctor.

In the psychiatric hospital, she felt alive when she gave advice. It made her feel she was helping people. She lives for people. And it distinguished her from the rest of them. They were her friends and she shared illness with them, but somehow she was different. Sometimes, this gave her comfort. Other times she held onto them as anchors in the madness they were swimming through together. Those times she found comfort in being the same as them. Exactly the same.

The doctor is sick. On the discharge sheet, 18 days after admission, her acceptance of this fact (“judgment and insight”) was judged “fair.” This is because the doctor does not believe in her diagnosis. She does not want to be sick. She wants to be the person she was before—minus those highs and lows. She would trade in the agitated anxious state that caused her to drop out of her pediatric rotation. She would trade in the days spent in bed in college, while everyone seemed to be having fun. She would trade in the Google searches of “suicide methods.” She would trade in the panic that caused her to stop her rotation, and therefore caused her to stop playing with the pediatric patients in the playroom at night, after her clinical duties were finished. In the playroom she was not a doctor or a medical student. She was just someone’s playmate. She held the little hand of her little patient and she felt like she was exactly where she was supposed to be. She knew she belonged when she helped her patients forget they were sick.

The doctor is sick. She is drinking hard lemonade, even though it makes the dizziness worse. The doctor has a swollen face and swollen fingers and her wedding ring does not fit anymore. She has gained 10, no, 15 lb because of the medicine, and she knows her husband has noticed. The doctor knows that she has enough pills beside her bed to end her life, but she also knows she is calm now. She is calm in a way she has not felt for as long as she can remember. She thinks back on college, on that 2-month period when she slept until 2 PM, and got out of bed only to smoke marijuana and change the CD on her stereo. She thinks back on the way she pulled the blanket over her head and she remembers that she wanted to be dead.

The doctor remembers writing her treatises later that year on the meaning of life, of the world, of peace and joy and love, on her desktop computer. She wrote and wrote and wrote, as she often did, and sleep did not seem very necessary or desired. She felt she was more connected to the world than anyone else on the planet. She felt more intensely than anyone else on the planet. She ran 5 miles a day, 15 miles on Saturdays. Tears streamed down her face as she bicycled back from her volunteer work with the elderly. She felt so much love and she felt so different from everyone else. Tears came again when she read literature; she felt alive with politics and meaning and urgency. Her heart pounded and she felt words run through her mind that told her to keep working, harder, and that she was capable of more efficient, more emotive, more effective, more productive work than anyone else on the planet. She had more insight than anyone else on the planet. But all of this was directed to help other people, and so she was connected to the whole world.

The doctor feels sick now as she recalls those events. Now she fears her past is part of this illness. Those thoughts and actions that were her proudest moments, the organizations that offered her awards and accolades, the papers that got high marks—those were just the consequence of neurotransmitters being sucked in and spat out in the wrong ratios. It is that simple. Something we can fix with around 10 pills a day, pills that will make the doctor better but will make the doctor sick. What about the doctor’s sense of humor? What about her energy? What about her wild dancing and her disinhibition? What about her ability to be the life of a party even when she is stone cold sober and everyone else has had 4 or 5 drinks? What about her accomplishments and her intensity? What about her ever-present belief that the world’s people are all connected, and she is to play a small but important, even vital, role in bringing them together? Sick, sick, all sick.

As a patient in the psychiatric hospital, the doctor would dance sometimes. She would be dancing, twirling, laughing, making others laugh. Then, on the same day, she would burst into tears and sit in her room, blanket over head, turning over the possibilities for a painless but sure death. She didn’t have much time to think on it because soon it would be time to line up for medicine.

Next … it’s time for her office hours, to reassure other patients, to pretend she is a doctor. But soon enough … the shrink beckons her for the daily session, and she is reminded of his infinite wisdom and her relative ignorance. She nods and agrees with some of what he says, believes it even when she is talking to him in his little room, but not later, when she is back in bed, nighttime, waiting for nightmares. The psychiatrist says that her frantic sleepless days before Christmas, the ones where her friends couldn’t understand why she couldn’t even sit down for lunch (“You’re going to have a stroke!” a less tactful one declared), the ones where she feigned listening to someone talking while in her head she entertained a disorganized, discordant symphony of thoughts trying to hammer out a requiem, a death march … those days were a “mixed state.” Mumbo jumbo. Nonsense. She tells herself she is just moody. At least now there are moments of heady delicious delight, no matter if they are brief.

So the doctor is improving! And she has reason to doubt their boxes and their labels, as she reads on this illness in rare moments when her mind is still, and she finds there is controversy surrounding every diagnosis and delineation. And so that is fuel for her disapproving, disbelieving fire. All of this is just an expression of eccentricity, she tells herself, and these lousy doctors don’t appreciate someone “as brilliant and beautiful as me.” But later, watching the nurses as they fill out their assessments of the day, she wonders how sick they think she really is, and she hates herself and this lunatic frenzy and she is embarrassed and ashamed.

If she does not believe she is sick, then she has to blame herself, and that hurts. But she can handle that pain and that bleeding, for she alone can suffer pain and bleeding like no others, and that is part of what makes her beautiful. But she is not sick …. According to them, the doctor is sick every day and so she stays in the hospital. She retorts, “Of course that is what they say. Isn’t that their job, to call me crazy?” And then, “If I was not crazy, wouldn’t that put them out of business?”

Nightmares have tormented the doctor since she was a child. But lately they are more twisted. They pull her out of the safety of the day such that she plunges, screaming, down, head-first, into black night, afraid. Some of her medicines exacerbate nightmares. In one awful dream, she is a patient, then a doctor, then a patient again, and she keeps waking up inside the dream to be transformed into doctor or patient, one then the other; it never stops. So first she is giving medicines, then she is being intubated, then she is finishing rounds, then she is enduring electroconvulsive therapy. Finally she drops out of the dream as if from the sky, and she is shivering and afraid.

Now, as she dozes, she awakens to every noise, and the shadows look like people, and she knows the nightmares wait for her again, so she fights sleep. Paxil made her hear voices (the psychiatrists proclaimed this “classic” for her illness; she shrugged her shoulders in response) and so now she listens carefully, holding her breath, in bed, trying to hear voices. She thought she heard something. Of course, now she is hypersensitive. Now it is hard not to describe everything as “classic” for the illness. If she thinks about it, from junior high school onwards she was “classic.” What nonsense! Her vision is 20/20 in hindsight. Who wouldn’t find madness in their past if they looked hard enough?

The doctor is sick. The night lasts forever. Somebody opens the door because, at this hospital, they check every 15 minutes, 24 hours per day, to make sure the doctor has not slit her wrists or hanged herself or found another way to end her sick life. For this reason, they have confiscated her shoelaces, and she has to floss at the nurses’ station. She startles as they open the door, and screams out loud. They reassure her they are just checking on her, and now they are gone, and the doctor is left to imagine them walking down the corridor to the nurses’ station, shaking their heads, saying, “That doctor sure is sick!”.

Yes, the doctor is sick. Who is she anyway? She is not even a doctor! She is just a third-year medical student who is fighting, fists up, her descent into madness. Has she won? She is trying to find a way to accept what she is. Does that mean she is a winner or a loser? It is chronic, but manageable, bipolar madness. There are lots of other people like her. But it is still overwhelming, and she is not even sure she wants to join anybody else. She never defined herself as part of any group before. Now she tries to get back to normal—but what can that mean now, after all this time, after release from a mental hospital, after taking a leave from school, after swallowing 10 pills a day (every day, for the rest of her life?), after finding out she is so sick? It is time for her meds. She hasn’t told most of her classmates or her parents because she doesn’t want them to find out that the doctor is sick. She doesn’t want to know if the doctor is sick. She doesn’t want to ponder if the doctor can ever get well.

The doctor misses seeing her patients. Tears are in her eyes and she swallows her sadness as best as she can. She aims to keep a brave face, but she is sad for what she has lost. She tries to shake that off, but it keeps returning. Like a virus, it sneaks up on her and she is shivering, feverish with grief. She hears stories from her friends as they continue to round, heal, cut and sew, take histories, stay up all night, get yelled at by senior physicians, and she wants so much to be there. She is in nowhere land. To some, a few, those who know the twisted tale of the last few months, she is sick. To those who know nothing of it, she is her usual slightly eccentric self, but well. But really she knows she is a liar and a fraud. Because somewhere in the middle she exists alone.

Well, no, she is not alone. Her husband stands by her and he is wonderful. He holds her and laughs with her and tells her she is beautiful and amazing. But she misses seeing lots of people; she thrives on people. Doesn’t anyone understand that she needs people to be alive? Is that so wrong? Is that so sick? She feels sorry for herself, sorry for what she must give up, sorry that she must graduate a year later, sorry that she cannot be with people, sorry that she feels so sorry so much of the time. And then she gets angry with herself for feeling so sorry and being so sick.

Every now and then, the doctor sees another side of things. She surfs the Internet and reads books and she finds out about lots of smart and creative and beautiful people who were sick like she is. These people have twisted, wonderful abilities but so many of them plunged to their death or swallowed pills or died so young. They wrote books or composed symphonies or made people laugh or created works of art but then they died. And so she is left feeling strong and beautiful sometimes, but also lonely and sad that all those souls have deserted her. She is sad that they have left her in this madness, and she must fight to stay alive all by herself. Then, every now and then, there are flickers of wisdom and insight and she knows she will stay alive and she will create beautiful things too, one day.

The doctor is sick. Getting sick stinks. She admits, “Nobody, especially not me, counted on the doctor getting sick. Please! Enough!”

She concedes: “I won’t forget this. I promise. OK, I have learned my lesson now. Please, enough of this!”

She pleads: “I need the doctor to get well. I am afraid of being the doctor that is sick, so afraid.”

She ponders: “Does this mean I will never be free? Does this mean I will never be well? Does this mean I will never be a mother? Oh, God, does this mean I will never be a doctor?”

Then there is silence because she asks these questions of herself, and she has no answers, and no office hours today.

Somebody better call a doctor.

Acknowledgment
The author is grateful for the support of her medical school and residency program during training.

Unprecedented collaboration among 900 genetics investigators across 40 countries led to creation of the highly productive Psychiatric Genomics Consortium (PGC), which is analyzing 400,000 individual DNA samples.¹ The Consortium has an open-source approach, with data freely available to all who are interested.^a

The PGC recently published the results of a large Genome Wide Association Study (GWAS) of 36,989 people with schizophrenia and 113,075 controls. Investigators discovered 108 genetic loci (each containing as many as 26 genes), adding up to 341 protein-coding risk genes for schizophrenia, distributed across all 23 chromosomes.² One of these risk genes, on chromosome 6, is in the major histocompatibility complex and has the strongest association with schizophrenia (P = 10^–31). This finding provides insight that schizophrenia might be related to immune dysfunction, supported by evidence for neuro-inflammation and elevated pro-inflammatory biomarkers in this syndrome.³

In addition to heritable risk genes, the PGC has found many copy number variants (CNVs) and rare de novo mutations that are found significantly more often (10-fold or greater) in schizophrenia. But, as reflected by the 50% concordance rate for schizophrenia in monozygotic twins, non-genetic pathways to schizophrenia obviously exist; this is especially so through adverse events during pregnancy, which can disrupt brain development in a manner similar to disruption caused by risk genes, CNVs, and mutations.

The most exciting consequence of these breakthroughs?These genetic discoveries have great implications for novel drug development for the hundreds of biological subtypes of schizophrenia. At latest count, 23,345 genes that code for proteins, the building blocks of the body, are found in the human set of 23 chromosomes.² Approximately 7,000 of those genes are druggable and can open the way to developing new agents. In fact, identifying potential targets for pharmacotherapeutic intervention is the major goal of conducting a GWAS.⁴

What it means to be ‘druggable.’ Two conditions must be met for a gene to be druggable: First, it must code for a protein with folds that can interact with chemical compounds; second, that protein must be associated with a human disease.⁵ A drug that interacts with several target proteins (eg, kinases, proteases, transporters, enzymes) is considered promiscuous. After such a drug is found to have efficacy in 1 disease, it can be repurposed for treating other diseases. Such repositioning of an already approved drug for other conditions could save the pharmaceutical industry an enormous amount of time and billions of research and development dollars in developing new drugs for psychiatric illnesses that might have been used to treat various other medical conditions.

To exploit the principle of re-purposing, Lencz and Malhotra² examined the 341 coding genes associated with schizophrenia, to determine whether available drugs interact with the proteins produced by some of those genes. They identified 40 druggable genes (11.7% of the 341) and reported that:

• 27 coding genes (7.92% of the 341) are drug targets⁶
• 20 of the 40 druggable genes are already approved by the FDA to treat a range of medical disorders, including glaucoma, epilepsy, hypertension, angina, irritable bowel syndrome, incontinence, smoking cessation, nausea, hypertension, prostate cancer, type 2 diabetes mellitus, pulmonary fibrosis, and acute promyelocytic leukemia; in addition, some genes act as a diuretic or an nonsteroidal anti-inflammatory drug
• another 20 druggable genes are not approved for use but are in clinical trials for disorders such as Alzheimer’s disease, heart failure, neuropathic pain, depression, cancer, immune-supported acne psoriasis, and myeloma.

The opportunity to repurpose some of those promiscuous drugs for various medical indications for the treatment of schizophrenia is exciting, and presents Pandora’s box of new mechanisms of action.⁷ It is intriguing how therapeutic mechanisms for a wide range of unrelated medical conditions may have commonality with the neurobiological underpinnings of a serious brain disorder such as schizophrenia.

Journey from genome to clinicPsychiatrists should be heartened by this translational research into the pharmacotherapeutic promise of emerging genetic advances. The parched terrain of psychopharmacology—the result of a drought of truly innovative medications for serious psychiatric brain disorders—soon may be drenched by a shower of translational discoveries from druggable genes.⁸ An auspicious scientific journey, from the genome to the clinic, has begun in earnest.

That is great news for our patients, and uplifting to us as well. Breakthroughs to cure intractable and persistent psychiatric brain disorders will not only vanquish disability and restore functioning, but also will be a powerful, long-awaited antidote to the virulent stigma of mental illness.

^aAvailable at http://pgc.unc.edu/downloads.

Unprecedented collaboration among 900 genetics investigators across 40 countries led to creation of the highly productive Psychiatric Genomics Consortium (PGC), which is analyzing 400,000 individual DNA samples.¹ The Consortium has an open-source approach, with data freely available to all who are interested.^a

The PGC recently published the results of a large Genome Wide Association Study (GWAS) of 36,989 people with schizophrenia and 113,075 controls. Investigators discovered 108 genetic loci (each containing as many as 26 genes), adding up to 341 protein-coding risk genes for schizophrenia, distributed across all 23 chromosomes.² One of these risk genes, on chromosome 6, is in the major histocompatibility complex and has the strongest association with schizophrenia (P = 10^–31). This finding provides insight that schizophrenia might be related to immune dysfunction, supported by evidence for neuro-inflammation and elevated pro-inflammatory biomarkers in this syndrome.³

In addition to heritable risk genes, the PGC has found many copy number variants (CNVs) and rare de novo mutations that are found significantly more often (10-fold or greater) in schizophrenia. But, as reflected by the 50% concordance rate for schizophrenia in monozygotic twins, non-genetic pathways to schizophrenia obviously exist; this is especially so through adverse events during pregnancy, which can disrupt brain development in a manner similar to disruption caused by risk genes, CNVs, and mutations.

The most exciting consequence of these breakthroughs?These genetic discoveries have great implications for novel drug development for the hundreds of biological subtypes of schizophrenia. At latest count, 23,345 genes that code for proteins, the building blocks of the body, are found in the human set of 23 chromosomes.² Approximately 7,000 of those genes are druggable and can open the way to developing new agents. In fact, identifying potential targets for pharmacotherapeutic intervention is the major goal of conducting a GWAS.⁴

What it means to be ‘druggable.’ Two conditions must be met for a gene to be druggable: First, it must code for a protein with folds that can interact with chemical compounds; second, that protein must be associated with a human disease.⁵ A drug that interacts with several target proteins (eg, kinases, proteases, transporters, enzymes) is considered promiscuous. After such a drug is found to have efficacy in 1 disease, it can be repurposed for treating other diseases. Such repositioning of an already approved drug for other conditions could save the pharmaceutical industry an enormous amount of time and billions of research and development dollars in developing new drugs for psychiatric illnesses that might have been used to treat various other medical conditions.

To exploit the principle of re-purposing, Lencz and Malhotra² examined the 341 coding genes associated with schizophrenia, to determine whether available drugs interact with the proteins produced by some of those genes. They identified 40 druggable genes (11.7% of the 341) and reported that:

• 27 coding genes (7.92% of the 341) are drug targets⁶
• 20 of the 40 druggable genes are already approved by the FDA to treat a range of medical disorders, including glaucoma, epilepsy, hypertension, angina, irritable bowel syndrome, incontinence, smoking cessation, nausea, hypertension, prostate cancer, type 2 diabetes mellitus, pulmonary fibrosis, and acute promyelocytic leukemia; in addition, some genes act as a diuretic or an nonsteroidal anti-inflammatory drug
• another 20 druggable genes are not approved for use but are in clinical trials for disorders such as Alzheimer’s disease, heart failure, neuropathic pain, depression, cancer, immune-supported acne psoriasis, and myeloma.

The opportunity to repurpose some of those promiscuous drugs for various medical indications for the treatment of schizophrenia is exciting, and presents Pandora’s box of new mechanisms of action.⁷ It is intriguing how therapeutic mechanisms for a wide range of unrelated medical conditions may have commonality with the neurobiological underpinnings of a serious brain disorder such as schizophrenia.

Journey from genome to clinicPsychiatrists should be heartened by this translational research into the pharmacotherapeutic promise of emerging genetic advances. The parched terrain of psychopharmacology—the result of a drought of truly innovative medications for serious psychiatric brain disorders—soon may be drenched by a shower of translational discoveries from druggable genes.⁸ An auspicious scientific journey, from the genome to the clinic, has begun in earnest.

That is great news for our patients, and uplifting to us as well. Breakthroughs to cure intractable and persistent psychiatric brain disorders will not only vanquish disability and restore functioning, but also will be a powerful, long-awaited antidote to the virulent stigma of mental illness.

^aAvailable at http://pgc.unc.edu/downloads.

Unprecedented collaboration among 900 genetics investigators across 40 countries led to creation of the highly productive Psychiatric Genomics Consortium (PGC), which is analyzing 400,000 individual DNA samples.¹ The Consortium has an open-source approach, with data freely available to all who are interested.^a

The PGC recently published the results of a large Genome Wide Association Study (GWAS) of 36,989 people with schizophrenia and 113,075 controls. Investigators discovered 108 genetic loci (each containing as many as 26 genes), adding up to 341 protein-coding risk genes for schizophrenia, distributed across all 23 chromosomes.² One of these risk genes, on chromosome 6, is in the major histocompatibility complex and has the strongest association with schizophrenia (P = 10^–31). This finding provides insight that schizophrenia might be related to immune dysfunction, supported by evidence for neuro-inflammation and elevated pro-inflammatory biomarkers in this syndrome.³

In addition to heritable risk genes, the PGC has found many copy number variants (CNVs) and rare de novo mutations that are found significantly more often (10-fold or greater) in schizophrenia. But, as reflected by the 50% concordance rate for schizophrenia in monozygotic twins, non-genetic pathways to schizophrenia obviously exist; this is especially so through adverse events during pregnancy, which can disrupt brain development in a manner similar to disruption caused by risk genes, CNVs, and mutations.

The most exciting consequence of these breakthroughs?These genetic discoveries have great implications for novel drug development for the hundreds of biological subtypes of schizophrenia. At latest count, 23,345 genes that code for proteins, the building blocks of the body, are found in the human set of 23 chromosomes.² Approximately 7,000 of those genes are druggable and can open the way to developing new agents. In fact, identifying potential targets for pharmacotherapeutic intervention is the major goal of conducting a GWAS.⁴

What it means to be ‘druggable.’ Two conditions must be met for a gene to be druggable: First, it must code for a protein with folds that can interact with chemical compounds; second, that protein must be associated with a human disease.⁵ A drug that interacts with several target proteins (eg, kinases, proteases, transporters, enzymes) is considered promiscuous. After such a drug is found to have efficacy in 1 disease, it can be repurposed for treating other diseases. Such repositioning of an already approved drug for other conditions could save the pharmaceutical industry an enormous amount of time and billions of research and development dollars in developing new drugs for psychiatric illnesses that might have been used to treat various other medical conditions.

To exploit the principle of re-purposing, Lencz and Malhotra² examined the 341 coding genes associated with schizophrenia, to determine whether available drugs interact with the proteins produced by some of those genes. They identified 40 druggable genes (11.7% of the 341) and reported that:

• 27 coding genes (7.92% of the 341) are drug targets⁶
• 20 of the 40 druggable genes are already approved by the FDA to treat a range of medical disorders, including glaucoma, epilepsy, hypertension, angina, irritable bowel syndrome, incontinence, smoking cessation, nausea, hypertension, prostate cancer, type 2 diabetes mellitus, pulmonary fibrosis, and acute promyelocytic leukemia; in addition, some genes act as a diuretic or an nonsteroidal anti-inflammatory drug
• another 20 druggable genes are not approved for use but are in clinical trials for disorders such as Alzheimer’s disease, heart failure, neuropathic pain, depression, cancer, immune-supported acne psoriasis, and myeloma.

The opportunity to repurpose some of those promiscuous drugs for various medical indications for the treatment of schizophrenia is exciting, and presents Pandora’s box of new mechanisms of action.⁷ It is intriguing how therapeutic mechanisms for a wide range of unrelated medical conditions may have commonality with the neurobiological underpinnings of a serious brain disorder such as schizophrenia.

Journey from genome to clinicPsychiatrists should be heartened by this translational research into the pharmacotherapeutic promise of emerging genetic advances. The parched terrain of psychopharmacology—the result of a drought of truly innovative medications for serious psychiatric brain disorders—soon may be drenched by a shower of translational discoveries from druggable genes.⁸ An auspicious scientific journey, from the genome to the clinic, has begun in earnest.

That is great news for our patients, and uplifting to us as well. Breakthroughs to cure intractable and persistent psychiatric brain disorders will not only vanquish disability and restore functioning, but also will be a powerful, long-awaited antidote to the virulent stigma of mental illness.

^aAvailable at http://pgc.unc.edu/downloads.

Chronic obstructive pulmonary disease (COPD) usually is not diagnosed until clinically apparent and moderately advanced. Patients might not notice chronic dyspnea and smoker’s cough, or might consider their symptoms “normal” and not seek medical care. Delayed diagnosis is particularly prevalent in the psychiatric population, in which co-existing medical problems tend to remain unrecognized and untreated.¹

Life expectancy of people with serious mental illness (SMI) is 13 to 30 years less than that of the general population—a gap that has widened over time.² Pulmonary disease is a leading cause of elevated mortality risk in SMI, along with cardiovascular and infectious disease, diabetes, and barriers to care. Having a comorbid mental illness triples the mortality risk of chronic lower respiratory disease (Table 1).³

This article describes how you can intervene and improve quality of life for your patients with COPD by:

• asking all patients, especially smokers, if they are experiencing classic symptoms of COPD
• advocating for and supporting smoking cessation efforts
• avoiding drug interactions and off-target dosing related to COPD and nicotine replacement therapy
• considering, if feasible, a switch from typical to atypical antipsychotic therapy, which could reduce smoking behavior.

What is COPD?
COPD is preventable and treatable. It is characterized by “persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lungs to inhaled noxious particles or gases.”⁴

Smoking tobacco is the greatest risk factor for developing COPD.⁵ An estimated 50% to 80% of people with schizophrenia are smokers, as are 55% of people with bipolar disorder.⁶ COPD is a leading cause of morbidity and mortality worldwide,^7,8 and its prevalence is projected to increase as the global population and smoking rates grow.⁹

A simplified schema of the pathophysiology of COPD implicates 4 lung areas: parenchyma, pulmonary vasculature, central airways, and peripheral airways.¹⁰ Variation in the areas affected and severity of change contributes to the disease’s heterogeneous presentation, which can include pulmonary hypertension, hypersecretion of mucus, ciliary dysfunction, airway hyperinflation, and impaired gas exchange.^11,12 Many of these features lead to systemic effects as well, particularly on cardiac function.

When to test a patient for COPD
Early diagnosis and treatment can substantially improve quality-of-life outcomes for patients with COPD. The clinical approach (Figure 1) begins with recognizing classic symptoms. Consider COPD in any patient with:

• dyspnea (particularly if becoming worse, persistent, or associated with exercise)
• chronic cough
• chronic sputum production
• history of risk-factor exposure (particularly tobacco smoke)
• family history of COPD.⁴

If the history and physical exam suggest COPD (Table 2), spirometry is the most reliable test to quantify and characterize lung dysfunction. It is not indicated as a screening tool for healthy adults or appropriate when a patient is acutely ill. Forced expiratory volume in the first second of expiration divided by the measured forced vital capacity (FEV1/FVC) < 0.7 defines clinical COPD and determines the need for pharmacologic intervention. Laboratory studies could be useful in certain clinical scenarios, such as serum testing for alpha₁-antitrypsin deficiency in patients age <45 with emphysema. Plain film imaging might be useful to support a COPD diagnosis or rule out alternate diagnoses.

Psychopharmacology issues with comorbid COPD
Pharmacotherapy for psychiatric disorders can exacerbate comorbid COPD. For example, long-term use of phenothiazine-related typical antipsychotics for schizophrenia has been linked to an increased incidence of COPD.¹³ Antipsychotic side effects such as acute laryngeal dystonia and tardive dyskinesia, most commonly seen with first-generation antipsychotic use, can aggravate dyspnea caused by COPD. Opioids and most hypnotics, sedatives, and anxiolytics suppress the respiratory drive, and therefore should be used with caution in patients with COPD.

Carefully monitor serum levels of medications before and during attempts at smoking cessation. Nicotine’s induction of the cytochrome P450 1A2 system increases the metabolism of antipsychotics such as clozapine, fluvoxamine, olanzapine, and haloperidol. As a result, potentially toxic drug levels can occur when a smoker tries to quit.¹⁴

Screen patients with COPD for co­morbid psychiatric conditions. New psychiatric symptoms can emerge after COPD has been diagnosed, even in patients without pre-existing psychopathology.

Anxiety is a particularly common COPD comorbidity that can be difficult to manage. Selective serotonin reuptake inhibitors, buspirone, cognitive-behavioral therapy, and pulmonary rehabilitation can be helpful, although the effect of antidepressants on respiration is controversial. Nortriptyline has been shown to be effective in treating both anxiety and depressive symptoms in patients with COPD.¹⁵ Avoid using hypnotics to manage sleep problems related to COPD; instead, focus on minimizing sleep disturbance by limiting cough and dyspnea.

Antipsychotics and nicotine metabolism
Multiple studies have focused on the interplay among nicotine, dopamine, and antipsychotic agents. Nicotine receptors are present in the ventral tegmental dopaminergic cell bodies, which induce the release of dopamine and other neurotransmitters when stimulated. Smoking has been noted to increase in patients administered haloperidol (a dopamine antagonist) and to decrease with administration of bromocriptine (a dopamine agonist).¹⁶ This suggests that psychiatric patients might smoke to overcome the dopamine blockade caused by most typical antipsychotics, therefore alleviating their negative and extrapyramidal side effects.¹⁷

Alternatively, some studies suggest that a difference in dopamine receptor occupancy between typical and atypical antipsychotics leads to different effects on smoking behavior.¹⁸ When used long term, typical antipsychotics might increase dopamine receptors or dopamine sensitivity, and thus reinforce the positive effect of nicotine by increasing the number of receptors that can be stimulated, whereas atypical antipsychotics help stimulate the release of dopamine directly through partial agonist of serotonin 5-HT1A receptors.^19,20 Atypical antipsychotics also appear to decrease cue-elicited cravings in people who are not mentally ill, whereas haloperidol does not.²¹

Based on these findings, switching patients with COPD from a typical to an atypical antipsychotic, if feasible, might make smoking cessation more manageable.²² Multiple studies have shown that clozapine is the preferred atypical antipsychotic because it is associated with the most significant decrease in smoking behaviors.²³

First-line therapy: Nicotine replacement
Smoking cessation slows the progression of COPD and leads to marked improvements in cough, expectoration, breathlessness, and wheezing.^24,25 Nicotine replacement therapy (NRT)—gum, inhaler, lozenges, nasal spray, and skin patch—is considered first-line pharmacotherapy. These nicotine substitutes can decrease withdrawal symptoms, although they do not appear to be as effective for light smokers (eg, <10 cigarettes/d), compared with heavy smokers (eg, ≥20 cigarettes/d).²⁶

Long-term smoking abstinence can be improved with combination therapies. A nicotine patch, kept in place for as long as 24 hours, often is used with a nicotine gum or nasal spray. Another option combines the patch with a first-line, non-NRT intervention, such as sustained-release bupropion. Use bupropion with caution in psychiatric patients, however. Do not combine it with a monoamine oxidase inhibitor, and do not prescribe it to patients with an eating disorder or history of seizures.²⁶ Bupropion could induce mania in patients with bipolar disorder.

Varenicline, a nicotinic receptor partial agonist indicated to aid in smoking cessation, has been shown to reduce pleasure gained from tobacco as well as cravings. It can increase the likelihood of abstinence from smoking for as long as 1 year, but it also can provoke behavioral changes, depressed mood, and suicidal ideation. These risks—described in an FDA black-box warning of serious neuropsychiatric events—warrant due caution when prescribing varenicline to patients with depression. The FDA also has warned that varenicline could lead to decreased alcohol tolerance and atypically aggressive behavior during intoxication, which is of particular concern because of the high rate of alcohol use among people with SMI.

Motivating and supporting change
When counseling patients with mental illness about smoking cessation, consider unique motivations that, if disregarded, could undermine your efforts. As described above, smoking can ameliorate negative and extrapyramidal symptoms associated with typical antipsychotics. This could explain the significantly higher rates of smoking associated with typical antipsychotics, compared with atypical antipsychotics.²⁷ Patients also could use smoking as self-medication for depression and anxiety. Therefore, take care to offer alternate methods for coping, along with smoking cessation recommendations.²²

Screen all adult patients for tobacco use, and offer prompt cessation counseling and pharmacologic interventions._²⁸As a motivational intervention, the “5 As” framework—ask, advise, assess, assist, arrange—can help gauge patients’ smoking status and willingness to quit, as well as emphasize the importance of establishing a concrete, manageable plan.²⁹

Keep in mind the barriers all patients face in their fight to quit smoking, such as nicotine withdrawal, weight gain, and loss of a coping mechanism for stress.²⁹ Patients with schizophrenia can be motivated to quit smoking and participate in treatment for nicotine dependence.³⁰

Besides encouraging smoking cessation, you can educate patients in behaviors that will improve COPD symptoms and management. These include:

• reducing the risk of lung infections through vaccinations (influenza yearly, pneumonia once in adulthood) and avoiding crowds during peak cold and influenza season
• participating in physical activity, which could slow lung function decline
• adhering to prescribed medication
• eating a balanced diet
• seeking medical care early during an exacerbation.

Coaching patients in symptom control
Smoking cessation may have the greatest long-term benefit for patients with COPD, but symptom management is important as well (Figure 2). Pharmacotherapy for COPD usually is advanced in steps, but a more aggressive approach may be necessary for patients presenting with severe symptoms.

Mainstays of COPD therapy are inhaled bronchodilators, consisting of β2 agonists and anticholinergics, alone or in combination. Short-acting formulations are used for mild and intermittent symptoms; long-acting bronchodilators are added if symptoms persist.⁴ When dyspnea, wheezing, and activity intolerance are not well-controlled with bronchodilators, an inhaled corticosteroid can be tried, either alone or in combination with a long-acting bronchodilator.⁴

Adherence to medical recommendations is critical for successful COPD management, but inhaled therapy can be difficult for psychiatric patients—especially patients with cognitive or functional impairment. Asking them to demonstrate their inhaler technique can help assess treatment effectiveness.³¹

Referral to a pulmonologist is strongly advised in cases of:

• advanced, end-stage COPD (FEV1 <50% predicted value despite adherence to recommended treatment, or rapid decline of FEV1)
• COPD in patients age <50
• frequent exacerbations
• possible complications related to chronic heart failure
• indications for oxygen treatment (eg, resting or ambulatory oxygen saturation ≤88% or PaO₂ ≤55 mm Hg).³²

Chronic obstructive pulmonary disease (COPD) usually is not diagnosed until clinically apparent and moderately advanced. Patients might not notice chronic dyspnea and smoker’s cough, or might consider their symptoms “normal” and not seek medical care. Delayed diagnosis is particularly prevalent in the psychiatric population, in which co-existing medical problems tend to remain unrecognized and untreated.¹

Life expectancy of people with serious mental illness (SMI) is 13 to 30 years less than that of the general population—a gap that has widened over time.² Pulmonary disease is a leading cause of elevated mortality risk in SMI, along with cardiovascular and infectious disease, diabetes, and barriers to care. Having a comorbid mental illness triples the mortality risk of chronic lower respiratory disease (Table 1).³

This article describes how you can intervene and improve quality of life for your patients with COPD by:

• asking all patients, especially smokers, if they are experiencing classic symptoms of COPD
• advocating for and supporting smoking cessation efforts
• avoiding drug interactions and off-target dosing related to COPD and nicotine replacement therapy
• considering, if feasible, a switch from typical to atypical antipsychotic therapy, which could reduce smoking behavior.

What is COPD?
COPD is preventable and treatable. It is characterized by “persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lungs to inhaled noxious particles or gases.”⁴

Smoking tobacco is the greatest risk factor for developing COPD.⁵ An estimated 50% to 80% of people with schizophrenia are smokers, as are 55% of people with bipolar disorder.⁶ COPD is a leading cause of morbidity and mortality worldwide,^7,8 and its prevalence is projected to increase as the global population and smoking rates grow.⁹

A simplified schema of the pathophysiology of COPD implicates 4 lung areas: parenchyma, pulmonary vasculature, central airways, and peripheral airways.¹⁰ Variation in the areas affected and severity of change contributes to the disease’s heterogeneous presentation, which can include pulmonary hypertension, hypersecretion of mucus, ciliary dysfunction, airway hyperinflation, and impaired gas exchange.^11,12 Many of these features lead to systemic effects as well, particularly on cardiac function.

When to test a patient for COPD
Early diagnosis and treatment can substantially improve quality-of-life outcomes for patients with COPD. The clinical approach (Figure 1) begins with recognizing classic symptoms. Consider COPD in any patient with:

• dyspnea (particularly if becoming worse, persistent, or associated with exercise)
• chronic cough
• chronic sputum production
• history of risk-factor exposure (particularly tobacco smoke)
• family history of COPD.⁴

If the history and physical exam suggest COPD (Table 2), spirometry is the most reliable test to quantify and characterize lung dysfunction. It is not indicated as a screening tool for healthy adults or appropriate when a patient is acutely ill. Forced expiratory volume in the first second of expiration divided by the measured forced vital capacity (FEV1/FVC) < 0.7 defines clinical COPD and determines the need for pharmacologic intervention. Laboratory studies could be useful in certain clinical scenarios, such as serum testing for alpha₁-antitrypsin deficiency in patients age <45 with emphysema. Plain film imaging might be useful to support a COPD diagnosis or rule out alternate diagnoses.

Psychopharmacology issues with comorbid COPD
Pharmacotherapy for psychiatric disorders can exacerbate comorbid COPD. For example, long-term use of phenothiazine-related typical antipsychotics for schizophrenia has been linked to an increased incidence of COPD.¹³ Antipsychotic side effects such as acute laryngeal dystonia and tardive dyskinesia, most commonly seen with first-generation antipsychotic use, can aggravate dyspnea caused by COPD. Opioids and most hypnotics, sedatives, and anxiolytics suppress the respiratory drive, and therefore should be used with caution in patients with COPD.

Carefully monitor serum levels of medications before and during attempts at smoking cessation. Nicotine’s induction of the cytochrome P450 1A2 system increases the metabolism of antipsychotics such as clozapine, fluvoxamine, olanzapine, and haloperidol. As a result, potentially toxic drug levels can occur when a smoker tries to quit.¹⁴

Screen patients with COPD for co­morbid psychiatric conditions. New psychiatric symptoms can emerge after COPD has been diagnosed, even in patients without pre-existing psychopathology.

Anxiety is a particularly common COPD comorbidity that can be difficult to manage. Selective serotonin reuptake inhibitors, buspirone, cognitive-behavioral therapy, and pulmonary rehabilitation can be helpful, although the effect of antidepressants on respiration is controversial. Nortriptyline has been shown to be effective in treating both anxiety and depressive symptoms in patients with COPD.¹⁵ Avoid using hypnotics to manage sleep problems related to COPD; instead, focus on minimizing sleep disturbance by limiting cough and dyspnea.

Antipsychotics and nicotine metabolism
Multiple studies have focused on the interplay among nicotine, dopamine, and antipsychotic agents. Nicotine receptors are present in the ventral tegmental dopaminergic cell bodies, which induce the release of dopamine and other neurotransmitters when stimulated. Smoking has been noted to increase in patients administered haloperidol (a dopamine antagonist) and to decrease with administration of bromocriptine (a dopamine agonist).¹⁶ This suggests that psychiatric patients might smoke to overcome the dopamine blockade caused by most typical antipsychotics, therefore alleviating their negative and extrapyramidal side effects.¹⁷

Alternatively, some studies suggest that a difference in dopamine receptor occupancy between typical and atypical antipsychotics leads to different effects on smoking behavior.¹⁸ When used long term, typical antipsychotics might increase dopamine receptors or dopamine sensitivity, and thus reinforce the positive effect of nicotine by increasing the number of receptors that can be stimulated, whereas atypical antipsychotics help stimulate the release of dopamine directly through partial agonist of serotonin 5-HT1A receptors.^19,20 Atypical antipsychotics also appear to decrease cue-elicited cravings in people who are not mentally ill, whereas haloperidol does not.²¹

Based on these findings, switching patients with COPD from a typical to an atypical antipsychotic, if feasible, might make smoking cessation more manageable.²² Multiple studies have shown that clozapine is the preferred atypical antipsychotic because it is associated with the most significant decrease in smoking behaviors.²³

First-line therapy: Nicotine replacement
Smoking cessation slows the progression of COPD and leads to marked improvements in cough, expectoration, breathlessness, and wheezing.^24,25 Nicotine replacement therapy (NRT)—gum, inhaler, lozenges, nasal spray, and skin patch—is considered first-line pharmacotherapy. These nicotine substitutes can decrease withdrawal symptoms, although they do not appear to be as effective for light smokers (eg, <10 cigarettes/d), compared with heavy smokers (eg, ≥20 cigarettes/d).²⁶

Long-term smoking abstinence can be improved with combination therapies. A nicotine patch, kept in place for as long as 24 hours, often is used with a nicotine gum or nasal spray. Another option combines the patch with a first-line, non-NRT intervention, such as sustained-release bupropion. Use bupropion with caution in psychiatric patients, however. Do not combine it with a monoamine oxidase inhibitor, and do not prescribe it to patients with an eating disorder or history of seizures.²⁶ Bupropion could induce mania in patients with bipolar disorder.

Varenicline, a nicotinic receptor partial agonist indicated to aid in smoking cessation, has been shown to reduce pleasure gained from tobacco as well as cravings. It can increase the likelihood of abstinence from smoking for as long as 1 year, but it also can provoke behavioral changes, depressed mood, and suicidal ideation. These risks—described in an FDA black-box warning of serious neuropsychiatric events—warrant due caution when prescribing varenicline to patients with depression. The FDA also has warned that varenicline could lead to decreased alcohol tolerance and atypically aggressive behavior during intoxication, which is of particular concern because of the high rate of alcohol use among people with SMI.

Motivating and supporting change
When counseling patients with mental illness about smoking cessation, consider unique motivations that, if disregarded, could undermine your efforts. As described above, smoking can ameliorate negative and extrapyramidal symptoms associated with typical antipsychotics. This could explain the significantly higher rates of smoking associated with typical antipsychotics, compared with atypical antipsychotics.²⁷ Patients also could use smoking as self-medication for depression and anxiety. Therefore, take care to offer alternate methods for coping, along with smoking cessation recommendations.²²

Screen all adult patients for tobacco use, and offer prompt cessation counseling and pharmacologic interventions._²⁸As a motivational intervention, the “5 As” framework—ask, advise, assess, assist, arrange—can help gauge patients’ smoking status and willingness to quit, as well as emphasize the importance of establishing a concrete, manageable plan.²⁹

Keep in mind the barriers all patients face in their fight to quit smoking, such as nicotine withdrawal, weight gain, and loss of a coping mechanism for stress.²⁹ Patients with schizophrenia can be motivated to quit smoking and participate in treatment for nicotine dependence.³⁰

Besides encouraging smoking cessation, you can educate patients in behaviors that will improve COPD symptoms and management. These include:

• reducing the risk of lung infections through vaccinations (influenza yearly, pneumonia once in adulthood) and avoiding crowds during peak cold and influenza season
• participating in physical activity, which could slow lung function decline
• adhering to prescribed medication
• eating a balanced diet
• seeking medical care early during an exacerbation.

Coaching patients in symptom control
Smoking cessation may have the greatest long-term benefit for patients with COPD, but symptom management is important as well (Figure 2). Pharmacotherapy for COPD usually is advanced in steps, but a more aggressive approach may be necessary for patients presenting with severe symptoms.

Mainstays of COPD therapy are inhaled bronchodilators, consisting of β2 agonists and anticholinergics, alone or in combination. Short-acting formulations are used for mild and intermittent symptoms; long-acting bronchodilators are added if symptoms persist.⁴ When dyspnea, wheezing, and activity intolerance are not well-controlled with bronchodilators, an inhaled corticosteroid can be tried, either alone or in combination with a long-acting bronchodilator.⁴

Adherence to medical recommendations is critical for successful COPD management, but inhaled therapy can be difficult for psychiatric patients—especially patients with cognitive or functional impairment. Asking them to demonstrate their inhaler technique can help assess treatment effectiveness.³¹

Referral to a pulmonologist is strongly advised in cases of:

• advanced, end-stage COPD (FEV1 <50% predicted value despite adherence to recommended treatment, or rapid decline of FEV1)
• COPD in patients age <50
• frequent exacerbations
• possible complications related to chronic heart failure
• indications for oxygen treatment (eg, resting or ambulatory oxygen saturation ≤88% or PaO₂ ≤55 mm Hg).³²

Chronic obstructive pulmonary disease (COPD) usually is not diagnosed until clinically apparent and moderately advanced. Patients might not notice chronic dyspnea and smoker’s cough, or might consider their symptoms “normal” and not seek medical care. Delayed diagnosis is particularly prevalent in the psychiatric population, in which co-existing medical problems tend to remain unrecognized and untreated.¹

Life expectancy of people with serious mental illness (SMI) is 13 to 30 years less than that of the general population—a gap that has widened over time.² Pulmonary disease is a leading cause of elevated mortality risk in SMI, along with cardiovascular and infectious disease, diabetes, and barriers to care. Having a comorbid mental illness triples the mortality risk of chronic lower respiratory disease (Table 1).³

This article describes how you can intervene and improve quality of life for your patients with COPD by:

• asking all patients, especially smokers, if they are experiencing classic symptoms of COPD
• advocating for and supporting smoking cessation efforts
• avoiding drug interactions and off-target dosing related to COPD and nicotine replacement therapy
• considering, if feasible, a switch from typical to atypical antipsychotic therapy, which could reduce smoking behavior.

What is COPD?
COPD is preventable and treatable. It is characterized by “persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lungs to inhaled noxious particles or gases.”⁴

Smoking tobacco is the greatest risk factor for developing COPD.⁵ An estimated 50% to 80% of people with schizophrenia are smokers, as are 55% of people with bipolar disorder.⁶ COPD is a leading cause of morbidity and mortality worldwide,^7,8 and its prevalence is projected to increase as the global population and smoking rates grow.⁹

A simplified schema of the pathophysiology of COPD implicates 4 lung areas: parenchyma, pulmonary vasculature, central airways, and peripheral airways.¹⁰ Variation in the areas affected and severity of change contributes to the disease’s heterogeneous presentation, which can include pulmonary hypertension, hypersecretion of mucus, ciliary dysfunction, airway hyperinflation, and impaired gas exchange.^11,12 Many of these features lead to systemic effects as well, particularly on cardiac function.

When to test a patient for COPD
Early diagnosis and treatment can substantially improve quality-of-life outcomes for patients with COPD. The clinical approach (Figure 1) begins with recognizing classic symptoms. Consider COPD in any patient with:

• dyspnea (particularly if becoming worse, persistent, or associated with exercise)
• chronic cough
• chronic sputum production
• history of risk-factor exposure (particularly tobacco smoke)
• family history of COPD.⁴

If the history and physical exam suggest COPD (Table 2), spirometry is the most reliable test to quantify and characterize lung dysfunction. It is not indicated as a screening tool for healthy adults or appropriate when a patient is acutely ill. Forced expiratory volume in the first second of expiration divided by the measured forced vital capacity (FEV1/FVC) < 0.7 defines clinical COPD and determines the need for pharmacologic intervention. Laboratory studies could be useful in certain clinical scenarios, such as serum testing for alpha₁-antitrypsin deficiency in patients age <45 with emphysema. Plain film imaging might be useful to support a COPD diagnosis or rule out alternate diagnoses.

Psychopharmacology issues with comorbid COPD
Pharmacotherapy for psychiatric disorders can exacerbate comorbid COPD. For example, long-term use of phenothiazine-related typical antipsychotics for schizophrenia has been linked to an increased incidence of COPD.¹³ Antipsychotic side effects such as acute laryngeal dystonia and tardive dyskinesia, most commonly seen with first-generation antipsychotic use, can aggravate dyspnea caused by COPD. Opioids and most hypnotics, sedatives, and anxiolytics suppress the respiratory drive, and therefore should be used with caution in patients with COPD.

Carefully monitor serum levels of medications before and during attempts at smoking cessation. Nicotine’s induction of the cytochrome P450 1A2 system increases the metabolism of antipsychotics such as clozapine, fluvoxamine, olanzapine, and haloperidol. As a result, potentially toxic drug levels can occur when a smoker tries to quit.¹⁴

Screen patients with COPD for co­morbid psychiatric conditions. New psychiatric symptoms can emerge after COPD has been diagnosed, even in patients without pre-existing psychopathology.

Anxiety is a particularly common COPD comorbidity that can be difficult to manage. Selective serotonin reuptake inhibitors, buspirone, cognitive-behavioral therapy, and pulmonary rehabilitation can be helpful, although the effect of antidepressants on respiration is controversial. Nortriptyline has been shown to be effective in treating both anxiety and depressive symptoms in patients with COPD.¹⁵ Avoid using hypnotics to manage sleep problems related to COPD; instead, focus on minimizing sleep disturbance by limiting cough and dyspnea.

Antipsychotics and nicotine metabolism
Multiple studies have focused on the interplay among nicotine, dopamine, and antipsychotic agents. Nicotine receptors are present in the ventral tegmental dopaminergic cell bodies, which induce the release of dopamine and other neurotransmitters when stimulated. Smoking has been noted to increase in patients administered haloperidol (a dopamine antagonist) and to decrease with administration of bromocriptine (a dopamine agonist).¹⁶ This suggests that psychiatric patients might smoke to overcome the dopamine blockade caused by most typical antipsychotics, therefore alleviating their negative and extrapyramidal side effects.¹⁷

Alternatively, some studies suggest that a difference in dopamine receptor occupancy between typical and atypical antipsychotics leads to different effects on smoking behavior.¹⁸ When used long term, typical antipsychotics might increase dopamine receptors or dopamine sensitivity, and thus reinforce the positive effect of nicotine by increasing the number of receptors that can be stimulated, whereas atypical antipsychotics help stimulate the release of dopamine directly through partial agonist of serotonin 5-HT1A receptors.^19,20 Atypical antipsychotics also appear to decrease cue-elicited cravings in people who are not mentally ill, whereas haloperidol does not.²¹

Based on these findings, switching patients with COPD from a typical to an atypical antipsychotic, if feasible, might make smoking cessation more manageable.²² Multiple studies have shown that clozapine is the preferred atypical antipsychotic because it is associated with the most significant decrease in smoking behaviors.²³

First-line therapy: Nicotine replacement
Smoking cessation slows the progression of COPD and leads to marked improvements in cough, expectoration, breathlessness, and wheezing.^24,25 Nicotine replacement therapy (NRT)—gum, inhaler, lozenges, nasal spray, and skin patch—is considered first-line pharmacotherapy. These nicotine substitutes can decrease withdrawal symptoms, although they do not appear to be as effective for light smokers (eg, <10 cigarettes/d), compared with heavy smokers (eg, ≥20 cigarettes/d).²⁶

Long-term smoking abstinence can be improved with combination therapies. A nicotine patch, kept in place for as long as 24 hours, often is used with a nicotine gum or nasal spray. Another option combines the patch with a first-line, non-NRT intervention, such as sustained-release bupropion. Use bupropion with caution in psychiatric patients, however. Do not combine it with a monoamine oxidase inhibitor, and do not prescribe it to patients with an eating disorder or history of seizures.²⁶ Bupropion could induce mania in patients with bipolar disorder.

Varenicline, a nicotinic receptor partial agonist indicated to aid in smoking cessation, has been shown to reduce pleasure gained from tobacco as well as cravings. It can increase the likelihood of abstinence from smoking for as long as 1 year, but it also can provoke behavioral changes, depressed mood, and suicidal ideation. These risks—described in an FDA black-box warning of serious neuropsychiatric events—warrant due caution when prescribing varenicline to patients with depression. The FDA also has warned that varenicline could lead to decreased alcohol tolerance and atypically aggressive behavior during intoxication, which is of particular concern because of the high rate of alcohol use among people with SMI.

Motivating and supporting change
When counseling patients with mental illness about smoking cessation, consider unique motivations that, if disregarded, could undermine your efforts. As described above, smoking can ameliorate negative and extrapyramidal symptoms associated with typical antipsychotics. This could explain the significantly higher rates of smoking associated with typical antipsychotics, compared with atypical antipsychotics.²⁷ Patients also could use smoking as self-medication for depression and anxiety. Therefore, take care to offer alternate methods for coping, along with smoking cessation recommendations.²²

Screen all adult patients for tobacco use, and offer prompt cessation counseling and pharmacologic interventions._²⁸As a motivational intervention, the “5 As” framework—ask, advise, assess, assist, arrange—can help gauge patients’ smoking status and willingness to quit, as well as emphasize the importance of establishing a concrete, manageable plan.²⁹

Keep in mind the barriers all patients face in their fight to quit smoking, such as nicotine withdrawal, weight gain, and loss of a coping mechanism for stress.²⁹ Patients with schizophrenia can be motivated to quit smoking and participate in treatment for nicotine dependence.³⁰

Besides encouraging smoking cessation, you can educate patients in behaviors that will improve COPD symptoms and management. These include:

• reducing the risk of lung infections through vaccinations (influenza yearly, pneumonia once in adulthood) and avoiding crowds during peak cold and influenza season
• participating in physical activity, which could slow lung function decline
• adhering to prescribed medication
• eating a balanced diet
• seeking medical care early during an exacerbation.

Coaching patients in symptom control
Smoking cessation may have the greatest long-term benefit for patients with COPD, but symptom management is important as well (Figure 2). Pharmacotherapy for COPD usually is advanced in steps, but a more aggressive approach may be necessary for patients presenting with severe symptoms.

Mainstays of COPD therapy are inhaled bronchodilators, consisting of β2 agonists and anticholinergics, alone or in combination. Short-acting formulations are used for mild and intermittent symptoms; long-acting bronchodilators are added if symptoms persist.⁴ When dyspnea, wheezing, and activity intolerance are not well-controlled with bronchodilators, an inhaled corticosteroid can be tried, either alone or in combination with a long-acting bronchodilator.⁴

Adherence to medical recommendations is critical for successful COPD management, but inhaled therapy can be difficult for psychiatric patients—especially patients with cognitive or functional impairment. Asking them to demonstrate their inhaler technique can help assess treatment effectiveness.³¹

Referral to a pulmonologist is strongly advised in cases of:

• advanced, end-stage COPD (FEV1 <50% predicted value despite adherence to recommended treatment, or rapid decline of FEV1)
• COPD in patients age <50
• frequent exacerbations
• possible complications related to chronic heart failure
• indications for oxygen treatment (eg, resting or ambulatory oxygen saturation ≤88% or PaO₂ ≤55 mm Hg).³²

Consider 3 observations:

• Evidence is mounting that cytokine abnormalities are present in schizophrenia (Box^1-8).
• Reduced arterial compliance (change in volume divided by change in pressure [ΔV/ΔP] in an artery during the cardiac cycle) is an early marker of cardiovascular disease (CVD) and a robust predictor of mortality, and is associated with cytokine abnormalities.
• People with schizophrenia experience increased mortality from CVD.

Taken together, the 3 statements hint at a hypothesis: a common inflammatory process involving cytokine imbalance is associated with symptoms of schizophrenia, reduced arterial compliance, and CVD.

Anti-inflammatory therapeutics that target specific cytokines might both decrease psychiatric symptoms and reduce cardiac mortality in people with schizophrenia. In this article, we (1) highlight the potential role of anti-inflammatory medications in reducing both psychiatric symptoms and cardiac mortality in people with schizophrenia and (2) review the pathophysiological basis of this inflammatory commonality and the evidence for its presence in schizophrenia.

The ‘membrane hypothesis’ of schizophrenia
In this hypothesis, a disturbance in the synthesis and structure of membrane phospholipids results in a subsequent disturbance in the function of neuronal membrane proteins, which might be associated with symptoms and mortality in schizophrenia.^9-12 The synaptic vesicle protein synaptophysin, a marker for synaptic density, was found to be decreased in postmortem tissue from the gyrus cinguli in 11 patients with schizophrenia, compared with 13 controls.¹⁰ Intracellular phospholipases A₂ (inPLA₂) act as key enzymes in cell membrane repair and remodeling and in neuroplasticity, neurodevelopment, apoptosis, synaptic pruning, neurodegenerative processes, and neuroinflammation.

In a study, people with first-episode schizophrenia (n = 24) who were drug-naïve or off antipsychotic medication were compared with 25 healthy controls using voxel-based morphometry analysis of T₁ high-resolution MRI. inPLA₂ activity was increased in the patient group compared with controls; the analysis revealed abnormalities of the frontal and medial temporal cortices, hippocampus, and left-middle and superior temporal gyri in first-episode patients.¹¹ In another study, inPLA₂ activity was increased in 35 people with first-episode schizophrenia, compared with 22 controls, and was associated with symptom severity and outcome after 12 weeks of antipsychotic treatment.¹²

Early CVD mortality in schizophrenia
People with schizophrenia have an elevated rate of CVD compared with the general population; in part, this elevation is linked to magnified risk factors for CVD, including obesity, metabolic syndrome, cigarette smoking, and diabetes^13-17; furthermore, most antipsychotics can cause or worsen metabolic syndrome.¹⁷

CVD is one of the most common causes of death among people with schizophrenia.^17,18 Their life expectancy is reported to be 51 to 61 years—20 to 25 years less than what is seen in the general population.^19-21

Arterial compliance in schizophrenia
Reduced arterial compliance has been found to be a robust predictor of athero­sclerosis, stroke, and myocardial infarction^22-29:

• In 376 subjects who had routine diagnostic coronary angiography associated with coronary stenosis, arterial compliance was reduced significantly—even after controlling for age, sex, smoking, diabetes, hypertension, hyperlipidemia, and obesity.²⁴

In a cross-sectional study, 63 male U.S. veterans age 18 to 70 who had a psychiatric diagnosis (16 taking quetiapine, 19 taking risperidone, and 28 treated in the past but off antipsychotics for 2 months) had significantly reduced compliance in thigh- and calf-level arteries than male controls (n = 111), adjusting for body mass index and Framingham Risk Score (FRS). Of the 63 patients, 23 had a diagnosis of schizophrenia or schizoaffective disorder.³⁰ (The FRS is an estimate of a person’s 10-year cardiovascular risk, calculated using age, sex, total cholesterol, high-density lipoprotein, smoker or not, systolic blood pressure, and whether taking an antihypertensive or not. Compliance was measured using computerized plethysmography). Although not statistically significant, secondary analyses from this data set (n = 77, including men for whom factors for metabolic syndrome were available) showed that calf-level compliance (1.82 vs 2.06 mL) and thigh-level compliance (3.6 vs 4.26 mL; P = .06) were reduced in subjects with schizophrenia, compared with those who had another psychiatric diagnosis.³¹

• In another study, arterial compliance was significantly reduced in 10 subjects with schizophrenia, compared with 10 healthy controls.³²
• Last, reduced total arterial compliance has been shown to be a robust predictor of mortality in older people, compared with reduced local or regional arterial compliance.³³

Cytokine abnormalities in arterial compliance
The mechanism by which reduced arterial compliance is associated with cardiovascular pathology is not entirely clear. Arterial compliance is a predictor of cardiovascular disorders independent of hypertension.³⁴ Two studies show that vascular inflammation is associated with reduced arterial compliance.^35,36 Reduced arterial compliance is associated with increased angiotensin II activity; increased nicotinamide adenine dinucleotide phosphate oxidase activity; reduced nitric oxide activity; and increased reactive oxygen species.^37-39 Angiotensin-II signaling activates transforming growth factor-β, tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-17, IL-6, and C-reactive protein (CRP)—all of which are associated with reduced arterial compliance.^39-46 In addition, high-sensitivity CRP is significantly associated with reduced arterial compliance.^47-49

The overlap of cytokine abnormalities linked to schizophrenia and to arterial compliance is depicted in the Figure.

Anti-inflammatory medications and arterial compliance
Evidence suggests that anti-inflammatory medications increase arterial compliance:

• In 10 patients who had coronary artery disease or diabetes, or both, simvastatin (40 mg/d) was administered for 4 months. Arterial compliance improved in all 10 after 2 months of treatment and increased by 34% after 4 months.²⁷
• Evidence also suggests that the use of omega-3 fatty acids was associated with increased arterial compliance in people with dyslipidemia.⁵⁰
• Last, in people with rheumatoid arthritis, infliximab, a monoclonal antibody against TNF-Symbol Stdα, reduced aortic inflammation; this effect correlated with an increase in aortic compliance.⁵¹

Anti-inflammatory medications in schizophrenia
Two studies have yielded notable findings:

• A meta-analysis of 5 randomized controlled trials (RCTs) involving 264 subjects, comprising 4 studies of celecoxib and 1 of acetylsalicylic acid, had an effect size of 0.43 on total symptom severity. Investigators argued that acetylsalicylic acid might have the additional benefit of decreasing the risk of cardiac death in schizophrenia.⁵²
• A review of 26 RCTs examined the efficacy of anti-inflammatory medications on symptom severity in schizophrenia. Acetylsalicylic acid, N-acetylcysteine, and estrogens had an effect size of 0.3, 0.45, and 0.51, respectively.⁵³

Significance of these findings
A revelation that cytokine abnormalities are associated with schizophrenia symptoms and co-occurring somatic illness might offer an important new avenue of therapeutic discovery. On average, people with schizophrenia die 20 to 25 years earlier than the general population; CVD is the major cause of their death. Measuring arterial compliance, a novel noninvasive technology in psychiatry, as well as metabolic parameters, could serve as an early biomarker for assessing risk of CVD.

Implications for psychiatric practice. If inflammation plays a role in CVD in schizophrenia—either independently of factors such as metabolic syndrome, obesity, and smoking, or on the causal pathway linking these factors to reduced arterial compliance and to CVD—treatment with anti-inflammatory medications might reduce the alarming disparity of mortality that accompanies schizophrenia. In short, anti-inflammatory medications may offer a double benefit in this setting. Furthermore, success in this approach could spur clarification of the role of abnormal cytokines in other psychiatric disorders.

At this time, for your patients, consider that anti-inflammatory medications routinely used in medical practice, such as nonsteroidal anti-inflammatory drugs, omega-3 fatty acids, and statins, might alleviate psychiatric symptoms and might reduce cardiovascular mortality in schizophrenia.

Future directions
Perhaps only a limited number of cytokines are common to schizophrenia and reduced arterial compliance. Targeting those specific cytokines might, however, provide the dual benefit in schizophrenia of:

• alleviating symptoms
• reducing the rate of CVD-related mortality.

Studies are warranted to determine the value of (1) anti-inflammatory medications, such as N-acetylcysteine and infliximab and (2) anti-inflammatory combination therapy for this dual purpose. In fact, recruitment of subjects is underway for a study, Anti-Inflammatory Combination Therapy for the Treatment of Schizophrenia, at the University of Maryland (ClinicalTrials.gov Identifier: NCT01514682).

Consider 3 observations:

• Evidence is mounting that cytokine abnormalities are present in schizophrenia (Box^1-8).
• Reduced arterial compliance (change in volume divided by change in pressure [ΔV/ΔP] in an artery during the cardiac cycle) is an early marker of cardiovascular disease (CVD) and a robust predictor of mortality, and is associated with cytokine abnormalities.
• People with schizophrenia experience increased mortality from CVD.

Taken together, the 3 statements hint at a hypothesis: a common inflammatory process involving cytokine imbalance is associated with symptoms of schizophrenia, reduced arterial compliance, and CVD.

Anti-inflammatory therapeutics that target specific cytokines might both decrease psychiatric symptoms and reduce cardiac mortality in people with schizophrenia. In this article, we (1) highlight the potential role of anti-inflammatory medications in reducing both psychiatric symptoms and cardiac mortality in people with schizophrenia and (2) review the pathophysiological basis of this inflammatory commonality and the evidence for its presence in schizophrenia.

The ‘membrane hypothesis’ of schizophrenia
In this hypothesis, a disturbance in the synthesis and structure of membrane phospholipids results in a subsequent disturbance in the function of neuronal membrane proteins, which might be associated with symptoms and mortality in schizophrenia.^9-12 The synaptic vesicle protein synaptophysin, a marker for synaptic density, was found to be decreased in postmortem tissue from the gyrus cinguli in 11 patients with schizophrenia, compared with 13 controls.¹⁰ Intracellular phospholipases A₂ (inPLA₂) act as key enzymes in cell membrane repair and remodeling and in neuroplasticity, neurodevelopment, apoptosis, synaptic pruning, neurodegenerative processes, and neuroinflammation.

In a study, people with first-episode schizophrenia (n = 24) who were drug-naïve or off antipsychotic medication were compared with 25 healthy controls using voxel-based morphometry analysis of T₁ high-resolution MRI. inPLA₂ activity was increased in the patient group compared with controls; the analysis revealed abnormalities of the frontal and medial temporal cortices, hippocampus, and left-middle and superior temporal gyri in first-episode patients.¹¹ In another study, inPLA₂ activity was increased in 35 people with first-episode schizophrenia, compared with 22 controls, and was associated with symptom severity and outcome after 12 weeks of antipsychotic treatment.¹²

Early CVD mortality in schizophrenia
People with schizophrenia have an elevated rate of CVD compared with the general population; in part, this elevation is linked to magnified risk factors for CVD, including obesity, metabolic syndrome, cigarette smoking, and diabetes^13-17; furthermore, most antipsychotics can cause or worsen metabolic syndrome.¹⁷

CVD is one of the most common causes of death among people with schizophrenia.^17,18 Their life expectancy is reported to be 51 to 61 years—20 to 25 years less than what is seen in the general population.^19-21

Arterial compliance in schizophrenia
Reduced arterial compliance has been found to be a robust predictor of athero­sclerosis, stroke, and myocardial infarction^22-29:

• In 376 subjects who had routine diagnostic coronary angiography associated with coronary stenosis, arterial compliance was reduced significantly—even after controlling for age, sex, smoking, diabetes, hypertension, hyperlipidemia, and obesity.²⁴

In a cross-sectional study, 63 male U.S. veterans age 18 to 70 who had a psychiatric diagnosis (16 taking quetiapine, 19 taking risperidone, and 28 treated in the past but off antipsychotics for 2 months) had significantly reduced compliance in thigh- and calf-level arteries than male controls (n = 111), adjusting for body mass index and Framingham Risk Score (FRS). Of the 63 patients, 23 had a diagnosis of schizophrenia or schizoaffective disorder.³⁰ (The FRS is an estimate of a person’s 10-year cardiovascular risk, calculated using age, sex, total cholesterol, high-density lipoprotein, smoker or not, systolic blood pressure, and whether taking an antihypertensive or not. Compliance was measured using computerized plethysmography). Although not statistically significant, secondary analyses from this data set (n = 77, including men for whom factors for metabolic syndrome were available) showed that calf-level compliance (1.82 vs 2.06 mL) and thigh-level compliance (3.6 vs 4.26 mL; P = .06) were reduced in subjects with schizophrenia, compared with those who had another psychiatric diagnosis.³¹

• In another study, arterial compliance was significantly reduced in 10 subjects with schizophrenia, compared with 10 healthy controls.³²
• Last, reduced total arterial compliance has been shown to be a robust predictor of mortality in older people, compared with reduced local or regional arterial compliance.³³

Cytokine abnormalities in arterial compliance
The mechanism by which reduced arterial compliance is associated with cardiovascular pathology is not entirely clear. Arterial compliance is a predictor of cardiovascular disorders independent of hypertension.³⁴ Two studies show that vascular inflammation is associated with reduced arterial compliance.^35,36 Reduced arterial compliance is associated with increased angiotensin II activity; increased nicotinamide adenine dinucleotide phosphate oxidase activity; reduced nitric oxide activity; and increased reactive oxygen species.^37-39 Angiotensin-II signaling activates transforming growth factor-β, tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-17, IL-6, and C-reactive protein (CRP)—all of which are associated with reduced arterial compliance.^39-46 In addition, high-sensitivity CRP is significantly associated with reduced arterial compliance.^47-49

The overlap of cytokine abnormalities linked to schizophrenia and to arterial compliance is depicted in the Figure.

Anti-inflammatory medications and arterial compliance
Evidence suggests that anti-inflammatory medications increase arterial compliance:

• In 10 patients who had coronary artery disease or diabetes, or both, simvastatin (40 mg/d) was administered for 4 months. Arterial compliance improved in all 10 after 2 months of treatment and increased by 34% after 4 months.²⁷
• Evidence also suggests that the use of omega-3 fatty acids was associated with increased arterial compliance in people with dyslipidemia.⁵⁰
• Last, in people with rheumatoid arthritis, infliximab, a monoclonal antibody against TNF-Symbol Stdα, reduced aortic inflammation; this effect correlated with an increase in aortic compliance.⁵¹

Anti-inflammatory medications in schizophrenia
Two studies have yielded notable findings:

• A meta-analysis of 5 randomized controlled trials (RCTs) involving 264 subjects, comprising 4 studies of celecoxib and 1 of acetylsalicylic acid, had an effect size of 0.43 on total symptom severity. Investigators argued that acetylsalicylic acid might have the additional benefit of decreasing the risk of cardiac death in schizophrenia.⁵²
• A review of 26 RCTs examined the efficacy of anti-inflammatory medications on symptom severity in schizophrenia. Acetylsalicylic acid, N-acetylcysteine, and estrogens had an effect size of 0.3, 0.45, and 0.51, respectively.⁵³

Significance of these findings
A revelation that cytokine abnormalities are associated with schizophrenia symptoms and co-occurring somatic illness might offer an important new avenue of therapeutic discovery. On average, people with schizophrenia die 20 to 25 years earlier than the general population; CVD is the major cause of their death. Measuring arterial compliance, a novel noninvasive technology in psychiatry, as well as metabolic parameters, could serve as an early biomarker for assessing risk of CVD.

Implications for psychiatric practice. If inflammation plays a role in CVD in schizophrenia—either independently of factors such as metabolic syndrome, obesity, and smoking, or on the causal pathway linking these factors to reduced arterial compliance and to CVD—treatment with anti-inflammatory medications might reduce the alarming disparity of mortality that accompanies schizophrenia. In short, anti-inflammatory medications may offer a double benefit in this setting. Furthermore, success in this approach could spur clarification of the role of abnormal cytokines in other psychiatric disorders.

At this time, for your patients, consider that anti-inflammatory medications routinely used in medical practice, such as nonsteroidal anti-inflammatory drugs, omega-3 fatty acids, and statins, might alleviate psychiatric symptoms and might reduce cardiovascular mortality in schizophrenia.

Future directions
Perhaps only a limited number of cytokines are common to schizophrenia and reduced arterial compliance. Targeting those specific cytokines might, however, provide the dual benefit in schizophrenia of:

• alleviating symptoms
• reducing the rate of CVD-related mortality.

Studies are warranted to determine the value of (1) anti-inflammatory medications, such as N-acetylcysteine and infliximab and (2) anti-inflammatory combination therapy for this dual purpose. In fact, recruitment of subjects is underway for a study, Anti-Inflammatory Combination Therapy for the Treatment of Schizophrenia, at the University of Maryland (ClinicalTrials.gov Identifier: NCT01514682).

Consider 3 observations:

• Evidence is mounting that cytokine abnormalities are present in schizophrenia (Box^1-8).
• Reduced arterial compliance (change in volume divided by change in pressure [ΔV/ΔP] in an artery during the cardiac cycle) is an early marker of cardiovascular disease (CVD) and a robust predictor of mortality, and is associated with cytokine abnormalities.
• People with schizophrenia experience increased mortality from CVD.

Taken together, the 3 statements hint at a hypothesis: a common inflammatory process involving cytokine imbalance is associated with symptoms of schizophrenia, reduced arterial compliance, and CVD.

Anti-inflammatory therapeutics that target specific cytokines might both decrease psychiatric symptoms and reduce cardiac mortality in people with schizophrenia. In this article, we (1) highlight the potential role of anti-inflammatory medications in reducing both psychiatric symptoms and cardiac mortality in people with schizophrenia and (2) review the pathophysiological basis of this inflammatory commonality and the evidence for its presence in schizophrenia.

The ‘membrane hypothesis’ of schizophrenia
In this hypothesis, a disturbance in the synthesis and structure of membrane phospholipids results in a subsequent disturbance in the function of neuronal membrane proteins, which might be associated with symptoms and mortality in schizophrenia.^9-12 The synaptic vesicle protein synaptophysin, a marker for synaptic density, was found to be decreased in postmortem tissue from the gyrus cinguli in 11 patients with schizophrenia, compared with 13 controls.¹⁰ Intracellular phospholipases A₂ (inPLA₂) act as key enzymes in cell membrane repair and remodeling and in neuroplasticity, neurodevelopment, apoptosis, synaptic pruning, neurodegenerative processes, and neuroinflammation.

In a study, people with first-episode schizophrenia (n = 24) who were drug-naïve or off antipsychotic medication were compared with 25 healthy controls using voxel-based morphometry analysis of T₁ high-resolution MRI. inPLA₂ activity was increased in the patient group compared with controls; the analysis revealed abnormalities of the frontal and medial temporal cortices, hippocampus, and left-middle and superior temporal gyri in first-episode patients.¹¹ In another study, inPLA₂ activity was increased in 35 people with first-episode schizophrenia, compared with 22 controls, and was associated with symptom severity and outcome after 12 weeks of antipsychotic treatment.¹²

Early CVD mortality in schizophrenia
People with schizophrenia have an elevated rate of CVD compared with the general population; in part, this elevation is linked to magnified risk factors for CVD, including obesity, metabolic syndrome, cigarette smoking, and diabetes^13-17; furthermore, most antipsychotics can cause or worsen metabolic syndrome.¹⁷

CVD is one of the most common causes of death among people with schizophrenia.^17,18 Their life expectancy is reported to be 51 to 61 years—20 to 25 years less than what is seen in the general population.^19-21

Arterial compliance in schizophrenia
Reduced arterial compliance has been found to be a robust predictor of athero­sclerosis, stroke, and myocardial infarction^22-29:

• In 376 subjects who had routine diagnostic coronary angiography associated with coronary stenosis, arterial compliance was reduced significantly—even after controlling for age, sex, smoking, diabetes, hypertension, hyperlipidemia, and obesity.²⁴

In a cross-sectional study, 63 male U.S. veterans age 18 to 70 who had a psychiatric diagnosis (16 taking quetiapine, 19 taking risperidone, and 28 treated in the past but off antipsychotics for 2 months) had significantly reduced compliance in thigh- and calf-level arteries than male controls (n = 111), adjusting for body mass index and Framingham Risk Score (FRS). Of the 63 patients, 23 had a diagnosis of schizophrenia or schizoaffective disorder.³⁰ (The FRS is an estimate of a person’s 10-year cardiovascular risk, calculated using age, sex, total cholesterol, high-density lipoprotein, smoker or not, systolic blood pressure, and whether taking an antihypertensive or not. Compliance was measured using computerized plethysmography). Although not statistically significant, secondary analyses from this data set (n = 77, including men for whom factors for metabolic syndrome were available) showed that calf-level compliance (1.82 vs 2.06 mL) and thigh-level compliance (3.6 vs 4.26 mL; P = .06) were reduced in subjects with schizophrenia, compared with those who had another psychiatric diagnosis.³¹

• In another study, arterial compliance was significantly reduced in 10 subjects with schizophrenia, compared with 10 healthy controls.³²
• Last, reduced total arterial compliance has been shown to be a robust predictor of mortality in older people, compared with reduced local or regional arterial compliance.³³

Cytokine abnormalities in arterial compliance
The mechanism by which reduced arterial compliance is associated with cardiovascular pathology is not entirely clear. Arterial compliance is a predictor of cardiovascular disorders independent of hypertension.³⁴ Two studies show that vascular inflammation is associated with reduced arterial compliance.^35,36 Reduced arterial compliance is associated with increased angiotensin II activity; increased nicotinamide adenine dinucleotide phosphate oxidase activity; reduced nitric oxide activity; and increased reactive oxygen species.^37-39 Angiotensin-II signaling activates transforming growth factor-β, tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-17, IL-6, and C-reactive protein (CRP)—all of which are associated with reduced arterial compliance.^39-46 In addition, high-sensitivity CRP is significantly associated with reduced arterial compliance.^47-49

The overlap of cytokine abnormalities linked to schizophrenia and to arterial compliance is depicted in the Figure.

Anti-inflammatory medications and arterial compliance
Evidence suggests that anti-inflammatory medications increase arterial compliance:

• In 10 patients who had coronary artery disease or diabetes, or both, simvastatin (40 mg/d) was administered for 4 months. Arterial compliance improved in all 10 after 2 months of treatment and increased by 34% after 4 months.²⁷
• Evidence also suggests that the use of omega-3 fatty acids was associated with increased arterial compliance in people with dyslipidemia.⁵⁰
• Last, in people with rheumatoid arthritis, infliximab, a monoclonal antibody against TNF-Symbol Stdα, reduced aortic inflammation; this effect correlated with an increase in aortic compliance.⁵¹

Anti-inflammatory medications in schizophrenia
Two studies have yielded notable findings:

• A meta-analysis of 5 randomized controlled trials (RCTs) involving 264 subjects, comprising 4 studies of celecoxib and 1 of acetylsalicylic acid, had an effect size of 0.43 on total symptom severity. Investigators argued that acetylsalicylic acid might have the additional benefit of decreasing the risk of cardiac death in schizophrenia.⁵²
• A review of 26 RCTs examined the efficacy of anti-inflammatory medications on symptom severity in schizophrenia. Acetylsalicylic acid, N-acetylcysteine, and estrogens had an effect size of 0.3, 0.45, and 0.51, respectively.⁵³

Significance of these findings
A revelation that cytokine abnormalities are associated with schizophrenia symptoms and co-occurring somatic illness might offer an important new avenue of therapeutic discovery. On average, people with schizophrenia die 20 to 25 years earlier than the general population; CVD is the major cause of their death. Measuring arterial compliance, a novel noninvasive technology in psychiatry, as well as metabolic parameters, could serve as an early biomarker for assessing risk of CVD.

Implications for psychiatric practice. If inflammation plays a role in CVD in schizophrenia—either independently of factors such as metabolic syndrome, obesity, and smoking, or on the causal pathway linking these factors to reduced arterial compliance and to CVD—treatment with anti-inflammatory medications might reduce the alarming disparity of mortality that accompanies schizophrenia. In short, anti-inflammatory medications may offer a double benefit in this setting. Furthermore, success in this approach could spur clarification of the role of abnormal cytokines in other psychiatric disorders.

At this time, for your patients, consider that anti-inflammatory medications routinely used in medical practice, such as nonsteroidal anti-inflammatory drugs, omega-3 fatty acids, and statins, might alleviate psychiatric symptoms and might reduce cardiovascular mortality in schizophrenia.

Future directions
Perhaps only a limited number of cytokines are common to schizophrenia and reduced arterial compliance. Targeting those specific cytokines might, however, provide the dual benefit in schizophrenia of:

• alleviating symptoms
• reducing the rate of CVD-related mortality.

Studies are warranted to determine the value of (1) anti-inflammatory medications, such as N-acetylcysteine and infliximab and (2) anti-inflammatory combination therapy for this dual purpose. In fact, recruitment of subjects is underway for a study, Anti-Inflammatory Combination Therapy for the Treatment of Schizophrenia, at the University of Maryland (ClinicalTrials.gov Identifier: NCT01514682).

The Diagnosis: Primary Cutaneous Carcinosarcoma

A generous shave biopsy and debulking performed on the initial visit revealed an infiltrating tumor consisting of malignant epithelial and stromal components (Figure). The basaloid and squamoid epithelial cells were keratin positive. The stromal cells demonstrated positivity for CD10 but were keratin negative. The epithelial portion of the tumor was composed mostly of basaloid islands of cells with nuclear pleomorphism, scattered mitoses, and focal sebaceous differentiation. The mesenchymal portion of the tumor displayed florid pleomorphism and polymorphism, with many large atypical cells and proliferation. A diagnosis of primary cutaneous carcinosarcoma (PCC) was rendered. Head and neck computed tomography showed tumor penetration of less than 1 cm into scalp soft tissues with no involvement of the underlying bone. There was some evidence of swelling of the supragaleal soft tissues without indication of perineural spread. An 11-mm hyperlucent lower cervical lymph node on the left side that likely represented an incidental finding was noted. Surgical excision with margin evaluation was recommended, but the patient declined. He instead received radiation therapy to the left side of the posterior scalp with a total dose of 30 Gy at 6 Gy per fraction and 1 fraction daily. The patient was found to have a well-healed scar with no evidence of recurrence at 4-week follow-up and again at 5 months after radiation therapy.

A generous shave biopsy and debulking performed on the initial visit revealed an inflitrating tumor consisting on malignant epithelial and stromal components (A-C)(H&E; original magnifications ×10, ×20, and ×40, respectively).

Primary cutaneous carcinosarcoma is a rare biphasic neoplasm of unknown etiology that is characterized by the presence of both malignant epithelial and mesenchymal components.¹ Carcinosarcomas have been reported in both the male and female reproductive tracts, urinary tract, gastrointestinal tract, lungs, breasts, larynx, thymus, and thyroid but is uncommon as a primary neoplasm of the skin.² Epidermal PCC occurs with greater frequency in males than in females and typically presents in the eighth or ninth decades of life.³ These tumors tend to arise in sun-exposed regions, most commonly on the face and scalp.²

Morphologically, PCCs typically are exophytic growths that often feature surface ulceration and may or may not bleed upon palpation.⁴ Primary cutaneous carcinosarcomas may present as long-standing lesions that have undergone rapid transformation in the weeks preceding presentation.⁴ It is not uncommon for PCC lesions to carry the clinical diagnosis of squamous cell carcinoma, which suggests notable morphologic overlap between these entities. Histopathologically, PCC shows a basal cell carcinoma and/or a squamous cell carcinoma epithelial component intimately admixed with a sarcomatous component.⁵ The mesenchymal component of PCC typically resembles a superficial malignant fibrous histiocytoma characterized by pleomorphic nuclei and cytoplasm, necrosis, and an increased number of mitotic figures.² Immunohistochemistry can be beneficial in the diagnosis of PCC. A combination of p63 and AE1/AE3 stains can be used to confirm cells of epithelial origin. Staining with vimentin, CD10, or caldesmon can help to delineate the mesenchymal component of PCC.

Epidermal PCC most commonly affects elderly individuals with a history of extensive sun exposure. It has been suggested that p53 mutations due to UV damage are key in tumor formation for both epithelial and mesenchymal elements.⁵ Literature supports a monoclonal origin for the epithelial and mesenchymal components of this tumor; however, there is insufficient evidence.⁶ Surgical excision is the primary treatment modality for epidermal PCC, but adjuvant or substitutive radiotherapy has been used in some cases.⁴ The prognosis of PCC is notably better than its visceral counterpart due to early diagnosis and treatment of easily visible lesions. Epidermal PCC has a 70% 5-year disease-free survival rate, while adnexal PCC tends to occur in younger patients and has a 25% 5-year disease-free survival rate.³ Due to the rarity of reported cases and limited follow-up, the long-term prognosis for PCC remains unclear.

We report an unusual case of PCC on the scalp that was successfully treated with radiation therapy alone. This modality should be considered in patients with large tumors who refuse surgery or are not good surgical candidates.

The Diagnosis: Primary Cutaneous Carcinosarcoma

A generous shave biopsy and debulking performed on the initial visit revealed an infiltrating tumor consisting of malignant epithelial and stromal components (Figure). The basaloid and squamoid epithelial cells were keratin positive. The stromal cells demonstrated positivity for CD10 but were keratin negative. The epithelial portion of the tumor was composed mostly of basaloid islands of cells with nuclear pleomorphism, scattered mitoses, and focal sebaceous differentiation. The mesenchymal portion of the tumor displayed florid pleomorphism and polymorphism, with many large atypical cells and proliferation. A diagnosis of primary cutaneous carcinosarcoma (PCC) was rendered. Head and neck computed tomography showed tumor penetration of less than 1 cm into scalp soft tissues with no involvement of the underlying bone. There was some evidence of swelling of the supragaleal soft tissues without indication of perineural spread. An 11-mm hyperlucent lower cervical lymph node on the left side that likely represented an incidental finding was noted. Surgical excision with margin evaluation was recommended, but the patient declined. He instead received radiation therapy to the left side of the posterior scalp with a total dose of 30 Gy at 6 Gy per fraction and 1 fraction daily. The patient was found to have a well-healed scar with no evidence of recurrence at 4-week follow-up and again at 5 months after radiation therapy.

A generous shave biopsy and debulking performed on the initial visit revealed an inflitrating tumor consisting on malignant epithelial and stromal components (A-C)(H&E; original magnifications ×10, ×20, and ×40, respectively).

Primary cutaneous carcinosarcoma is a rare biphasic neoplasm of unknown etiology that is characterized by the presence of both malignant epithelial and mesenchymal components.¹ Carcinosarcomas have been reported in both the male and female reproductive tracts, urinary tract, gastrointestinal tract, lungs, breasts, larynx, thymus, and thyroid but is uncommon as a primary neoplasm of the skin.² Epidermal PCC occurs with greater frequency in males than in females and typically presents in the eighth or ninth decades of life.³ These tumors tend to arise in sun-exposed regions, most commonly on the face and scalp.²

Morphologically, PCCs typically are exophytic growths that often feature surface ulceration and may or may not bleed upon palpation.⁴ Primary cutaneous carcinosarcomas may present as long-standing lesions that have undergone rapid transformation in the weeks preceding presentation.⁴ It is not uncommon for PCC lesions to carry the clinical diagnosis of squamous cell carcinoma, which suggests notable morphologic overlap between these entities. Histopathologically, PCC shows a basal cell carcinoma and/or a squamous cell carcinoma epithelial component intimately admixed with a sarcomatous component.⁵ The mesenchymal component of PCC typically resembles a superficial malignant fibrous histiocytoma characterized by pleomorphic nuclei and cytoplasm, necrosis, and an increased number of mitotic figures.² Immunohistochemistry can be beneficial in the diagnosis of PCC. A combination of p63 and AE1/AE3 stains can be used to confirm cells of epithelial origin. Staining with vimentin, CD10, or caldesmon can help to delineate the mesenchymal component of PCC.

Epidermal PCC most commonly affects elderly individuals with a history of extensive sun exposure. It has been suggested that p53 mutations due to UV damage are key in tumor formation for both epithelial and mesenchymal elements.⁵ Literature supports a monoclonal origin for the epithelial and mesenchymal components of this tumor; however, there is insufficient evidence.⁶ Surgical excision is the primary treatment modality for epidermal PCC, but adjuvant or substitutive radiotherapy has been used in some cases.⁴ The prognosis of PCC is notably better than its visceral counterpart due to early diagnosis and treatment of easily visible lesions. Epidermal PCC has a 70% 5-year disease-free survival rate, while adnexal PCC tends to occur in younger patients and has a 25% 5-year disease-free survival rate.³ Due to the rarity of reported cases and limited follow-up, the long-term prognosis for PCC remains unclear.

We report an unusual case of PCC on the scalp that was successfully treated with radiation therapy alone. This modality should be considered in patients with large tumors who refuse surgery or are not good surgical candidates.

The Diagnosis: Primary Cutaneous Carcinosarcoma

A generous shave biopsy and debulking performed on the initial visit revealed an infiltrating tumor consisting of malignant epithelial and stromal components (Figure). The basaloid and squamoid epithelial cells were keratin positive. The stromal cells demonstrated positivity for CD10 but were keratin negative. The epithelial portion of the tumor was composed mostly of basaloid islands of cells with nuclear pleomorphism, scattered mitoses, and focal sebaceous differentiation. The mesenchymal portion of the tumor displayed florid pleomorphism and polymorphism, with many large atypical cells and proliferation. A diagnosis of primary cutaneous carcinosarcoma (PCC) was rendered. Head and neck computed tomography showed tumor penetration of less than 1 cm into scalp soft tissues with no involvement of the underlying bone. There was some evidence of swelling of the supragaleal soft tissues without indication of perineural spread. An 11-mm hyperlucent lower cervical lymph node on the left side that likely represented an incidental finding was noted. Surgical excision with margin evaluation was recommended, but the patient declined. He instead received radiation therapy to the left side of the posterior scalp with a total dose of 30 Gy at 6 Gy per fraction and 1 fraction daily. The patient was found to have a well-healed scar with no evidence of recurrence at 4-week follow-up and again at 5 months after radiation therapy.

A generous shave biopsy and debulking performed on the initial visit revealed an inflitrating tumor consisting on malignant epithelial and stromal components (A-C)(H&E; original magnifications ×10, ×20, and ×40, respectively).

Primary cutaneous carcinosarcoma is a rare biphasic neoplasm of unknown etiology that is characterized by the presence of both malignant epithelial and mesenchymal components.¹ Carcinosarcomas have been reported in both the male and female reproductive tracts, urinary tract, gastrointestinal tract, lungs, breasts, larynx, thymus, and thyroid but is uncommon as a primary neoplasm of the skin.² Epidermal PCC occurs with greater frequency in males than in females and typically presents in the eighth or ninth decades of life.³ These tumors tend to arise in sun-exposed regions, most commonly on the face and scalp.²

Morphologically, PCCs typically are exophytic growths that often feature surface ulceration and may or may not bleed upon palpation.⁴ Primary cutaneous carcinosarcomas may present as long-standing lesions that have undergone rapid transformation in the weeks preceding presentation.⁴ It is not uncommon for PCC lesions to carry the clinical diagnosis of squamous cell carcinoma, which suggests notable morphologic overlap between these entities. Histopathologically, PCC shows a basal cell carcinoma and/or a squamous cell carcinoma epithelial component intimately admixed with a sarcomatous component.⁵ The mesenchymal component of PCC typically resembles a superficial malignant fibrous histiocytoma characterized by pleomorphic nuclei and cytoplasm, necrosis, and an increased number of mitotic figures.² Immunohistochemistry can be beneficial in the diagnosis of PCC. A combination of p63 and AE1/AE3 stains can be used to confirm cells of epithelial origin. Staining with vimentin, CD10, or caldesmon can help to delineate the mesenchymal component of PCC.

Epidermal PCC most commonly affects elderly individuals with a history of extensive sun exposure. It has been suggested that p53 mutations due to UV damage are key in tumor formation for both epithelial and mesenchymal elements.⁵ Literature supports a monoclonal origin for the epithelial and mesenchymal components of this tumor; however, there is insufficient evidence.⁶ Surgical excision is the primary treatment modality for epidermal PCC, but adjuvant or substitutive radiotherapy has been used in some cases.⁴ The prognosis of PCC is notably better than its visceral counterpart due to early diagnosis and treatment of easily visible lesions. Epidermal PCC has a 70% 5-year disease-free survival rate, while adnexal PCC tends to occur in younger patients and has a 25% 5-year disease-free survival rate.³ Due to the rarity of reported cases and limited follow-up, the long-term prognosis for PCC remains unclear.

We report an unusual case of PCC on the scalp that was successfully treated with radiation therapy alone. This modality should be considered in patients with large tumors who refuse surgery or are not good surgical candidates.

Many older patients are concerned about their memory. The “worried well” may come into your office with a list of things they can’t recall, yet they remember each “deficit” quite well. Anticipatory anxiety about one’s own decline is common, and is most often concerned with changes in memory.^1,2

Patients with dementia or early cognitive decline often are oblivious to their cognitive changes, however. Of particular concern is progressive dementia, especially Alzheimer’s disease (AD). Although jokes about “senior moments” are common, concern about AD incurs deep-seated worry. It is essential for clinicians to differentiate normal cognitive changes of aging—particularly those in memory—from early signs of neurodegenerative disease (Table 1³).

In this article, we review typical memory changes in persons age >65, and differentiate these from mild cognitive impairment (MCI), an increasingly recognized prodrome of AD. Clinicians armed with knowledge of MCI are able to reassure the worried well, or recommend neuropsychological testing as indicated.

Is memory change inevitable with aging?
Memory loss is a common problem in aging, with variable severity. Research is establishing norms in cognitive functioning through the ninth decade of life.⁴ Controversy about sampling, measures, and methods abound,⁵ and drives prolific research on the subject, which is beyond the scope of this article. It has been demonstrated that there are a few “optimally aging” persons who avoid memory decline altogether.^5,6 Most researchers and clinicians agree, however, that memory change is pervasive with advancing age.

Memory change follows a gradient with recent memories lost to a greater degree than remote memories (Ribot’s Law).⁷ Forgetfulness is characteristic of normal aging, and frequently manifests with misplaced objects and short-term lapses. However, this is not pathological—as long as the item or memory is recalled within 24 to 48 hours.

Compared with younger adults, healthy older adults are less efficient at encoding new information. Subsequently, they have more difficulty retrieving data, particularly after a delay. The time needed to learn and use new information increases, which is referred to as processing inefficiency. This influences changes in test performance across all cognitive domains, with decreases in measures of mental processing speed, working memory, and problem-solving.

Many patients who complain about “forgetfulness” are experiencing this normal change. It is not uncommon for a patient to offer a list of things she has forgotten recently, along with the dates and circumstances in which she forgot them. Because she sometimes forgets things, but remembers them later, there likely is nothing to worry about. If reminders—such as her list—help, this too is a good sign, because it shows her resourcefulness in using accommodations. If the patient is managing her normal activities, reassurance is warranted.

Mild cognitive impairment
Since at least 1958,⁸ clinical observations and research have recognized a prodrome that differentiates cognitive changes predictive of dementia from those that represent typical aging. Several studies and methods have converged toward consensus that MCI is a valid construct for that purpose, with ecological validity and sound predictive value. Clinical value is evident when a patient does not meet criteria for MCI; in this case, the clinician can reassure the worried well with conviction.

Revealing the diagnosis of MCI to patients requires sensitivity and assurance that you will reevaluate the condition annually. Although there is no evidence-based remedy for MCI or means to slow its progression to dementia, data are rapidly accruing regarding the value of lifestyle changes and other nonpharmacologic interventions.⁹

Recognizing MCI most simply requires 2 criteria:

The patient’s expressed concern about decline in cognitive functioning from a previous level of performance. Alternately, a caretaker’s report is valuable because the patient might lack insight. You are not looking for an inability to perform activities of daily living, which is indicative of frank dementia; rather, you want to determine whether the person’s independence in functional abilities is preserved, although less efficient. Patients might repeatedly report occurrences of new problems, although modest, in some cases. Although problems with memory often are the most frequently reported symptoms, changes can be observed in any cognitive domain. Uncharacteristic inability to understand instructions, frustration with new tasks, and inflexibility are common.

Quantified clinical assessment that the patient’s cognitive decline exceeds norms of his age cohort. Clinicians are already familiar with many of these tests (5-minute recall, clock face drawing, etc.). For MCI, we recommend the Montreal Cognitive Assessment (MoCA), which is specifically designed for MCI.¹⁰ It takes only 10 minutes to administer. Multiple versions of the MoCA, and instructions for its administration are available for provider use at www.mocatest.org.

When these criteria are met—a decline in previous functioning and an objective clinical confirmation—referral for neuropsychological testing is recommended. Subtypes of MCI—amnestic and non-amnestic—have been employed to specify the subtype (amnesic) that is most consistent with prodromal AD. However, this dichotomous scheme does not adequately explain or capture the heterogeneity of MCI.^11,12

Medical considerations
Just as all domains of cognition are correlated to some degree, the overall health status of a person influences evaluation of memory. Variables, such as fatigue, test anxiety, mood, motivation, visual and auditory acuity, education, language fluency, attention, and pain, affect test performance. In addition, clinician rapport and the manner in which tests are administered must be considered.

Depression can mimic MCI. A depressed patient often has poor expectations of himself and slowed thinking, and might exaggerate symptoms. He might give up on tests or refuse to complete them. His presentation initially could suggest cognitive decline, but depression is revealed when the clinician pays attention to vegetative signs (insomnia, poor appetite) or suicidal ideation. There is growing evidence that subjective complaints of memory loss are more frequently associated with depression than with objective measures of cognitive impairment.^13,14

Other treatable conditions can present with cognitive change (the so-called reversible dementias). A deficiency of vitamin B₁₂, thiamine, or folate often is seen because quality of nutrition generally decreases with age. Hyponatremia and dehydration can present with confusion and memory impairment. Other treatable conditions include:

• cerebral vasculitis, which could improve with immune suppressants
• endocrine diseases, which might respond to hormonal or surgical treatment
• normal pressure hydrocephalus, which can be relieved by surgical placement of a shunt.

Take a complete history. What exactly is the nature of the patient or caregiver’s complaint? You need to attempt to engage the patient in conversation, observing his behavior during the evaluation. Is there notable delay in response, difficulty in attention and focus, or in understanding questions?

The content of speech is an indicator of the patient’s information processing. Ask the patient to recite as many animals from the jungle as possible. Most people can come up with at least 15. The person with MCI will likely name fewer animals, but may respond well to cueing, and perform better in recognition (eg, pictures or drawings) vs retrieval. When asked to describe a typical day, the patient may offer a vague, nonchalant response eg, “I keep busy watching the news.” This kind of response may be evidence of confabulation; with further questioning, he is unable to identify current issues of interest.

Substance abuse. It is essential that clinicians recognize that elders are not exempt from alcohol and other drug abuse that affects cognition. Skilled history taking, including attention to non-verbal responses, is indicated. A defensive tone, rolling of eyes, or silent yet affirmative nodding are means by which caregivers offer essential “clues” to the provider.

A quick screening tool for the office is valuable; many clinicians are most familiar with the Mini-Mental State Examination or the Saint Louis University Mental Status Examination, which are known to be sensitive in detecting memory problems and other cognitive defects. As we noted, the MoCA is now recommended for differentiating more subtle changes of MCI.^10,15 It is important to remember that common conditions such as an urinary tract infection or trauma after anesthesia for routine procedures such as colonoscopy can cause cognitive impairment. Again, eliciting history from a family member is valuable because the patient may have forgotten vital data.

A good physical exam is important when evaluating for dementia. Look for any neurologic anomaly. Check for disinhibition of primitive reflexes, eg, abnormal grasp or snout response or Babinski sign. Compare the symmetry and strength of deep tendon reflexes. Look for neurologic soft signs. Any pathological reflex response can be an important clue about neurodegeneration or space-occupying lesions. We recall seeing a 62-year-old man whose spouse brought him for evaluation for new-onset reckless driving and marked inattention to personal hygiene that developed over the previous 3 months. On examination, he appeared disheveled and had a dull affect, although disinhibited and careless. His mentation and gait were slowed. He denied distress of any kind. Frontal release signs were noted on exam. An MRI revealed a space-occupying lesion of the frontal lobe measuring 3 cm wide with a thickness of 2 cm, which pathology confirmed as a benign tumor.

Always check for arrhythmia and hypertension. These are significant risk factors for ischemic brain disease, multiple-infarct stroke, or other forms of vascular dementia. A shuffling gait suggests Parkinson’s disease, or even Lewy body dementia, or medication-related conditions, for example, from antipsychotics.

Take a medication history. Many common treatments for anxiety and insomnia can cause symptoms that mimic dementia. Digitalis toxicity results in poor recall and confusion. Combinations of common medicines (antacids, antihistamines, and others) compete for metabolic pathways and lead to altered mental status. Referencing the Beers List¹⁶ is valuable; anticholinergics, benzodiazepines, and narcotic analgesics are of special concern. The latter could still be useful for comfort care at the end of life.

It is common for seniors to take a variety of untested and unproven supplements in the hope of preventing or lessening memory problems. In addition to incurring significant costs, the indiscriminate use of supplements poses risks of toxicity, including unintended interactions with prescribed medications. Many older adults do not disclose their use of these supplements to providers because they do not consider them “medicine.”

Labs. The next level of evaluation calls for a basic laboratory workup. Check complete blood count, liver enzymes, thyroid function tests, vitamin D, B₁₂ and folate levels; perform urinalysis and a complete metabolic panel. Look at a general hormone panel; abnormal values could reveal a pituitary adenoma. (In the past 33 years, the first author has found 42 pituitary tumors in the workup of mental status change.)

We use imaging, such as a CT or MRI of the brain, in almost all cases of suspected dementia. Cerebral atrophy, space-occupying lesions, and shifting of the ventricles often correspond with cognitive decline.

Treatment
Effective treatment of dementia remains elusive. Other than for the “reversible dementias,” pharmacotherapy has shown less progress than had been expected. Donepezil, galantamine, rivastigmine, and memantine could slow disease progression in some cases. There have been many studies for dementia preventives and treatments. Extensive reviews and meta-analyses, including those of randomized controlled trials^17-19 abound for a variety of herbs, supplements, and antioxidants; none have shown compelling results. Table 2 lists Institute of Medicine recommendations supported by evidence that could reduce effects of cognitive aging.²⁰

Summing up
Older adults are a heterogeneous group. Intellectual capacity does not diminish with advancing age. Many elders now exceed expectations for productivity, athletic ability, scientific achievement, and the creative arts. Others live longer with diminished quality of life, their health compromised by progressive neurodegenerative disease.

Age-associated memory change often is exaggerated and feared by older adults and, regrettably, is associated with inevitable functional impairment and is seen as heralding the loss of autonomy. The worried well are anxious, although the stigma associated with cognitive decline may preclude confiding their concerns.

Providers need the tools and acumen to treat patients along an increasingly long continuum of time, including conveyance of evidence-based encouragement toward optimal health and vitality.

Many older patients are concerned about their memory. The “worried well” may come into your office with a list of things they can’t recall, yet they remember each “deficit” quite well. Anticipatory anxiety about one’s own decline is common, and is most often concerned with changes in memory.^1,2

Patients with dementia or early cognitive decline often are oblivious to their cognitive changes, however. Of particular concern is progressive dementia, especially Alzheimer’s disease (AD). Although jokes about “senior moments” are common, concern about AD incurs deep-seated worry. It is essential for clinicians to differentiate normal cognitive changes of aging—particularly those in memory—from early signs of neurodegenerative disease (Table 1³).

In this article, we review typical memory changes in persons age >65, and differentiate these from mild cognitive impairment (MCI), an increasingly recognized prodrome of AD. Clinicians armed with knowledge of MCI are able to reassure the worried well, or recommend neuropsychological testing as indicated.

Is memory change inevitable with aging?
Memory loss is a common problem in aging, with variable severity. Research is establishing norms in cognitive functioning through the ninth decade of life.⁴ Controversy about sampling, measures, and methods abound,⁵ and drives prolific research on the subject, which is beyond the scope of this article. It has been demonstrated that there are a few “optimally aging” persons who avoid memory decline altogether.^5,6 Most researchers and clinicians agree, however, that memory change is pervasive with advancing age.

Memory change follows a gradient with recent memories lost to a greater degree than remote memories (Ribot’s Law).⁷ Forgetfulness is characteristic of normal aging, and frequently manifests with misplaced objects and short-term lapses. However, this is not pathological—as long as the item or memory is recalled within 24 to 48 hours.

Compared with younger adults, healthy older adults are less efficient at encoding new information. Subsequently, they have more difficulty retrieving data, particularly after a delay. The time needed to learn and use new information increases, which is referred to as processing inefficiency. This influences changes in test performance across all cognitive domains, with decreases in measures of mental processing speed, working memory, and problem-solving.

Many patients who complain about “forgetfulness” are experiencing this normal change. It is not uncommon for a patient to offer a list of things she has forgotten recently, along with the dates and circumstances in which she forgot them. Because she sometimes forgets things, but remembers them later, there likely is nothing to worry about. If reminders—such as her list—help, this too is a good sign, because it shows her resourcefulness in using accommodations. If the patient is managing her normal activities, reassurance is warranted.

Mild cognitive impairment
Since at least 1958,⁸ clinical observations and research have recognized a prodrome that differentiates cognitive changes predictive of dementia from those that represent typical aging. Several studies and methods have converged toward consensus that MCI is a valid construct for that purpose, with ecological validity and sound predictive value. Clinical value is evident when a patient does not meet criteria for MCI; in this case, the clinician can reassure the worried well with conviction.

Revealing the diagnosis of MCI to patients requires sensitivity and assurance that you will reevaluate the condition annually. Although there is no evidence-based remedy for MCI or means to slow its progression to dementia, data are rapidly accruing regarding the value of lifestyle changes and other nonpharmacologic interventions.⁹

Recognizing MCI most simply requires 2 criteria:

The patient’s expressed concern about decline in cognitive functioning from a previous level of performance. Alternately, a caretaker’s report is valuable because the patient might lack insight. You are not looking for an inability to perform activities of daily living, which is indicative of frank dementia; rather, you want to determine whether the person’s independence in functional abilities is preserved, although less efficient. Patients might repeatedly report occurrences of new problems, although modest, in some cases. Although problems with memory often are the most frequently reported symptoms, changes can be observed in any cognitive domain. Uncharacteristic inability to understand instructions, frustration with new tasks, and inflexibility are common.

Quantified clinical assessment that the patient’s cognitive decline exceeds norms of his age cohort. Clinicians are already familiar with many of these tests (5-minute recall, clock face drawing, etc.). For MCI, we recommend the Montreal Cognitive Assessment (MoCA), which is specifically designed for MCI.¹⁰ It takes only 10 minutes to administer. Multiple versions of the MoCA, and instructions for its administration are available for provider use at www.mocatest.org.

When these criteria are met—a decline in previous functioning and an objective clinical confirmation—referral for neuropsychological testing is recommended. Subtypes of MCI—amnestic and non-amnestic—have been employed to specify the subtype (amnesic) that is most consistent with prodromal AD. However, this dichotomous scheme does not adequately explain or capture the heterogeneity of MCI.^11,12

Medical considerations
Just as all domains of cognition are correlated to some degree, the overall health status of a person influences evaluation of memory. Variables, such as fatigue, test anxiety, mood, motivation, visual and auditory acuity, education, language fluency, attention, and pain, affect test performance. In addition, clinician rapport and the manner in which tests are administered must be considered.

Depression can mimic MCI. A depressed patient often has poor expectations of himself and slowed thinking, and might exaggerate symptoms. He might give up on tests or refuse to complete them. His presentation initially could suggest cognitive decline, but depression is revealed when the clinician pays attention to vegetative signs (insomnia, poor appetite) or suicidal ideation. There is growing evidence that subjective complaints of memory loss are more frequently associated with depression than with objective measures of cognitive impairment.^13,14

Other treatable conditions can present with cognitive change (the so-called reversible dementias). A deficiency of vitamin B₁₂, thiamine, or folate often is seen because quality of nutrition generally decreases with age. Hyponatremia and dehydration can present with confusion and memory impairment. Other treatable conditions include:

• cerebral vasculitis, which could improve with immune suppressants
• endocrine diseases, which might respond to hormonal or surgical treatment
• normal pressure hydrocephalus, which can be relieved by surgical placement of a shunt.

Take a complete history. What exactly is the nature of the patient or caregiver’s complaint? You need to attempt to engage the patient in conversation, observing his behavior during the evaluation. Is there notable delay in response, difficulty in attention and focus, or in understanding questions?

The content of speech is an indicator of the patient’s information processing. Ask the patient to recite as many animals from the jungle as possible. Most people can come up with at least 15. The person with MCI will likely name fewer animals, but may respond well to cueing, and perform better in recognition (eg, pictures or drawings) vs retrieval. When asked to describe a typical day, the patient may offer a vague, nonchalant response eg, “I keep busy watching the news.” This kind of response may be evidence of confabulation; with further questioning, he is unable to identify current issues of interest.

Substance abuse. It is essential that clinicians recognize that elders are not exempt from alcohol and other drug abuse that affects cognition. Skilled history taking, including attention to non-verbal responses, is indicated. A defensive tone, rolling of eyes, or silent yet affirmative nodding are means by which caregivers offer essential “clues” to the provider.

A quick screening tool for the office is valuable; many clinicians are most familiar with the Mini-Mental State Examination or the Saint Louis University Mental Status Examination, which are known to be sensitive in detecting memory problems and other cognitive defects. As we noted, the MoCA is now recommended for differentiating more subtle changes of MCI.^10,15 It is important to remember that common conditions such as an urinary tract infection or trauma after anesthesia for routine procedures such as colonoscopy can cause cognitive impairment. Again, eliciting history from a family member is valuable because the patient may have forgotten vital data.

A good physical exam is important when evaluating for dementia. Look for any neurologic anomaly. Check for disinhibition of primitive reflexes, eg, abnormal grasp or snout response or Babinski sign. Compare the symmetry and strength of deep tendon reflexes. Look for neurologic soft signs. Any pathological reflex response can be an important clue about neurodegeneration or space-occupying lesions. We recall seeing a 62-year-old man whose spouse brought him for evaluation for new-onset reckless driving and marked inattention to personal hygiene that developed over the previous 3 months. On examination, he appeared disheveled and had a dull affect, although disinhibited and careless. His mentation and gait were slowed. He denied distress of any kind. Frontal release signs were noted on exam. An MRI revealed a space-occupying lesion of the frontal lobe measuring 3 cm wide with a thickness of 2 cm, which pathology confirmed as a benign tumor.

Always check for arrhythmia and hypertension. These are significant risk factors for ischemic brain disease, multiple-infarct stroke, or other forms of vascular dementia. A shuffling gait suggests Parkinson’s disease, or even Lewy body dementia, or medication-related conditions, for example, from antipsychotics.

Take a medication history. Many common treatments for anxiety and insomnia can cause symptoms that mimic dementia. Digitalis toxicity results in poor recall and confusion. Combinations of common medicines (antacids, antihistamines, and others) compete for metabolic pathways and lead to altered mental status. Referencing the Beers List¹⁶ is valuable; anticholinergics, benzodiazepines, and narcotic analgesics are of special concern. The latter could still be useful for comfort care at the end of life.

It is common for seniors to take a variety of untested and unproven supplements in the hope of preventing or lessening memory problems. In addition to incurring significant costs, the indiscriminate use of supplements poses risks of toxicity, including unintended interactions with prescribed medications. Many older adults do not disclose their use of these supplements to providers because they do not consider them “medicine.”

Labs. The next level of evaluation calls for a basic laboratory workup. Check complete blood count, liver enzymes, thyroid function tests, vitamin D, B₁₂ and folate levels; perform urinalysis and a complete metabolic panel. Look at a general hormone panel; abnormal values could reveal a pituitary adenoma. (In the past 33 years, the first author has found 42 pituitary tumors in the workup of mental status change.)

We use imaging, such as a CT or MRI of the brain, in almost all cases of suspected dementia. Cerebral atrophy, space-occupying lesions, and shifting of the ventricles often correspond with cognitive decline.

Treatment
Effective treatment of dementia remains elusive. Other than for the “reversible dementias,” pharmacotherapy has shown less progress than had been expected. Donepezil, galantamine, rivastigmine, and memantine could slow disease progression in some cases. There have been many studies for dementia preventives and treatments. Extensive reviews and meta-analyses, including those of randomized controlled trials^17-19 abound for a variety of herbs, supplements, and antioxidants; none have shown compelling results. Table 2 lists Institute of Medicine recommendations supported by evidence that could reduce effects of cognitive aging.²⁰

Summing up
Older adults are a heterogeneous group. Intellectual capacity does not diminish with advancing age. Many elders now exceed expectations for productivity, athletic ability, scientific achievement, and the creative arts. Others live longer with diminished quality of life, their health compromised by progressive neurodegenerative disease.

Age-associated memory change often is exaggerated and feared by older adults and, regrettably, is associated with inevitable functional impairment and is seen as heralding the loss of autonomy. The worried well are anxious, although the stigma associated with cognitive decline may preclude confiding their concerns.

Providers need the tools and acumen to treat patients along an increasingly long continuum of time, including conveyance of evidence-based encouragement toward optimal health and vitality.

Many older patients are concerned about their memory. The “worried well” may come into your office with a list of things they can’t recall, yet they remember each “deficit” quite well. Anticipatory anxiety about one’s own decline is common, and is most often concerned with changes in memory.^1,2

Patients with dementia or early cognitive decline often are oblivious to their cognitive changes, however. Of particular concern is progressive dementia, especially Alzheimer’s disease (AD). Although jokes about “senior moments” are common, concern about AD incurs deep-seated worry. It is essential for clinicians to differentiate normal cognitive changes of aging—particularly those in memory—from early signs of neurodegenerative disease (Table 1³).

In this article, we review typical memory changes in persons age >65, and differentiate these from mild cognitive impairment (MCI), an increasingly recognized prodrome of AD. Clinicians armed with knowledge of MCI are able to reassure the worried well, or recommend neuropsychological testing as indicated.

Is memory change inevitable with aging?
Memory loss is a common problem in aging, with variable severity. Research is establishing norms in cognitive functioning through the ninth decade of life.⁴ Controversy about sampling, measures, and methods abound,⁵ and drives prolific research on the subject, which is beyond the scope of this article. It has been demonstrated that there are a few “optimally aging” persons who avoid memory decline altogether.^5,6 Most researchers and clinicians agree, however, that memory change is pervasive with advancing age.

Memory change follows a gradient with recent memories lost to a greater degree than remote memories (Ribot’s Law).⁷ Forgetfulness is characteristic of normal aging, and frequently manifests with misplaced objects and short-term lapses. However, this is not pathological—as long as the item or memory is recalled within 24 to 48 hours.

Compared with younger adults, healthy older adults are less efficient at encoding new information. Subsequently, they have more difficulty retrieving data, particularly after a delay. The time needed to learn and use new information increases, which is referred to as processing inefficiency. This influences changes in test performance across all cognitive domains, with decreases in measures of mental processing speed, working memory, and problem-solving.

Many patients who complain about “forgetfulness” are experiencing this normal change. It is not uncommon for a patient to offer a list of things she has forgotten recently, along with the dates and circumstances in which she forgot them. Because she sometimes forgets things, but remembers them later, there likely is nothing to worry about. If reminders—such as her list—help, this too is a good sign, because it shows her resourcefulness in using accommodations. If the patient is managing her normal activities, reassurance is warranted.

Mild cognitive impairment
Since at least 1958,⁸ clinical observations and research have recognized a prodrome that differentiates cognitive changes predictive of dementia from those that represent typical aging. Several studies and methods have converged toward consensus that MCI is a valid construct for that purpose, with ecological validity and sound predictive value. Clinical value is evident when a patient does not meet criteria for MCI; in this case, the clinician can reassure the worried well with conviction.

Revealing the diagnosis of MCI to patients requires sensitivity and assurance that you will reevaluate the condition annually. Although there is no evidence-based remedy for MCI or means to slow its progression to dementia, data are rapidly accruing regarding the value of lifestyle changes and other nonpharmacologic interventions.⁹

Recognizing MCI most simply requires 2 criteria:

The patient’s expressed concern about decline in cognitive functioning from a previous level of performance. Alternately, a caretaker’s report is valuable because the patient might lack insight. You are not looking for an inability to perform activities of daily living, which is indicative of frank dementia; rather, you want to determine whether the person’s independence in functional abilities is preserved, although less efficient. Patients might repeatedly report occurrences of new problems, although modest, in some cases. Although problems with memory often are the most frequently reported symptoms, changes can be observed in any cognitive domain. Uncharacteristic inability to understand instructions, frustration with new tasks, and inflexibility are common.

Quantified clinical assessment that the patient’s cognitive decline exceeds norms of his age cohort. Clinicians are already familiar with many of these tests (5-minute recall, clock face drawing, etc.). For MCI, we recommend the Montreal Cognitive Assessment (MoCA), which is specifically designed for MCI.¹⁰ It takes only 10 minutes to administer. Multiple versions of the MoCA, and instructions for its administration are available for provider use at www.mocatest.org.

When these criteria are met—a decline in previous functioning and an objective clinical confirmation—referral for neuropsychological testing is recommended. Subtypes of MCI—amnestic and non-amnestic—have been employed to specify the subtype (amnesic) that is most consistent with prodromal AD. However, this dichotomous scheme does not adequately explain or capture the heterogeneity of MCI.^11,12

Medical considerations
Just as all domains of cognition are correlated to some degree, the overall health status of a person influences evaluation of memory. Variables, such as fatigue, test anxiety, mood, motivation, visual and auditory acuity, education, language fluency, attention, and pain, affect test performance. In addition, clinician rapport and the manner in which tests are administered must be considered.

Depression can mimic MCI. A depressed patient often has poor expectations of himself and slowed thinking, and might exaggerate symptoms. He might give up on tests or refuse to complete them. His presentation initially could suggest cognitive decline, but depression is revealed when the clinician pays attention to vegetative signs (insomnia, poor appetite) or suicidal ideation. There is growing evidence that subjective complaints of memory loss are more frequently associated with depression than with objective measures of cognitive impairment.^13,14

Other treatable conditions can present with cognitive change (the so-called reversible dementias). A deficiency of vitamin B₁₂, thiamine, or folate often is seen because quality of nutrition generally decreases with age. Hyponatremia and dehydration can present with confusion and memory impairment. Other treatable conditions include:

• cerebral vasculitis, which could improve with immune suppressants
• endocrine diseases, which might respond to hormonal or surgical treatment
• normal pressure hydrocephalus, which can be relieved by surgical placement of a shunt.

Take a complete history. What exactly is the nature of the patient or caregiver’s complaint? You need to attempt to engage the patient in conversation, observing his behavior during the evaluation. Is there notable delay in response, difficulty in attention and focus, or in understanding questions?

The content of speech is an indicator of the patient’s information processing. Ask the patient to recite as many animals from the jungle as possible. Most people can come up with at least 15. The person with MCI will likely name fewer animals, but may respond well to cueing, and perform better in recognition (eg, pictures or drawings) vs retrieval. When asked to describe a typical day, the patient may offer a vague, nonchalant response eg, “I keep busy watching the news.” This kind of response may be evidence of confabulation; with further questioning, he is unable to identify current issues of interest.

Substance abuse. It is essential that clinicians recognize that elders are not exempt from alcohol and other drug abuse that affects cognition. Skilled history taking, including attention to non-verbal responses, is indicated. A defensive tone, rolling of eyes, or silent yet affirmative nodding are means by which caregivers offer essential “clues” to the provider.

A quick screening tool for the office is valuable; many clinicians are most familiar with the Mini-Mental State Examination or the Saint Louis University Mental Status Examination, which are known to be sensitive in detecting memory problems and other cognitive defects. As we noted, the MoCA is now recommended for differentiating more subtle changes of MCI.^10,15 It is important to remember that common conditions such as an urinary tract infection or trauma after anesthesia for routine procedures such as colonoscopy can cause cognitive impairment. Again, eliciting history from a family member is valuable because the patient may have forgotten vital data.

A good physical exam is important when evaluating for dementia. Look for any neurologic anomaly. Check for disinhibition of primitive reflexes, eg, abnormal grasp or snout response or Babinski sign. Compare the symmetry and strength of deep tendon reflexes. Look for neurologic soft signs. Any pathological reflex response can be an important clue about neurodegeneration or space-occupying lesions. We recall seeing a 62-year-old man whose spouse brought him for evaluation for new-onset reckless driving and marked inattention to personal hygiene that developed over the previous 3 months. On examination, he appeared disheveled and had a dull affect, although disinhibited and careless. His mentation and gait were slowed. He denied distress of any kind. Frontal release signs were noted on exam. An MRI revealed a space-occupying lesion of the frontal lobe measuring 3 cm wide with a thickness of 2 cm, which pathology confirmed as a benign tumor.

Always check for arrhythmia and hypertension. These are significant risk factors for ischemic brain disease, multiple-infarct stroke, or other forms of vascular dementia. A shuffling gait suggests Parkinson’s disease, or even Lewy body dementia, or medication-related conditions, for example, from antipsychotics.

Take a medication history. Many common treatments for anxiety and insomnia can cause symptoms that mimic dementia. Digitalis toxicity results in poor recall and confusion. Combinations of common medicines (antacids, antihistamines, and others) compete for metabolic pathways and lead to altered mental status. Referencing the Beers List¹⁶ is valuable; anticholinergics, benzodiazepines, and narcotic analgesics are of special concern. The latter could still be useful for comfort care at the end of life.

It is common for seniors to take a variety of untested and unproven supplements in the hope of preventing or lessening memory problems. In addition to incurring significant costs, the indiscriminate use of supplements poses risks of toxicity, including unintended interactions with prescribed medications. Many older adults do not disclose their use of these supplements to providers because they do not consider them “medicine.”

Labs. The next level of evaluation calls for a basic laboratory workup. Check complete blood count, liver enzymes, thyroid function tests, vitamin D, B₁₂ and folate levels; perform urinalysis and a complete metabolic panel. Look at a general hormone panel; abnormal values could reveal a pituitary adenoma. (In the past 33 years, the first author has found 42 pituitary tumors in the workup of mental status change.)

We use imaging, such as a CT or MRI of the brain, in almost all cases of suspected dementia. Cerebral atrophy, space-occupying lesions, and shifting of the ventricles often correspond with cognitive decline.

Treatment
Effective treatment of dementia remains elusive. Other than for the “reversible dementias,” pharmacotherapy has shown less progress than had been expected. Donepezil, galantamine, rivastigmine, and memantine could slow disease progression in some cases. There have been many studies for dementia preventives and treatments. Extensive reviews and meta-analyses, including those of randomized controlled trials^17-19 abound for a variety of herbs, supplements, and antioxidants; none have shown compelling results. Table 2 lists Institute of Medicine recommendations supported by evidence that could reduce effects of cognitive aging.²⁰

Summing up
Older adults are a heterogeneous group. Intellectual capacity does not diminish with advancing age. Many elders now exceed expectations for productivity, athletic ability, scientific achievement, and the creative arts. Others live longer with diminished quality of life, their health compromised by progressive neurodegenerative disease.

Age-associated memory change often is exaggerated and feared by older adults and, regrettably, is associated with inevitable functional impairment and is seen as heralding the loss of autonomy. The worried well are anxious, although the stigma associated with cognitive decline may preclude confiding their concerns.

Providers need the tools and acumen to treat patients along an increasingly long continuum of time, including conveyance of evidence-based encouragement toward optimal health and vitality.

If an individual with schizophrenia presents to the emergency department, there’s about a 1 in 2 chance that person will wind up in an inpatient psychiatric bed, or transferred to a residential psychiatric facility. As reimbursement to hospitals for psychiatric beds decreases, there’s decreasing incentive for hospitals to maintain inpatient psychiatry services.

Decreasing numbers of hospital beds means strategic thinking about outpatient services is more important than ever, to help avert the crises that bring patients to EDs and to run-ins with the justice system. In some parts of the country, though, the downstream effects of cutbacks and increased demand are overwhelming the system.

For Dr. Carl C. Bell, the combination of shrinking resources and growing need feels like a prescription for disaster in Chicago. Dr. Bell, a psychiatrist who has spent decades providing community mental health services there, saw a relatively robust mental health infrastructure crumble when municipal belt tightening resulted in the consolidation of 13 mental health centers down to just 6.

As individuals with serious mental illness lost access to such outpatient resources as therapy, medication management, supported housing, and employment assistance, jail populations swelled. The Cook County jail became known as “the largest mental health center in the state of Illinois,” said Dr. Bell. He’s not sure he sees a good solution for the near term, but he holds out hope that innovative solutions are on the horizon.

Telepsychiatry offers an eminently workable solution to scarcity and geographic separation in some areas. Dr. David Baldes, a psychiatrist at St. Luke’s Health Care System in Duluth, Minn., “sees” patients via his computer several hours a week. He’s able to care for the sickest of the patients with mental illness served by primary care clinics along the Iron Range in northern Minnesota, helping keep this population out of the emergency department and fending off brushes with the law that are all too common among those with serious mental illnesses such as schizophrenia and severe bipolar disorder.

Erin Metzger

“The people I see tend to be really sick,” said Dr. Baldes, “and the number of psychiatrists per capita is basically zero” on the Iron Range. Although the area is served by a federally funded community mental health center, it’s extremely difficult to attract and retain psychiatrists to the remote area.

His ability to provide care for patients with serious mental illness helps their primary care providers “not feel so much like they’re on an island,” he said. He enjoys the collaboration and support he’s able to provide for the primary physicians as well.

Getting things started wasn’t hard: “The technology was actually quite simple to set up,” he said, noting that psychiatry is an ideal discipline for virtual care. “We don’t touch the patient. Our exam is our conversation with the patient,” he said.

Another advantage of telepsychiatry, Dr. Baldes said, is that there’s no stigma associated with visiting one’s primary care provider. “My patients go to their regular doctor’s office, they check in with the receptionist, and nobody really knows why they are there.” This can be a particular advantage in some of the more conservative rural communities served by the St. Luke’s program.

This mode of care soon feels completely natural for physician and patient, he said. “Especially for our generation; we’re very comfortable with FaceTime, with Skype, and generally with communicating electronically,” Dr. Baldes said.

“What patients really want is to be able to do these visits from their home,” he said. Because of privacy and security concerns, patients still go to the primary care office to have their virtual visits with Dr. Baldes.

Telepsychiatry’s promise is not limited to rural areas. “Any time people are resource limited, transportation is always an issue,” Dr. Baldes said. The suburbs and exurbs of many American cities are increasingly populated by low-income individuals forced out of gentrifying city centers into areas with fewer mental health resources and fewer transportation options. Telepsychiatry could be useful in many settings, he said.

A more fully integrated suite of services, the Collaborative Care Model (CCM), has been piloted in five locations nationwide and was the subject of an April 14, 2016, congressional briefing. This care model goes beyond co-location and collaboration to encompass a specific set of team members providing specific services, with ongoing tracking of validated outcome measures.

Dr. Erik Vanderlip, professor of psychiatry and medical informatics at the University of Oklahoma, Tulsa, coauthored a recent report sharing evidence of the successful implementation of collaborative care. He said the CCM really represents a shift in thinking. “The lack of psychiatric beds isn’t the problem. The problem is the lack of affordable, accessible, high-quality mental health services,” and collaborative care seeks to meet that need.

Dr. Vanderlip is a double-boarded psychiatrist and family medicine physician; he said that during training, “I discovered quickly that we have to redesign the way we deliver health care services to meet the needs of the most vulnerable.” He began working with Dr. Wayne Katon, now deceased, who pioneered the collaborative care model in Washington state.

In practice, this means that a psychiatrist works with a primary care provider and other team members to provide intensive care and monitoring. Clinical trials have shown impressive results in the treatment of depression, with response rates approaching 70%, Dr. Vanderlip said. “This stuff is the solution,” he said.

“So you have these little ‘teamlets’ of the psychiatrist, the primary care provider, the care manager, and the nurse working together to take care of a cohort of patients,” Dr. Vanderlip said. Typically, a care manager will have from 40 to as many as 100 patients under his or her care.

Key to measuring the success of the care model is an objective, validated measure that changes in relation to improvement or worsening of the target chronic condition. For example, in depression, that measure is the Patient Health Questionnaire (PHQ-9).

In the CCM, a psychiatrist will log in to the secure patient management system and pull up the entire registry of the care manager’s patients. One by one, patients are briefly reviewed, and the care plan and medications are adjusted as needed. The psychiatrist completes a brief note for each patient during the session; notes have a disclaimer that makes clear that the physician did not have a face-to-face encounter with the patient.

The psychiatrists also are available for “curbside” consults to the primary care provider, so they may collaborate on patients’ care plans. For one care manager’s panel of 40-100 patients, a psychiatrist will typically devote about a half day per week of consultative time.

Dr. Vanderlip has found that for some psychiatrists, the new role of “care quarterback” can be a tough sell. “Providers have a hard time comprehending that they are not going to see people directly.” Most psychiatrists involved in collaborative care also see patients in the traditional model as well, he said.

A critical piece of the puzzle for the success of integrated care is reimbursement – and the CCM now has its own CPT code. “There’s reimbursement for the psychiatrist’s time, for the care manager’s time, and for the primary care provider’s time,” Dr. Vanderlip said. The American Psychiatric Association is in discussion with the Centers for Medicare & Medicaid Services and the American Medical Association to fine-tune valuation.

“This is a great candidate for value-based reimbursement,” Dr. Vanderlip said. Depression scores can be tracked over time; successful care teams could be rewarded – and less successful ones docked – depending on patient outcome measures.

As reimbursers seek to find more ways to recognize the burden that chronic care places on the health care system, collaborative care should find more takers. “Collaborative care is chronic care incarnate,” Dr. Vanderlip said. He said he thinks it’s the solution for the care crunch in America. “This is not a bed shortage problem,” he reiterated.

Availability of inpatient services wide ranging

The number of psychiatric hospital beds per capita varies widely by state, as does the availability of psychiatrists and outpatient mental health facilities. In 2011, the American Hospital Association reported that psychiatric bed allocations ranged from a low of about 5 beds per 100,000 persons in Colorado to a high of more than 50 beds per 100,000 persons in both Missouri and Mississippi.

Reported rates of hospital admission among adults with a diagnosis of any mental illness also varies, from 1.1% in Louisiana, to 4.9% in New York (2010-2011 Substance Abuse and Mental Health Services Administration report).

State-by-state estimates of the prevalence of serious mental illness in adults ranges from just under 3% to about 7% (2012 revised SAMHSA report).

[email protected]

On Twitter @karioakes

If an individual with schizophrenia presents to the emergency department, there’s about a 1 in 2 chance that person will wind up in an inpatient psychiatric bed, or transferred to a residential psychiatric facility. As reimbursement to hospitals for psychiatric beds decreases, there’s decreasing incentive for hospitals to maintain inpatient psychiatry services.

Decreasing numbers of hospital beds means strategic thinking about outpatient services is more important than ever, to help avert the crises that bring patients to EDs and to run-ins with the justice system. In some parts of the country, though, the downstream effects of cutbacks and increased demand are overwhelming the system.

For Dr. Carl C. Bell, the combination of shrinking resources and growing need feels like a prescription for disaster in Chicago. Dr. Bell, a psychiatrist who has spent decades providing community mental health services there, saw a relatively robust mental health infrastructure crumble when municipal belt tightening resulted in the consolidation of 13 mental health centers down to just 6.

As individuals with serious mental illness lost access to such outpatient resources as therapy, medication management, supported housing, and employment assistance, jail populations swelled. The Cook County jail became known as “the largest mental health center in the state of Illinois,” said Dr. Bell. He’s not sure he sees a good solution for the near term, but he holds out hope that innovative solutions are on the horizon.

Telepsychiatry offers an eminently workable solution to scarcity and geographic separation in some areas. Dr. David Baldes, a psychiatrist at St. Luke’s Health Care System in Duluth, Minn., “sees” patients via his computer several hours a week. He’s able to care for the sickest of the patients with mental illness served by primary care clinics along the Iron Range in northern Minnesota, helping keep this population out of the emergency department and fending off brushes with the law that are all too common among those with serious mental illnesses such as schizophrenia and severe bipolar disorder.

Erin Metzger

“The people I see tend to be really sick,” said Dr. Baldes, “and the number of psychiatrists per capita is basically zero” on the Iron Range. Although the area is served by a federally funded community mental health center, it’s extremely difficult to attract and retain psychiatrists to the remote area.

His ability to provide care for patients with serious mental illness helps their primary care providers “not feel so much like they’re on an island,” he said. He enjoys the collaboration and support he’s able to provide for the primary physicians as well.

Getting things started wasn’t hard: “The technology was actually quite simple to set up,” he said, noting that psychiatry is an ideal discipline for virtual care. “We don’t touch the patient. Our exam is our conversation with the patient,” he said.

Another advantage of telepsychiatry, Dr. Baldes said, is that there’s no stigma associated with visiting one’s primary care provider. “My patients go to their regular doctor’s office, they check in with the receptionist, and nobody really knows why they are there.” This can be a particular advantage in some of the more conservative rural communities served by the St. Luke’s program.

This mode of care soon feels completely natural for physician and patient, he said. “Especially for our generation; we’re very comfortable with FaceTime, with Skype, and generally with communicating electronically,” Dr. Baldes said.

“What patients really want is to be able to do these visits from their home,” he said. Because of privacy and security concerns, patients still go to the primary care office to have their virtual visits with Dr. Baldes.

Telepsychiatry’s promise is not limited to rural areas. “Any time people are resource limited, transportation is always an issue,” Dr. Baldes said. The suburbs and exurbs of many American cities are increasingly populated by low-income individuals forced out of gentrifying city centers into areas with fewer mental health resources and fewer transportation options. Telepsychiatry could be useful in many settings, he said.

A more fully integrated suite of services, the Collaborative Care Model (CCM), has been piloted in five locations nationwide and was the subject of an April 14, 2016, congressional briefing. This care model goes beyond co-location and collaboration to encompass a specific set of team members providing specific services, with ongoing tracking of validated outcome measures.

Dr. Erik Vanderlip, professor of psychiatry and medical informatics at the University of Oklahoma, Tulsa, coauthored a recent report sharing evidence of the successful implementation of collaborative care. He said the CCM really represents a shift in thinking. “The lack of psychiatric beds isn’t the problem. The problem is the lack of affordable, accessible, high-quality mental health services,” and collaborative care seeks to meet that need.

Dr. Vanderlip is a double-boarded psychiatrist and family medicine physician; he said that during training, “I discovered quickly that we have to redesign the way we deliver health care services to meet the needs of the most vulnerable.” He began working with Dr. Wayne Katon, now deceased, who pioneered the collaborative care model in Washington state.

In practice, this means that a psychiatrist works with a primary care provider and other team members to provide intensive care and monitoring. Clinical trials have shown impressive results in the treatment of depression, with response rates approaching 70%, Dr. Vanderlip said. “This stuff is the solution,” he said.

“So you have these little ‘teamlets’ of the psychiatrist, the primary care provider, the care manager, and the nurse working together to take care of a cohort of patients,” Dr. Vanderlip said. Typically, a care manager will have from 40 to as many as 100 patients under his or her care.

Key to measuring the success of the care model is an objective, validated measure that changes in relation to improvement or worsening of the target chronic condition. For example, in depression, that measure is the Patient Health Questionnaire (PHQ-9).

In the CCM, a psychiatrist will log in to the secure patient management system and pull up the entire registry of the care manager’s patients. One by one, patients are briefly reviewed, and the care plan and medications are adjusted as needed. The psychiatrist completes a brief note for each patient during the session; notes have a disclaimer that makes clear that the physician did not have a face-to-face encounter with the patient.

The psychiatrists also are available for “curbside” consults to the primary care provider, so they may collaborate on patients’ care plans. For one care manager’s panel of 40-100 patients, a psychiatrist will typically devote about a half day per week of consultative time.

Dr. Vanderlip has found that for some psychiatrists, the new role of “care quarterback” can be a tough sell. “Providers have a hard time comprehending that they are not going to see people directly.” Most psychiatrists involved in collaborative care also see patients in the traditional model as well, he said.

A critical piece of the puzzle for the success of integrated care is reimbursement – and the CCM now has its own CPT code. “There’s reimbursement for the psychiatrist’s time, for the care manager’s time, and for the primary care provider’s time,” Dr. Vanderlip said. The American Psychiatric Association is in discussion with the Centers for Medicare & Medicaid Services and the American Medical Association to fine-tune valuation.

“This is a great candidate for value-based reimbursement,” Dr. Vanderlip said. Depression scores can be tracked over time; successful care teams could be rewarded – and less successful ones docked – depending on patient outcome measures.

As reimbursers seek to find more ways to recognize the burden that chronic care places on the health care system, collaborative care should find more takers. “Collaborative care is chronic care incarnate,” Dr. Vanderlip said. He said he thinks it’s the solution for the care crunch in America. “This is not a bed shortage problem,” he reiterated.

Availability of inpatient services wide ranging

The number of psychiatric hospital beds per capita varies widely by state, as does the availability of psychiatrists and outpatient mental health facilities. In 2011, the American Hospital Association reported that psychiatric bed allocations ranged from a low of about 5 beds per 100,000 persons in Colorado to a high of more than 50 beds per 100,000 persons in both Missouri and Mississippi.

Reported rates of hospital admission among adults with a diagnosis of any mental illness also varies, from 1.1% in Louisiana, to 4.9% in New York (2010-2011 Substance Abuse and Mental Health Services Administration report).

State-by-state estimates of the prevalence of serious mental illness in adults ranges from just under 3% to about 7% (2012 revised SAMHSA report).

[email protected]

On Twitter @karioakes

If an individual with schizophrenia presents to the emergency department, there’s about a 1 in 2 chance that person will wind up in an inpatient psychiatric bed, or transferred to a residential psychiatric facility. As reimbursement to hospitals for psychiatric beds decreases, there’s decreasing incentive for hospitals to maintain inpatient psychiatry services.

Decreasing numbers of hospital beds means strategic thinking about outpatient services is more important than ever, to help avert the crises that bring patients to EDs and to run-ins with the justice system. In some parts of the country, though, the downstream effects of cutbacks and increased demand are overwhelming the system.

For Dr. Carl C. Bell, the combination of shrinking resources and growing need feels like a prescription for disaster in Chicago. Dr. Bell, a psychiatrist who has spent decades providing community mental health services there, saw a relatively robust mental health infrastructure crumble when municipal belt tightening resulted in the consolidation of 13 mental health centers down to just 6.

As individuals with serious mental illness lost access to such outpatient resources as therapy, medication management, supported housing, and employment assistance, jail populations swelled. The Cook County jail became known as “the largest mental health center in the state of Illinois,” said Dr. Bell. He’s not sure he sees a good solution for the near term, but he holds out hope that innovative solutions are on the horizon.

Telepsychiatry offers an eminently workable solution to scarcity and geographic separation in some areas. Dr. David Baldes, a psychiatrist at St. Luke’s Health Care System in Duluth, Minn., “sees” patients via his computer several hours a week. He’s able to care for the sickest of the patients with mental illness served by primary care clinics along the Iron Range in northern Minnesota, helping keep this population out of the emergency department and fending off brushes with the law that are all too common among those with serious mental illnesses such as schizophrenia and severe bipolar disorder.

Erin Metzger

“The people I see tend to be really sick,” said Dr. Baldes, “and the number of psychiatrists per capita is basically zero” on the Iron Range. Although the area is served by a federally funded community mental health center, it’s extremely difficult to attract and retain psychiatrists to the remote area.

His ability to provide care for patients with serious mental illness helps their primary care providers “not feel so much like they’re on an island,” he said. He enjoys the collaboration and support he’s able to provide for the primary physicians as well.

Getting things started wasn’t hard: “The technology was actually quite simple to set up,” he said, noting that psychiatry is an ideal discipline for virtual care. “We don’t touch the patient. Our exam is our conversation with the patient,” he said.

Another advantage of telepsychiatry, Dr. Baldes said, is that there’s no stigma associated with visiting one’s primary care provider. “My patients go to their regular doctor’s office, they check in with the receptionist, and nobody really knows why they are there.” This can be a particular advantage in some of the more conservative rural communities served by the St. Luke’s program.

This mode of care soon feels completely natural for physician and patient, he said. “Especially for our generation; we’re very comfortable with FaceTime, with Skype, and generally with communicating electronically,” Dr. Baldes said.

“What patients really want is to be able to do these visits from their home,” he said. Because of privacy and security concerns, patients still go to the primary care office to have their virtual visits with Dr. Baldes.

Telepsychiatry’s promise is not limited to rural areas. “Any time people are resource limited, transportation is always an issue,” Dr. Baldes said. The suburbs and exurbs of many American cities are increasingly populated by low-income individuals forced out of gentrifying city centers into areas with fewer mental health resources and fewer transportation options. Telepsychiatry could be useful in many settings, he said.

A more fully integrated suite of services, the Collaborative Care Model (CCM), has been piloted in five locations nationwide and was the subject of an April 14, 2016, congressional briefing. This care model goes beyond co-location and collaboration to encompass a specific set of team members providing specific services, with ongoing tracking of validated outcome measures.

Dr. Erik Vanderlip, professor of psychiatry and medical informatics at the University of Oklahoma, Tulsa, coauthored a recent report sharing evidence of the successful implementation of collaborative care. He said the CCM really represents a shift in thinking. “The lack of psychiatric beds isn’t the problem. The problem is the lack of affordable, accessible, high-quality mental health services,” and collaborative care seeks to meet that need.

Dr. Vanderlip is a double-boarded psychiatrist and family medicine physician; he said that during training, “I discovered quickly that we have to redesign the way we deliver health care services to meet the needs of the most vulnerable.” He began working with Dr. Wayne Katon, now deceased, who pioneered the collaborative care model in Washington state.

In practice, this means that a psychiatrist works with a primary care provider and other team members to provide intensive care and monitoring. Clinical trials have shown impressive results in the treatment of depression, with response rates approaching 70%, Dr. Vanderlip said. “This stuff is the solution,” he said.

“So you have these little ‘teamlets’ of the psychiatrist, the primary care provider, the care manager, and the nurse working together to take care of a cohort of patients,” Dr. Vanderlip said. Typically, a care manager will have from 40 to as many as 100 patients under his or her care.

Key to measuring the success of the care model is an objective, validated measure that changes in relation to improvement or worsening of the target chronic condition. For example, in depression, that measure is the Patient Health Questionnaire (PHQ-9).

In the CCM, a psychiatrist will log in to the secure patient management system and pull up the entire registry of the care manager’s patients. One by one, patients are briefly reviewed, and the care plan and medications are adjusted as needed. The psychiatrist completes a brief note for each patient during the session; notes have a disclaimer that makes clear that the physician did not have a face-to-face encounter with the patient.

The psychiatrists also are available for “curbside” consults to the primary care provider, so they may collaborate on patients’ care plans. For one care manager’s panel of 40-100 patients, a psychiatrist will typically devote about a half day per week of consultative time.

Dr. Vanderlip has found that for some psychiatrists, the new role of “care quarterback” can be a tough sell. “Providers have a hard time comprehending that they are not going to see people directly.” Most psychiatrists involved in collaborative care also see patients in the traditional model as well, he said.

A critical piece of the puzzle for the success of integrated care is reimbursement – and the CCM now has its own CPT code. “There’s reimbursement for the psychiatrist’s time, for the care manager’s time, and for the primary care provider’s time,” Dr. Vanderlip said. The American Psychiatric Association is in discussion with the Centers for Medicare & Medicaid Services and the American Medical Association to fine-tune valuation.

“This is a great candidate for value-based reimbursement,” Dr. Vanderlip said. Depression scores can be tracked over time; successful care teams could be rewarded – and less successful ones docked – depending on patient outcome measures.

As reimbursers seek to find more ways to recognize the burden that chronic care places on the health care system, collaborative care should find more takers. “Collaborative care is chronic care incarnate,” Dr. Vanderlip said. He said he thinks it’s the solution for the care crunch in America. “This is not a bed shortage problem,” he reiterated.

Availability of inpatient services wide ranging

The number of psychiatric hospital beds per capita varies widely by state, as does the availability of psychiatrists and outpatient mental health facilities. In 2011, the American Hospital Association reported that psychiatric bed allocations ranged from a low of about 5 beds per 100,000 persons in Colorado to a high of more than 50 beds per 100,000 persons in both Missouri and Mississippi.

Reported rates of hospital admission among adults with a diagnosis of any mental illness also varies, from 1.1% in Louisiana, to 4.9% in New York (2010-2011 Substance Abuse and Mental Health Services Administration report).

State-by-state estimates of the prevalence of serious mental illness in adults ranges from just under 3% to about 7% (2012 revised SAMHSA report).

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The term “psychotherapy” describes a variety of talk-based treatments for psychiatric illnesses. Its fundamental premise is that there are determinants of mood, anxiety, and behavior that are not fully in our conscious awareness. By becoming more aware or by developing skills in managing thoughts and feelings, patients can get relief from symptoms that often impair functioning. The focus on unconscious thoughts, feelings, and behaviors is the central principle of dynamic psychotherapy in which the therapist listens to the patients speak freely about important people and events in their day-to-day lives and takes note of themes that emerge. Eventually they offer “interpretations” to their patients about these patterns, and ways that current problems may connect to powerful experiences from their earlier lives.

Dynamic psychotherapy is often contrasted with supportive psychotherapy. This is not cheerleading, but instead refers to supporting the healthy ability to think about oneself, one’s thoughts and emotions, and one’s needs, and the tension that these can create with the expectations of society. In working with children and adolescents, therapists are almost always supporting the age-appropriate development of some of these skills, particularly if a child has gotten developmentally stuck because of depressive, anxious, or attentional symptoms. There are almost always supportive elements in psychotherapy with a school-age or teenage child.

For children with anxiety disorders or mild to moderate depression, cognitive-behavioral therapy (CBT) is an evidence-based first-line treatment. CBT is a structured psychotherapy that helps patients to identify specific thoughts that trigger or follow their mood or anxiety symptoms, and then sets about establishing new (less-distorted) thoughts or practicing avoided behaviors to help learn new responses. It appears to be especially effective for anxiety disorders (such as social phobia, panic disorder, and generalized anxiety disorder) and for obsessive-compulsive disorder. There are specialized types of CBT that can be offered to patients (including children) who have been exposed to trauma and even for teenagers experiencing psychotic symptoms. It should be noted that one of the reasons that CBT has a robust evidence base supporting its use is that it is one of the most structured types of psychotherapy. It is standardized, reproducible, and easier to study than most other varieties of psychotherapy. Practicing CBT requires specific training, so in looking for a CBT therapist, one needs to ask whether she is CBT trained, and even whether she is trained in the type of CBT specific for the disorder you are treating.

A relative of CBT is dialectical behavioral therapy or DBT, developed to treat borderline personality disorder, a maladaptive pattern of identity uncertainty, emotional instability, and impulsivity that often starts in adolescence, causing stormy relationships and poor self-regulation that can contribute to self-injury, substance abuse, and chronic suicidality. DBT focuses on cognitive patterns, and utilizes a patient’s strengths to build new skills at managing challenging thoughts and feelings. The “dialectic” relates to interpersonal relationships, as this is where these patients often have great difficulty. High-quality DBT is often done with both individual and group therapy sessions. There is substantial evidence supporting the efficacy of this therapy in patients with borderline personality disorder.

Play therapy generally refers to the use of play (with toys, dolls, art, or games) in therapy with the youngest children. Such young children are unlikely to speak in a fluid manner about their relationships or struggles, as they may lack some of the cognitive means to be self-reflective. So instead, a therapist will watch for themes in their play (aggression, cheating, repetitive stories with dolls or art) that may reflect important themes, that they will then work on in play or in speaking, as tolerated. Therapists of older children also may use play to help these children feel more comfortable as they proceed with CBT or another talk therapy.

While gathering data from parents is always part of therapy for children, family therapy brings the whole family into a room with the therapist, who focuses on the roles each person may play in the family and patterns of communication (verbal and otherwise) that may be contributing to a young person’s symptoms. Family therapy can be very important in treating anorexia nervosa, somatoform illnesses, and conduct disorder in children and adolescents. While it can be a complex type of therapy to study, there is significant evidence supporting its efficacy in these very challenging disorders of youth.

There is a growing body of evidence in adults demonstrating neuroimaging changes after effective psychotherapies. Several studies of patients with OCD who were successfully treated with CBT have demonstrated decreased metabolism in the right caudate nucleus, and those treated effectively for phobias showed decreased activity in the limbic and paralimbic areas. Interestingly, patients with OCD and phobias who were effectively treated with selective serotonin reuptake inhibitors demonstrated these same changes on functional neuroimaging (Mol Psychiatry. 2006 Jun;11[6]:528-38.). An Italian meta-analysis of patients treated for major depression with medications (usually selective serotonin reuptake inhibitors) or with psychotherapy (usually CBT) demonstrated different, and possibly complementary brain changes in the two treatment groups (Brain Imaging Behav. 2015 Jul 12. [Epub ahead of print]). With time, these studies may help us to better understand the nature of specific illnesses and more about neuroplasticity, and may even help us to understand when medications, therapy, or both are indicated.

©AlexRaths/Thinkstock

Finally, it is worth noting that multiple studies indicate that one of the most consistent predictors of a positive outcome in psychotherapy is the presence of a strong treatment alliance between the therapist and the patient. Studies have demonstrated that a strong alliance was a better predictor of positive outcomes than type of psychotherapy, and seemed to be a strong predictor of positive outcomes even in cases where the treatment was pharmacologic. This makes it critical that when you are trying to help your patient find a “good therapist,” you consider whether the patient may need a specialized therapy (CBT, DBT, or family therapy). But you should also instruct your patient and their parents that it is very important that they like their therapist, that after several meetings they should feel comfortable meeting and talking honestly with him, and that they should feel that the therapist cares about them and is committed to their health and well-being.

Dr. Swick is an attending psychiatrist in the division of child psychiatry at Massachusetts General Hospital, Boston, and director of the Parenting at a Challenging Time (PACT) Program at the Vernon Cancer Center at Newton (Mass.) Wellesley Hospital. Dr. Jellinek is professor of psychiatry and of pediatrics at Harvard Medical School, Boston. Email them at [email protected].

The term “psychotherapy” describes a variety of talk-based treatments for psychiatric illnesses. Its fundamental premise is that there are determinants of mood, anxiety, and behavior that are not fully in our conscious awareness. By becoming more aware or by developing skills in managing thoughts and feelings, patients can get relief from symptoms that often impair functioning. The focus on unconscious thoughts, feelings, and behaviors is the central principle of dynamic psychotherapy in which the therapist listens to the patients speak freely about important people and events in their day-to-day lives and takes note of themes that emerge. Eventually they offer “interpretations” to their patients about these patterns, and ways that current problems may connect to powerful experiences from their earlier lives.

Dynamic psychotherapy is often contrasted with supportive psychotherapy. This is not cheerleading, but instead refers to supporting the healthy ability to think about oneself, one’s thoughts and emotions, and one’s needs, and the tension that these can create with the expectations of society. In working with children and adolescents, therapists are almost always supporting the age-appropriate development of some of these skills, particularly if a child has gotten developmentally stuck because of depressive, anxious, or attentional symptoms. There are almost always supportive elements in psychotherapy with a school-age or teenage child.

For children with anxiety disorders or mild to moderate depression, cognitive-behavioral therapy (CBT) is an evidence-based first-line treatment. CBT is a structured psychotherapy that helps patients to identify specific thoughts that trigger or follow their mood or anxiety symptoms, and then sets about establishing new (less-distorted) thoughts or practicing avoided behaviors to help learn new responses. It appears to be especially effective for anxiety disorders (such as social phobia, panic disorder, and generalized anxiety disorder) and for obsessive-compulsive disorder. There are specialized types of CBT that can be offered to patients (including children) who have been exposed to trauma and even for teenagers experiencing psychotic symptoms. It should be noted that one of the reasons that CBT has a robust evidence base supporting its use is that it is one of the most structured types of psychotherapy. It is standardized, reproducible, and easier to study than most other varieties of psychotherapy. Practicing CBT requires specific training, so in looking for a CBT therapist, one needs to ask whether she is CBT trained, and even whether she is trained in the type of CBT specific for the disorder you are treating.

A relative of CBT is dialectical behavioral therapy or DBT, developed to treat borderline personality disorder, a maladaptive pattern of identity uncertainty, emotional instability, and impulsivity that often starts in adolescence, causing stormy relationships and poor self-regulation that can contribute to self-injury, substance abuse, and chronic suicidality. DBT focuses on cognitive patterns, and utilizes a patient’s strengths to build new skills at managing challenging thoughts and feelings. The “dialectic” relates to interpersonal relationships, as this is where these patients often have great difficulty. High-quality DBT is often done with both individual and group therapy sessions. There is substantial evidence supporting the efficacy of this therapy in patients with borderline personality disorder.

Play therapy generally refers to the use of play (with toys, dolls, art, or games) in therapy with the youngest children. Such young children are unlikely to speak in a fluid manner about their relationships or struggles, as they may lack some of the cognitive means to be self-reflective. So instead, a therapist will watch for themes in their play (aggression, cheating, repetitive stories with dolls or art) that may reflect important themes, that they will then work on in play or in speaking, as tolerated. Therapists of older children also may use play to help these children feel more comfortable as they proceed with CBT or another talk therapy.

While gathering data from parents is always part of therapy for children, family therapy brings the whole family into a room with the therapist, who focuses on the roles each person may play in the family and patterns of communication (verbal and otherwise) that may be contributing to a young person’s symptoms. Family therapy can be very important in treating anorexia nervosa, somatoform illnesses, and conduct disorder in children and adolescents. While it can be a complex type of therapy to study, there is significant evidence supporting its efficacy in these very challenging disorders of youth.

There is a growing body of evidence in adults demonstrating neuroimaging changes after effective psychotherapies. Several studies of patients with OCD who were successfully treated with CBT have demonstrated decreased metabolism in the right caudate nucleus, and those treated effectively for phobias showed decreased activity in the limbic and paralimbic areas. Interestingly, patients with OCD and phobias who were effectively treated with selective serotonin reuptake inhibitors demonstrated these same changes on functional neuroimaging (Mol Psychiatry. 2006 Jun;11[6]:528-38.). An Italian meta-analysis of patients treated for major depression with medications (usually selective serotonin reuptake inhibitors) or with psychotherapy (usually CBT) demonstrated different, and possibly complementary brain changes in the two treatment groups (Brain Imaging Behav. 2015 Jul 12. [Epub ahead of print]). With time, these studies may help us to better understand the nature of specific illnesses and more about neuroplasticity, and may even help us to understand when medications, therapy, or both are indicated.

©AlexRaths/Thinkstock

Finally, it is worth noting that multiple studies indicate that one of the most consistent predictors of a positive outcome in psychotherapy is the presence of a strong treatment alliance between the therapist and the patient. Studies have demonstrated that a strong alliance was a better predictor of positive outcomes than type of psychotherapy, and seemed to be a strong predictor of positive outcomes even in cases where the treatment was pharmacologic. This makes it critical that when you are trying to help your patient find a “good therapist,” you consider whether the patient may need a specialized therapy (CBT, DBT, or family therapy). But you should also instruct your patient and their parents that it is very important that they like their therapist, that after several meetings they should feel comfortable meeting and talking honestly with him, and that they should feel that the therapist cares about them and is committed to their health and well-being.

Dr. Swick is an attending psychiatrist in the division of child psychiatry at Massachusetts General Hospital, Boston, and director of the Parenting at a Challenging Time (PACT) Program at the Vernon Cancer Center at Newton (Mass.) Wellesley Hospital. Dr. Jellinek is professor of psychiatry and of pediatrics at Harvard Medical School, Boston. Email them at [email protected].

The term “psychotherapy” describes a variety of talk-based treatments for psychiatric illnesses. Its fundamental premise is that there are determinants of mood, anxiety, and behavior that are not fully in our conscious awareness. By becoming more aware or by developing skills in managing thoughts and feelings, patients can get relief from symptoms that often impair functioning. The focus on unconscious thoughts, feelings, and behaviors is the central principle of dynamic psychotherapy in which the therapist listens to the patients speak freely about important people and events in their day-to-day lives and takes note of themes that emerge. Eventually they offer “interpretations” to their patients about these patterns, and ways that current problems may connect to powerful experiences from their earlier lives.

Dynamic psychotherapy is often contrasted with supportive psychotherapy. This is not cheerleading, but instead refers to supporting the healthy ability to think about oneself, one’s thoughts and emotions, and one’s needs, and the tension that these can create with the expectations of society. In working with children and adolescents, therapists are almost always supporting the age-appropriate development of some of these skills, particularly if a child has gotten developmentally stuck because of depressive, anxious, or attentional symptoms. There are almost always supportive elements in psychotherapy with a school-age or teenage child.

For children with anxiety disorders or mild to moderate depression, cognitive-behavioral therapy (CBT) is an evidence-based first-line treatment. CBT is a structured psychotherapy that helps patients to identify specific thoughts that trigger or follow their mood or anxiety symptoms, and then sets about establishing new (less-distorted) thoughts or practicing avoided behaviors to help learn new responses. It appears to be especially effective for anxiety disorders (such as social phobia, panic disorder, and generalized anxiety disorder) and for obsessive-compulsive disorder. There are specialized types of CBT that can be offered to patients (including children) who have been exposed to trauma and even for teenagers experiencing psychotic symptoms. It should be noted that one of the reasons that CBT has a robust evidence base supporting its use is that it is one of the most structured types of psychotherapy. It is standardized, reproducible, and easier to study than most other varieties of psychotherapy. Practicing CBT requires specific training, so in looking for a CBT therapist, one needs to ask whether she is CBT trained, and even whether she is trained in the type of CBT specific for the disorder you are treating.

A relative of CBT is dialectical behavioral therapy or DBT, developed to treat borderline personality disorder, a maladaptive pattern of identity uncertainty, emotional instability, and impulsivity that often starts in adolescence, causing stormy relationships and poor self-regulation that can contribute to self-injury, substance abuse, and chronic suicidality. DBT focuses on cognitive patterns, and utilizes a patient’s strengths to build new skills at managing challenging thoughts and feelings. The “dialectic” relates to interpersonal relationships, as this is where these patients often have great difficulty. High-quality DBT is often done with both individual and group therapy sessions. There is substantial evidence supporting the efficacy of this therapy in patients with borderline personality disorder.

Play therapy generally refers to the use of play (with toys, dolls, art, or games) in therapy with the youngest children. Such young children are unlikely to speak in a fluid manner about their relationships or struggles, as they may lack some of the cognitive means to be self-reflective. So instead, a therapist will watch for themes in their play (aggression, cheating, repetitive stories with dolls or art) that may reflect important themes, that they will then work on in play or in speaking, as tolerated. Therapists of older children also may use play to help these children feel more comfortable as they proceed with CBT or another talk therapy.

While gathering data from parents is always part of therapy for children, family therapy brings the whole family into a room with the therapist, who focuses on the roles each person may play in the family and patterns of communication (verbal and otherwise) that may be contributing to a young person’s symptoms. Family therapy can be very important in treating anorexia nervosa, somatoform illnesses, and conduct disorder in children and adolescents. While it can be a complex type of therapy to study, there is significant evidence supporting its efficacy in these very challenging disorders of youth.

There is a growing body of evidence in adults demonstrating neuroimaging changes after effective psychotherapies. Several studies of patients with OCD who were successfully treated with CBT have demonstrated decreased metabolism in the right caudate nucleus, and those treated effectively for phobias showed decreased activity in the limbic and paralimbic areas. Interestingly, patients with OCD and phobias who were effectively treated with selective serotonin reuptake inhibitors demonstrated these same changes on functional neuroimaging (Mol Psychiatry. 2006 Jun;11[6]:528-38.). An Italian meta-analysis of patients treated for major depression with medications (usually selective serotonin reuptake inhibitors) or with psychotherapy (usually CBT) demonstrated different, and possibly complementary brain changes in the two treatment groups (Brain Imaging Behav. 2015 Jul 12. [Epub ahead of print]). With time, these studies may help us to better understand the nature of specific illnesses and more about neuroplasticity, and may even help us to understand when medications, therapy, or both are indicated.

©AlexRaths/Thinkstock

Finally, it is worth noting that multiple studies indicate that one of the most consistent predictors of a positive outcome in psychotherapy is the presence of a strong treatment alliance between the therapist and the patient. Studies have demonstrated that a strong alliance was a better predictor of positive outcomes than type of psychotherapy, and seemed to be a strong predictor of positive outcomes even in cases where the treatment was pharmacologic. This makes it critical that when you are trying to help your patient find a “good therapist,” you consider whether the patient may need a specialized therapy (CBT, DBT, or family therapy). But you should also instruct your patient and their parents that it is very important that they like their therapist, that after several meetings they should feel comfortable meeting and talking honestly with him, and that they should feel that the therapist cares about them and is committed to their health and well-being.

Dr. Swick is an attending psychiatrist in the division of child psychiatry at Massachusetts General Hospital, Boston, and director of the Parenting at a Challenging Time (PACT) Program at the Vernon Cancer Center at Newton (Mass.) Wellesley Hospital. Dr. Jellinek is professor of psychiatry and of pediatrics at Harvard Medical School, Boston. Email them at [email protected].