Cases That Test Your Skills

CASE: New-onset psychosis

Ms. T, age 26, presents to the psychiatric emergency room after a 1-week change in behavior. According to her family, Ms. T began to experience hyperactivity, increased rate of speech, and decreased sleep after her mother passed away 1 week ago. On the day of presentation, Ms. T had returned to work after a week’s hiatus. Coworkers brought her to the hospital when Ms. T threw herself on the floor and flailed about. Family members report that Ms. T had been complaining of headache that day and during the preceding week. In the emergency room, the patient is intrusive and easily distractible, although able to give a history.

Ms. T has no psychiatric history. Her family history is positive for bipolar spectrum illness. Our initial consideration is that Ms. T is experiencing mania or psychotic symptoms triggered by the recent loss of her mother. Ms. T is evaluated in the medical emergency room to rule out a primary medical illness. Standard labs and head CT are normal, so she is returned to the psychiatric emergency room. She becomes severely agitated and requires multiple IM antipsychotics—2 courses of haloperidol, 10 mg; 2 courses of ziprasidone, 20 mg; and olanzapine, 10 mg. She is admitted to the inpatient psychiatric service with a diagnosis of psychosis not otherwise specified.

Soon after admission, Ms. T suffers a witnessed generalized tonic-clonic seizure and is transferred to the internal medicine service. After the seizure she is awake but minimally responsive. She does not display purposeful movements, opens her eyes but can follow the examiner only on occasion, and displays periodic facial grimacing. In addition, Ms. T is intermittently hypoxic—requiring supplemental oxygen via nasal cannula—and febrile, with persistent tachycardia. Electroencephalography (EEG) shows nonconvulsive status epilepticus involving the bilateral temporal regions.

Ms. T is transferred to the neurosurgical intensive care unit for monitoring and IV anticonvulsants. Subsequent EEGs demonstrate generalized slowing but no epileptiform activity. An infectious workup is negative. Head MRI shows bilateral cerebellar T2/FLAIR increased signal, which is a nonspecific finding. Cerebrospinal fluid (CSF) studies show lymphocytic pleocytosis and oligoclonal bands. These findings suggest a CSF humoral immune response; an extensive laboratory workup is otherwise largely unremarkable ( Table 1 ).

The authors’ observations

We consider that Ms. T may have schizophrenia. Schizophrenia onset is insidious, often with prodromal symptoms occurring months to years before diagnosis.^1,2 In Ms. T, the onset of the disturbance was brief; her family noted a change in behavior for only 1 week before presentation. Given this history, brief psychotic disorder remains high on the differential diagnosis because Ms. T’s disorganized speech and behavior occurred seeming in relation to her mother’s death.

Bipolar disorder is characterized by strong heritability, with risks increasing if there is a first-degree relative with the illness. The hallmark of bipolar I disorder is a manic episode, which presents as:

• decreased need for sleep
  
• grandiosity
  
• flight of ideas
  
• reckless or thoughtless behaviors
  
• increased energy
  
• increased productivity
  
• expansive or irritable mood.
  

This diagnosis seems to fit well with our patient, who for 1 week had increased rate of speech, hyperactivity, and decreased need for sleep. She also has a positive family history of bipolar illness. Often patients with bipolar disorder experience a prodrome characterized by periods of depressed mood and periods that appear similar to mania but are not as obvious or severe.^1,2 Ms. T lacks this history.

Psychiatric symptoms secondary to seizure disorder are well documented. Cognitive, mood, anxiety, and psychotic phenomena may occur in up to 50% of patients with seizures.³ Typically, these symptoms are categorized as occurring during a seizure, after a seizure (post-ictal), or between seizures (interictal).

Manic syndromes secondary to seizure disorders present in an atypical manner with irritability and hyperactivity. Psychotic syndromes, on the other hand, appear with more classic schizophrenia-type symptoms:

• paranoia and persecutory delusions
  
• auditory and visual hallucinations
  
• amotivation
  
• apathy
  
• flattened affect
  
• disorganization.³
  

Ms. T had no history of witnessed seizure activity; however, the observed seizure early in her admission warranted exploring a possible underlying general medical condition.

Paraneoplastic syndromes may be associated with mood changes and other psychiatric symptoms.^4-6 Diagnosis is contingent on discovering the primary neoplasm, with or without specific paraneoplastic antibodies. Treatment is tailored to the oncologic process.

Table 1

Ms. T’s laboratory workup*

Test	Result
C-reactive protein	0.7
Erythrocyte sedimentation rate	5
Cryptococcal antigen (serum)	Negative
Antinuclear antibody	Negative
CSF lymphocytes	88
CSF nucleated cells	200
CSF RBC	33
CSF glucose	44
CSF protein	45
CSF igG index	1.2
CSF oligoclonal bands	Present
CSF: cerebrospinal fluid; igG: immunoglobulin G; RBC: red blood cell
*Results were negative for gonorrhea, chlamydia, lupus, human immunodeficiency virus, syphilis, Lyme disease, varicella zoster virus, West Nile virus, herpes simplex virus, Epstein-Barr virus, cytomegalovirus, tuberculosis, and California, St. Louis, eastern equine, and western equine encephalitis

 

EVALUATION: A medical cause

The psychiatry consultation-liaison service is asked to further evaluate Ms. T for psychiatric contributions to her continued altered mental status. Ms. T remains in restraints and receives fosphenytoin, 200 mg bid; levetiracetam, 1,000 mg bid; and lorazepam as needed for agitation. Following consultation, the team considers a working diagnosis of an autoimmune encephalopathy based on the negative infectious workup, the patient’s demographics, and the clinical picture (psychiatric symptoms, seizure, and encephalopathy). Ms. T undergoes 5 courses of plasma exchange with no effect. Catatonia is considered, but the patient does not demonstrate significant change with numerous doses of lorazepam.

Because Ms. T does not improve, the team starts a more specific paraneoplastic workup. MRI reveals a 9-mm lesion on her right ovary. Corticosteroids, including IV methylprednisolone, 1 g/d, are started. Ms. T’s clinical presentation improves; soon after scheduled corticosteroid dosing, she is taken to the operating room for right salpingo-oophorectomy. Surgical pathology later confirms the lesion as a mature teratoma. A standard paraneoplastic panel is negative; a separate test for anti-NMDA (N-methyl-D-aspartate) receptor antibodies is positive, however, and confirms the diagnosis of ovarian mass-associated anti-NMDA receptor limbic encephalitis.

Paraneoplastic syndromes

This case represents the interface between a complicated medical phenomenon and psychiatric symptomatology. Mood changes (typically depression), memory problems, paranoia, hypersomnolence, aggressive behavior, agitation, and catatonia have been associated with paraneoplastic syndromes.^4-6

Common malignant associations include small cell lung carcinoma (most common) and breast, stomach, colon, renal, bladder, ovarian, uterine, testicular, cell line, and thymic cancers. Research strongly suggests an autoimmune mechanism: tumor-related antibodies cross-react with similar antigens in the neurologic system. Paraneoplastic symptoms often precede symptoms of the malignancy, and the diagnosis is suggested by positive imaging and a paraneoplastic panel.

Definitive treatment is that which is appropriate for the specific neoplasm. Other successful therapies include immunosuppressants (including corticosteroids) and, less often, intravenous immunoglobulin (IVIg) or plasma exchange (when laboratory testing confirms known antibodies).⁷ Prognosis is highly variable, from complete recovery to death; antibody-positive cases may portend a more guarded prognosis.⁴

Anti-NMDA receptor limbic encephalitis is a paraneoplastic syndrome associated with ovarian teratomas and antibodies specific to the glutamate receptor. It is thought to be an autoimmune phenomenon whereby tumor-related antibodies elicit an immune response within certain parts of the neurologic system. Ms. T represents a typical clinical presentation of this syndrome—she is a young, otherwise healthy woman with:

• preceding headache
  
• new-onset psychotic symptoms
  
• seizure activity (particularly in the temporal lobes)
  
• central hypoventilation
  
• hyperthermia and tachycardia
  
• dyskinesia and catatonia-like symptoms.⁵
  

The course of anti-NMDA receptor limbic encephalitis typically progresses in distinct phases from prodromal symptoms to psychosis to unresponsiveness and hypoventilation to dysautonomia and dyskinesia.^4,5 Anti-NMDA receptor antibody identification is not included in standard paraneoplastic panels but can be specifically ordered from the University of Pennsylvania and Mayo Medical Laboratories.

TREATMENT: Rapid improvement

After removal of the dermoid lesion and IV corticosteroids, Ms. T exhibits rapid improvement. She begins acknowledging others in the room, making eye contact for nearly the first time during this hospitalization, and starts recognizing family members. She also begins verbalizing, responding appropriately to questions in 1 or 2 words. After a 34-day hospital stay, Ms. T is transferred to another facility for rehabilitation; her medication list consists of a corticosteroid taper from prednisone, 20 mg/d, over 2 weeks; fosphenytoin, 200 mg bid; and levetiracetam, 1,000 mg bid.

She eventually is discharged from the rehabilitation facility with noted improvement in multiple domains: she demonstrates cognitive improvement and can walk short distances. She continues to require 24-hour care and exhibits intermittent agitation.

The authors’ observations

We present the case of a patient with a specific paraneoplastic disorder—anti-NMDA receptor limbic encephalitis—with symptoms mimicking those seen in psychiatric disorders such as schizophrenia and bipolar disorder. These similarities complicate recognition and treatment of the underlying disorder.

Ms. T had a complicated yet typical presentation of anti-NMDA receptor limbic encephalitis ( Table 2 ) that was initially mistaken for a manic episode with psychotic features. The diagnosis was made more complex by the death of her mother 1 week before presentation, which could have precipitated her symptom onset. Similar case reports have appeared in neurologic and—less frequently—psychiatric literature ( Box ).^5,7-10

Commonly, patients with paraneoplastic limbic encephalitis experience a protracted hospital stay and extensive medical workup with long inpatient psychiatry stays before more severe physical manifestations—such as seizure activity and autonomic instability—prompt transfer to medical or neurologic services.

 

⁵ Ms. T spent time on psychiatric, internal medicine, and neurologic services before her team established a definitive diagnosis.

Because neurobehavioral symptoms predominate early in the course of paraneoplastic illness,⁵ psychiatrists should prepare to be the first medical point of contact for these patients.

Table 2

Anti-NMDA receptor encephalitis: Symptoms, findings, and treatment

Typical presentation
Young female Prodromal symptoms New onset psychosis, anxiety, or mood symptoms Catatonia Coma Seizure activity (typically bilateral temporal lobe activity on EEG) Hypoventilation Autonomic instability Dyskinesia
Laboratory and radiologic findings
CSF or serum antibodies CSF pleocytosis and elevated protein, normal glucose Background slowing or sharp-wave activity on EEG Temporal lobe abnormalities
Treatment
Tumor resection Immunosuppressants (typically corticosteroids) Intravenous immunoglobulin Plasmapheresis
CSF: cerebrospinal fluid; EEG: electroencephalography; NMDA: N-methyl-D-aspartate

Box

Related resource

• Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol. 2008;7(4):327-340.
  

Drug brand names

• Fosphenytoin • Cerebyx
  
• Haloperidol • Haldol
  
• Levetiracetam • Keppra
  
• Lorazepam • Ativan
  
• Methylprednisolone • Medrol, Depo-Medrol, others
  
• Olanzapine • Zyprexa
  
• Prednisone • Deltasone, Meticorten
  
• Ziprasidone • Geodon
  

Disclosures

Drs. Cavalieri and Southammakosane report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. White is a consultant for Pfizer Inc.

CASE: New-onset psychosis

Ms. T, age 26, presents to the psychiatric emergency room after a 1-week change in behavior. According to her family, Ms. T began to experience hyperactivity, increased rate of speech, and decreased sleep after her mother passed away 1 week ago. On the day of presentation, Ms. T had returned to work after a week’s hiatus. Coworkers brought her to the hospital when Ms. T threw herself on the floor and flailed about. Family members report that Ms. T had been complaining of headache that day and during the preceding week. In the emergency room, the patient is intrusive and easily distractible, although able to give a history.

Ms. T has no psychiatric history. Her family history is positive for bipolar spectrum illness. Our initial consideration is that Ms. T is experiencing mania or psychotic symptoms triggered by the recent loss of her mother. Ms. T is evaluated in the medical emergency room to rule out a primary medical illness. Standard labs and head CT are normal, so she is returned to the psychiatric emergency room. She becomes severely agitated and requires multiple IM antipsychotics—2 courses of haloperidol, 10 mg; 2 courses of ziprasidone, 20 mg; and olanzapine, 10 mg. She is admitted to the inpatient psychiatric service with a diagnosis of psychosis not otherwise specified.

Soon after admission, Ms. T suffers a witnessed generalized tonic-clonic seizure and is transferred to the internal medicine service. After the seizure she is awake but minimally responsive. She does not display purposeful movements, opens her eyes but can follow the examiner only on occasion, and displays periodic facial grimacing. In addition, Ms. T is intermittently hypoxic—requiring supplemental oxygen via nasal cannula—and febrile, with persistent tachycardia. Electroencephalography (EEG) shows nonconvulsive status epilepticus involving the bilateral temporal regions.

Ms. T is transferred to the neurosurgical intensive care unit for monitoring and IV anticonvulsants. Subsequent EEGs demonstrate generalized slowing but no epileptiform activity. An infectious workup is negative. Head MRI shows bilateral cerebellar T2/FLAIR increased signal, which is a nonspecific finding. Cerebrospinal fluid (CSF) studies show lymphocytic pleocytosis and oligoclonal bands. These findings suggest a CSF humoral immune response; an extensive laboratory workup is otherwise largely unremarkable ( Table 1 ).

The authors’ observations

We consider that Ms. T may have schizophrenia. Schizophrenia onset is insidious, often with prodromal symptoms occurring months to years before diagnosis.^1,2 In Ms. T, the onset of the disturbance was brief; her family noted a change in behavior for only 1 week before presentation. Given this history, brief psychotic disorder remains high on the differential diagnosis because Ms. T’s disorganized speech and behavior occurred seeming in relation to her mother’s death.

Bipolar disorder is characterized by strong heritability, with risks increasing if there is a first-degree relative with the illness. The hallmark of bipolar I disorder is a manic episode, which presents as:

• decreased need for sleep
  
• grandiosity
  
• flight of ideas
  
• reckless or thoughtless behaviors
  
• increased energy
  
• increased productivity
  
• expansive or irritable mood.
  

This diagnosis seems to fit well with our patient, who for 1 week had increased rate of speech, hyperactivity, and decreased need for sleep. She also has a positive family history of bipolar illness. Often patients with bipolar disorder experience a prodrome characterized by periods of depressed mood and periods that appear similar to mania but are not as obvious or severe.^1,2 Ms. T lacks this history.

Psychiatric symptoms secondary to seizure disorder are well documented. Cognitive, mood, anxiety, and psychotic phenomena may occur in up to 50% of patients with seizures.³ Typically, these symptoms are categorized as occurring during a seizure, after a seizure (post-ictal), or between seizures (interictal).

Manic syndromes secondary to seizure disorders present in an atypical manner with irritability and hyperactivity. Psychotic syndromes, on the other hand, appear with more classic schizophrenia-type symptoms:

• paranoia and persecutory delusions
  
• auditory and visual hallucinations
  
• amotivation
  
• apathy
  
• flattened affect
  
• disorganization.³
  

Ms. T had no history of witnessed seizure activity; however, the observed seizure early in her admission warranted exploring a possible underlying general medical condition.

Paraneoplastic syndromes may be associated with mood changes and other psychiatric symptoms.^4-6 Diagnosis is contingent on discovering the primary neoplasm, with or without specific paraneoplastic antibodies. Treatment is tailored to the oncologic process.

Table 1

Ms. T’s laboratory workup*

Test	Result
C-reactive protein	0.7
Erythrocyte sedimentation rate	5
Cryptococcal antigen (serum)	Negative
Antinuclear antibody	Negative
CSF lymphocytes	88
CSF nucleated cells	200
CSF RBC	33
CSF glucose	44
CSF protein	45
CSF igG index	1.2
CSF oligoclonal bands	Present
CSF: cerebrospinal fluid; igG: immunoglobulin G; RBC: red blood cell
*Results were negative for gonorrhea, chlamydia, lupus, human immunodeficiency virus, syphilis, Lyme disease, varicella zoster virus, West Nile virus, herpes simplex virus, Epstein-Barr virus, cytomegalovirus, tuberculosis, and California, St. Louis, eastern equine, and western equine encephalitis

 

EVALUATION: A medical cause

The psychiatry consultation-liaison service is asked to further evaluate Ms. T for psychiatric contributions to her continued altered mental status. Ms. T remains in restraints and receives fosphenytoin, 200 mg bid; levetiracetam, 1,000 mg bid; and lorazepam as needed for agitation. Following consultation, the team considers a working diagnosis of an autoimmune encephalopathy based on the negative infectious workup, the patient’s demographics, and the clinical picture (psychiatric symptoms, seizure, and encephalopathy). Ms. T undergoes 5 courses of plasma exchange with no effect. Catatonia is considered, but the patient does not demonstrate significant change with numerous doses of lorazepam.

Because Ms. T does not improve, the team starts a more specific paraneoplastic workup. MRI reveals a 9-mm lesion on her right ovary. Corticosteroids, including IV methylprednisolone, 1 g/d, are started. Ms. T’s clinical presentation improves; soon after scheduled corticosteroid dosing, she is taken to the operating room for right salpingo-oophorectomy. Surgical pathology later confirms the lesion as a mature teratoma. A standard paraneoplastic panel is negative; a separate test for anti-NMDA (N-methyl-D-aspartate) receptor antibodies is positive, however, and confirms the diagnosis of ovarian mass-associated anti-NMDA receptor limbic encephalitis.

Paraneoplastic syndromes

This case represents the interface between a complicated medical phenomenon and psychiatric symptomatology. Mood changes (typically depression), memory problems, paranoia, hypersomnolence, aggressive behavior, agitation, and catatonia have been associated with paraneoplastic syndromes.^4-6

Common malignant associations include small cell lung carcinoma (most common) and breast, stomach, colon, renal, bladder, ovarian, uterine, testicular, cell line, and thymic cancers. Research strongly suggests an autoimmune mechanism: tumor-related antibodies cross-react with similar antigens in the neurologic system. Paraneoplastic symptoms often precede symptoms of the malignancy, and the diagnosis is suggested by positive imaging and a paraneoplastic panel.

Definitive treatment is that which is appropriate for the specific neoplasm. Other successful therapies include immunosuppressants (including corticosteroids) and, less often, intravenous immunoglobulin (IVIg) or plasma exchange (when laboratory testing confirms known antibodies).⁷ Prognosis is highly variable, from complete recovery to death; antibody-positive cases may portend a more guarded prognosis.⁴

Anti-NMDA receptor limbic encephalitis is a paraneoplastic syndrome associated with ovarian teratomas and antibodies specific to the glutamate receptor. It is thought to be an autoimmune phenomenon whereby tumor-related antibodies elicit an immune response within certain parts of the neurologic system. Ms. T represents a typical clinical presentation of this syndrome—she is a young, otherwise healthy woman with:

• preceding headache
  
• new-onset psychotic symptoms
  
• seizure activity (particularly in the temporal lobes)
  
• central hypoventilation
  
• hyperthermia and tachycardia
  
• dyskinesia and catatonia-like symptoms.⁵
  

The course of anti-NMDA receptor limbic encephalitis typically progresses in distinct phases from prodromal symptoms to psychosis to unresponsiveness and hypoventilation to dysautonomia and dyskinesia.^4,5 Anti-NMDA receptor antibody identification is not included in standard paraneoplastic panels but can be specifically ordered from the University of Pennsylvania and Mayo Medical Laboratories.

TREATMENT: Rapid improvement

After removal of the dermoid lesion and IV corticosteroids, Ms. T exhibits rapid improvement. She begins acknowledging others in the room, making eye contact for nearly the first time during this hospitalization, and starts recognizing family members. She also begins verbalizing, responding appropriately to questions in 1 or 2 words. After a 34-day hospital stay, Ms. T is transferred to another facility for rehabilitation; her medication list consists of a corticosteroid taper from prednisone, 20 mg/d, over 2 weeks; fosphenytoin, 200 mg bid; and levetiracetam, 1,000 mg bid.

She eventually is discharged from the rehabilitation facility with noted improvement in multiple domains: she demonstrates cognitive improvement and can walk short distances. She continues to require 24-hour care and exhibits intermittent agitation.

The authors’ observations

We present the case of a patient with a specific paraneoplastic disorder—anti-NMDA receptor limbic encephalitis—with symptoms mimicking those seen in psychiatric disorders such as schizophrenia and bipolar disorder. These similarities complicate recognition and treatment of the underlying disorder.

Ms. T had a complicated yet typical presentation of anti-NMDA receptor limbic encephalitis ( Table 2 ) that was initially mistaken for a manic episode with psychotic features. The diagnosis was made more complex by the death of her mother 1 week before presentation, which could have precipitated her symptom onset. Similar case reports have appeared in neurologic and—less frequently—psychiatric literature ( Box ).^5,7-10

Commonly, patients with paraneoplastic limbic encephalitis experience a protracted hospital stay and extensive medical workup with long inpatient psychiatry stays before more severe physical manifestations—such as seizure activity and autonomic instability—prompt transfer to medical or neurologic services.

 

⁵ Ms. T spent time on psychiatric, internal medicine, and neurologic services before her team established a definitive diagnosis.

Because neurobehavioral symptoms predominate early in the course of paraneoplastic illness,⁵ psychiatrists should prepare to be the first medical point of contact for these patients.

Table 2

Anti-NMDA receptor encephalitis: Symptoms, findings, and treatment

Typical presentation
Young female Prodromal symptoms New onset psychosis, anxiety, or mood symptoms Catatonia Coma Seizure activity (typically bilateral temporal lobe activity on EEG) Hypoventilation Autonomic instability Dyskinesia
Laboratory and radiologic findings
CSF or serum antibodies CSF pleocytosis and elevated protein, normal glucose Background slowing or sharp-wave activity on EEG Temporal lobe abnormalities
Treatment
Tumor resection Immunosuppressants (typically corticosteroids) Intravenous immunoglobulin Plasmapheresis
CSF: cerebrospinal fluid; EEG: electroencephalography; NMDA: N-methyl-D-aspartate

Box

Related resource

• Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol. 2008;7(4):327-340.
  

Drug brand names

• Fosphenytoin • Cerebyx
  
• Haloperidol • Haldol
  
• Levetiracetam • Keppra
  
• Lorazepam • Ativan
  
• Methylprednisolone • Medrol, Depo-Medrol, others
  
• Olanzapine • Zyprexa
  
• Prednisone • Deltasone, Meticorten
  
• Ziprasidone • Geodon
  

Disclosures

Drs. Cavalieri and Southammakosane report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. White is a consultant for Pfizer Inc.

CASE: New-onset psychosis

Ms. T, age 26, presents to the psychiatric emergency room after a 1-week change in behavior. According to her family, Ms. T began to experience hyperactivity, increased rate of speech, and decreased sleep after her mother passed away 1 week ago. On the day of presentation, Ms. T had returned to work after a week’s hiatus. Coworkers brought her to the hospital when Ms. T threw herself on the floor and flailed about. Family members report that Ms. T had been complaining of headache that day and during the preceding week. In the emergency room, the patient is intrusive and easily distractible, although able to give a history.

Ms. T has no psychiatric history. Her family history is positive for bipolar spectrum illness. Our initial consideration is that Ms. T is experiencing mania or psychotic symptoms triggered by the recent loss of her mother. Ms. T is evaluated in the medical emergency room to rule out a primary medical illness. Standard labs and head CT are normal, so she is returned to the psychiatric emergency room. She becomes severely agitated and requires multiple IM antipsychotics—2 courses of haloperidol, 10 mg; 2 courses of ziprasidone, 20 mg; and olanzapine, 10 mg. She is admitted to the inpatient psychiatric service with a diagnosis of psychosis not otherwise specified.

Soon after admission, Ms. T suffers a witnessed generalized tonic-clonic seizure and is transferred to the internal medicine service. After the seizure she is awake but minimally responsive. She does not display purposeful movements, opens her eyes but can follow the examiner only on occasion, and displays periodic facial grimacing. In addition, Ms. T is intermittently hypoxic—requiring supplemental oxygen via nasal cannula—and febrile, with persistent tachycardia. Electroencephalography (EEG) shows nonconvulsive status epilepticus involving the bilateral temporal regions.

Ms. T is transferred to the neurosurgical intensive care unit for monitoring and IV anticonvulsants. Subsequent EEGs demonstrate generalized slowing but no epileptiform activity. An infectious workup is negative. Head MRI shows bilateral cerebellar T2/FLAIR increased signal, which is a nonspecific finding. Cerebrospinal fluid (CSF) studies show lymphocytic pleocytosis and oligoclonal bands. These findings suggest a CSF humoral immune response; an extensive laboratory workup is otherwise largely unremarkable ( Table 1 ).

The authors’ observations

We consider that Ms. T may have schizophrenia. Schizophrenia onset is insidious, often with prodromal symptoms occurring months to years before diagnosis.^1,2 In Ms. T, the onset of the disturbance was brief; her family noted a change in behavior for only 1 week before presentation. Given this history, brief psychotic disorder remains high on the differential diagnosis because Ms. T’s disorganized speech and behavior occurred seeming in relation to her mother’s death.

Bipolar disorder is characterized by strong heritability, with risks increasing if there is a first-degree relative with the illness. The hallmark of bipolar I disorder is a manic episode, which presents as:

• decreased need for sleep
  
• grandiosity
  
• flight of ideas
  
• reckless or thoughtless behaviors
  
• increased energy
  
• increased productivity
  
• expansive or irritable mood.
  

This diagnosis seems to fit well with our patient, who for 1 week had increased rate of speech, hyperactivity, and decreased need for sleep. She also has a positive family history of bipolar illness. Often patients with bipolar disorder experience a prodrome characterized by periods of depressed mood and periods that appear similar to mania but are not as obvious or severe.^1,2 Ms. T lacks this history.

Psychiatric symptoms secondary to seizure disorder are well documented. Cognitive, mood, anxiety, and psychotic phenomena may occur in up to 50% of patients with seizures.³ Typically, these symptoms are categorized as occurring during a seizure, after a seizure (post-ictal), or between seizures (interictal).

Manic syndromes secondary to seizure disorders present in an atypical manner with irritability and hyperactivity. Psychotic syndromes, on the other hand, appear with more classic schizophrenia-type symptoms:

• paranoia and persecutory delusions
  
• auditory and visual hallucinations
  
• amotivation
  
• apathy
  
• flattened affect
  
• disorganization.³
  

Ms. T had no history of witnessed seizure activity; however, the observed seizure early in her admission warranted exploring a possible underlying general medical condition.

Paraneoplastic syndromes may be associated with mood changes and other psychiatric symptoms.^4-6 Diagnosis is contingent on discovering the primary neoplasm, with or without specific paraneoplastic antibodies. Treatment is tailored to the oncologic process.

Table 1

Ms. T’s laboratory workup*

Test	Result
C-reactive protein	0.7
Erythrocyte sedimentation rate	5
Cryptococcal antigen (serum)	Negative
Antinuclear antibody	Negative
CSF lymphocytes	88
CSF nucleated cells	200
CSF RBC	33
CSF glucose	44
CSF protein	45
CSF igG index	1.2
CSF oligoclonal bands	Present
CSF: cerebrospinal fluid; igG: immunoglobulin G; RBC: red blood cell
*Results were negative for gonorrhea, chlamydia, lupus, human immunodeficiency virus, syphilis, Lyme disease, varicella zoster virus, West Nile virus, herpes simplex virus, Epstein-Barr virus, cytomegalovirus, tuberculosis, and California, St. Louis, eastern equine, and western equine encephalitis

 

EVALUATION: A medical cause

The psychiatry consultation-liaison service is asked to further evaluate Ms. T for psychiatric contributions to her continued altered mental status. Ms. T remains in restraints and receives fosphenytoin, 200 mg bid; levetiracetam, 1,000 mg bid; and lorazepam as needed for agitation. Following consultation, the team considers a working diagnosis of an autoimmune encephalopathy based on the negative infectious workup, the patient’s demographics, and the clinical picture (psychiatric symptoms, seizure, and encephalopathy). Ms. T undergoes 5 courses of plasma exchange with no effect. Catatonia is considered, but the patient does not demonstrate significant change with numerous doses of lorazepam.

Because Ms. T does not improve, the team starts a more specific paraneoplastic workup. MRI reveals a 9-mm lesion on her right ovary. Corticosteroids, including IV methylprednisolone, 1 g/d, are started. Ms. T’s clinical presentation improves; soon after scheduled corticosteroid dosing, she is taken to the operating room for right salpingo-oophorectomy. Surgical pathology later confirms the lesion as a mature teratoma. A standard paraneoplastic panel is negative; a separate test for anti-NMDA (N-methyl-D-aspartate) receptor antibodies is positive, however, and confirms the diagnosis of ovarian mass-associated anti-NMDA receptor limbic encephalitis.

Paraneoplastic syndromes

This case represents the interface between a complicated medical phenomenon and psychiatric symptomatology. Mood changes (typically depression), memory problems, paranoia, hypersomnolence, aggressive behavior, agitation, and catatonia have been associated with paraneoplastic syndromes.^4-6

Common malignant associations include small cell lung carcinoma (most common) and breast, stomach, colon, renal, bladder, ovarian, uterine, testicular, cell line, and thymic cancers. Research strongly suggests an autoimmune mechanism: tumor-related antibodies cross-react with similar antigens in the neurologic system. Paraneoplastic symptoms often precede symptoms of the malignancy, and the diagnosis is suggested by positive imaging and a paraneoplastic panel.

Definitive treatment is that which is appropriate for the specific neoplasm. Other successful therapies include immunosuppressants (including corticosteroids) and, less often, intravenous immunoglobulin (IVIg) or plasma exchange (when laboratory testing confirms known antibodies).⁷ Prognosis is highly variable, from complete recovery to death; antibody-positive cases may portend a more guarded prognosis.⁴

Anti-NMDA receptor limbic encephalitis is a paraneoplastic syndrome associated with ovarian teratomas and antibodies specific to the glutamate receptor. It is thought to be an autoimmune phenomenon whereby tumor-related antibodies elicit an immune response within certain parts of the neurologic system. Ms. T represents a typical clinical presentation of this syndrome—she is a young, otherwise healthy woman with:

• preceding headache
  
• new-onset psychotic symptoms
  
• seizure activity (particularly in the temporal lobes)
  
• central hypoventilation
  
• hyperthermia and tachycardia
  
• dyskinesia and catatonia-like symptoms.⁵
  

The course of anti-NMDA receptor limbic encephalitis typically progresses in distinct phases from prodromal symptoms to psychosis to unresponsiveness and hypoventilation to dysautonomia and dyskinesia.^4,5 Anti-NMDA receptor antibody identification is not included in standard paraneoplastic panels but can be specifically ordered from the University of Pennsylvania and Mayo Medical Laboratories.

TREATMENT: Rapid improvement

After removal of the dermoid lesion and IV corticosteroids, Ms. T exhibits rapid improvement. She begins acknowledging others in the room, making eye contact for nearly the first time during this hospitalization, and starts recognizing family members. She also begins verbalizing, responding appropriately to questions in 1 or 2 words. After a 34-day hospital stay, Ms. T is transferred to another facility for rehabilitation; her medication list consists of a corticosteroid taper from prednisone, 20 mg/d, over 2 weeks; fosphenytoin, 200 mg bid; and levetiracetam, 1,000 mg bid.

She eventually is discharged from the rehabilitation facility with noted improvement in multiple domains: she demonstrates cognitive improvement and can walk short distances. She continues to require 24-hour care and exhibits intermittent agitation.

The authors’ observations

We present the case of a patient with a specific paraneoplastic disorder—anti-NMDA receptor limbic encephalitis—with symptoms mimicking those seen in psychiatric disorders such as schizophrenia and bipolar disorder. These similarities complicate recognition and treatment of the underlying disorder.

Ms. T had a complicated yet typical presentation of anti-NMDA receptor limbic encephalitis ( Table 2 ) that was initially mistaken for a manic episode with psychotic features. The diagnosis was made more complex by the death of her mother 1 week before presentation, which could have precipitated her symptom onset. Similar case reports have appeared in neurologic and—less frequently—psychiatric literature ( Box ).^5,7-10

Commonly, patients with paraneoplastic limbic encephalitis experience a protracted hospital stay and extensive medical workup with long inpatient psychiatry stays before more severe physical manifestations—such as seizure activity and autonomic instability—prompt transfer to medical or neurologic services.

 

⁵ Ms. T spent time on psychiatric, internal medicine, and neurologic services before her team established a definitive diagnosis.

Because neurobehavioral symptoms predominate early in the course of paraneoplastic illness,⁵ psychiatrists should prepare to be the first medical point of contact for these patients.

Table 2

Anti-NMDA receptor encephalitis: Symptoms, findings, and treatment

Typical presentation
Young female Prodromal symptoms New onset psychosis, anxiety, or mood symptoms Catatonia Coma Seizure activity (typically bilateral temporal lobe activity on EEG) Hypoventilation Autonomic instability Dyskinesia
Laboratory and radiologic findings
CSF or serum antibodies CSF pleocytosis and elevated protein, normal glucose Background slowing or sharp-wave activity on EEG Temporal lobe abnormalities
Treatment
Tumor resection Immunosuppressants (typically corticosteroids) Intravenous immunoglobulin Plasmapheresis
CSF: cerebrospinal fluid; EEG: electroencephalography; NMDA: N-methyl-D-aspartate

Box

Related resource

• Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol. 2008;7(4):327-340.
  

Drug brand names

• Fosphenytoin • Cerebyx
  
• Haloperidol • Haldol
  
• Levetiracetam • Keppra
  
• Lorazepam • Ativan
  
• Methylprednisolone • Medrol, Depo-Medrol, others
  
• Olanzapine • Zyprexa
  
• Prednisone • Deltasone, Meticorten
  
• Ziprasidone • Geodon
  

Disclosures

Drs. Cavalieri and Southammakosane report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. White is a consultant for Pfizer Inc.

CASE: First-episode mania

Mrs. P, age 47, is brought to the emergency department (ED) because her family is concerned about her behavioral changes over the last week. Her husband reports that Mrs. P has become hyper-religious and talkative. She has been perseverating on numbers and dates and incessantly calling people. Mrs. P reports increased energy and decreased need for sleep. On examination, she has pressured speech. She has no psychiatric history; however, for the past year, she has been taking sertraline, 100 mg/d, and desipramine, 25 mg/d, which her primary care physician prescribed for unknown reasons.

Mrs. P has struggled with chronic back pain for years, but an MRI of her spine is negative. Her family strongly believes that for the past 3 years Mrs. P has been receiving too many medications from her pain management specialist. Six weeks before her current presentation, she was receiving methadone, 40 mg/d, hydrocodone, at least 20 mg/d, and tramadol, 400 mg/d in divided doses. She also was taking an unknown dose of at least 1 benzodiazepine.

Mrs. P’s husband notes she stopped taking methadone abruptly approximately 5 weeks ago. However, about 3 weeks ago, Mrs. P accidentally overdosed on opioids and was hospitalized for several days. Urine drug screen at the time was positive for acetaminophen, salicylate, propoxyphene, opiate, benzodiazepine, and tricyclic antidepressant.

Mrs. P’s medical history includes auditory nerve loss from birth; her mother had German measles (rubella). Mrs. P never learned American Sign Language. She underwent cochlear implant surgery 1 year ago and now has only mild difficulties speaking.

The authors’ observations

Manic symptoms are common in patients with comorbid medical disorders and present a diagnostic challenge. Obtaining an accurate history from the patient may be difficult. Such evaluations often require extensive investigation and collection of data from multiple sources, including:

• medical records
• family members
• patient observation.

Mrs. P’s history is marked by contradicting data from these sources. For example, her family says she stopped taking “pain medications” 5 weeks ago, but 2 weeks later her urine drug screen showed opioids.

Both illicit drugs and prescribed medications can precipitate manic symptoms. From medical records and drug testing, it was evident that Mrs. P had a history of medication abuse/overdose/misuse.

Mania also has been associated with substance withdrawal. Mrs. P allegedly stopped taking methadone 4 weeks before the onset of manic symptoms. Methadone is a synthetic opioid with a pharmacokinetic and pharmacodynamic profile that presents clinical challenges, including:

• large interindividual variability in methadone pharmacokinetics
• lack of reliable equianalgesic conversion ratio to and from other opioids
• potential for multiple drug interactions and complex pharmacodynamics.

An opioid’s half-life determines the onset and duration of withdrawal syndrome symptoms.¹ Methadone metabolism is predominantly mediated by CYP3A4, CYP2B6, CYP2D6, and to some extent by CYP2C19.¹ We performed genetic testing to help evaluate how Mrs. P metabolized medications. Mrs. P had a normal genotype for CYP2D6, which meant that she should process opioids at a normal rate; however, she was heterozygous for CYP2C19*2 polymorphism, so it is possible that methadone stayed in her system longer than average.

Evidence documenting methadone drug interactions is limited (Table 1).¹ Mrs. P was taking sertraline and desipramine; both have potent effects via 2D6 inhibition that could increase plasma methadone concentration. Other evidence indicates that benzodiazepines and methadone may have synergistic interactions that could increase opioid sedation or respiratory depression.¹

Table 1

Is a drug interaction with methadone causing Mrs. P’s mania?

Medication class/agent	Effect on methadone level	Effect on methadone metabolism	Additional effects of interaction
Selective serotonin reuptake inhibitors
Fluvoxamine	Increase	Inhibition	Opioid toxicity
Fluoxetine	Increase	Inhibition	Torsades de pointes
Paroxetine	Increase	Inhibition	Decreased hepatic metabolism
Sertraline*	Increase	Autoinduction	Torsades de pointes
Citalopram	—	—	Torsades de pointes
Tricyclic antidepressants
Desipramine*	—	Inhibition	Increased desipramine levels/inhibition of desipramine metabolism
Amitriptyline	Increase methadone clearance	—	Torsades de pointes/prolonged QT interval
Anti-inflammatory drugs
NSAIDs*	—	—	Enhanced analgesia/opioid-sparing effect
Aspirin*	—	—	Paradoxical activation of platelet receptors
Benzodiazepines
Alprazolam	—	—	CNS depression/sedation/overdose
Diazepam*	—	Inhibition	Additive depressant effects
Opioid agonists
Dextromethorphan	—	Inhibition (not significant)	Increased side effects, especially sleepiness and drowsiness
Tramadol*	—	—	Well tolerated
Nicotine	Decrease		Can increase smoking rate
*Medications taken by Mrs. P
NSAIDs: nonsteroidal anti-inflammatory drugs
Source: Reference 1

EVALUATION: Few clues

In our ED, Mrs. P’s urine drug abuse screen is positive for salicylate and benzodiazepine only. Findings from physical examination, vital signs, ECG, and chest radiography are within normal limits. Internal medicine consultation is unremarkable. Mrs. P’s laboratory investigation is notable for an elevated white blood cell count, but this normalizes over a week.

Mrs. P shows no evidence of infection and is normoglycemic. B12 and folate are within normal limits. Serum electrolytes, liver function testing, sensitive thyroid stimulating hormone, and C-reactive protein are within normal limits. Urinalysis is negative except for a small amount of hemoglobin. Her creatine kinase (CK) is in the upper normal range. Human immunodeficiency virus (HIV) and syphilis testing is negative. Ceruloplasmin level also is normal. Heavy metal screen is negative. Head MRI and CT from previous hospitalizations were unremarkable.

 

The authors’ observations

Our first step was to clarify Mrs. P’s diagnosis. In reviewing differential diagnoses, we considered:

• serotonin syndrome
• benzodiazepine withdrawal syndrome
• antidepressant-induced mania
• adrenergic toxicity
• malignant hyperthermia
• heat stroke
• infectious causes.

Our index of suspicion for serotonin syndrome was low because Mrs. P didn’t meet criteria required for diagnosis. Relevant signs and symptoms included confusion, elevated mood (major) and agitation, nervousness, insomnia, and low blood pressure (minor).

Based on concerns about medication interactions, we discontinued sertraline and desipramine. According to the patient’s sister, Mrs. P’s manic symptoms markedly responded to PRN doses of lorazepam. We prescribed lorazepam, 1 mg every 6 hours, and observed Mrs. P for signs and symptoms of benzodiazepine withdrawal.

HISTORY: OTC drug use

According to Mrs. P’s mother, after her daughter abruptly discontinued methadone, she began to have very strong headaches, which she treated with Excedrin or Excedrin Sinus. The mother said that 4 days before Mrs. P came to the ED, she found her daughter holding 4 tablets of Excedrin and an empty bottle. Unfortunately her mother was unable to say what type of Excedrin it was. When the treatment team asks Mrs. P how many pills she usually takes, she says she doesn’t know but usually until the pain stops.

The authors’ observations

Management of secondary mania should focus on treating the underlying condition (Algorithm). Neurology categorizes mania into 3 categories:²

• confusional-delirious states
• manic symptoms associated with focal or multifocal cerebral lesions
• affective disorders (manic-depressive and depressive psychoses).

Medical workup ruled out common secondary causes of psychosis. Collaborative information from relatives revealed no family history of mental illness.

Patients with hearing loss and deafness have been shown to be at increased risk for psychotic disorders compared with the general population. Severe sensory deficits early in Mrs. P’s life may have influenced the orderly development of neural connections in her sensory cortex and association areas.³ Mrs. P was deaf for the first 45 years of life. It could be hypothesized that her sensory deficits significantly influenced her ability to reality test. After receiving a cochlear implant, Mrs. P rapidly went from no auditory stimulation to marked improvement. This stressor might precipitate psychotic symptoms. However, her presentation seemed to be characterized more by manic symptoms or an agitated delirium. It also did not fit temporally with her presentation.

We begin to suspect that Mrs. P’s mania is substance-induced. Excedrin, an over-the-counter medication, contains aspirin and caffeine. Excedrin Sinus also contains phenylephrine. Amphetamines, caffeine, ephedrine, pseudoephedrine, and phenylpropanolamine have all been linked to manic-like psychotic episodes.

Concerns about the illicit conversion of pseudoephedrine into methamphetamine obliged pharmaceutical companies in the United States to switch product formulations to phenylephrine in 2005,⁴ although some “behind-the-counter” medications may contain pseudoephedrine. Phenylephrine is a relatively selective α1 agonist with weak α2 adrenoceptor agonist activity and low β agonist activity. It is very similar to pseudo-ephedrine, which is known to be implicated in the development of manic symptoms.^5,6

Pseudoephedrine can raise CK levels and cause rhabdomyolysis.^7,8 Mrs. P’s CK level was 176 (normal range 36 to 176 U/L) 4 days after her initial presentation, and she had a moderate amount of myoglobin in her urine. Her creatinine was normal. The patient was taking excessive amounts of caffeine and—if she was using Excedrin Sinus—pseudoephedrine or phenylephrine. We were unable to determine whether her Excedrin contained pseudoephedrine or phenylephrine. In addition, she was going through opioid withdrawal and reported problems with her sleep. There was also a question of Mrs. P’s unknown methadone use combined with its decreased clearance secondary to medication interactions.

While previously hospitalized for overdose, Mrs. P tested positive for propoxyphene. Excessive use of propoxyphene also can cause numerous adverse reactions. Some of that could have explained why Mrs. P’s presentation includes nervousness, CNS stimulation, excitement, insomnia, and restlessness.⁵

Based on multiple factors, we believe Mrs. P meets DSM-IV-TR criteria for substance-induced mood disorder (Table 2).⁹ This diagnosis is supported by Mrs. P’s history of complex polypharmacy, excessive caffeine use, sleep deprivation, and possible opioid withdrawal.

Algorithm: Managing substance-induced manic disorder

CK: creatine kinase; CRP: C-reactive protein; CT: computed tomography; EEG: electroencephalogram; HIV: human immunodeficiency virus; MRI: magnetic resonance imaging; VDRL: venereal disease research laboratoryTable 2

DSM-IV-TR criteria for substance-induced mood disorder*

A. A prominent and persistent disturbance in mood predominates in the clinical picture and is characterized by either (or both) of the following:   1. depressed mood or markedly diminished interest or pleasure in all, or almost all, activities   2. elevated, expansive, or irritable mood
B. There is evidence from the history, physical examination, or laboratory findings of:   1. the symptoms in Criterion A developed during, or within 1 month of, substance intoxication or withdrawal, or   2. medication use is etiologically related to the disturbance
C. The disturbance is not better accounted for by a mood disorder that is not substance-induced
D. The disturbance does not occur exclusively during the course of a delirium
E. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning
Minimal criteria are A plus B plus E
*Make this diagnosis only when mood symptoms are in excess of those usually associated with substance intoxication or substance withdrawal syndrome and when symptoms are sufficiently severe to warrant independent clinical attention
Source: Reference 9

 

TREATMENT: Escalating symptoms

While hospitalized, Mrs. P focuses solely on receiving pain medication. She does not know why she is in the hospital. She is easily distractible, intermittently intrusive, and disorganized and tangential in her thought process.

Two days after admission, her uncontrolled behavior escalates and she has marked psychomotor agitation. She is confused but remains oriented to time, place, and person. We start treatment with risperidone, 0.5 mg each morning and 1 mg at bedtime, because this agent is well tolerated, efficacious, and easily titrated to symptom response. Mrs. P’s symptoms improve, but she does not return to her reported baseline. Two days later, we increase risperidone to 1 mg every morning and 2 mg at bedtime. On the 6th day of hospitalization, Mrs. P is more organized and able to follow simple commands. She denies auditory or visual hallucinations. On the 10th day, she improves markedly and is back to her baseline level of functioning.

We perform psychological testing, including the Wechsler Adult Intelligence Scale (WAIS III) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS, Form A). The results show global neurocognitive deficits. Mrs. P’s intellectual skill is significantly below average, with verbal abilities reflecting functioning in the mildly retarded range. Nonverbal skills were stronger but still below average. Mrs. P’s capacity to learn and retain new information and to understand even modestly complex concepts is quite limited.

Because of Mrs. P’s long history of poly-substance abuse, inability to process information, and chronic back pain, we judge her to be at high risk for relapse. However, Mrs. P and her family are not interested in chemical dependence treatment.

This left us facing a difficult clinical situation. Mrs. P had a pattern of presenting to multiple physicians and eventually receiving narcotics. Her family provided transportation for her to these appointments but also was concerned about her drug use. With the patient and her family, we carefully outline Mrs. P’s treatment needs, including:

• medication monitoring by a psychiatrist after discharge
• a single, consistent primary care physician to manage her care
• a treatment plan shared by all clinicians involved in her care.

We review with Mrs. P and her family the benefits of behavioral approaches to chronic pain management. They agree to our recommendation that the family control Mrs. P’s medication supply. We discharge her on risperidone, 0.5 mg each morning and 1 mg at bedtime, and she is scheduled for follow-up with a local psychiatrist.

Related resource

• Krauthammer C, Klerman GL. Manic syndromes associated with antecedent physical illness or drugs. Arch Gen Psychiatry. 1978;35(11):1333-1339.

Drug brand names

• Alprazolam • Xanax
• Amitriptyline • Elavil
• Citalopram • Celexa
• Desipramine • Norpramin
• Diazepam • Valium
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Hydrocodone • Vicodin, Lortab, others
• Lorazepam • Ativan
• Methadone • Dolophine, Methadose
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Propoxyphene • Darvon, Darvocet, others
• Risperidone • Risperdal
• Sertraline • Zoloft
• Tramadol • Ultram

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: First-episode mania

Mrs. P, age 47, is brought to the emergency department (ED) because her family is concerned about her behavioral changes over the last week. Her husband reports that Mrs. P has become hyper-religious and talkative. She has been perseverating on numbers and dates and incessantly calling people. Mrs. P reports increased energy and decreased need for sleep. On examination, she has pressured speech. She has no psychiatric history; however, for the past year, she has been taking sertraline, 100 mg/d, and desipramine, 25 mg/d, which her primary care physician prescribed for unknown reasons.

Mrs. P has struggled with chronic back pain for years, but an MRI of her spine is negative. Her family strongly believes that for the past 3 years Mrs. P has been receiving too many medications from her pain management specialist. Six weeks before her current presentation, she was receiving methadone, 40 mg/d, hydrocodone, at least 20 mg/d, and tramadol, 400 mg/d in divided doses. She also was taking an unknown dose of at least 1 benzodiazepine.

Mrs. P’s husband notes she stopped taking methadone abruptly approximately 5 weeks ago. However, about 3 weeks ago, Mrs. P accidentally overdosed on opioids and was hospitalized for several days. Urine drug screen at the time was positive for acetaminophen, salicylate, propoxyphene, opiate, benzodiazepine, and tricyclic antidepressant.

Mrs. P’s medical history includes auditory nerve loss from birth; her mother had German measles (rubella). Mrs. P never learned American Sign Language. She underwent cochlear implant surgery 1 year ago and now has only mild difficulties speaking.

The authors’ observations

Manic symptoms are common in patients with comorbid medical disorders and present a diagnostic challenge. Obtaining an accurate history from the patient may be difficult. Such evaluations often require extensive investigation and collection of data from multiple sources, including:

• medical records
• family members
• patient observation.

Mrs. P’s history is marked by contradicting data from these sources. For example, her family says she stopped taking “pain medications” 5 weeks ago, but 2 weeks later her urine drug screen showed opioids.

Both illicit drugs and prescribed medications can precipitate manic symptoms. From medical records and drug testing, it was evident that Mrs. P had a history of medication abuse/overdose/misuse.

Mania also has been associated with substance withdrawal. Mrs. P allegedly stopped taking methadone 4 weeks before the onset of manic symptoms. Methadone is a synthetic opioid with a pharmacokinetic and pharmacodynamic profile that presents clinical challenges, including:

• large interindividual variability in methadone pharmacokinetics
• lack of reliable equianalgesic conversion ratio to and from other opioids
• potential for multiple drug interactions and complex pharmacodynamics.

An opioid’s half-life determines the onset and duration of withdrawal syndrome symptoms.¹ Methadone metabolism is predominantly mediated by CYP3A4, CYP2B6, CYP2D6, and to some extent by CYP2C19.¹ We performed genetic testing to help evaluate how Mrs. P metabolized medications. Mrs. P had a normal genotype for CYP2D6, which meant that she should process opioids at a normal rate; however, she was heterozygous for CYP2C19*2 polymorphism, so it is possible that methadone stayed in her system longer than average.

Evidence documenting methadone drug interactions is limited (Table 1).¹ Mrs. P was taking sertraline and desipramine; both have potent effects via 2D6 inhibition that could increase plasma methadone concentration. Other evidence indicates that benzodiazepines and methadone may have synergistic interactions that could increase opioid sedation or respiratory depression.¹

Table 1

Is a drug interaction with methadone causing Mrs. P’s mania?

Medication class/agent	Effect on methadone level	Effect on methadone metabolism	Additional effects of interaction
Selective serotonin reuptake inhibitors
Fluvoxamine	Increase	Inhibition	Opioid toxicity
Fluoxetine	Increase	Inhibition	Torsades de pointes
Paroxetine	Increase	Inhibition	Decreased hepatic metabolism
Sertraline*	Increase	Autoinduction	Torsades de pointes
Citalopram	—	—	Torsades de pointes
Tricyclic antidepressants
Desipramine*	—	Inhibition	Increased desipramine levels/inhibition of desipramine metabolism
Amitriptyline	Increase methadone clearance	—	Torsades de pointes/prolonged QT interval
Anti-inflammatory drugs
NSAIDs*	—	—	Enhanced analgesia/opioid-sparing effect
Aspirin*	—	—	Paradoxical activation of platelet receptors
Benzodiazepines
Alprazolam	—	—	CNS depression/sedation/overdose
Diazepam*	—	Inhibition	Additive depressant effects
Opioid agonists
Dextromethorphan	—	Inhibition (not significant)	Increased side effects, especially sleepiness and drowsiness
Tramadol*	—	—	Well tolerated
Nicotine	Decrease		Can increase smoking rate
*Medications taken by Mrs. P
NSAIDs: nonsteroidal anti-inflammatory drugs
Source: Reference 1

EVALUATION: Few clues

In our ED, Mrs. P’s urine drug abuse screen is positive for salicylate and benzodiazepine only. Findings from physical examination, vital signs, ECG, and chest radiography are within normal limits. Internal medicine consultation is unremarkable. Mrs. P’s laboratory investigation is notable for an elevated white blood cell count, but this normalizes over a week.

Mrs. P shows no evidence of infection and is normoglycemic. B12 and folate are within normal limits. Serum electrolytes, liver function testing, sensitive thyroid stimulating hormone, and C-reactive protein are within normal limits. Urinalysis is negative except for a small amount of hemoglobin. Her creatine kinase (CK) is in the upper normal range. Human immunodeficiency virus (HIV) and syphilis testing is negative. Ceruloplasmin level also is normal. Heavy metal screen is negative. Head MRI and CT from previous hospitalizations were unremarkable.

 

The authors’ observations

Our first step was to clarify Mrs. P’s diagnosis. In reviewing differential diagnoses, we considered:

• serotonin syndrome
• benzodiazepine withdrawal syndrome
• antidepressant-induced mania
• adrenergic toxicity
• malignant hyperthermia
• heat stroke
• infectious causes.

Our index of suspicion for serotonin syndrome was low because Mrs. P didn’t meet criteria required for diagnosis. Relevant signs and symptoms included confusion, elevated mood (major) and agitation, nervousness, insomnia, and low blood pressure (minor).

Based on concerns about medication interactions, we discontinued sertraline and desipramine. According to the patient’s sister, Mrs. P’s manic symptoms markedly responded to PRN doses of lorazepam. We prescribed lorazepam, 1 mg every 6 hours, and observed Mrs. P for signs and symptoms of benzodiazepine withdrawal.

HISTORY: OTC drug use

According to Mrs. P’s mother, after her daughter abruptly discontinued methadone, she began to have very strong headaches, which she treated with Excedrin or Excedrin Sinus. The mother said that 4 days before Mrs. P came to the ED, she found her daughter holding 4 tablets of Excedrin and an empty bottle. Unfortunately her mother was unable to say what type of Excedrin it was. When the treatment team asks Mrs. P how many pills she usually takes, she says she doesn’t know but usually until the pain stops.

The authors’ observations

Management of secondary mania should focus on treating the underlying condition (Algorithm). Neurology categorizes mania into 3 categories:²

• confusional-delirious states
• manic symptoms associated with focal or multifocal cerebral lesions
• affective disorders (manic-depressive and depressive psychoses).

Medical workup ruled out common secondary causes of psychosis. Collaborative information from relatives revealed no family history of mental illness.

Patients with hearing loss and deafness have been shown to be at increased risk for psychotic disorders compared with the general population. Severe sensory deficits early in Mrs. P’s life may have influenced the orderly development of neural connections in her sensory cortex and association areas.³ Mrs. P was deaf for the first 45 years of life. It could be hypothesized that her sensory deficits significantly influenced her ability to reality test. After receiving a cochlear implant, Mrs. P rapidly went from no auditory stimulation to marked improvement. This stressor might precipitate psychotic symptoms. However, her presentation seemed to be characterized more by manic symptoms or an agitated delirium. It also did not fit temporally with her presentation.

We begin to suspect that Mrs. P’s mania is substance-induced. Excedrin, an over-the-counter medication, contains aspirin and caffeine. Excedrin Sinus also contains phenylephrine. Amphetamines, caffeine, ephedrine, pseudoephedrine, and phenylpropanolamine have all been linked to manic-like psychotic episodes.

Concerns about the illicit conversion of pseudoephedrine into methamphetamine obliged pharmaceutical companies in the United States to switch product formulations to phenylephrine in 2005,⁴ although some “behind-the-counter” medications may contain pseudoephedrine. Phenylephrine is a relatively selective α1 agonist with weak α2 adrenoceptor agonist activity and low β agonist activity. It is very similar to pseudo-ephedrine, which is known to be implicated in the development of manic symptoms.^5,6

Pseudoephedrine can raise CK levels and cause rhabdomyolysis.^7,8 Mrs. P’s CK level was 176 (normal range 36 to 176 U/L) 4 days after her initial presentation, and she had a moderate amount of myoglobin in her urine. Her creatinine was normal. The patient was taking excessive amounts of caffeine and—if she was using Excedrin Sinus—pseudoephedrine or phenylephrine. We were unable to determine whether her Excedrin contained pseudoephedrine or phenylephrine. In addition, she was going through opioid withdrawal and reported problems with her sleep. There was also a question of Mrs. P’s unknown methadone use combined with its decreased clearance secondary to medication interactions.

While previously hospitalized for overdose, Mrs. P tested positive for propoxyphene. Excessive use of propoxyphene also can cause numerous adverse reactions. Some of that could have explained why Mrs. P’s presentation includes nervousness, CNS stimulation, excitement, insomnia, and restlessness.⁵

Based on multiple factors, we believe Mrs. P meets DSM-IV-TR criteria for substance-induced mood disorder (Table 2).⁹ This diagnosis is supported by Mrs. P’s history of complex polypharmacy, excessive caffeine use, sleep deprivation, and possible opioid withdrawal.

Algorithm: Managing substance-induced manic disorder

CK: creatine kinase; CRP: C-reactive protein; CT: computed tomography; EEG: electroencephalogram; HIV: human immunodeficiency virus; MRI: magnetic resonance imaging; VDRL: venereal disease research laboratoryTable 2

DSM-IV-TR criteria for substance-induced mood disorder*

A. A prominent and persistent disturbance in mood predominates in the clinical picture and is characterized by either (or both) of the following:   1. depressed mood or markedly diminished interest or pleasure in all, or almost all, activities   2. elevated, expansive, or irritable mood
B. There is evidence from the history, physical examination, or laboratory findings of:   1. the symptoms in Criterion A developed during, or within 1 month of, substance intoxication or withdrawal, or   2. medication use is etiologically related to the disturbance
C. The disturbance is not better accounted for by a mood disorder that is not substance-induced
D. The disturbance does not occur exclusively during the course of a delirium
E. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning
Minimal criteria are A plus B plus E
*Make this diagnosis only when mood symptoms are in excess of those usually associated with substance intoxication or substance withdrawal syndrome and when symptoms are sufficiently severe to warrant independent clinical attention
Source: Reference 9

 

TREATMENT: Escalating symptoms

While hospitalized, Mrs. P focuses solely on receiving pain medication. She does not know why she is in the hospital. She is easily distractible, intermittently intrusive, and disorganized and tangential in her thought process.

Two days after admission, her uncontrolled behavior escalates and she has marked psychomotor agitation. She is confused but remains oriented to time, place, and person. We start treatment with risperidone, 0.5 mg each morning and 1 mg at bedtime, because this agent is well tolerated, efficacious, and easily titrated to symptom response. Mrs. P’s symptoms improve, but she does not return to her reported baseline. Two days later, we increase risperidone to 1 mg every morning and 2 mg at bedtime. On the 6th day of hospitalization, Mrs. P is more organized and able to follow simple commands. She denies auditory or visual hallucinations. On the 10th day, she improves markedly and is back to her baseline level of functioning.

We perform psychological testing, including the Wechsler Adult Intelligence Scale (WAIS III) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS, Form A). The results show global neurocognitive deficits. Mrs. P’s intellectual skill is significantly below average, with verbal abilities reflecting functioning in the mildly retarded range. Nonverbal skills were stronger but still below average. Mrs. P’s capacity to learn and retain new information and to understand even modestly complex concepts is quite limited.

Because of Mrs. P’s long history of poly-substance abuse, inability to process information, and chronic back pain, we judge her to be at high risk for relapse. However, Mrs. P and her family are not interested in chemical dependence treatment.

This left us facing a difficult clinical situation. Mrs. P had a pattern of presenting to multiple physicians and eventually receiving narcotics. Her family provided transportation for her to these appointments but also was concerned about her drug use. With the patient and her family, we carefully outline Mrs. P’s treatment needs, including:

• medication monitoring by a psychiatrist after discharge
• a single, consistent primary care physician to manage her care
• a treatment plan shared by all clinicians involved in her care.

We review with Mrs. P and her family the benefits of behavioral approaches to chronic pain management. They agree to our recommendation that the family control Mrs. P’s medication supply. We discharge her on risperidone, 0.5 mg each morning and 1 mg at bedtime, and she is scheduled for follow-up with a local psychiatrist.

Related resource

• Krauthammer C, Klerman GL. Manic syndromes associated with antecedent physical illness or drugs. Arch Gen Psychiatry. 1978;35(11):1333-1339.

Drug brand names

• Alprazolam • Xanax
• Amitriptyline • Elavil
• Citalopram • Celexa
• Desipramine • Norpramin
• Diazepam • Valium
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Hydrocodone • Vicodin, Lortab, others
• Lorazepam • Ativan
• Methadone • Dolophine, Methadose
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Propoxyphene • Darvon, Darvocet, others
• Risperidone • Risperdal
• Sertraline • Zoloft
• Tramadol • Ultram

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: First-episode mania

Mrs. P, age 47, is brought to the emergency department (ED) because her family is concerned about her behavioral changes over the last week. Her husband reports that Mrs. P has become hyper-religious and talkative. She has been perseverating on numbers and dates and incessantly calling people. Mrs. P reports increased energy and decreased need for sleep. On examination, she has pressured speech. She has no psychiatric history; however, for the past year, she has been taking sertraline, 100 mg/d, and desipramine, 25 mg/d, which her primary care physician prescribed for unknown reasons.

Mrs. P has struggled with chronic back pain for years, but an MRI of her spine is negative. Her family strongly believes that for the past 3 years Mrs. P has been receiving too many medications from her pain management specialist. Six weeks before her current presentation, she was receiving methadone, 40 mg/d, hydrocodone, at least 20 mg/d, and tramadol, 400 mg/d in divided doses. She also was taking an unknown dose of at least 1 benzodiazepine.

Mrs. P’s husband notes she stopped taking methadone abruptly approximately 5 weeks ago. However, about 3 weeks ago, Mrs. P accidentally overdosed on opioids and was hospitalized for several days. Urine drug screen at the time was positive for acetaminophen, salicylate, propoxyphene, opiate, benzodiazepine, and tricyclic antidepressant.

Mrs. P’s medical history includes auditory nerve loss from birth; her mother had German measles (rubella). Mrs. P never learned American Sign Language. She underwent cochlear implant surgery 1 year ago and now has only mild difficulties speaking.

The authors’ observations

Manic symptoms are common in patients with comorbid medical disorders and present a diagnostic challenge. Obtaining an accurate history from the patient may be difficult. Such evaluations often require extensive investigation and collection of data from multiple sources, including:

• medical records
• family members
• patient observation.

Mrs. P’s history is marked by contradicting data from these sources. For example, her family says she stopped taking “pain medications” 5 weeks ago, but 2 weeks later her urine drug screen showed opioids.

Both illicit drugs and prescribed medications can precipitate manic symptoms. From medical records and drug testing, it was evident that Mrs. P had a history of medication abuse/overdose/misuse.

Mania also has been associated with substance withdrawal. Mrs. P allegedly stopped taking methadone 4 weeks before the onset of manic symptoms. Methadone is a synthetic opioid with a pharmacokinetic and pharmacodynamic profile that presents clinical challenges, including:

• large interindividual variability in methadone pharmacokinetics
• lack of reliable equianalgesic conversion ratio to and from other opioids
• potential for multiple drug interactions and complex pharmacodynamics.

An opioid’s half-life determines the onset and duration of withdrawal syndrome symptoms.¹ Methadone metabolism is predominantly mediated by CYP3A4, CYP2B6, CYP2D6, and to some extent by CYP2C19.¹ We performed genetic testing to help evaluate how Mrs. P metabolized medications. Mrs. P had a normal genotype for CYP2D6, which meant that she should process opioids at a normal rate; however, she was heterozygous for CYP2C19*2 polymorphism, so it is possible that methadone stayed in her system longer than average.

Evidence documenting methadone drug interactions is limited (Table 1).¹ Mrs. P was taking sertraline and desipramine; both have potent effects via 2D6 inhibition that could increase plasma methadone concentration. Other evidence indicates that benzodiazepines and methadone may have synergistic interactions that could increase opioid sedation or respiratory depression.¹

Table 1

Is a drug interaction with methadone causing Mrs. P’s mania?

Medication class/agent	Effect on methadone level	Effect on methadone metabolism	Additional effects of interaction
Selective serotonin reuptake inhibitors
Fluvoxamine	Increase	Inhibition	Opioid toxicity
Fluoxetine	Increase	Inhibition	Torsades de pointes
Paroxetine	Increase	Inhibition	Decreased hepatic metabolism
Sertraline*	Increase	Autoinduction	Torsades de pointes
Citalopram	—	—	Torsades de pointes
Tricyclic antidepressants
Desipramine*	—	Inhibition	Increased desipramine levels/inhibition of desipramine metabolism
Amitriptyline	Increase methadone clearance	—	Torsades de pointes/prolonged QT interval
Anti-inflammatory drugs
NSAIDs*	—	—	Enhanced analgesia/opioid-sparing effect
Aspirin*	—	—	Paradoxical activation of platelet receptors
Benzodiazepines
Alprazolam	—	—	CNS depression/sedation/overdose
Diazepam*	—	Inhibition	Additive depressant effects
Opioid agonists
Dextromethorphan	—	Inhibition (not significant)	Increased side effects, especially sleepiness and drowsiness
Tramadol*	—	—	Well tolerated
Nicotine	Decrease		Can increase smoking rate
*Medications taken by Mrs. P
NSAIDs: nonsteroidal anti-inflammatory drugs
Source: Reference 1

EVALUATION: Few clues

In our ED, Mrs. P’s urine drug abuse screen is positive for salicylate and benzodiazepine only. Findings from physical examination, vital signs, ECG, and chest radiography are within normal limits. Internal medicine consultation is unremarkable. Mrs. P’s laboratory investigation is notable for an elevated white blood cell count, but this normalizes over a week.

Mrs. P shows no evidence of infection and is normoglycemic. B12 and folate are within normal limits. Serum electrolytes, liver function testing, sensitive thyroid stimulating hormone, and C-reactive protein are within normal limits. Urinalysis is negative except for a small amount of hemoglobin. Her creatine kinase (CK) is in the upper normal range. Human immunodeficiency virus (HIV) and syphilis testing is negative. Ceruloplasmin level also is normal. Heavy metal screen is negative. Head MRI and CT from previous hospitalizations were unremarkable.

 

The authors’ observations

Our first step was to clarify Mrs. P’s diagnosis. In reviewing differential diagnoses, we considered:

• serotonin syndrome
• benzodiazepine withdrawal syndrome
• antidepressant-induced mania
• adrenergic toxicity
• malignant hyperthermia
• heat stroke
• infectious causes.

Our index of suspicion for serotonin syndrome was low because Mrs. P didn’t meet criteria required for diagnosis. Relevant signs and symptoms included confusion, elevated mood (major) and agitation, nervousness, insomnia, and low blood pressure (minor).

Based on concerns about medication interactions, we discontinued sertraline and desipramine. According to the patient’s sister, Mrs. P’s manic symptoms markedly responded to PRN doses of lorazepam. We prescribed lorazepam, 1 mg every 6 hours, and observed Mrs. P for signs and symptoms of benzodiazepine withdrawal.

HISTORY: OTC drug use

According to Mrs. P’s mother, after her daughter abruptly discontinued methadone, she began to have very strong headaches, which she treated with Excedrin or Excedrin Sinus. The mother said that 4 days before Mrs. P came to the ED, she found her daughter holding 4 tablets of Excedrin and an empty bottle. Unfortunately her mother was unable to say what type of Excedrin it was. When the treatment team asks Mrs. P how many pills she usually takes, she says she doesn’t know but usually until the pain stops.

The authors’ observations

Management of secondary mania should focus on treating the underlying condition (Algorithm). Neurology categorizes mania into 3 categories:²

• confusional-delirious states
• manic symptoms associated with focal or multifocal cerebral lesions
• affective disorders (manic-depressive and depressive psychoses).

Medical workup ruled out common secondary causes of psychosis. Collaborative information from relatives revealed no family history of mental illness.

Patients with hearing loss and deafness have been shown to be at increased risk for psychotic disorders compared with the general population. Severe sensory deficits early in Mrs. P’s life may have influenced the orderly development of neural connections in her sensory cortex and association areas.³ Mrs. P was deaf for the first 45 years of life. It could be hypothesized that her sensory deficits significantly influenced her ability to reality test. After receiving a cochlear implant, Mrs. P rapidly went from no auditory stimulation to marked improvement. This stressor might precipitate psychotic symptoms. However, her presentation seemed to be characterized more by manic symptoms or an agitated delirium. It also did not fit temporally with her presentation.

We begin to suspect that Mrs. P’s mania is substance-induced. Excedrin, an over-the-counter medication, contains aspirin and caffeine. Excedrin Sinus also contains phenylephrine. Amphetamines, caffeine, ephedrine, pseudoephedrine, and phenylpropanolamine have all been linked to manic-like psychotic episodes.

Concerns about the illicit conversion of pseudoephedrine into methamphetamine obliged pharmaceutical companies in the United States to switch product formulations to phenylephrine in 2005,⁴ although some “behind-the-counter” medications may contain pseudoephedrine. Phenylephrine is a relatively selective α1 agonist with weak α2 adrenoceptor agonist activity and low β agonist activity. It is very similar to pseudo-ephedrine, which is known to be implicated in the development of manic symptoms.^5,6

Pseudoephedrine can raise CK levels and cause rhabdomyolysis.^7,8 Mrs. P’s CK level was 176 (normal range 36 to 176 U/L) 4 days after her initial presentation, and she had a moderate amount of myoglobin in her urine. Her creatinine was normal. The patient was taking excessive amounts of caffeine and—if she was using Excedrin Sinus—pseudoephedrine or phenylephrine. We were unable to determine whether her Excedrin contained pseudoephedrine or phenylephrine. In addition, she was going through opioid withdrawal and reported problems with her sleep. There was also a question of Mrs. P’s unknown methadone use combined with its decreased clearance secondary to medication interactions.

While previously hospitalized for overdose, Mrs. P tested positive for propoxyphene. Excessive use of propoxyphene also can cause numerous adverse reactions. Some of that could have explained why Mrs. P’s presentation includes nervousness, CNS stimulation, excitement, insomnia, and restlessness.⁵

Based on multiple factors, we believe Mrs. P meets DSM-IV-TR criteria for substance-induced mood disorder (Table 2).⁹ This diagnosis is supported by Mrs. P’s history of complex polypharmacy, excessive caffeine use, sleep deprivation, and possible opioid withdrawal.

Algorithm: Managing substance-induced manic disorder

CK: creatine kinase; CRP: C-reactive protein; CT: computed tomography; EEG: electroencephalogram; HIV: human immunodeficiency virus; MRI: magnetic resonance imaging; VDRL: venereal disease research laboratoryTable 2

DSM-IV-TR criteria for substance-induced mood disorder*

A. A prominent and persistent disturbance in mood predominates in the clinical picture and is characterized by either (or both) of the following:   1. depressed mood or markedly diminished interest or pleasure in all, or almost all, activities   2. elevated, expansive, or irritable mood
B. There is evidence from the history, physical examination, or laboratory findings of:   1. the symptoms in Criterion A developed during, or within 1 month of, substance intoxication or withdrawal, or   2. medication use is etiologically related to the disturbance
C. The disturbance is not better accounted for by a mood disorder that is not substance-induced
D. The disturbance does not occur exclusively during the course of a delirium
E. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning
Minimal criteria are A plus B plus E
*Make this diagnosis only when mood symptoms are in excess of those usually associated with substance intoxication or substance withdrawal syndrome and when symptoms are sufficiently severe to warrant independent clinical attention
Source: Reference 9

 

TREATMENT: Escalating symptoms

While hospitalized, Mrs. P focuses solely on receiving pain medication. She does not know why she is in the hospital. She is easily distractible, intermittently intrusive, and disorganized and tangential in her thought process.

Two days after admission, her uncontrolled behavior escalates and she has marked psychomotor agitation. She is confused but remains oriented to time, place, and person. We start treatment with risperidone, 0.5 mg each morning and 1 mg at bedtime, because this agent is well tolerated, efficacious, and easily titrated to symptom response. Mrs. P’s symptoms improve, but she does not return to her reported baseline. Two days later, we increase risperidone to 1 mg every morning and 2 mg at bedtime. On the 6th day of hospitalization, Mrs. P is more organized and able to follow simple commands. She denies auditory or visual hallucinations. On the 10th day, she improves markedly and is back to her baseline level of functioning.

We perform psychological testing, including the Wechsler Adult Intelligence Scale (WAIS III) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS, Form A). The results show global neurocognitive deficits. Mrs. P’s intellectual skill is significantly below average, with verbal abilities reflecting functioning in the mildly retarded range. Nonverbal skills were stronger but still below average. Mrs. P’s capacity to learn and retain new information and to understand even modestly complex concepts is quite limited.

Because of Mrs. P’s long history of poly-substance abuse, inability to process information, and chronic back pain, we judge her to be at high risk for relapse. However, Mrs. P and her family are not interested in chemical dependence treatment.

This left us facing a difficult clinical situation. Mrs. P had a pattern of presenting to multiple physicians and eventually receiving narcotics. Her family provided transportation for her to these appointments but also was concerned about her drug use. With the patient and her family, we carefully outline Mrs. P’s treatment needs, including:

• medication monitoring by a psychiatrist after discharge
• a single, consistent primary care physician to manage her care
• a treatment plan shared by all clinicians involved in her care.

We review with Mrs. P and her family the benefits of behavioral approaches to chronic pain management. They agree to our recommendation that the family control Mrs. P’s medication supply. We discharge her on risperidone, 0.5 mg each morning and 1 mg at bedtime, and she is scheduled for follow-up with a local psychiatrist.

Related resource

• Krauthammer C, Klerman GL. Manic syndromes associated with antecedent physical illness or drugs. Arch Gen Psychiatry. 1978;35(11):1333-1339.

Drug brand names

• Alprazolam • Xanax
• Amitriptyline • Elavil
• Citalopram • Celexa
• Desipramine • Norpramin
• Diazepam • Valium
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Haloperidol • Haldol
• Hydrocodone • Vicodin, Lortab, others
• Lorazepam • Ativan
• Methadone • Dolophine, Methadose
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Propoxyphene • Darvon, Darvocet, others
• Risperidone • Risperdal
• Sertraline • Zoloft
• Tramadol • Ultram

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Unable to communicate

Mrs. A, age 44, is airlifted to the emergency room after a motor vehicle accident in which she was the restrained front seat passenger. She was on the way to a mental health follow-up appointment with her husband, who died on the scene, and 24-year-old son, who sustained multiple injuries. At the accident scene, Mrs. A was awake and responded to all questions by saying, “I don’t know.” No other history could be obtained. She was carrying documents from a local psychiatric facility that stated she had been discharged 1 month ago with a diagnosis of psychotic disorder, not otherwise specified (NOS). Her discharge medications were olanzapine, 15 mg at bedtime; escitalopram, 20 mg/d; lamotrigine, 100 mg/d; zolpidem, 10 mg as needed at bedtime; and diazepam, 5 mg tid.

Initial assessment reveals mild concussion, nondisplaced fractures of the left C7 and T1 transverse processes, and fracture of the posterior left first rib. Mrs. A is admitted to the trauma surgery service. Soon after, nurses report that Mrs. A is not able to report symptoms. Psychiatry service is consulted to evaluate her continued confusion and inability to communicate.

The authors’ observations

I (NJ) first see Mrs. A in the trauma step-down unit. She is lying in bed with a cervical collar and looks older than her stated age. As soon as I enter the room, Mrs. A greets me with “I don’t know.” She is awake, alert, and appears to listen to all questions, but responds only with “I don’t know.” She is able to follow simple commands to squeeze my fingers and move her extremities.

Mrs. A seems anxious because of my repeated attempts to communicate. Her affect is restricted, and her speech is limited to “I don’t know” but fluent. She does not appear to be responding to internal stimuli. Neurologic examination, including cranial nerves and reflexes, is normal. A chart review reveals that her psychiatric medications have been continued upon admission.

HISTORY: Always nervous

We contact Mrs. A’s son, who also was admitted to the hospital, for more information. He reports that his mother has a long history of “nerve problems,” which he describes as “crying and feeling sad and nervous.” He says Mrs. A’s mother also had these problems, and Mrs. A’s childhood was difficult (Table 1). Because of this condition, Mrs. A lives alone in a trailer next to the house where her husband and children live.

Mrs. A’s son said that she had a “nervous breakdown” a few months ago, was admitted to the local psychiatric facility, and since then had been saying only, “I don’t know.” She can communicate her wishes by pointing at “Yes” or “No” written on paper. At home, she can perform all activities of daily living (ADLs), including paying bills. He denies that his mother engages in drug abuse.

We obtain Mrs. A’s treatment records from the psychiatric facility and learn she was admitted with a history of confusion, auditory and visual hallucinations, and crying episodes. She had a history of noncompliance with outpatient medications, which included diazepam, duloxetine, and ziprasidone. Upon admission to that facility, Mrs. A was alert but disoriented to place and time. She answered questions slowly but was brief, sometimes incoherent, and having auditory and visual hallucinations.

During that hospitalization, clinicians established a working diagnosis of psychotic disorder, NOS. Mrs. A was noted to have a urinary tract infection, which they treated with amoxicillin/clavulanate. Ziprasidone was discontinued and olanzapine was started. Escitalopram and lamotrigine were added. Mrs. A’s hallucinations gradually resolved, and she was able to perform ADLs. However, she did not communicate much and started answering most questions with “I don’t know.” At discharge, she was sent home to the care of her sister and husband.

Since then, Mrs. A had been taking her medications regularly but did not show improvement in her speech or methods of communication.

The authors’ observations

Aphasia and related language disorders may present as a manifestation of stroke,¹ head injury,² status epilepticus,³ cerebral tumors,⁴ or neurodegenerative diseases.⁵ Language disorders commonly seen in psychiatric patients include selective mutism and aphonia. There is limited literature on aphasia as a manifestation of psychiatric illnesses; an extensive search reveals only 3 studies.⁶ We found case reports highlighting the difficulty in establishing a differential diagnosis among schizophrenic speech and status epilepticus

 

⁷ and frontotemporal⁸ and stroke-related⁹ speech disorder. Neuroimaging studies may be helpful in differentiating language disorders from psychosis. For example, evidence of lesions in the language centers of the brain is found in some cases of aphasia, and enlarged ventricles is a common finding in patients with schizophrenia. We considered all of these possibilities when evaluating Mrs. A (Table 2).

Table 1

Mrs. A’s family and personal history of ‘nerve problems’

Childhood	Mrs. A’s mother had ‘nerve problems.’ Her father physically abused Mrs. A. She received a ninth-grade education
Adult life	Married at age 17, Mrs. A had her first child at age 19, second child at age 20, and third child at age 21. She never obtained employment but raised her children with her husband
Last 2 years	Mrs. A lived in a trailer next to the house where her husband lived with 2 of their children. Family reports Mrs. A’s ’nerve problems’ were the reason for the separation. They state they took care of her needs and made sure she took her medications
Last 2 months	Mrs. A was admitted to a local psychiatric facility with confusion, hallucinations, crying spells, and decreased speech. After discharge, she could perform activities of daily living, but her speech did not improve
Present	Mrs. A is a passenger in a motor vehicle accident that results in her husband’s death and multiple injuries to her son. She is admitted to our hospital

Table 2

What is the cause of Mrs. A’s speech difficulties?

Possible diagnosis	Finding that ruled it out
Primary progressive aphasia	Subacute onset with rapid progression
Frontotemporal dementia	Inconclusive mild frontotemporal atrophy on brain MRI
Nonconvulsive status epilepticus	Normal EEG
Conversion disorder	Uncommon presentation: Mrs. A is beyond usual age of onset, and symptoms have lasted >1 month
Broca’s aphasia/CVA	No corresponding organic lesions on MRI
Factitious disorder	No motivation to assume the sick role
Psychotic speech	No other evidence of psychosis
CVA: cerebrovascular accident; EEG: electroencephalography; MRI: magnetic resonance imaging

TREATMENT: An abbreviated stay

A week after admission, Mrs. A is deemed medically stable. Head CT reveals a small, calcified left parietal meningioma that did not correlate with her symptoms (Table 3). Brain MRI shows mild frontotemporal atrophy that was considered inconclusive evidence for a diagnosis of frontotemporal dementia; there is no evidence of infarction, tumors, or other enhancing lesions that may have explained Mrs. A’s symptoms. A 12-lead EEG shows no abnormalities, which rules out a seizure disorder.

Neurology consult rules out concussion syndrome. Over several different evaluations, Mrs. A is noted to follow commands, perform ADLs, and walk. She is able to write her name legibly but is unable to write anything else or to perform a clock-drawing test.

A speech pathology evaluation is requested. A speech pathologist diagnoses Mrs. A with expressive aphasia—impaired ability to speak and write—with some receptive component, meaning her ability to comprehend spoken words also is impaired.

Mrs. A’s speech status does not change, and she remains unable to communicate. She is discharged 10 days after admission with scheduled outpatient follow-up.

Table 3

Findings of Mrs. A’s neurologic testing

Test	Result
Head CT	1-cm dural-based lesion in the left posterior parietal region
Brain MRI	Mild, inconclusive frontotemporal atrophy
EEG	Normal
CT: computed tomography; EEG: electroencephalography; MRI: magnetic resonance imaging

The authors’ observations

At discharge, it seemed likely that Mrs. A may have early symptoms of a neurodegenerative illness, such as frontotemporal dementia, or the aphasia may be a manifestation of chronic psychotic depression. We wanted to follow up with neuropsychological testing and PET scan before establishing a definitive psychiatric diagnosis and modifying the treatment plan.

Unfortunately, Mrs. A was lost to follow-up. We contacted her family several times, but they were unable to bring her back for further evaluation because of financial issues and the distance they would have had to travel.

Related resources

• The Academy of Aphasia. www.academyofaphasia.org.
  
• The National Aphasia Association. www.aphasia.org.
  

Drug brand names

• Amoxicillin/clavulanate • Augmentin
  
• Diazepam • Valium
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Lamotrigine • Lamictal
  
• Olanzapine • Zyprexa
  
• Ziprasidone • Geodon
  
• Zolpidem • Ambien
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Unable to communicate

Mrs. A, age 44, is airlifted to the emergency room after a motor vehicle accident in which she was the restrained front seat passenger. She was on the way to a mental health follow-up appointment with her husband, who died on the scene, and 24-year-old son, who sustained multiple injuries. At the accident scene, Mrs. A was awake and responded to all questions by saying, “I don’t know.” No other history could be obtained. She was carrying documents from a local psychiatric facility that stated she had been discharged 1 month ago with a diagnosis of psychotic disorder, not otherwise specified (NOS). Her discharge medications were olanzapine, 15 mg at bedtime; escitalopram, 20 mg/d; lamotrigine, 100 mg/d; zolpidem, 10 mg as needed at bedtime; and diazepam, 5 mg tid.

Initial assessment reveals mild concussion, nondisplaced fractures of the left C7 and T1 transverse processes, and fracture of the posterior left first rib. Mrs. A is admitted to the trauma surgery service. Soon after, nurses report that Mrs. A is not able to report symptoms. Psychiatry service is consulted to evaluate her continued confusion and inability to communicate.

The authors’ observations

I (NJ) first see Mrs. A in the trauma step-down unit. She is lying in bed with a cervical collar and looks older than her stated age. As soon as I enter the room, Mrs. A greets me with “I don’t know.” She is awake, alert, and appears to listen to all questions, but responds only with “I don’t know.” She is able to follow simple commands to squeeze my fingers and move her extremities.

Mrs. A seems anxious because of my repeated attempts to communicate. Her affect is restricted, and her speech is limited to “I don’t know” but fluent. She does not appear to be responding to internal stimuli. Neurologic examination, including cranial nerves and reflexes, is normal. A chart review reveals that her psychiatric medications have been continued upon admission.

HISTORY: Always nervous

We contact Mrs. A’s son, who also was admitted to the hospital, for more information. He reports that his mother has a long history of “nerve problems,” which he describes as “crying and feeling sad and nervous.” He says Mrs. A’s mother also had these problems, and Mrs. A’s childhood was difficult (Table 1). Because of this condition, Mrs. A lives alone in a trailer next to the house where her husband and children live.

Mrs. A’s son said that she had a “nervous breakdown” a few months ago, was admitted to the local psychiatric facility, and since then had been saying only, “I don’t know.” She can communicate her wishes by pointing at “Yes” or “No” written on paper. At home, she can perform all activities of daily living (ADLs), including paying bills. He denies that his mother engages in drug abuse.

We obtain Mrs. A’s treatment records from the psychiatric facility and learn she was admitted with a history of confusion, auditory and visual hallucinations, and crying episodes. She had a history of noncompliance with outpatient medications, which included diazepam, duloxetine, and ziprasidone. Upon admission to that facility, Mrs. A was alert but disoriented to place and time. She answered questions slowly but was brief, sometimes incoherent, and having auditory and visual hallucinations.

During that hospitalization, clinicians established a working diagnosis of psychotic disorder, NOS. Mrs. A was noted to have a urinary tract infection, which they treated with amoxicillin/clavulanate. Ziprasidone was discontinued and olanzapine was started. Escitalopram and lamotrigine were added. Mrs. A’s hallucinations gradually resolved, and she was able to perform ADLs. However, she did not communicate much and started answering most questions with “I don’t know.” At discharge, she was sent home to the care of her sister and husband.

Since then, Mrs. A had been taking her medications regularly but did not show improvement in her speech or methods of communication.

The authors’ observations

Aphasia and related language disorders may present as a manifestation of stroke,¹ head injury,² status epilepticus,³ cerebral tumors,⁴ or neurodegenerative diseases.⁵ Language disorders commonly seen in psychiatric patients include selective mutism and aphonia. There is limited literature on aphasia as a manifestation of psychiatric illnesses; an extensive search reveals only 3 studies.⁶ We found case reports highlighting the difficulty in establishing a differential diagnosis among schizophrenic speech and status epilepticus

 

⁷ and frontotemporal⁸ and stroke-related⁹ speech disorder. Neuroimaging studies may be helpful in differentiating language disorders from psychosis. For example, evidence of lesions in the language centers of the brain is found in some cases of aphasia, and enlarged ventricles is a common finding in patients with schizophrenia. We considered all of these possibilities when evaluating Mrs. A (Table 2).

Table 1

Mrs. A’s family and personal history of ‘nerve problems’

Childhood	Mrs. A’s mother had ‘nerve problems.’ Her father physically abused Mrs. A. She received a ninth-grade education
Adult life	Married at age 17, Mrs. A had her first child at age 19, second child at age 20, and third child at age 21. She never obtained employment but raised her children with her husband
Last 2 years	Mrs. A lived in a trailer next to the house where her husband lived with 2 of their children. Family reports Mrs. A’s ’nerve problems’ were the reason for the separation. They state they took care of her needs and made sure she took her medications
Last 2 months	Mrs. A was admitted to a local psychiatric facility with confusion, hallucinations, crying spells, and decreased speech. After discharge, she could perform activities of daily living, but her speech did not improve
Present	Mrs. A is a passenger in a motor vehicle accident that results in her husband’s death and multiple injuries to her son. She is admitted to our hospital

Table 2

What is the cause of Mrs. A’s speech difficulties?

Possible diagnosis	Finding that ruled it out
Primary progressive aphasia	Subacute onset with rapid progression
Frontotemporal dementia	Inconclusive mild frontotemporal atrophy on brain MRI
Nonconvulsive status epilepticus	Normal EEG
Conversion disorder	Uncommon presentation: Mrs. A is beyond usual age of onset, and symptoms have lasted >1 month
Broca’s aphasia/CVA	No corresponding organic lesions on MRI
Factitious disorder	No motivation to assume the sick role
Psychotic speech	No other evidence of psychosis
CVA: cerebrovascular accident; EEG: electroencephalography; MRI: magnetic resonance imaging

TREATMENT: An abbreviated stay

A week after admission, Mrs. A is deemed medically stable. Head CT reveals a small, calcified left parietal meningioma that did not correlate with her symptoms (Table 3). Brain MRI shows mild frontotemporal atrophy that was considered inconclusive evidence for a diagnosis of frontotemporal dementia; there is no evidence of infarction, tumors, or other enhancing lesions that may have explained Mrs. A’s symptoms. A 12-lead EEG shows no abnormalities, which rules out a seizure disorder.

Neurology consult rules out concussion syndrome. Over several different evaluations, Mrs. A is noted to follow commands, perform ADLs, and walk. She is able to write her name legibly but is unable to write anything else or to perform a clock-drawing test.

A speech pathology evaluation is requested. A speech pathologist diagnoses Mrs. A with expressive aphasia—impaired ability to speak and write—with some receptive component, meaning her ability to comprehend spoken words also is impaired.

Mrs. A’s speech status does not change, and she remains unable to communicate. She is discharged 10 days after admission with scheduled outpatient follow-up.

Table 3

Findings of Mrs. A’s neurologic testing

Test	Result
Head CT	1-cm dural-based lesion in the left posterior parietal region
Brain MRI	Mild, inconclusive frontotemporal atrophy
EEG	Normal
CT: computed tomography; EEG: electroencephalography; MRI: magnetic resonance imaging

The authors’ observations

At discharge, it seemed likely that Mrs. A may have early symptoms of a neurodegenerative illness, such as frontotemporal dementia, or the aphasia may be a manifestation of chronic psychotic depression. We wanted to follow up with neuropsychological testing and PET scan before establishing a definitive psychiatric diagnosis and modifying the treatment plan.

Unfortunately, Mrs. A was lost to follow-up. We contacted her family several times, but they were unable to bring her back for further evaluation because of financial issues and the distance they would have had to travel.

Related resources

• The Academy of Aphasia. www.academyofaphasia.org.
  
• The National Aphasia Association. www.aphasia.org.
  

Drug brand names

• Amoxicillin/clavulanate • Augmentin
  
• Diazepam • Valium
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Lamotrigine • Lamictal
  
• Olanzapine • Zyprexa
  
• Ziprasidone • Geodon
  
• Zolpidem • Ambien
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Unable to communicate

Mrs. A, age 44, is airlifted to the emergency room after a motor vehicle accident in which she was the restrained front seat passenger. She was on the way to a mental health follow-up appointment with her husband, who died on the scene, and 24-year-old son, who sustained multiple injuries. At the accident scene, Mrs. A was awake and responded to all questions by saying, “I don’t know.” No other history could be obtained. She was carrying documents from a local psychiatric facility that stated she had been discharged 1 month ago with a diagnosis of psychotic disorder, not otherwise specified (NOS). Her discharge medications were olanzapine, 15 mg at bedtime; escitalopram, 20 mg/d; lamotrigine, 100 mg/d; zolpidem, 10 mg as needed at bedtime; and diazepam, 5 mg tid.

Initial assessment reveals mild concussion, nondisplaced fractures of the left C7 and T1 transverse processes, and fracture of the posterior left first rib. Mrs. A is admitted to the trauma surgery service. Soon after, nurses report that Mrs. A is not able to report symptoms. Psychiatry service is consulted to evaluate her continued confusion and inability to communicate.

The authors’ observations

I (NJ) first see Mrs. A in the trauma step-down unit. She is lying in bed with a cervical collar and looks older than her stated age. As soon as I enter the room, Mrs. A greets me with “I don’t know.” She is awake, alert, and appears to listen to all questions, but responds only with “I don’t know.” She is able to follow simple commands to squeeze my fingers and move her extremities.

Mrs. A seems anxious because of my repeated attempts to communicate. Her affect is restricted, and her speech is limited to “I don’t know” but fluent. She does not appear to be responding to internal stimuli. Neurologic examination, including cranial nerves and reflexes, is normal. A chart review reveals that her psychiatric medications have been continued upon admission.

HISTORY: Always nervous

We contact Mrs. A’s son, who also was admitted to the hospital, for more information. He reports that his mother has a long history of “nerve problems,” which he describes as “crying and feeling sad and nervous.” He says Mrs. A’s mother also had these problems, and Mrs. A’s childhood was difficult (Table 1). Because of this condition, Mrs. A lives alone in a trailer next to the house where her husband and children live.

Mrs. A’s son said that she had a “nervous breakdown” a few months ago, was admitted to the local psychiatric facility, and since then had been saying only, “I don’t know.” She can communicate her wishes by pointing at “Yes” or “No” written on paper. At home, she can perform all activities of daily living (ADLs), including paying bills. He denies that his mother engages in drug abuse.

We obtain Mrs. A’s treatment records from the psychiatric facility and learn she was admitted with a history of confusion, auditory and visual hallucinations, and crying episodes. She had a history of noncompliance with outpatient medications, which included diazepam, duloxetine, and ziprasidone. Upon admission to that facility, Mrs. A was alert but disoriented to place and time. She answered questions slowly but was brief, sometimes incoherent, and having auditory and visual hallucinations.

During that hospitalization, clinicians established a working diagnosis of psychotic disorder, NOS. Mrs. A was noted to have a urinary tract infection, which they treated with amoxicillin/clavulanate. Ziprasidone was discontinued and olanzapine was started. Escitalopram and lamotrigine were added. Mrs. A’s hallucinations gradually resolved, and she was able to perform ADLs. However, she did not communicate much and started answering most questions with “I don’t know.” At discharge, she was sent home to the care of her sister and husband.

Since then, Mrs. A had been taking her medications regularly but did not show improvement in her speech or methods of communication.

The authors’ observations

Aphasia and related language disorders may present as a manifestation of stroke,¹ head injury,² status epilepticus,³ cerebral tumors,⁴ or neurodegenerative diseases.⁵ Language disorders commonly seen in psychiatric patients include selective mutism and aphonia. There is limited literature on aphasia as a manifestation of psychiatric illnesses; an extensive search reveals only 3 studies.⁶ We found case reports highlighting the difficulty in establishing a differential diagnosis among schizophrenic speech and status epilepticus

 

⁷ and frontotemporal⁸ and stroke-related⁹ speech disorder. Neuroimaging studies may be helpful in differentiating language disorders from psychosis. For example, evidence of lesions in the language centers of the brain is found in some cases of aphasia, and enlarged ventricles is a common finding in patients with schizophrenia. We considered all of these possibilities when evaluating Mrs. A (Table 2).

Table 1

Mrs. A’s family and personal history of ‘nerve problems’

Childhood	Mrs. A’s mother had ‘nerve problems.’ Her father physically abused Mrs. A. She received a ninth-grade education
Adult life	Married at age 17, Mrs. A had her first child at age 19, second child at age 20, and third child at age 21. She never obtained employment but raised her children with her husband
Last 2 years	Mrs. A lived in a trailer next to the house where her husband lived with 2 of their children. Family reports Mrs. A’s ’nerve problems’ were the reason for the separation. They state they took care of her needs and made sure she took her medications
Last 2 months	Mrs. A was admitted to a local psychiatric facility with confusion, hallucinations, crying spells, and decreased speech. After discharge, she could perform activities of daily living, but her speech did not improve
Present	Mrs. A is a passenger in a motor vehicle accident that results in her husband’s death and multiple injuries to her son. She is admitted to our hospital

Table 2

What is the cause of Mrs. A’s speech difficulties?

Possible diagnosis	Finding that ruled it out
Primary progressive aphasia	Subacute onset with rapid progression
Frontotemporal dementia	Inconclusive mild frontotemporal atrophy on brain MRI
Nonconvulsive status epilepticus	Normal EEG
Conversion disorder	Uncommon presentation: Mrs. A is beyond usual age of onset, and symptoms have lasted >1 month
Broca’s aphasia/CVA	No corresponding organic lesions on MRI
Factitious disorder	No motivation to assume the sick role
Psychotic speech	No other evidence of psychosis
CVA: cerebrovascular accident; EEG: electroencephalography; MRI: magnetic resonance imaging

TREATMENT: An abbreviated stay

A week after admission, Mrs. A is deemed medically stable. Head CT reveals a small, calcified left parietal meningioma that did not correlate with her symptoms (Table 3). Brain MRI shows mild frontotemporal atrophy that was considered inconclusive evidence for a diagnosis of frontotemporal dementia; there is no evidence of infarction, tumors, or other enhancing lesions that may have explained Mrs. A’s symptoms. A 12-lead EEG shows no abnormalities, which rules out a seizure disorder.

Neurology consult rules out concussion syndrome. Over several different evaluations, Mrs. A is noted to follow commands, perform ADLs, and walk. She is able to write her name legibly but is unable to write anything else or to perform a clock-drawing test.

A speech pathology evaluation is requested. A speech pathologist diagnoses Mrs. A with expressive aphasia—impaired ability to speak and write—with some receptive component, meaning her ability to comprehend spoken words also is impaired.

Mrs. A’s speech status does not change, and she remains unable to communicate. She is discharged 10 days after admission with scheduled outpatient follow-up.

Table 3

Findings of Mrs. A’s neurologic testing

Test	Result
Head CT	1-cm dural-based lesion in the left posterior parietal region
Brain MRI	Mild, inconclusive frontotemporal atrophy
EEG	Normal
CT: computed tomography; EEG: electroencephalography; MRI: magnetic resonance imaging

The authors’ observations

At discharge, it seemed likely that Mrs. A may have early symptoms of a neurodegenerative illness, such as frontotemporal dementia, or the aphasia may be a manifestation of chronic psychotic depression. We wanted to follow up with neuropsychological testing and PET scan before establishing a definitive psychiatric diagnosis and modifying the treatment plan.

Unfortunately, Mrs. A was lost to follow-up. We contacted her family several times, but they were unable to bring her back for further evaluation because of financial issues and the distance they would have had to travel.

Related resources

• The Academy of Aphasia. www.academyofaphasia.org.
  
• The National Aphasia Association. www.aphasia.org.
  

Drug brand names

• Amoxicillin/clavulanate • Augmentin
  
• Diazepam • Valium
  
• Duloxetine • Cymbalta
  
• Escitalopram • Lexapro
  
• Lamotrigine • Lamictal
  
• Olanzapine • Zyprexa
  
• Ziprasidone • Geodon
  
• Zolpidem • Ambien
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Spirits replacing body parts

Mrs. P, age 63, is admitted involuntarily to our inpatient unit after elopement from another emergency room the prior day. For several weeks she had been leaving her house multiple times and wandering the streets in the middle of each night.

Mrs. P is experiencing auditory and visual hallucinations of evil spirits and religious and hypersexual delusions. She cannot recognize her face and believes her voice has been replaced by another’s. She also thinks that her face, nose, lips, voice, and abdomen are not her own. She believes evil spirits that reside within her body are continuously replacing her body parts. She claims these spirits inhabit her left vaginal wall, deposit money there, and are sexually assaulting her each night. She feels that a constant battle between good and evil spirits occurs within her body. She is very angry and states she does not need medication but rather an exorcism.

During her admission, Mrs. P continues to display psychomotor agitation, pressured speech, disorganized thought, religious and hypersexual delusions, grandiosity, and auditory and visual hallucinations. A workup that included a basic metabolic panel, complete blood count, thyroid tests, and abdominal/pelvic CT finds no medical causes for her symptoms. Ob/Gyn is consulted, but Mrs. P refuses a vaginal ultrasound.

The author’s observations

Mrs. P demonstrated symptoms consistent with both mood and thought disorders. Her symptoms of pressured speech, grandiosity, hypersexuality, and decreased need for sleep suggest a manic episode in bipolar disorder. The thought disorganization, delusions, and hallucinations were in line with psychosis.

HISTORY: Failed medications

Mrs. P was first hospitalized at age 29 and has had multiple inpatient admissions for mania, depression, and psychosis. As an outpatient, she was noncompliant with her medications and regularly decompensated and required acute inpatient admission.

Past failed medication trials include risperidone, risperidone long-acting injection, paliperidone, ziprasidone, quetiapine, haloperidol, lamotrigine, and valproic acid. These trials failed because of intolerable side effects or lack of efficacy. She takes lithium, 600 mg every morning and 900 mg at bedtime, for mood stabilization but refuses to try antipsychotics again because she feels the devil is going to attack her through the medications.

The authors’ observations

During her initial hospitalization at age 29, Mrs. P was diagnosed with schizophrenia. In subsequent years she appeared more manic, so her diagnosis was changed to schizoaffective disorder-bipolar type.

Based on our clinical interview, we decide that Mrs. P exhibits a variant of Capgras syndrome, a type of delusional misidentification syndrome in which a person believes other people are not their true selves but have been replaced by identical imposters ( Table ).¹ Patients will at some level recognize a person, but they cannot experience the familiarity that is usually felt when seeing that person. Mrs. P’s case was unusual because instead of believing her loved ones were imposters, she could not recognize herself—her body, face, and voice were foreign to her.

We consider and rule out other misidentification syndromes, including mirrored-self misidentification, a condition in which patients cannot recognize themselves (and sometimes others) in a mirror. Mrs. P’s inability to recognize herself is not limited to her reflection. She is adamant that her hands and a part of her abdomen are not her own but another woman’s. She maintains this delusion even when looking directly at herself.

Breen² argued that a face-processing deficit alone may not account for a mirror delusion; an inability to understand mirror spatial relations in reflections also may be present. Similar to Capgras, in mirrored-self misidentification there may be a perceptual deficit as well as a reasoning deficit that allows the patient to hold on to the delusion. In both delusions, there is a failure of reality testing.³

Table

4 types of delusional misidentification syndromes

Syndrome	Delusion
Capgras syndrome	Belief that a loved one has been replaced by an identical impostor
Fregoli delusion	Belief that different people are actually the same person in disguise
Intermetamorphosis	Belief that one has switched identities with another individual or that others believe the afflicted to be someone else
Subjective doubles	Belief there exists a double of oneself living a separate life
Source: Reference 1

Capgras syndrome

Capgras syndrome, which is also called Capgras delusion, is seen primarily in a psychiatric context—most commonly in functional or organic psychotic illnesses⁴ —and secondarily in neurologic cases. In a retrospective study of 920 inpatient psychiatric admissions, the prevalence of Capgras syndrome was 1.3%; one-half of these patients had schizophrenia.

 

⁴

Capgras syndrome can be triggered by systemic infections, thyroid dysfunction, concussion, or intoxication. It is seen with head injury, toxic encephalopathy, and dementia.⁵

Joseph Capgras first described this syndrome in 1923. He discovered it by studying brain-injured patients who had prosopagnosia—the inability to recognize familiar faces. Patients with prosopagnosia are not delusional and understand that their inability to recognize faces is an impairment. Brain-injured patients with prosopagnosia had an autonomic arousal (measured by galvanic skin response) with familiar faces and thus unconscious face recognition was intact.⁵

Ellis et al⁶ described Capgras syndrome as being a “reverse” of prosopagnosia. They felt that in patients with Capgras, the conscious ability to recognize a face is intact, but the patient cannot produce an emotional response that usually occurs when seeing a familiar face. Thus, patients can recognize a person but feel that something is “off” or “wrong” and believe that the person must be an “imposter.” This hypothesis was supported by a 1997 study of 5 patients with schizophrenia who had Capgras.⁷

Hirstein et al⁸ showed similar findings in a case study of a patient who developed Capgras after a brain injury. These researchers felt that there was a relationship between Capgras and the inability to link successive memories (because of the lack of emotional recognition). They hypothesized that there was a disconnect between the temporal cortex (where faces are recognized) and the limbic system (which is involved in emotions) ( Box ).^6-9

Breen² reviewed 69 case reports of Capgras that had brain imaging results. Twenty-seven had normal brain imaging, 31 had global atrophy or bilateral brain damage, 2 had global atrophy and a right focal lesion, and 6 had a right hemispheric lesion. Thus, Capgras can occur in patients with normal or abnormal brain imaging.

Young⁹ developed an interactionist model of Capgras syndrome, in which a patient’s delusional belief allows the patient to explain his or her confusion and give the experience meaning. The experience then validates the belief, which makes the belief resistant to revision.

Asomatognosia is a type of misidentification syndrome in which a patient misidentifies or is not aware of the condition of a part of his or her body. It is seen with right hemispheric brain lesions, left hemiplegia, left-sided sensory loss, and left hemispatial neglect.¹⁰ Some clinicians believe that asomatognosia is a Capgras syndrome for the unrecognized body part.¹⁰ Because Mrs. P refused brain imaging, it is unclear whether she has asomatognosia.

The main treatment of Capgras syndrome is pharmacotherapy with antipsychotics and cognitive-behavioral therapy (CBT) to help with fixed delusions.

Box

TREATMENT: Pharmacotherapy

At admission, Mrs. P was taking only lithium for mood stabilization because she refused to take antipsychotics. During her stay, she reluctantly agrees to start haloperidol, which is titrated up to 20 mg bid. She experiences delusions related to the Devil attacking her via the haloperidol and thus is switched to fluphenazine, titrated up to 20 mg bid. She feels that liquid fluphenazine agrees with her the most, so she is stabilized and eventually discharged with this formulation. Switching to a depot formulation would have improved compliance, but Mrs. P adamantly resists this.

As her psychotic symptoms begin to resolve, Mrs. P begins to feel she is getting her body parts back. For example, she feels her face is her own but her nose is still not hers. During Mrs. P’s hospitalization, these bodily delusions lessen and eventually clear.

 

Other aspects of her psychosis and mania also resolve. She has some residual religious delusions at discharge but feels she has her body back and overall is much improved. Upon discharge Mrs. P is encouraged to follow up with a therapist for CBT, but she feels she does not need therapy and wants only to speak with her priest, even after most of her symptoms resolve. She also declines neuropsychological counseling.

Related resources

• Denes G. Capgras delusion. Neurol Sci. 2007;28:163-164.
  
• Coltheart M, Langdon R, McKay R. Schizophrenia and monothematic delusions. Schizophr Bull. 2007;33:642-647. http://schizophreniabulletin.oxfordjournals.org/cgi/content/full/33/3/642.
  

Drug brand names

• Fluphenazine • Prolixin
  
• Haloperidol • Haldol
  
• Lamotrigine • Lamictal
  
• Lithium • Eskalith, Lithobid
  
• Paliperidone • Invega
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Risperidone long-acting injection • Risperdal Consta
  
• Valproic acid • Depakote
  
• Ziprasidone • Geodon
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Spirits replacing body parts

Mrs. P, age 63, is admitted involuntarily to our inpatient unit after elopement from another emergency room the prior day. For several weeks she had been leaving her house multiple times and wandering the streets in the middle of each night.

Mrs. P is experiencing auditory and visual hallucinations of evil spirits and religious and hypersexual delusions. She cannot recognize her face and believes her voice has been replaced by another’s. She also thinks that her face, nose, lips, voice, and abdomen are not her own. She believes evil spirits that reside within her body are continuously replacing her body parts. She claims these spirits inhabit her left vaginal wall, deposit money there, and are sexually assaulting her each night. She feels that a constant battle between good and evil spirits occurs within her body. She is very angry and states she does not need medication but rather an exorcism.

During her admission, Mrs. P continues to display psychomotor agitation, pressured speech, disorganized thought, religious and hypersexual delusions, grandiosity, and auditory and visual hallucinations. A workup that included a basic metabolic panel, complete blood count, thyroid tests, and abdominal/pelvic CT finds no medical causes for her symptoms. Ob/Gyn is consulted, but Mrs. P refuses a vaginal ultrasound.

The author’s observations

Mrs. P demonstrated symptoms consistent with both mood and thought disorders. Her symptoms of pressured speech, grandiosity, hypersexuality, and decreased need for sleep suggest a manic episode in bipolar disorder. The thought disorganization, delusions, and hallucinations were in line with psychosis.

HISTORY: Failed medications

Mrs. P was first hospitalized at age 29 and has had multiple inpatient admissions for mania, depression, and psychosis. As an outpatient, she was noncompliant with her medications and regularly decompensated and required acute inpatient admission.

Past failed medication trials include risperidone, risperidone long-acting injection, paliperidone, ziprasidone, quetiapine, haloperidol, lamotrigine, and valproic acid. These trials failed because of intolerable side effects or lack of efficacy. She takes lithium, 600 mg every morning and 900 mg at bedtime, for mood stabilization but refuses to try antipsychotics again because she feels the devil is going to attack her through the medications.

The authors’ observations

During her initial hospitalization at age 29, Mrs. P was diagnosed with schizophrenia. In subsequent years she appeared more manic, so her diagnosis was changed to schizoaffective disorder-bipolar type.

Based on our clinical interview, we decide that Mrs. P exhibits a variant of Capgras syndrome, a type of delusional misidentification syndrome in which a person believes other people are not their true selves but have been replaced by identical imposters ( Table ).¹ Patients will at some level recognize a person, but they cannot experience the familiarity that is usually felt when seeing that person. Mrs. P’s case was unusual because instead of believing her loved ones were imposters, she could not recognize herself—her body, face, and voice were foreign to her.

We consider and rule out other misidentification syndromes, including mirrored-self misidentification, a condition in which patients cannot recognize themselves (and sometimes others) in a mirror. Mrs. P’s inability to recognize herself is not limited to her reflection. She is adamant that her hands and a part of her abdomen are not her own but another woman’s. She maintains this delusion even when looking directly at herself.

Breen² argued that a face-processing deficit alone may not account for a mirror delusion; an inability to understand mirror spatial relations in reflections also may be present. Similar to Capgras, in mirrored-self misidentification there may be a perceptual deficit as well as a reasoning deficit that allows the patient to hold on to the delusion. In both delusions, there is a failure of reality testing.³

Table

4 types of delusional misidentification syndromes

Syndrome	Delusion
Capgras syndrome	Belief that a loved one has been replaced by an identical impostor
Fregoli delusion	Belief that different people are actually the same person in disguise
Intermetamorphosis	Belief that one has switched identities with another individual or that others believe the afflicted to be someone else
Subjective doubles	Belief there exists a double of oneself living a separate life
Source: Reference 1

Capgras syndrome

Capgras syndrome, which is also called Capgras delusion, is seen primarily in a psychiatric context—most commonly in functional or organic psychotic illnesses⁴ —and secondarily in neurologic cases. In a retrospective study of 920 inpatient psychiatric admissions, the prevalence of Capgras syndrome was 1.3%; one-half of these patients had schizophrenia.

 

⁴

Capgras syndrome can be triggered by systemic infections, thyroid dysfunction, concussion, or intoxication. It is seen with head injury, toxic encephalopathy, and dementia.⁵

Joseph Capgras first described this syndrome in 1923. He discovered it by studying brain-injured patients who had prosopagnosia—the inability to recognize familiar faces. Patients with prosopagnosia are not delusional and understand that their inability to recognize faces is an impairment. Brain-injured patients with prosopagnosia had an autonomic arousal (measured by galvanic skin response) with familiar faces and thus unconscious face recognition was intact.⁵

Ellis et al⁶ described Capgras syndrome as being a “reverse” of prosopagnosia. They felt that in patients with Capgras, the conscious ability to recognize a face is intact, but the patient cannot produce an emotional response that usually occurs when seeing a familiar face. Thus, patients can recognize a person but feel that something is “off” or “wrong” and believe that the person must be an “imposter.” This hypothesis was supported by a 1997 study of 5 patients with schizophrenia who had Capgras.⁷

Hirstein et al⁸ showed similar findings in a case study of a patient who developed Capgras after a brain injury. These researchers felt that there was a relationship between Capgras and the inability to link successive memories (because of the lack of emotional recognition). They hypothesized that there was a disconnect between the temporal cortex (where faces are recognized) and the limbic system (which is involved in emotions) ( Box ).^6-9

Breen² reviewed 69 case reports of Capgras that had brain imaging results. Twenty-seven had normal brain imaging, 31 had global atrophy or bilateral brain damage, 2 had global atrophy and a right focal lesion, and 6 had a right hemispheric lesion. Thus, Capgras can occur in patients with normal or abnormal brain imaging.

Young⁹ developed an interactionist model of Capgras syndrome, in which a patient’s delusional belief allows the patient to explain his or her confusion and give the experience meaning. The experience then validates the belief, which makes the belief resistant to revision.

Asomatognosia is a type of misidentification syndrome in which a patient misidentifies or is not aware of the condition of a part of his or her body. It is seen with right hemispheric brain lesions, left hemiplegia, left-sided sensory loss, and left hemispatial neglect.¹⁰ Some clinicians believe that asomatognosia is a Capgras syndrome for the unrecognized body part.¹⁰ Because Mrs. P refused brain imaging, it is unclear whether she has asomatognosia.

The main treatment of Capgras syndrome is pharmacotherapy with antipsychotics and cognitive-behavioral therapy (CBT) to help with fixed delusions.

Box

TREATMENT: Pharmacotherapy

At admission, Mrs. P was taking only lithium for mood stabilization because she refused to take antipsychotics. During her stay, she reluctantly agrees to start haloperidol, which is titrated up to 20 mg bid. She experiences delusions related to the Devil attacking her via the haloperidol and thus is switched to fluphenazine, titrated up to 20 mg bid. She feels that liquid fluphenazine agrees with her the most, so she is stabilized and eventually discharged with this formulation. Switching to a depot formulation would have improved compliance, but Mrs. P adamantly resists this.

As her psychotic symptoms begin to resolve, Mrs. P begins to feel she is getting her body parts back. For example, she feels her face is her own but her nose is still not hers. During Mrs. P’s hospitalization, these bodily delusions lessen and eventually clear.

 

Other aspects of her psychosis and mania also resolve. She has some residual religious delusions at discharge but feels she has her body back and overall is much improved. Upon discharge Mrs. P is encouraged to follow up with a therapist for CBT, but she feels she does not need therapy and wants only to speak with her priest, even after most of her symptoms resolve. She also declines neuropsychological counseling.

Related resources

• Denes G. Capgras delusion. Neurol Sci. 2007;28:163-164.
  
• Coltheart M, Langdon R, McKay R. Schizophrenia and monothematic delusions. Schizophr Bull. 2007;33:642-647. http://schizophreniabulletin.oxfordjournals.org/cgi/content/full/33/3/642.
  

Drug brand names

• Fluphenazine • Prolixin
  
• Haloperidol • Haldol
  
• Lamotrigine • Lamictal
  
• Lithium • Eskalith, Lithobid
  
• Paliperidone • Invega
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Risperidone long-acting injection • Risperdal Consta
  
• Valproic acid • Depakote
  
• Ziprasidone • Geodon
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Spirits replacing body parts

Mrs. P, age 63, is admitted involuntarily to our inpatient unit after elopement from another emergency room the prior day. For several weeks she had been leaving her house multiple times and wandering the streets in the middle of each night.

Mrs. P is experiencing auditory and visual hallucinations of evil spirits and religious and hypersexual delusions. She cannot recognize her face and believes her voice has been replaced by another’s. She also thinks that her face, nose, lips, voice, and abdomen are not her own. She believes evil spirits that reside within her body are continuously replacing her body parts. She claims these spirits inhabit her left vaginal wall, deposit money there, and are sexually assaulting her each night. She feels that a constant battle between good and evil spirits occurs within her body. She is very angry and states she does not need medication but rather an exorcism.

During her admission, Mrs. P continues to display psychomotor agitation, pressured speech, disorganized thought, religious and hypersexual delusions, grandiosity, and auditory and visual hallucinations. A workup that included a basic metabolic panel, complete blood count, thyroid tests, and abdominal/pelvic CT finds no medical causes for her symptoms. Ob/Gyn is consulted, but Mrs. P refuses a vaginal ultrasound.

The author’s observations

Mrs. P demonstrated symptoms consistent with both mood and thought disorders. Her symptoms of pressured speech, grandiosity, hypersexuality, and decreased need for sleep suggest a manic episode in bipolar disorder. The thought disorganization, delusions, and hallucinations were in line with psychosis.

HISTORY: Failed medications

Mrs. P was first hospitalized at age 29 and has had multiple inpatient admissions for mania, depression, and psychosis. As an outpatient, she was noncompliant with her medications and regularly decompensated and required acute inpatient admission.

Past failed medication trials include risperidone, risperidone long-acting injection, paliperidone, ziprasidone, quetiapine, haloperidol, lamotrigine, and valproic acid. These trials failed because of intolerable side effects or lack of efficacy. She takes lithium, 600 mg every morning and 900 mg at bedtime, for mood stabilization but refuses to try antipsychotics again because she feels the devil is going to attack her through the medications.

The authors’ observations

During her initial hospitalization at age 29, Mrs. P was diagnosed with schizophrenia. In subsequent years she appeared more manic, so her diagnosis was changed to schizoaffective disorder-bipolar type.

Based on our clinical interview, we decide that Mrs. P exhibits a variant of Capgras syndrome, a type of delusional misidentification syndrome in which a person believes other people are not their true selves but have been replaced by identical imposters ( Table ).¹ Patients will at some level recognize a person, but they cannot experience the familiarity that is usually felt when seeing that person. Mrs. P’s case was unusual because instead of believing her loved ones were imposters, she could not recognize herself—her body, face, and voice were foreign to her.

We consider and rule out other misidentification syndromes, including mirrored-self misidentification, a condition in which patients cannot recognize themselves (and sometimes others) in a mirror. Mrs. P’s inability to recognize herself is not limited to her reflection. She is adamant that her hands and a part of her abdomen are not her own but another woman’s. She maintains this delusion even when looking directly at herself.

Breen² argued that a face-processing deficit alone may not account for a mirror delusion; an inability to understand mirror spatial relations in reflections also may be present. Similar to Capgras, in mirrored-self misidentification there may be a perceptual deficit as well as a reasoning deficit that allows the patient to hold on to the delusion. In both delusions, there is a failure of reality testing.³

Table

4 types of delusional misidentification syndromes

Syndrome	Delusion
Capgras syndrome	Belief that a loved one has been replaced by an identical impostor
Fregoli delusion	Belief that different people are actually the same person in disguise
Intermetamorphosis	Belief that one has switched identities with another individual or that others believe the afflicted to be someone else
Subjective doubles	Belief there exists a double of oneself living a separate life
Source: Reference 1

Capgras syndrome

Capgras syndrome, which is also called Capgras delusion, is seen primarily in a psychiatric context—most commonly in functional or organic psychotic illnesses⁴ —and secondarily in neurologic cases. In a retrospective study of 920 inpatient psychiatric admissions, the prevalence of Capgras syndrome was 1.3%; one-half of these patients had schizophrenia.

 

⁴

Capgras syndrome can be triggered by systemic infections, thyroid dysfunction, concussion, or intoxication. It is seen with head injury, toxic encephalopathy, and dementia.⁵

Joseph Capgras first described this syndrome in 1923. He discovered it by studying brain-injured patients who had prosopagnosia—the inability to recognize familiar faces. Patients with prosopagnosia are not delusional and understand that their inability to recognize faces is an impairment. Brain-injured patients with prosopagnosia had an autonomic arousal (measured by galvanic skin response) with familiar faces and thus unconscious face recognition was intact.⁵

Ellis et al⁶ described Capgras syndrome as being a “reverse” of prosopagnosia. They felt that in patients with Capgras, the conscious ability to recognize a face is intact, but the patient cannot produce an emotional response that usually occurs when seeing a familiar face. Thus, patients can recognize a person but feel that something is “off” or “wrong” and believe that the person must be an “imposter.” This hypothesis was supported by a 1997 study of 5 patients with schizophrenia who had Capgras.⁷

Hirstein et al⁸ showed similar findings in a case study of a patient who developed Capgras after a brain injury. These researchers felt that there was a relationship between Capgras and the inability to link successive memories (because of the lack of emotional recognition). They hypothesized that there was a disconnect between the temporal cortex (where faces are recognized) and the limbic system (which is involved in emotions) ( Box ).^6-9

Breen² reviewed 69 case reports of Capgras that had brain imaging results. Twenty-seven had normal brain imaging, 31 had global atrophy or bilateral brain damage, 2 had global atrophy and a right focal lesion, and 6 had a right hemispheric lesion. Thus, Capgras can occur in patients with normal or abnormal brain imaging.

Young⁹ developed an interactionist model of Capgras syndrome, in which a patient’s delusional belief allows the patient to explain his or her confusion and give the experience meaning. The experience then validates the belief, which makes the belief resistant to revision.

Asomatognosia is a type of misidentification syndrome in which a patient misidentifies or is not aware of the condition of a part of his or her body. It is seen with right hemispheric brain lesions, left hemiplegia, left-sided sensory loss, and left hemispatial neglect.¹⁰ Some clinicians believe that asomatognosia is a Capgras syndrome for the unrecognized body part.¹⁰ Because Mrs. P refused brain imaging, it is unclear whether she has asomatognosia.

The main treatment of Capgras syndrome is pharmacotherapy with antipsychotics and cognitive-behavioral therapy (CBT) to help with fixed delusions.

Box

TREATMENT: Pharmacotherapy

At admission, Mrs. P was taking only lithium for mood stabilization because she refused to take antipsychotics. During her stay, she reluctantly agrees to start haloperidol, which is titrated up to 20 mg bid. She experiences delusions related to the Devil attacking her via the haloperidol and thus is switched to fluphenazine, titrated up to 20 mg bid. She feels that liquid fluphenazine agrees with her the most, so she is stabilized and eventually discharged with this formulation. Switching to a depot formulation would have improved compliance, but Mrs. P adamantly resists this.

As her psychotic symptoms begin to resolve, Mrs. P begins to feel she is getting her body parts back. For example, she feels her face is her own but her nose is still not hers. During Mrs. P’s hospitalization, these bodily delusions lessen and eventually clear.

 

Other aspects of her psychosis and mania also resolve. She has some residual religious delusions at discharge but feels she has her body back and overall is much improved. Upon discharge Mrs. P is encouraged to follow up with a therapist for CBT, but she feels she does not need therapy and wants only to speak with her priest, even after most of her symptoms resolve. She also declines neuropsychological counseling.

Related resources

• Denes G. Capgras delusion. Neurol Sci. 2007;28:163-164.
  
• Coltheart M, Langdon R, McKay R. Schizophrenia and monothematic delusions. Schizophr Bull. 2007;33:642-647. http://schizophreniabulletin.oxfordjournals.org/cgi/content/full/33/3/642.
  

Drug brand names

• Fluphenazine • Prolixin
  
• Haloperidol • Haldol
  
• Lamotrigine • Lamictal
  
• Lithium • Eskalith, Lithobid
  
• Paliperidone • Invega
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Risperidone long-acting injection • Risperdal Consta
  
• Valproic acid • Depakote
  
• Ziprasidone • Geodon
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: A ‘high utilizer’

Ms. Y, a 49-year-old intensive care registered nurse, is admitted to the psychiatric hospital for suicidal ideation for the eighth time in 1 year. Ms. Y has chronic suicidal ideation with multiple attempts and has been on disability for 3 years for treatment of severe depression. She has been hospitalized for depression with suicide ideation 49 times since her divorce 6 years ago. She is prescribed fluoxetine, 60 mg/d, quetiapine, 400 mg/d, and clonazepam, 2 mg/d.

Ms. Y reports the same series of events that preceded her previous hospitalizations: severe insomnia led to a worsening of her other depressive symptoms, including intense suicidal ideation. In an attempt to sleep, she took “a couple” of extra clonazepam. She called her therapist, who was alarmed by her slurred speech and pleas for help. A friend drove Ms. Y to the hospital, where she was directly admitted without being evaluated in the emergency room (ER).

The authors’ observations

Ms. Y possesses 7 of the 11 characteristics of a high utilizer of psychiatric services (Table 1),^1,2 defined as a patient who is:

• 2 standard deviations above the mean number of visits to an urban psychiatric emergency service in 6 months or
  
• has 4 inpatient admissions in a quarter or 6 inpatient admissions in 1 year.
  

Ms. Y always is directly admitted because she refuses to go through the ER for evaluation. She seems to know just how much medication to take to remain medically stable. She receives special treatment—she can call her therapist, ask for admission, and have her request granted. Until now, Ms. Y’s care providers have condoned her entitlement.

Table 1

Common characteristics of high utilizers* of psychiatric services

Homelessness
Developmental delays
Enrolled in a mental health plan
History of voluntary and involuntary hospitalization
Personality disorders
Likely to be uncooperative
Substance abuse or dependence (or history)
History of incarceration
Unreliable social support
Young Caucasian women
* Defined as having either 2 standard deviations above the mean number of visits to an urban psychiatric emergency service in 6 months or 4 inpatient admissions in a quarter or 6 inpatient admissions in 1 year
Source: References 1,2

The author’s observations

Because previous hospitalizations and courses of ECT have provided Ms. Y with only minimal, short-lived improvement, the treatment team decides to reconsider her diagnosis and treatment plan. Ms. Y’s first psychiatrist diagnosed her with major depressive disorder. After thoroughly interviewing Ms. Y and reviewing her history, the hospital psychiatrist determines that she meets criteria for borderline personality disorder (BPD) in addition to major depression. The psychiatrist explains this diagnosis to Ms. Y, provides her with education and support, and recommends dialectical behavioral therapy (DBT) and case management. She rejects the new diagnosis and treatment plan and pleads for help establishing treatment with a new psychiatrist.

The team at the psychiatric hospital feels Ms. Y needs to receive ongoing treatment from a psychiatrist. In the hope that she will be able to establish a therapeutic alliance with a new psychiatrist and therapist, they decide to continue working with Ms. Y if she accepts the BPD diagnosis and agrees to undergo DBT.

EVALUATION: A troubling pattern

Before Ms. Y’s husband divorced her, she had not received psychiatric care and had no psychiatric diagnosis. During the contentious divorce, she experienced depressive symptoms that later intensified, and she was unable to return to her previous high level of functioning.

Ms. Y became suicidal and was hospitalized for the first time shortly after the divorce was finalized and her ex-husband remarried. She began treatment with a psychiatrist, whom she idealized and saw for 5 years.

When this psychiatrist—who had been one of the few stable relationships in Ms. Y’s life—moved to another state, Ms. Y experienced a rapid recurrence of depression. She began treatment with 3 other psychiatrists but fired them because they “never understand me” like her first psychiatrist did, and she never felt she received the consistent, supportive care she deserved. She become suicidal and again required psychiatric hospitalization. This pattern continued up to her current admission.

The authors’ observations

Ms. Y briefly returns to work between hospitalizations but is not able to tolerate the stress. At one point she was admitted to an out-of-state facility; after this 2-month stay, she remained out of the local psychiatric hospital for 6 months but then became unable to function and was readmitted to the local psychiatric hospital.

 

When interviewed, Ms. Y describes feeling hopeless, empty, and alone each time 2 of her 3 children return to college after summer break. Her youngest child lives at home but is involved in extracurricular high school activities, and doesn’t seem to need her. Ms. Y is estranged from both parents. Her social support is unreliable because she tends to push others away and isolate herself.

Her children report that in recent months Ms. Y’s functioning has deteriorated and they are frustrated with her. Ms. Y repeatedly takes more clonazepam than prescribed but adamantly justifies her actions, saying she takes extra doses to sleep or relax. She seems to “run to the hospital” each time she faces a challenge or has a responsibility to fulfill. Many of her hospitalizations coincided with special occasions, such as her children’s birthdays, graduations, and holidays.

The authors’ observations

Because she has no history of mania, Ms. Y does not meet criteria for bipolar affective disorder. Her multidisciplinary treatment team feels she is too fragile to transfer care to new providers or to foster care, so we schedule a care conference and carefully compose a 6-month contract to formally articulate limits and boundaries within which we will continue to treat her.

The contract specifies that Ms. Y will participate in DBT, take her medications exactly as prescribed, and not receive any early refills of her prescriptions. We arrange with Ms. Y’s health plan to have a home healthcare agency provide her medications weekly. This benefit was not available to other health plan members. Ms. Y signs the contract.

TREATMENT: Contract violation

Ms. Y complies with the contract for 2 months, then abruptly fires her long-term therapist, whom she claims violated confidentiality by giving false information to another provider. At her next session, Ms. Y will not provide details about the alleged incident, and the issue never is resolved. She admits she did not start DBT and is not taking her medications as prescribed.

Ms. Y expresses her disagreement with the terms of the contract. She becomes very upset and asks for her care to be transferred to another psychiatrist. She demands to be followed at the current clinic because “I was born here.” She denies being actively suicidal and terminates the session early. That afternoon, she calls 1 of the inpatient psychiatrists and asks if he would treat her. She also calls the first psychiatrist she had seen to enlist help in obtaining care.

The authors’ observations

In Groves’ description of 4 types of “hateful patients,” Ms. Y represents a combination of an entitled demander and a manipulative help-rejecter. The behaviors and personality disorders associated with these types of patients—and effective management strategies—are listed in (Table 2).³ (Table 3) offers tips for successfully dealing with high utilizers of psychiatric services. High utilizers of medical services other than psychiatry are more likely than patients who are not high utilizers to have a psychiatric disorder (Box).^4-9

Box

Ms. Y’s entitlement interferes with her treatment—she has been allowed to dictate her treatment for years and, therefore, has not been managed effectively. She received resources that other patients did not, such as having weekly medication set up by a home healthcare nurse. Rules were bent to help Ms. Y, but allowing her to dictate treatment has made her so dependent that she worsened over time. Knowing that she was receiving special treatment appears to have strengthened her pathologic sense of entitlement.

Some members of our treatment team began to experience countertransference, which also interfered with Ms. Y’s treatment. They viewed her behavior as entitled, demanding, and manipulative and dreaded caring for her. Failing to recognize such defenses can lead to consequences such as malignant alienation—a progressive deterioration in the patient’s relationship with others that includes loss of sympathy and support from staff members—which can put a patient at high risk for suicide.¹⁰

 

After a lengthy discussion among several psychiatrists, therapists, nurses, and attorneys, the treatment team decided to terminate outpatient care for Ms. Y at our facility because of her chronic nonadherence to treatment recommendations. Ms. Y had manipulated numerous providers in our department, called multiple doctors in our facility to ask them to care for her, and asked her ex-husband to contact the department administration on her behalf. Her behavior bordered on harassment. In addition, the interventions we provided were making her worse, not better. Factors that influenced our decision included:

• fear of Ms. Y committing suicide
  
• fear of setting limits
  
• fear of being reported to the Medical Board
  
• fear of a lawsuit.
  

The team sent Ms. Y a registered letter explaining the reasons for the termination and providing referrals for other providers in the area. She was told that she retains access to the ER and can receive inpatient psychiatric care, provided she first is evaluated in the ER.

Table 2

Strategies for helping 4 types of ‘hateful patients’

Dependent clinger
Behaviors	Shows extreme gratitude with flattery
Associated personality traits/disorders	Codependent
Management strategies	As early and as tactfully as possible, set firm limits on the patient’s expectations for an intense doctor-patient relationship. Tell the patient that you have limits not only on knowledge and skill but also on time and stamina
Entitled demander
Behaviors	Intimidates, devalues, induces guilt, may try to control with threats; terrified of abandonment
Associated personality traits/disorders	Narcissistic, borderline personality disorder
Management strategies	Try to rechannel your patient’s feelings of entitlement into a partnership that acknowledges his or her entitlement not to unrealistic demands but to good medical care. Help your patient stop directing anger at the healthcare team
Manipulative help-rejecter
Behaviors	Resists treatment; may seem happy with treatment failures
Associated personality traits/disorders	Psychopathy, paranoia, borderline personality disorder, negativistic, passive/aggressive
Management strategies	Diminish your patient’s notion that losing the symptom or illness implies losing the doctor by ‘sharing’ your patient’s pessimism. Tell your patient that treatment may not cure the illness. Schedule regular follow-up visits
Self-destructive denier
Behaviors	Denial helps them survive
Associated personality traits/disorders	Borderline personality disorder, histrionic, schizoid, schizotypal
Management strategies	Recognize that this type of patient can make clinicians wish the patient would die and that the chance of helping a self-destructive denier is minimal. Lower unrealistic expectations of delivering perfect care. Evaluate the patient for a treatable mental illness, such as depression, anxiety, etc.
Source: Reference 3

Table 3

Tips for managing high utilizers

Establish a collaborative treatment plan with firm limits and expectations Document the treatment plan and encourage the patient to actively contribute Provide the patient with a copy of the plan Have the patient sign release of information for other care providers and have active contact with them for continuity and accountability Specify that the patient can obtain prescriptions or have medication dosages changed only by a psychiatrist or primary care provider Document an emergency department treatment plan to prevent unnecessary medication changes, obtaining narcotics or benzodiazepines if the patient has chemical dependency issues, etc. Involve the patient’s family
Acknowledge your feelings and countertransference Have regular contact with a mentor or colleague for consultation Ask yourself: Are you working harder than the patient? Is the patient capable of working harder or complying? Keep in mind the difference between mental illness and bad behavior
Explore your patient’s expectations and commitment to treatment by asking: ‘What do you consider as barriers to compliance or improvement?’ (Share your thoughts with the patient) ‘What are you willing to commit to in order to get better?’ ‘If I had a magic wand that I could wave and fix1 thing in your life right now, what would it be?’ or ‘What is the number 1 area in your life that is causing distress?’
Practice safely and proactively Determine if the patient has an undiagnosed psychiatric disorder Provide a phone call reminder for appointments Call if the patient does not show up for an appointment Document, document, document

OUTCOME: The pattern continues

Ms. Y continues to receive treatment with a different outpatient psychiatrist and therapist in the area. She has not been hospitalized for almost 2 years but her financial state has deteriorated and she has had a recurrence of depression. Ms. Y’s psychiatrist recently called the hospital to ask for direct admission on the patient’s behalf, stating that Ms. Y did not want to wait hours to be seen in the ER. Hospital staff explained that she needs to first come to the ER for evaluation. Ms. Y refused to come to the ER and was not admitted. About 1 month later, Ms. Y’s psychiatrist called again, and she was directly admitted to the psychiatric hospital.

 

Related resource

• National Suicide Prevention Lifeline. 1-800-273-TALK (8255). www.suicidepreventionlifeline.org.
  

Drug brand names

• Clonazepam • Klonopin
  
• Fluoxetine • Prozac
  
• Quetiapine • Seroquel
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or manufacturers of competing products.

CASE: A ‘high utilizer’

Ms. Y, a 49-year-old intensive care registered nurse, is admitted to the psychiatric hospital for suicidal ideation for the eighth time in 1 year. Ms. Y has chronic suicidal ideation with multiple attempts and has been on disability for 3 years for treatment of severe depression. She has been hospitalized for depression with suicide ideation 49 times since her divorce 6 years ago. She is prescribed fluoxetine, 60 mg/d, quetiapine, 400 mg/d, and clonazepam, 2 mg/d.

Ms. Y reports the same series of events that preceded her previous hospitalizations: severe insomnia led to a worsening of her other depressive symptoms, including intense suicidal ideation. In an attempt to sleep, she took “a couple” of extra clonazepam. She called her therapist, who was alarmed by her slurred speech and pleas for help. A friend drove Ms. Y to the hospital, where she was directly admitted without being evaluated in the emergency room (ER).

The authors’ observations

Ms. Y possesses 7 of the 11 characteristics of a high utilizer of psychiatric services (Table 1),^1,2 defined as a patient who is:

• 2 standard deviations above the mean number of visits to an urban psychiatric emergency service in 6 months or
  
• has 4 inpatient admissions in a quarter or 6 inpatient admissions in 1 year.
  

Ms. Y always is directly admitted because she refuses to go through the ER for evaluation. She seems to know just how much medication to take to remain medically stable. She receives special treatment—she can call her therapist, ask for admission, and have her request granted. Until now, Ms. Y’s care providers have condoned her entitlement.

Table 1

Common characteristics of high utilizers* of psychiatric services

Homelessness
Developmental delays
Enrolled in a mental health plan
History of voluntary and involuntary hospitalization
Personality disorders
Likely to be uncooperative
Substance abuse or dependence (or history)
History of incarceration
Unreliable social support
Young Caucasian women
* Defined as having either 2 standard deviations above the mean number of visits to an urban psychiatric emergency service in 6 months or 4 inpatient admissions in a quarter or 6 inpatient admissions in 1 year
Source: References 1,2

The author’s observations

Because previous hospitalizations and courses of ECT have provided Ms. Y with only minimal, short-lived improvement, the treatment team decides to reconsider her diagnosis and treatment plan. Ms. Y’s first psychiatrist diagnosed her with major depressive disorder. After thoroughly interviewing Ms. Y and reviewing her history, the hospital psychiatrist determines that she meets criteria for borderline personality disorder (BPD) in addition to major depression. The psychiatrist explains this diagnosis to Ms. Y, provides her with education and support, and recommends dialectical behavioral therapy (DBT) and case management. She rejects the new diagnosis and treatment plan and pleads for help establishing treatment with a new psychiatrist.

The team at the psychiatric hospital feels Ms. Y needs to receive ongoing treatment from a psychiatrist. In the hope that she will be able to establish a therapeutic alliance with a new psychiatrist and therapist, they decide to continue working with Ms. Y if she accepts the BPD diagnosis and agrees to undergo DBT.

EVALUATION: A troubling pattern

Before Ms. Y’s husband divorced her, she had not received psychiatric care and had no psychiatric diagnosis. During the contentious divorce, she experienced depressive symptoms that later intensified, and she was unable to return to her previous high level of functioning.

Ms. Y became suicidal and was hospitalized for the first time shortly after the divorce was finalized and her ex-husband remarried. She began treatment with a psychiatrist, whom she idealized and saw for 5 years.

When this psychiatrist—who had been one of the few stable relationships in Ms. Y’s life—moved to another state, Ms. Y experienced a rapid recurrence of depression. She began treatment with 3 other psychiatrists but fired them because they “never understand me” like her first psychiatrist did, and she never felt she received the consistent, supportive care she deserved. She become suicidal and again required psychiatric hospitalization. This pattern continued up to her current admission.

The authors’ observations

Ms. Y briefly returns to work between hospitalizations but is not able to tolerate the stress. At one point she was admitted to an out-of-state facility; after this 2-month stay, she remained out of the local psychiatric hospital for 6 months but then became unable to function and was readmitted to the local psychiatric hospital.

 

When interviewed, Ms. Y describes feeling hopeless, empty, and alone each time 2 of her 3 children return to college after summer break. Her youngest child lives at home but is involved in extracurricular high school activities, and doesn’t seem to need her. Ms. Y is estranged from both parents. Her social support is unreliable because she tends to push others away and isolate herself.

Her children report that in recent months Ms. Y’s functioning has deteriorated and they are frustrated with her. Ms. Y repeatedly takes more clonazepam than prescribed but adamantly justifies her actions, saying she takes extra doses to sleep or relax. She seems to “run to the hospital” each time she faces a challenge or has a responsibility to fulfill. Many of her hospitalizations coincided with special occasions, such as her children’s birthdays, graduations, and holidays.

The authors’ observations

Because she has no history of mania, Ms. Y does not meet criteria for bipolar affective disorder. Her multidisciplinary treatment team feels she is too fragile to transfer care to new providers or to foster care, so we schedule a care conference and carefully compose a 6-month contract to formally articulate limits and boundaries within which we will continue to treat her.

The contract specifies that Ms. Y will participate in DBT, take her medications exactly as prescribed, and not receive any early refills of her prescriptions. We arrange with Ms. Y’s health plan to have a home healthcare agency provide her medications weekly. This benefit was not available to other health plan members. Ms. Y signs the contract.

TREATMENT: Contract violation

Ms. Y complies with the contract for 2 months, then abruptly fires her long-term therapist, whom she claims violated confidentiality by giving false information to another provider. At her next session, Ms. Y will not provide details about the alleged incident, and the issue never is resolved. She admits she did not start DBT and is not taking her medications as prescribed.

Ms. Y expresses her disagreement with the terms of the contract. She becomes very upset and asks for her care to be transferred to another psychiatrist. She demands to be followed at the current clinic because “I was born here.” She denies being actively suicidal and terminates the session early. That afternoon, she calls 1 of the inpatient psychiatrists and asks if he would treat her. She also calls the first psychiatrist she had seen to enlist help in obtaining care.

The authors’ observations

In Groves’ description of 4 types of “hateful patients,” Ms. Y represents a combination of an entitled demander and a manipulative help-rejecter. The behaviors and personality disorders associated with these types of patients—and effective management strategies—are listed in (Table 2).³ (Table 3) offers tips for successfully dealing with high utilizers of psychiatric services. High utilizers of medical services other than psychiatry are more likely than patients who are not high utilizers to have a psychiatric disorder (Box).^4-9

Box

Ms. Y’s entitlement interferes with her treatment—she has been allowed to dictate her treatment for years and, therefore, has not been managed effectively. She received resources that other patients did not, such as having weekly medication set up by a home healthcare nurse. Rules were bent to help Ms. Y, but allowing her to dictate treatment has made her so dependent that she worsened over time. Knowing that she was receiving special treatment appears to have strengthened her pathologic sense of entitlement.

Some members of our treatment team began to experience countertransference, which also interfered with Ms. Y’s treatment. They viewed her behavior as entitled, demanding, and manipulative and dreaded caring for her. Failing to recognize such defenses can lead to consequences such as malignant alienation—a progressive deterioration in the patient’s relationship with others that includes loss of sympathy and support from staff members—which can put a patient at high risk for suicide.¹⁰

 

After a lengthy discussion among several psychiatrists, therapists, nurses, and attorneys, the treatment team decided to terminate outpatient care for Ms. Y at our facility because of her chronic nonadherence to treatment recommendations. Ms. Y had manipulated numerous providers in our department, called multiple doctors in our facility to ask them to care for her, and asked her ex-husband to contact the department administration on her behalf. Her behavior bordered on harassment. In addition, the interventions we provided were making her worse, not better. Factors that influenced our decision included:

• fear of Ms. Y committing suicide
  
• fear of setting limits
  
• fear of being reported to the Medical Board
  
• fear of a lawsuit.
  

The team sent Ms. Y a registered letter explaining the reasons for the termination and providing referrals for other providers in the area. She was told that she retains access to the ER and can receive inpatient psychiatric care, provided she first is evaluated in the ER.

Table 2

Strategies for helping 4 types of ‘hateful patients’

Dependent clinger
Behaviors	Shows extreme gratitude with flattery
Associated personality traits/disorders	Codependent
Management strategies	As early and as tactfully as possible, set firm limits on the patient’s expectations for an intense doctor-patient relationship. Tell the patient that you have limits not only on knowledge and skill but also on time and stamina
Entitled demander
Behaviors	Intimidates, devalues, induces guilt, may try to control with threats; terrified of abandonment
Associated personality traits/disorders	Narcissistic, borderline personality disorder
Management strategies	Try to rechannel your patient’s feelings of entitlement into a partnership that acknowledges his or her entitlement not to unrealistic demands but to good medical care. Help your patient stop directing anger at the healthcare team
Manipulative help-rejecter
Behaviors	Resists treatment; may seem happy with treatment failures
Associated personality traits/disorders	Psychopathy, paranoia, borderline personality disorder, negativistic, passive/aggressive
Management strategies	Diminish your patient’s notion that losing the symptom or illness implies losing the doctor by ‘sharing’ your patient’s pessimism. Tell your patient that treatment may not cure the illness. Schedule regular follow-up visits
Self-destructive denier
Behaviors	Denial helps them survive
Associated personality traits/disorders	Borderline personality disorder, histrionic, schizoid, schizotypal
Management strategies	Recognize that this type of patient can make clinicians wish the patient would die and that the chance of helping a self-destructive denier is minimal. Lower unrealistic expectations of delivering perfect care. Evaluate the patient for a treatable mental illness, such as depression, anxiety, etc.
Source: Reference 3

Table 3

Tips for managing high utilizers

Establish a collaborative treatment plan with firm limits and expectations Document the treatment plan and encourage the patient to actively contribute Provide the patient with a copy of the plan Have the patient sign release of information for other care providers and have active contact with them for continuity and accountability Specify that the patient can obtain prescriptions or have medication dosages changed only by a psychiatrist or primary care provider Document an emergency department treatment plan to prevent unnecessary medication changes, obtaining narcotics or benzodiazepines if the patient has chemical dependency issues, etc. Involve the patient’s family
Acknowledge your feelings and countertransference Have regular contact with a mentor or colleague for consultation Ask yourself: Are you working harder than the patient? Is the patient capable of working harder or complying? Keep in mind the difference between mental illness and bad behavior
Explore your patient’s expectations and commitment to treatment by asking: ‘What do you consider as barriers to compliance or improvement?’ (Share your thoughts with the patient) ‘What are you willing to commit to in order to get better?’ ‘If I had a magic wand that I could wave and fix1 thing in your life right now, what would it be?’ or ‘What is the number 1 area in your life that is causing distress?’
Practice safely and proactively Determine if the patient has an undiagnosed psychiatric disorder Provide a phone call reminder for appointments Call if the patient does not show up for an appointment Document, document, document

OUTCOME: The pattern continues

Ms. Y continues to receive treatment with a different outpatient psychiatrist and therapist in the area. She has not been hospitalized for almost 2 years but her financial state has deteriorated and she has had a recurrence of depression. Ms. Y’s psychiatrist recently called the hospital to ask for direct admission on the patient’s behalf, stating that Ms. Y did not want to wait hours to be seen in the ER. Hospital staff explained that she needs to first come to the ER for evaluation. Ms. Y refused to come to the ER and was not admitted. About 1 month later, Ms. Y’s psychiatrist called again, and she was directly admitted to the psychiatric hospital.

 

Related resource

• National Suicide Prevention Lifeline. 1-800-273-TALK (8255). www.suicidepreventionlifeline.org.
  

Drug brand names

• Clonazepam • Klonopin
  
• Fluoxetine • Prozac
  
• Quetiapine • Seroquel
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or manufacturers of competing products.

CASE: A ‘high utilizer’

Ms. Y, a 49-year-old intensive care registered nurse, is admitted to the psychiatric hospital for suicidal ideation for the eighth time in 1 year. Ms. Y has chronic suicidal ideation with multiple attempts and has been on disability for 3 years for treatment of severe depression. She has been hospitalized for depression with suicide ideation 49 times since her divorce 6 years ago. She is prescribed fluoxetine, 60 mg/d, quetiapine, 400 mg/d, and clonazepam, 2 mg/d.

Ms. Y reports the same series of events that preceded her previous hospitalizations: severe insomnia led to a worsening of her other depressive symptoms, including intense suicidal ideation. In an attempt to sleep, she took “a couple” of extra clonazepam. She called her therapist, who was alarmed by her slurred speech and pleas for help. A friend drove Ms. Y to the hospital, where she was directly admitted without being evaluated in the emergency room (ER).

The authors’ observations

Ms. Y possesses 7 of the 11 characteristics of a high utilizer of psychiatric services (Table 1),^1,2 defined as a patient who is:

• 2 standard deviations above the mean number of visits to an urban psychiatric emergency service in 6 months or
  
• has 4 inpatient admissions in a quarter or 6 inpatient admissions in 1 year.
  

Ms. Y always is directly admitted because she refuses to go through the ER for evaluation. She seems to know just how much medication to take to remain medically stable. She receives special treatment—she can call her therapist, ask for admission, and have her request granted. Until now, Ms. Y’s care providers have condoned her entitlement.

Table 1

Common characteristics of high utilizers* of psychiatric services

Homelessness
Developmental delays
Enrolled in a mental health plan
History of voluntary and involuntary hospitalization
Personality disorders
Likely to be uncooperative
Substance abuse or dependence (or history)
History of incarceration
Unreliable social support
Young Caucasian women
* Defined as having either 2 standard deviations above the mean number of visits to an urban psychiatric emergency service in 6 months or 4 inpatient admissions in a quarter or 6 inpatient admissions in 1 year
Source: References 1,2

The author’s observations

Because previous hospitalizations and courses of ECT have provided Ms. Y with only minimal, short-lived improvement, the treatment team decides to reconsider her diagnosis and treatment plan. Ms. Y’s first psychiatrist diagnosed her with major depressive disorder. After thoroughly interviewing Ms. Y and reviewing her history, the hospital psychiatrist determines that she meets criteria for borderline personality disorder (BPD) in addition to major depression. The psychiatrist explains this diagnosis to Ms. Y, provides her with education and support, and recommends dialectical behavioral therapy (DBT) and case management. She rejects the new diagnosis and treatment plan and pleads for help establishing treatment with a new psychiatrist.

The team at the psychiatric hospital feels Ms. Y needs to receive ongoing treatment from a psychiatrist. In the hope that she will be able to establish a therapeutic alliance with a new psychiatrist and therapist, they decide to continue working with Ms. Y if she accepts the BPD diagnosis and agrees to undergo DBT.

EVALUATION: A troubling pattern

Before Ms. Y’s husband divorced her, she had not received psychiatric care and had no psychiatric diagnosis. During the contentious divorce, she experienced depressive symptoms that later intensified, and she was unable to return to her previous high level of functioning.

Ms. Y became suicidal and was hospitalized for the first time shortly after the divorce was finalized and her ex-husband remarried. She began treatment with a psychiatrist, whom she idealized and saw for 5 years.

When this psychiatrist—who had been one of the few stable relationships in Ms. Y’s life—moved to another state, Ms. Y experienced a rapid recurrence of depression. She began treatment with 3 other psychiatrists but fired them because they “never understand me” like her first psychiatrist did, and she never felt she received the consistent, supportive care she deserved. She become suicidal and again required psychiatric hospitalization. This pattern continued up to her current admission.

The authors’ observations

Ms. Y briefly returns to work between hospitalizations but is not able to tolerate the stress. At one point she was admitted to an out-of-state facility; after this 2-month stay, she remained out of the local psychiatric hospital for 6 months but then became unable to function and was readmitted to the local psychiatric hospital.

 

When interviewed, Ms. Y describes feeling hopeless, empty, and alone each time 2 of her 3 children return to college after summer break. Her youngest child lives at home but is involved in extracurricular high school activities, and doesn’t seem to need her. Ms. Y is estranged from both parents. Her social support is unreliable because she tends to push others away and isolate herself.

Her children report that in recent months Ms. Y’s functioning has deteriorated and they are frustrated with her. Ms. Y repeatedly takes more clonazepam than prescribed but adamantly justifies her actions, saying she takes extra doses to sleep or relax. She seems to “run to the hospital” each time she faces a challenge or has a responsibility to fulfill. Many of her hospitalizations coincided with special occasions, such as her children’s birthdays, graduations, and holidays.

The authors’ observations

Because she has no history of mania, Ms. Y does not meet criteria for bipolar affective disorder. Her multidisciplinary treatment team feels she is too fragile to transfer care to new providers or to foster care, so we schedule a care conference and carefully compose a 6-month contract to formally articulate limits and boundaries within which we will continue to treat her.

The contract specifies that Ms. Y will participate in DBT, take her medications exactly as prescribed, and not receive any early refills of her prescriptions. We arrange with Ms. Y’s health plan to have a home healthcare agency provide her medications weekly. This benefit was not available to other health plan members. Ms. Y signs the contract.

TREATMENT: Contract violation

Ms. Y complies with the contract for 2 months, then abruptly fires her long-term therapist, whom she claims violated confidentiality by giving false information to another provider. At her next session, Ms. Y will not provide details about the alleged incident, and the issue never is resolved. She admits she did not start DBT and is not taking her medications as prescribed.

Ms. Y expresses her disagreement with the terms of the contract. She becomes very upset and asks for her care to be transferred to another psychiatrist. She demands to be followed at the current clinic because “I was born here.” She denies being actively suicidal and terminates the session early. That afternoon, she calls 1 of the inpatient psychiatrists and asks if he would treat her. She also calls the first psychiatrist she had seen to enlist help in obtaining care.

The authors’ observations

In Groves’ description of 4 types of “hateful patients,” Ms. Y represents a combination of an entitled demander and a manipulative help-rejecter. The behaviors and personality disorders associated with these types of patients—and effective management strategies—are listed in (Table 2).³ (Table 3) offers tips for successfully dealing with high utilizers of psychiatric services. High utilizers of medical services other than psychiatry are more likely than patients who are not high utilizers to have a psychiatric disorder (Box).^4-9

Box

Ms. Y’s entitlement interferes with her treatment—she has been allowed to dictate her treatment for years and, therefore, has not been managed effectively. She received resources that other patients did not, such as having weekly medication set up by a home healthcare nurse. Rules were bent to help Ms. Y, but allowing her to dictate treatment has made her so dependent that she worsened over time. Knowing that she was receiving special treatment appears to have strengthened her pathologic sense of entitlement.

Some members of our treatment team began to experience countertransference, which also interfered with Ms. Y’s treatment. They viewed her behavior as entitled, demanding, and manipulative and dreaded caring for her. Failing to recognize such defenses can lead to consequences such as malignant alienation—a progressive deterioration in the patient’s relationship with others that includes loss of sympathy and support from staff members—which can put a patient at high risk for suicide.¹⁰

 

After a lengthy discussion among several psychiatrists, therapists, nurses, and attorneys, the treatment team decided to terminate outpatient care for Ms. Y at our facility because of her chronic nonadherence to treatment recommendations. Ms. Y had manipulated numerous providers in our department, called multiple doctors in our facility to ask them to care for her, and asked her ex-husband to contact the department administration on her behalf. Her behavior bordered on harassment. In addition, the interventions we provided were making her worse, not better. Factors that influenced our decision included:

• fear of Ms. Y committing suicide
  
• fear of setting limits
  
• fear of being reported to the Medical Board
  
• fear of a lawsuit.
  

The team sent Ms. Y a registered letter explaining the reasons for the termination and providing referrals for other providers in the area. She was told that she retains access to the ER and can receive inpatient psychiatric care, provided she first is evaluated in the ER.

Table 2

Strategies for helping 4 types of ‘hateful patients’

Dependent clinger
Behaviors	Shows extreme gratitude with flattery
Associated personality traits/disorders	Codependent
Management strategies	As early and as tactfully as possible, set firm limits on the patient’s expectations for an intense doctor-patient relationship. Tell the patient that you have limits not only on knowledge and skill but also on time and stamina
Entitled demander
Behaviors	Intimidates, devalues, induces guilt, may try to control with threats; terrified of abandonment
Associated personality traits/disorders	Narcissistic, borderline personality disorder
Management strategies	Try to rechannel your patient’s feelings of entitlement into a partnership that acknowledges his or her entitlement not to unrealistic demands but to good medical care. Help your patient stop directing anger at the healthcare team
Manipulative help-rejecter
Behaviors	Resists treatment; may seem happy with treatment failures
Associated personality traits/disorders	Psychopathy, paranoia, borderline personality disorder, negativistic, passive/aggressive
Management strategies	Diminish your patient’s notion that losing the symptom or illness implies losing the doctor by ‘sharing’ your patient’s pessimism. Tell your patient that treatment may not cure the illness. Schedule regular follow-up visits
Self-destructive denier
Behaviors	Denial helps them survive
Associated personality traits/disorders	Borderline personality disorder, histrionic, schizoid, schizotypal
Management strategies	Recognize that this type of patient can make clinicians wish the patient would die and that the chance of helping a self-destructive denier is minimal. Lower unrealistic expectations of delivering perfect care. Evaluate the patient for a treatable mental illness, such as depression, anxiety, etc.
Source: Reference 3

Table 3

Tips for managing high utilizers

Establish a collaborative treatment plan with firm limits and expectations Document the treatment plan and encourage the patient to actively contribute Provide the patient with a copy of the plan Have the patient sign release of information for other care providers and have active contact with them for continuity and accountability Specify that the patient can obtain prescriptions or have medication dosages changed only by a psychiatrist or primary care provider Document an emergency department treatment plan to prevent unnecessary medication changes, obtaining narcotics or benzodiazepines if the patient has chemical dependency issues, etc. Involve the patient’s family
Acknowledge your feelings and countertransference Have regular contact with a mentor or colleague for consultation Ask yourself: Are you working harder than the patient? Is the patient capable of working harder or complying? Keep in mind the difference between mental illness and bad behavior
Explore your patient’s expectations and commitment to treatment by asking: ‘What do you consider as barriers to compliance or improvement?’ (Share your thoughts with the patient) ‘What are you willing to commit to in order to get better?’ ‘If I had a magic wand that I could wave and fix1 thing in your life right now, what would it be?’ or ‘What is the number 1 area in your life that is causing distress?’
Practice safely and proactively Determine if the patient has an undiagnosed psychiatric disorder Provide a phone call reminder for appointments Call if the patient does not show up for an appointment Document, document, document

OUTCOME: The pattern continues

Ms. Y continues to receive treatment with a different outpatient psychiatrist and therapist in the area. She has not been hospitalized for almost 2 years but her financial state has deteriorated and she has had a recurrence of depression. Ms. Y’s psychiatrist recently called the hospital to ask for direct admission on the patient’s behalf, stating that Ms. Y did not want to wait hours to be seen in the ER. Hospital staff explained that she needs to first come to the ER for evaluation. Ms. Y refused to come to the ER and was not admitted. About 1 month later, Ms. Y’s psychiatrist called again, and she was directly admitted to the psychiatric hospital.

 

Related resource

• National Suicide Prevention Lifeline. 1-800-273-TALK (8255). www.suicidepreventionlifeline.org.
  

Drug brand names

• Clonazepam • Klonopin
  
• Fluoxetine • Prozac
  
• Quetiapine • Seroquel
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or manufacturers of competing products.

CASE: Disabling anxiety

Mr. B, age 35, has a history of schizophrenia, chronic paranoid type and has been hospitalized more than 12 times since its onset 10 years ago. He received clozapine during his most recent hospitalization approximately 5 years ago and experienced full symptom response without the motor side effects he developed in response to other medications. He visits a psychiatrist monthly for medications and supportive psychotherapy, and he receives intensive case management and housing from a community mental health center.

When Mr. B is assigned to my (CK) care, his psychotic symptoms are in remission, but he complains of anxiety that leaves him almost homebound. He has intense fear of bridges, upper-floor windows, express buses, subways, riding in speeding vehicles, and having a seizure.

If Mr. B faces any of these triggers, he experiences harmful thoughts—such as jumping out a window or off a bridge—even though he does not endorse suicidality. These thoughts are intrusive, ego-dystonic, and ruminative. He avoids these triggers at all costs, which compromises his housing and employment opportunities. He experienced a single panic attack in the subway 1 year earlier. Mr. B firmly believes that any intense anxiety he experiences will trigger a psychotic episode. When faced with sudden urges, he believes his illness would interfere with his ability to control his impulses.

He reports that these symptoms started when he began clozapine and have worsened. Mr. B says he experiences a feeling of “uneasiness” approximately 2 hours after taking clozapine that is exacerbated if he faces a trigger. He describes the uneasiness as “the feeling of being about to have a seizure” during which he would “lose control” of his body.

When I begin treating Mr. B, he is receiving clozapine, 125 mg bid. In an effort to combat Mr. B’s anxiety, a previous psychiatrist had titrated clonazepam up to 5 mg/d as needed. Mr. B is compliant with his medications and appointments but refuses to change his psychotropic or psychotherapy regimen.

The authors’ observations

Approximately 50% of patients with schizophrenia have at least 1 anxiety disorder, and close to 30% meet criteria for >1 anxiety disorder.¹ Social anxiety disorder (SAD), generalized anxiety disorder, panic disorder, posttraumatic stress disorder, and obsessive-compulsive disorder (OCD) have been found comorbid with schizophrenia, with rates as high as 30% for each.¹

Possible causes of unusually high rates of anxiety disorders in schizophrenia include trauma history, delusional conviction and inflexibility of abstract thought,² and passive coping mechanisms.

Schizophrenic illnesses may be linked to anxiety antecedents such as panic or social phobia that:

• develop into more profound psychopathology
  
• or bring about anxiety symptoms, given the severity of the subjective psychotic experience.
  

In a twin pairs study, the schizophrenic twin had an almost threefold increase in rates of comorbid psychiatric disorders compared with their non-schizophrenic twins; social or environmental factors may not account for this.³

Comorbid OCD, panic disorder, and SAD frequently persist after remission of psychotic symptoms. Comorbid anxiety disorders may play a role in the psychotic symptoms themselves (such as panic and social anxiety related to paranoia, OCD, and bizarre behavior) and negatively impact quality of life.⁴

In patients with schizophrenia, higher anxiety levels are associated with:

• increased hallucinations
  
• poor psychosocial function
  
• hopelessness.⁵
  

Accurately assessing and diagnosing anxiety disorders in patients with schizophrenia is challenging because there is inconsistency among clinical interviewers (poor reliability scores), and anxiety scales are not as accurate as we would like them to be (poor construct validity).⁶ Treatment options for comorbid anxiety and schizophrenia include psychopharmacology and psychotherapy (Table 1).

Table 1

Treatment options for comorbid schizophrenia and anxiety

Modality	Options	Comments
Psychopharmacology	Antipsychotics Increase antipsychotic dose Change antipsychotic Add an atypical with serotonergic action (ziprasidone, aripiprazole)	Favor monotherapy at full dose for full trial period before considering adjunct therapy with a second antipsychotic, for which evidence is still equivocal
	Antidepressants SSRI SNRI	Avoid bupropion because of possible dopamine agonism
	Benzodiazepines	Weigh risks of sedation and potential for addiction vs benefits of immediate relief
	Gabapentin	Use high doses to obtain symptomatic response
Psychotherapy	CBT (for psychosis and anxiety) Supportive (for decompensating psychosis) Behavioral Activity and vocational
CBT: cognitive-behavioral therapy; SSRI: selective serotonin reuptake inhibitor; SNRI: serotonin-norepinephrine reuptake inhibitor

HISTORY: Propensity for violence

Mr. B was born in a large city and raised by his single mother. He denies childhood physical or sexual abuse. Mr. B reports engaging in violent activity since he was an adolescent, but this activity is undocumented because he has never been arrested. Mr. B still belongs to a gang he joined after being assaulted at age 16.

 

Mr. B was diagnosed with schizophrenia at age 20 following an overt psychotic episode and suicide attempt by hanging. During his psychotic episodes, he thinks groups of people are plotting to kill him. He hears people talking about him or voices telling him about others’ plots against him. Mr. B probably has experienced these symptoms since early childhood, as evidenced by reports of attention-deficit/hyperactivity disorder, oppositional defiant disorder, conduct disorder, and tics.

His health records contain no mention of anxiety symptoms until approximately 3 months after he started clozapine, when he reported brief episodes of unexplained phobia of windows and bridges. Approximately 1 year later, he reported obsessive-compulsive symptoms—ruminating and intrusive thoughts of jumping off a bridge with no suicidal intent. Mr. B’s outpatient therapist at the time believed these symptoms began before Mr. B started clozapine.

Numerous medication trials failed. Antipsychotics were ineffective or poorly tolerated because of motor side effects or intense sedation. Mr. B did not tolerate selective serotonin reuptake inhibitors (SSRIs) because of akathisia or sexual side effects. Mr. B had a history of poor medication compliance until he began clozapine treatment.

Mr. B used cannabis daily until 10 years ago. He smokes cigarettes and reports occasional alcohol use. He has no history of chronic substance or alcohol use, withdrawal symptoms, or complications from intoxication.

Mr. B is unemployed and receives Supplemental Security Income. He has never married or had children.

Medical comorbidities include a white blood cell count and absolute neutrophil count that have been chronically in the lower limit range, and dyslipidemia and diabetes, for which Mr. B receives statins and oral hypoglycemics. He has no history of seizures or brain trauma. His family history includes substance dependence on his mother’s side and schizophrenia in 2 paternal cousins.

The authors’ observations

Mr. B’s anxiety disorder has not been clearly elucidated. He does not seem to meet criteria for:

• panic disorder (only 1 panic attack)
  
• OCD (no compulsions to diminish anxiety)
  
• specific phobia (phobias were too broad and lacked fear of an object itself).
  

Box

In addition, he does not seem to have residual paranoia, akathisia, or drug-seeking behavior. Based on numerous evaluations, Mr. B’s anxiety symptoms seem most consistent with agoraphobia without panic (Table 2).

The phenomenology of his symptoms appears to be linked to his psychodynamic development, but previous therapists had not explored this. In addition, his relationships with his therapists, illness, and medications are complex. Mr. B is poorly engaged, lacks motivation toward recovery goals, and does not trust me. However, he holds high expectations of the potential damage or benefits of medication.

Table 2

Anxiety: How to differentiate disorders and symptoms

Disorder/symptom	Keys to differential diagnosis
Panic disorder	≥2 panic attacks
Agoraphobia	Fear of ‘no escape,’ ‘no options,’ ‘loss of control’
Generalized anxiety disorder	Constant worriers
Specific phobias	Fear of an object itself, not the response it will elicit within the patient
Obsessive-compulsive disorder	Patterns of intrusive thoughts followed by an action to undo or avoid anxiety
Residual paranoia	Feeling of insecurity associated with episodes of decompensation that have remained inter-episode
Drug-seeking behaviors	Secondary gain, in direct relationship to request for medication
Akathisia, other side effects	Inner restlessness that is constant, without trigger

Mr. B’s pharmacologic management is complicated by several relative contraindications. Clozapine may be associated with or increase the incidence of OCD, panic, and agoraphobia (Box).^7–9 Combining clonazepam with clozapine is not recommended because of the possibility of intense sedation. Even so, in a patient with a history of substance use and illegal activity—such as Mr. B—cautious use of benzodiazepines is warranted to avoid addiction or drug diversion.

Mr. B was taking clonazepam when our work began, and discontinuing it would have increased his risk for seizures and the possibility of him seeking illicit benzodiazepines. Furthermore, discontinuing clonazepam might have thwarted an emerging therapeutic relationship that would become key to enhancing his motivation and exploring the antisocial and narcissistic traits that were limiting his recovery.

 

I slowly increase the frequency of my sessions with Mr. B from monthly to biweekly to weekly. We focus on strengthening the therapeutic alliance, motivational enhancement, emotional expression, and verbal identification of feeling states. We explore anxiety symptoms and psychosis using cognitive-behavioral therapy techniques informed by psychodynamic aspects of his experience, with the goal of resuming his prior level of functionality, including employment.

I carefully and slowly change Mr. B’s medications. First I increase his clozapine to 300 mg/d in 150 mg divided doses in an attempt to cover the possibility of residual paranoia, and for anxiolytic sedation without introducing a new medication. However, Mr. B’s anxiety symptoms worsen, so I resume the baseline dosage (125 mg bid). I choose not to switch to another antipsychotic because the risk for psychotic decompensation outweighs the potential benefits. I lower clonazepam to 2 mg/d in split doses. I teach Mr. B anxiety management techniques, including distraction, exposure, and anxiety tolerance training.

Because Mr. B refuses to start an SSRI for his anxiety symptoms, I prescribe bupropion and monitor him closely for dopamine agonism as evidenced by a re-emergence of psychosis. Once again, his anxiety symptoms worsen.

I stop bupropion and switch Mr. B to gabapentin, titrated to 400 mg tid. I chose this medication because of its sedation properties and relatively safe side effect profile. Mr. B was willing to try gabapentin—which was first approved to treat epilepsy—because he was afraid of having a seizure and also because it is not associated with sexual side effects. Furthermore, its GABA-mimetic actions made it a plausible alternative to replicate the benefits he was getting from clonazepam.

TREATMENT: An effective drug

Mr. B tolerates gabapentin well and his anxiety symptoms are much more sporadic, shorter, and more easily controlled by conscious exercise. The content of his thoughts is less disastrous and less ego-dystonic. He feels less dysphoria associated with clozapine and does not need as much clonazepam. He overcomes his avoidance of all fear-provoking triggers except walking across bridges.

Mr. B and I explore issues of object relationships and intimacy, establishing emotionally significant relationships with others, and the association between these and his distrust and paranoia. We also investigate the relationship between his criminal activity and feelings of loneliness or lack of control. Mr. B is able to verbalize positive and negative feelings and to feel in cognitive control of them.

Mr. B continues his regimen of clozapine, clonazepam, and gabapentin. He moves to independent housing and applies for employment.

Related resource

• Garrett M, Lerman M. CBT for psychosis for long-term inpatients with a forensic history. Psychiatr Serv. 2007;58(5):712-713.
  

Drug brand names

• Aripiprazole • Abilify
  
• Bupropion • Wellbutrin
  
• Clonazepam • Klonopin
  
• Clozapine • Clozaril
  
• Gabapentin • Neurontin
  
• Olanzapine • Zyprexa
  
• Ziprasidone • Geodon
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Disabling anxiety

Mr. B, age 35, has a history of schizophrenia, chronic paranoid type and has been hospitalized more than 12 times since its onset 10 years ago. He received clozapine during his most recent hospitalization approximately 5 years ago and experienced full symptom response without the motor side effects he developed in response to other medications. He visits a psychiatrist monthly for medications and supportive psychotherapy, and he receives intensive case management and housing from a community mental health center.

When Mr. B is assigned to my (CK) care, his psychotic symptoms are in remission, but he complains of anxiety that leaves him almost homebound. He has intense fear of bridges, upper-floor windows, express buses, subways, riding in speeding vehicles, and having a seizure.

If Mr. B faces any of these triggers, he experiences harmful thoughts—such as jumping out a window or off a bridge—even though he does not endorse suicidality. These thoughts are intrusive, ego-dystonic, and ruminative. He avoids these triggers at all costs, which compromises his housing and employment opportunities. He experienced a single panic attack in the subway 1 year earlier. Mr. B firmly believes that any intense anxiety he experiences will trigger a psychotic episode. When faced with sudden urges, he believes his illness would interfere with his ability to control his impulses.

He reports that these symptoms started when he began clozapine and have worsened. Mr. B says he experiences a feeling of “uneasiness” approximately 2 hours after taking clozapine that is exacerbated if he faces a trigger. He describes the uneasiness as “the feeling of being about to have a seizure” during which he would “lose control” of his body.

When I begin treating Mr. B, he is receiving clozapine, 125 mg bid. In an effort to combat Mr. B’s anxiety, a previous psychiatrist had titrated clonazepam up to 5 mg/d as needed. Mr. B is compliant with his medications and appointments but refuses to change his psychotropic or psychotherapy regimen.

The authors’ observations

Approximately 50% of patients with schizophrenia have at least 1 anxiety disorder, and close to 30% meet criteria for >1 anxiety disorder.¹ Social anxiety disorder (SAD), generalized anxiety disorder, panic disorder, posttraumatic stress disorder, and obsessive-compulsive disorder (OCD) have been found comorbid with schizophrenia, with rates as high as 30% for each.¹

Possible causes of unusually high rates of anxiety disorders in schizophrenia include trauma history, delusional conviction and inflexibility of abstract thought,² and passive coping mechanisms.

Schizophrenic illnesses may be linked to anxiety antecedents such as panic or social phobia that:

• develop into more profound psychopathology
  
• or bring about anxiety symptoms, given the severity of the subjective psychotic experience.
  

In a twin pairs study, the schizophrenic twin had an almost threefold increase in rates of comorbid psychiatric disorders compared with their non-schizophrenic twins; social or environmental factors may not account for this.³

Comorbid OCD, panic disorder, and SAD frequently persist after remission of psychotic symptoms. Comorbid anxiety disorders may play a role in the psychotic symptoms themselves (such as panic and social anxiety related to paranoia, OCD, and bizarre behavior) and negatively impact quality of life.⁴

In patients with schizophrenia, higher anxiety levels are associated with:

• increased hallucinations
  
• poor psychosocial function
  
• hopelessness.⁵
  

Accurately assessing and diagnosing anxiety disorders in patients with schizophrenia is challenging because there is inconsistency among clinical interviewers (poor reliability scores), and anxiety scales are not as accurate as we would like them to be (poor construct validity).⁶ Treatment options for comorbid anxiety and schizophrenia include psychopharmacology and psychotherapy (Table 1).

Table 1

Treatment options for comorbid schizophrenia and anxiety

Modality	Options	Comments
Psychopharmacology	Antipsychotics Increase antipsychotic dose Change antipsychotic Add an atypical with serotonergic action (ziprasidone, aripiprazole)	Favor monotherapy at full dose for full trial period before considering adjunct therapy with a second antipsychotic, for which evidence is still equivocal
	Antidepressants SSRI SNRI	Avoid bupropion because of possible dopamine agonism
	Benzodiazepines	Weigh risks of sedation and potential for addiction vs benefits of immediate relief
	Gabapentin	Use high doses to obtain symptomatic response
Psychotherapy	CBT (for psychosis and anxiety) Supportive (for decompensating psychosis) Behavioral Activity and vocational
CBT: cognitive-behavioral therapy; SSRI: selective serotonin reuptake inhibitor; SNRI: serotonin-norepinephrine reuptake inhibitor

HISTORY: Propensity for violence

Mr. B was born in a large city and raised by his single mother. He denies childhood physical or sexual abuse. Mr. B reports engaging in violent activity since he was an adolescent, but this activity is undocumented because he has never been arrested. Mr. B still belongs to a gang he joined after being assaulted at age 16.

 

Mr. B was diagnosed with schizophrenia at age 20 following an overt psychotic episode and suicide attempt by hanging. During his psychotic episodes, he thinks groups of people are plotting to kill him. He hears people talking about him or voices telling him about others’ plots against him. Mr. B probably has experienced these symptoms since early childhood, as evidenced by reports of attention-deficit/hyperactivity disorder, oppositional defiant disorder, conduct disorder, and tics.

His health records contain no mention of anxiety symptoms until approximately 3 months after he started clozapine, when he reported brief episodes of unexplained phobia of windows and bridges. Approximately 1 year later, he reported obsessive-compulsive symptoms—ruminating and intrusive thoughts of jumping off a bridge with no suicidal intent. Mr. B’s outpatient therapist at the time believed these symptoms began before Mr. B started clozapine.

Numerous medication trials failed. Antipsychotics were ineffective or poorly tolerated because of motor side effects or intense sedation. Mr. B did not tolerate selective serotonin reuptake inhibitors (SSRIs) because of akathisia or sexual side effects. Mr. B had a history of poor medication compliance until he began clozapine treatment.

Mr. B used cannabis daily until 10 years ago. He smokes cigarettes and reports occasional alcohol use. He has no history of chronic substance or alcohol use, withdrawal symptoms, or complications from intoxication.

Mr. B is unemployed and receives Supplemental Security Income. He has never married or had children.

Medical comorbidities include a white blood cell count and absolute neutrophil count that have been chronically in the lower limit range, and dyslipidemia and diabetes, for which Mr. B receives statins and oral hypoglycemics. He has no history of seizures or brain trauma. His family history includes substance dependence on his mother’s side and schizophrenia in 2 paternal cousins.

The authors’ observations

Mr. B’s anxiety disorder has not been clearly elucidated. He does not seem to meet criteria for:

• panic disorder (only 1 panic attack)
  
• OCD (no compulsions to diminish anxiety)
  
• specific phobia (phobias were too broad and lacked fear of an object itself).
  

Box

In addition, he does not seem to have residual paranoia, akathisia, or drug-seeking behavior. Based on numerous evaluations, Mr. B’s anxiety symptoms seem most consistent with agoraphobia without panic (Table 2).

The phenomenology of his symptoms appears to be linked to his psychodynamic development, but previous therapists had not explored this. In addition, his relationships with his therapists, illness, and medications are complex. Mr. B is poorly engaged, lacks motivation toward recovery goals, and does not trust me. However, he holds high expectations of the potential damage or benefits of medication.

Table 2

Anxiety: How to differentiate disorders and symptoms

Disorder/symptom	Keys to differential diagnosis
Panic disorder	≥2 panic attacks
Agoraphobia	Fear of ‘no escape,’ ‘no options,’ ‘loss of control’
Generalized anxiety disorder	Constant worriers
Specific phobias	Fear of an object itself, not the response it will elicit within the patient
Obsessive-compulsive disorder	Patterns of intrusive thoughts followed by an action to undo or avoid anxiety
Residual paranoia	Feeling of insecurity associated with episodes of decompensation that have remained inter-episode
Drug-seeking behaviors	Secondary gain, in direct relationship to request for medication
Akathisia, other side effects	Inner restlessness that is constant, without trigger

Mr. B’s pharmacologic management is complicated by several relative contraindications. Clozapine may be associated with or increase the incidence of OCD, panic, and agoraphobia (Box).^7–9 Combining clonazepam with clozapine is not recommended because of the possibility of intense sedation. Even so, in a patient with a history of substance use and illegal activity—such as Mr. B—cautious use of benzodiazepines is warranted to avoid addiction or drug diversion.

Mr. B was taking clonazepam when our work began, and discontinuing it would have increased his risk for seizures and the possibility of him seeking illicit benzodiazepines. Furthermore, discontinuing clonazepam might have thwarted an emerging therapeutic relationship that would become key to enhancing his motivation and exploring the antisocial and narcissistic traits that were limiting his recovery.

 

I slowly increase the frequency of my sessions with Mr. B from monthly to biweekly to weekly. We focus on strengthening the therapeutic alliance, motivational enhancement, emotional expression, and verbal identification of feeling states. We explore anxiety symptoms and psychosis using cognitive-behavioral therapy techniques informed by psychodynamic aspects of his experience, with the goal of resuming his prior level of functionality, including employment.

I carefully and slowly change Mr. B’s medications. First I increase his clozapine to 300 mg/d in 150 mg divided doses in an attempt to cover the possibility of residual paranoia, and for anxiolytic sedation without introducing a new medication. However, Mr. B’s anxiety symptoms worsen, so I resume the baseline dosage (125 mg bid). I choose not to switch to another antipsychotic because the risk for psychotic decompensation outweighs the potential benefits. I lower clonazepam to 2 mg/d in split doses. I teach Mr. B anxiety management techniques, including distraction, exposure, and anxiety tolerance training.

Because Mr. B refuses to start an SSRI for his anxiety symptoms, I prescribe bupropion and monitor him closely for dopamine agonism as evidenced by a re-emergence of psychosis. Once again, his anxiety symptoms worsen.

I stop bupropion and switch Mr. B to gabapentin, titrated to 400 mg tid. I chose this medication because of its sedation properties and relatively safe side effect profile. Mr. B was willing to try gabapentin—which was first approved to treat epilepsy—because he was afraid of having a seizure and also because it is not associated with sexual side effects. Furthermore, its GABA-mimetic actions made it a plausible alternative to replicate the benefits he was getting from clonazepam.

TREATMENT: An effective drug

Mr. B tolerates gabapentin well and his anxiety symptoms are much more sporadic, shorter, and more easily controlled by conscious exercise. The content of his thoughts is less disastrous and less ego-dystonic. He feels less dysphoria associated with clozapine and does not need as much clonazepam. He overcomes his avoidance of all fear-provoking triggers except walking across bridges.

Mr. B and I explore issues of object relationships and intimacy, establishing emotionally significant relationships with others, and the association between these and his distrust and paranoia. We also investigate the relationship between his criminal activity and feelings of loneliness or lack of control. Mr. B is able to verbalize positive and negative feelings and to feel in cognitive control of them.

Mr. B continues his regimen of clozapine, clonazepam, and gabapentin. He moves to independent housing and applies for employment.

Related resource

• Garrett M, Lerman M. CBT for psychosis for long-term inpatients with a forensic history. Psychiatr Serv. 2007;58(5):712-713.
  

Drug brand names

• Aripiprazole • Abilify
  
• Bupropion • Wellbutrin
  
• Clonazepam • Klonopin
  
• Clozapine • Clozaril
  
• Gabapentin • Neurontin
  
• Olanzapine • Zyprexa
  
• Ziprasidone • Geodon
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Disabling anxiety

Mr. B, age 35, has a history of schizophrenia, chronic paranoid type and has been hospitalized more than 12 times since its onset 10 years ago. He received clozapine during his most recent hospitalization approximately 5 years ago and experienced full symptom response without the motor side effects he developed in response to other medications. He visits a psychiatrist monthly for medications and supportive psychotherapy, and he receives intensive case management and housing from a community mental health center.

When Mr. B is assigned to my (CK) care, his psychotic symptoms are in remission, but he complains of anxiety that leaves him almost homebound. He has intense fear of bridges, upper-floor windows, express buses, subways, riding in speeding vehicles, and having a seizure.

If Mr. B faces any of these triggers, he experiences harmful thoughts—such as jumping out a window or off a bridge—even though he does not endorse suicidality. These thoughts are intrusive, ego-dystonic, and ruminative. He avoids these triggers at all costs, which compromises his housing and employment opportunities. He experienced a single panic attack in the subway 1 year earlier. Mr. B firmly believes that any intense anxiety he experiences will trigger a psychotic episode. When faced with sudden urges, he believes his illness would interfere with his ability to control his impulses.

He reports that these symptoms started when he began clozapine and have worsened. Mr. B says he experiences a feeling of “uneasiness” approximately 2 hours after taking clozapine that is exacerbated if he faces a trigger. He describes the uneasiness as “the feeling of being about to have a seizure” during which he would “lose control” of his body.

When I begin treating Mr. B, he is receiving clozapine, 125 mg bid. In an effort to combat Mr. B’s anxiety, a previous psychiatrist had titrated clonazepam up to 5 mg/d as needed. Mr. B is compliant with his medications and appointments but refuses to change his psychotropic or psychotherapy regimen.

The authors’ observations

Approximately 50% of patients with schizophrenia have at least 1 anxiety disorder, and close to 30% meet criteria for >1 anxiety disorder.¹ Social anxiety disorder (SAD), generalized anxiety disorder, panic disorder, posttraumatic stress disorder, and obsessive-compulsive disorder (OCD) have been found comorbid with schizophrenia, with rates as high as 30% for each.¹

Possible causes of unusually high rates of anxiety disorders in schizophrenia include trauma history, delusional conviction and inflexibility of abstract thought,² and passive coping mechanisms.

Schizophrenic illnesses may be linked to anxiety antecedents such as panic or social phobia that:

• develop into more profound psychopathology
  
• or bring about anxiety symptoms, given the severity of the subjective psychotic experience.
  

In a twin pairs study, the schizophrenic twin had an almost threefold increase in rates of comorbid psychiatric disorders compared with their non-schizophrenic twins; social or environmental factors may not account for this.³

Comorbid OCD, panic disorder, and SAD frequently persist after remission of psychotic symptoms. Comorbid anxiety disorders may play a role in the psychotic symptoms themselves (such as panic and social anxiety related to paranoia, OCD, and bizarre behavior) and negatively impact quality of life.⁴

In patients with schizophrenia, higher anxiety levels are associated with:

• increased hallucinations
  
• poor psychosocial function
  
• hopelessness.⁵
  

Accurately assessing and diagnosing anxiety disorders in patients with schizophrenia is challenging because there is inconsistency among clinical interviewers (poor reliability scores), and anxiety scales are not as accurate as we would like them to be (poor construct validity).⁶ Treatment options for comorbid anxiety and schizophrenia include psychopharmacology and psychotherapy (Table 1).

Table 1

Treatment options for comorbid schizophrenia and anxiety

Modality	Options	Comments
Psychopharmacology	Antipsychotics Increase antipsychotic dose Change antipsychotic Add an atypical with serotonergic action (ziprasidone, aripiprazole)	Favor monotherapy at full dose for full trial period before considering adjunct therapy with a second antipsychotic, for which evidence is still equivocal
	Antidepressants SSRI SNRI	Avoid bupropion because of possible dopamine agonism
	Benzodiazepines	Weigh risks of sedation and potential for addiction vs benefits of immediate relief
	Gabapentin	Use high doses to obtain symptomatic response
Psychotherapy	CBT (for psychosis and anxiety) Supportive (for decompensating psychosis) Behavioral Activity and vocational
CBT: cognitive-behavioral therapy; SSRI: selective serotonin reuptake inhibitor; SNRI: serotonin-norepinephrine reuptake inhibitor

HISTORY: Propensity for violence

Mr. B was born in a large city and raised by his single mother. He denies childhood physical or sexual abuse. Mr. B reports engaging in violent activity since he was an adolescent, but this activity is undocumented because he has never been arrested. Mr. B still belongs to a gang he joined after being assaulted at age 16.

 

Mr. B was diagnosed with schizophrenia at age 20 following an overt psychotic episode and suicide attempt by hanging. During his psychotic episodes, he thinks groups of people are plotting to kill him. He hears people talking about him or voices telling him about others’ plots against him. Mr. B probably has experienced these symptoms since early childhood, as evidenced by reports of attention-deficit/hyperactivity disorder, oppositional defiant disorder, conduct disorder, and tics.

His health records contain no mention of anxiety symptoms until approximately 3 months after he started clozapine, when he reported brief episodes of unexplained phobia of windows and bridges. Approximately 1 year later, he reported obsessive-compulsive symptoms—ruminating and intrusive thoughts of jumping off a bridge with no suicidal intent. Mr. B’s outpatient therapist at the time believed these symptoms began before Mr. B started clozapine.

Numerous medication trials failed. Antipsychotics were ineffective or poorly tolerated because of motor side effects or intense sedation. Mr. B did not tolerate selective serotonin reuptake inhibitors (SSRIs) because of akathisia or sexual side effects. Mr. B had a history of poor medication compliance until he began clozapine treatment.

Mr. B used cannabis daily until 10 years ago. He smokes cigarettes and reports occasional alcohol use. He has no history of chronic substance or alcohol use, withdrawal symptoms, or complications from intoxication.

Mr. B is unemployed and receives Supplemental Security Income. He has never married or had children.

Medical comorbidities include a white blood cell count and absolute neutrophil count that have been chronically in the lower limit range, and dyslipidemia and diabetes, for which Mr. B receives statins and oral hypoglycemics. He has no history of seizures or brain trauma. His family history includes substance dependence on his mother’s side and schizophrenia in 2 paternal cousins.

The authors’ observations

Mr. B’s anxiety disorder has not been clearly elucidated. He does not seem to meet criteria for:

• panic disorder (only 1 panic attack)
  
• OCD (no compulsions to diminish anxiety)
  
• specific phobia (phobias were too broad and lacked fear of an object itself).
  

Box

In addition, he does not seem to have residual paranoia, akathisia, or drug-seeking behavior. Based on numerous evaluations, Mr. B’s anxiety symptoms seem most consistent with agoraphobia without panic (Table 2).

The phenomenology of his symptoms appears to be linked to his psychodynamic development, but previous therapists had not explored this. In addition, his relationships with his therapists, illness, and medications are complex. Mr. B is poorly engaged, lacks motivation toward recovery goals, and does not trust me. However, he holds high expectations of the potential damage or benefits of medication.

Table 2

Anxiety: How to differentiate disorders and symptoms

Disorder/symptom	Keys to differential diagnosis
Panic disorder	≥2 panic attacks
Agoraphobia	Fear of ‘no escape,’ ‘no options,’ ‘loss of control’
Generalized anxiety disorder	Constant worriers
Specific phobias	Fear of an object itself, not the response it will elicit within the patient
Obsessive-compulsive disorder	Patterns of intrusive thoughts followed by an action to undo or avoid anxiety
Residual paranoia	Feeling of insecurity associated with episodes of decompensation that have remained inter-episode
Drug-seeking behaviors	Secondary gain, in direct relationship to request for medication
Akathisia, other side effects	Inner restlessness that is constant, without trigger

Mr. B’s pharmacologic management is complicated by several relative contraindications. Clozapine may be associated with or increase the incidence of OCD, panic, and agoraphobia (Box).^7–9 Combining clonazepam with clozapine is not recommended because of the possibility of intense sedation. Even so, in a patient with a history of substance use and illegal activity—such as Mr. B—cautious use of benzodiazepines is warranted to avoid addiction or drug diversion.

Mr. B was taking clonazepam when our work began, and discontinuing it would have increased his risk for seizures and the possibility of him seeking illicit benzodiazepines. Furthermore, discontinuing clonazepam might have thwarted an emerging therapeutic relationship that would become key to enhancing his motivation and exploring the antisocial and narcissistic traits that were limiting his recovery.

 

I slowly increase the frequency of my sessions with Mr. B from monthly to biweekly to weekly. We focus on strengthening the therapeutic alliance, motivational enhancement, emotional expression, and verbal identification of feeling states. We explore anxiety symptoms and psychosis using cognitive-behavioral therapy techniques informed by psychodynamic aspects of his experience, with the goal of resuming his prior level of functionality, including employment.

I carefully and slowly change Mr. B’s medications. First I increase his clozapine to 300 mg/d in 150 mg divided doses in an attempt to cover the possibility of residual paranoia, and for anxiolytic sedation without introducing a new medication. However, Mr. B’s anxiety symptoms worsen, so I resume the baseline dosage (125 mg bid). I choose not to switch to another antipsychotic because the risk for psychotic decompensation outweighs the potential benefits. I lower clonazepam to 2 mg/d in split doses. I teach Mr. B anxiety management techniques, including distraction, exposure, and anxiety tolerance training.

Because Mr. B refuses to start an SSRI for his anxiety symptoms, I prescribe bupropion and monitor him closely for dopamine agonism as evidenced by a re-emergence of psychosis. Once again, his anxiety symptoms worsen.

I stop bupropion and switch Mr. B to gabapentin, titrated to 400 mg tid. I chose this medication because of its sedation properties and relatively safe side effect profile. Mr. B was willing to try gabapentin—which was first approved to treat epilepsy—because he was afraid of having a seizure and also because it is not associated with sexual side effects. Furthermore, its GABA-mimetic actions made it a plausible alternative to replicate the benefits he was getting from clonazepam.

TREATMENT: An effective drug

Mr. B tolerates gabapentin well and his anxiety symptoms are much more sporadic, shorter, and more easily controlled by conscious exercise. The content of his thoughts is less disastrous and less ego-dystonic. He feels less dysphoria associated with clozapine and does not need as much clonazepam. He overcomes his avoidance of all fear-provoking triggers except walking across bridges.

Mr. B and I explore issues of object relationships and intimacy, establishing emotionally significant relationships with others, and the association between these and his distrust and paranoia. We also investigate the relationship between his criminal activity and feelings of loneliness or lack of control. Mr. B is able to verbalize positive and negative feelings and to feel in cognitive control of them.

Mr. B continues his regimen of clozapine, clonazepam, and gabapentin. He moves to independent housing and applies for employment.

Related resource

• Garrett M, Lerman M. CBT for psychosis for long-term inpatients with a forensic history. Psychiatr Serv. 2007;58(5):712-713.
  

Drug brand names

• Aripiprazole • Abilify
  
• Bupropion • Wellbutrin
  
• Clonazepam • Klonopin
  
• Clozapine • Clozaril
  
• Gabapentin • Neurontin
  
• Olanzapine • Zyprexa
  
• Ziprasidone • Geodon
  

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Hypothermic and confused

Mr. S, age 38, is brought to the emergency room after being found unresponsive. He has a history of poorly controlled type I diabetes. On admission his core body temperature is 35.5°C (95.9°F), blood pressure is 98/70 mm Hg, respiration is 12 breaths per minute, and pulse is 88 beats per minute. The emergency room physician believes Mr. S has syndrome of inappropriate antidiuretic hormone of unknown cause and a urinary tract infection. As emergency room clinicians address these problems, Mr. S becomes increasingly confused and his responses to questioning do not make sense. His Mini-Mental State Examination score is 7/30, indicating severe cognitive impairment.

Further workup includes a brain MRI, which shows mild cerebral atrophy; HIV testing, which is negative; cosyntropin stimulation test, which indicates normal adrenal function; and a lumbar puncture, which indicates non-polio enterovirus. The hospital’s infectious disease service is consulted, but because Mr. S is not exhibiting encephalitis no intervention is recommended.

Several days after admission, Mr. S becomes agitated and has visual hallucinations. The medical team requests a psychiatric consultation. Although Mr. S initially reported he had no psychiatric history, he later reveals he had visual hallucinations and stopped eating an undetermined time prior to being admitted because he believed his food was poisoned. The patient’s father reports that for the past 3 to 4 months, Mr. S has had poor sleep, poor concentration, and pain in his back, stomach, and feet.

The psychiatrist decides the patient’s symptoms are the result of a long course of delirium secondary to his medical condition. He starts oral risperidone, 1 mg bid. Mr. S’ temperature at this time is 36.8°C. Mr. S fails to improve, so the psychiatrist initiates quetiapine, 100 mg qhs. Two days after starting the combination of risperidone and quetiapine, Mr. S’ temperature is 35.2°C.

The author’s observations

Body temperature dysregulation as a result of antipsychotic use can manifest as hyperthermia in the case of neuroleptic malignant syndrome or, less commonly, hypothermia.¹ Symptoms of hypothermia—defined as a core body temperature of Table 1).² However, a hypothermic patient can be asymptomatic.

A recent literature review³ evaluated hypothermia cases following antipsychotic use reported in the PubMed and Embase databases (43 case reports) and the World Health Organization’s database of adverse drug reactions (480 reports). In this sample:

• More than one-half of patients had schizophrenia, 41% were male, and the mean age was 49.
  
• The reported mean body temperature was 32.6°C, with a range of 20°C to 36.1°C.
  
• 80% of hypothermia episodes occurred during an antipsychotic start, change, or dosage increase.
  
• 57% occurred within 2 days of a start, change, or dosage increase, and 16% occurred between days 2 to 7.
  

Table 1

Hypothermia symptoms

Delirium
Slurred speech
Ataxia
Fatigue
Incoordination
Subjective coldness
Shivering
Bradycardia
Source: Reference 2

TREATMENT: Antipsychotic changes

Mr. S’ disorganized behavior continues, but a workup for delirium is negative. Because the patient experiences cogwheel rigidity, the psychiatrist decreases risperidone and titrates quetiapine to 150 mg bid. Mr. S’ temperature rises to 36.8°C, and risperidone is stopped. Because of Mr. S’ continued disorganized behavior and low blood pressure, the psychiatrist changes the antipsychotic to ziprasidone, 40 mg bid. Within 5 days of this switch, Mr. S’ temperature drops from 36.4°C to 35.4°C, and then slowly returns to normal.

Mr. S’ mental status continues to wax and wane. He is not eating and is losing weight. Because the psychiatrist feels that ziprasidone is causing sedation, he switches to aripiprazole, 10 mg/d, approximately 1 week later. On aripiprazole Mr. S exhibits low temperatures (35.7°C), hypotension, and a pulse of 106. Although his medical condition is stabilized, Mr. S reports hearing male voices mumbling to him and is paranoid, stating he believes people are out to get him.

The psychiatrist increases aripiprazole to 15 mg/d. Within 2 days Mr. S’ temperature drops to 34.7°C, then gradually normalizes over the next 7 days. Aripiprazole is increased to 20 mg. Mr. S’ mental status improves and he is fully oriented, but his temperature drops to 34.1°C. His blood glucose continues to fluctuate despite normal dietary intake.

The author’s observations

Antipsychotics can influence thermoregulation by effects on the anterior preoptic hypothalamus. One possible mechanism is related to effects on the serotonin system. Atypical antipsychotics—which have a strong affinity for 5-HT2A—seem to be implicated in this reaction.

Another possible mechanism is action on alpha-2 adrenergic receptors, which may increase the hypothermic effects by inhibiting peripheral responses to cooling such as vasoconstriction and shivering. In addition, mixing atypical antipsychotics with mood stabilizers and benzodiazepines contributes to this reaction.⁴

 

GABA may have a role in hypothermia. Experiments with rats have shown that L-methionine-DL-sulfoximine infusions into the dorsal raphe nucleus of rats slows serotonin turnover, which decreases the release of GABA synthesis, and both induce hypothermia.⁵

Other neurotransmitter systems involved include dopamine and norepinephrine and their increased metabolism. One study compared clozapine with risperidone, quetiapine, and olanzapine with regard to dopamine receptor affinity in rats.⁵ Clozapine had a greater affinity for D1 compared with D2 receptors. Researchers used antipsychotic-induced hypothermia to measure this. Clozapine, olanzapine, and risperidone produced dose-dependent hypothermia, which researchers were able to prevent by blocking the D1 receptor.

Other factors can contribute to hypothermia in patients taking antipsychotics, including:

• pre-existing brain damage
  
• lesions of the preoptic anterior hypothalamic region
  
• neurotensin, a thermoregulatory neuropeptide
  
• ambient temperature
  
• apathy and indifference resulting from antipsychotic use, which may dampen behavior aimed toward thermoregulation, such as using blankets when sleeping.
  

Some cases have suggested coexisting infections may play a role in temperature dysregulation.¹ Other compounding factors may include elevated thyroid-stimulating hormone and hypothyroidism at the time of temperature drop.¹

OUTCOME: Multiple infections

Mr. S remains hospitalized because of complications related to his diabetes, which contribute to fluctuations in mental status consistent with delirium. Two months into Mr. S’ hospital stay, the psychiatrist decides to address these symptoms by restarting risperidone, 0.5 mg in the morning and 1 mg in the evening. Within several days of restarting risperidone, Mr. S’ temperature drops from 37°C to 35.1°C. One day after another dose of risperidone, 0.5 mg, is added at noon, the patient’s temperature drops to 33.1°C. Mr. S continues to be lethargic and confused and is hypoglycemic.

Earlier that month, a blood culture from Mr. S was found to be positive for Clostridium difficile and Staphylococcus aureus. Both infections were treated and resolved, seemingly independent from the times Mr. S’ temperature dropped with addition of antipsychotics.

Mr. S eventually decompensates and is admitted to the ICU, where he is intubated. There, the patient has positive cultures for methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. While in the ICU Mr. S continues to receive risperidone, and his temperature drops to 30.5°C.

Mr. S improves and he is subsequently sent to the medical floor, then he is discharged to a long-term acute care facility. His temperature continues to range between 33°C and 34°C for 2 weeks, then returns to normal after all antipsychotics are discontinued.

The author’s observations

This case report documents periods of hypothermia in a male patient who received various antipsychotics during treatment. It appears that his hypothermia occurred in conjunction with starting and changing antipsychotics and increasing dosages (Table 2).

Mr. S’ case is unique in that it involves hypothermia apparently in response to multiple atypical antipsychotics in 1 patient over a prolonged time; to our knowledge, no other such cases exist. This was a complicated case of a patient with multiple serious comorbidities. We feel, however, that antipsychotics were the major contributor to Mr. S’ hypothermia because the drops in temperature occurred as discrete periods tied to times of antipsychotic use.

Close monitoring of drug serum levels—particularly when starting, changing, or increasing a dosage—may help prevent antipsychotic-induced hypothermia. Be vigilant for behavioral changes and problems that could contribute to hypothermia, such as social isolation and inappropriate dress, as well as comorbidities such as infection. It is unclear at what core body temperature to consider stopping an antipsychotic or decreasing the dosage.

Table 2

Mr. S’ temperature during hospitalization

Hospitalized day	Core body temperature (°C)*	Antipsychotic
Admission	35.5	None
8	36.8	Started risperidone, 1 mg bid
11	35.2	Added quetiapine, 100 mg po qhs
14	36.8	Stopped risperidone, increased quetiapine to 150 mg bid
18	35.4	Switched to ziprasidone, 40 mg bid
23	35.7	Switched to aripiprazole, 10 mg/d
30	34.7	Increased aripiprazole to 15 mg/d
38	34.1	Increased aripiprazole to 20 mg/d
76	33.1	Switched to risperidone, 0.5 mg am and noon and 1 mg qhs
107	37.0	None
*Normal core body temperature is 37°C (98.6°F)

Related resources

• Gibbons GM, Wein DA, Paula R. Profound hypothermia secondary to normal ziprasidone use. Am J Emerg Med. 2008;26(6):737.
  

Drug brand names

• Aripiprazole • Abilify
  
• Clozapine • Clozaril
  
• Olanzapine • Zyprexa
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Vancomycin • Vancocin
  
• Ziprasidone • Geodon
  

Disclosure

The authors report no financial relationship with an company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Hypothermic and confused

Mr. S, age 38, is brought to the emergency room after being found unresponsive. He has a history of poorly controlled type I diabetes. On admission his core body temperature is 35.5°C (95.9°F), blood pressure is 98/70 mm Hg, respiration is 12 breaths per minute, and pulse is 88 beats per minute. The emergency room physician believes Mr. S has syndrome of inappropriate antidiuretic hormone of unknown cause and a urinary tract infection. As emergency room clinicians address these problems, Mr. S becomes increasingly confused and his responses to questioning do not make sense. His Mini-Mental State Examination score is 7/30, indicating severe cognitive impairment.

Further workup includes a brain MRI, which shows mild cerebral atrophy; HIV testing, which is negative; cosyntropin stimulation test, which indicates normal adrenal function; and a lumbar puncture, which indicates non-polio enterovirus. The hospital’s infectious disease service is consulted, but because Mr. S is not exhibiting encephalitis no intervention is recommended.

Several days after admission, Mr. S becomes agitated and has visual hallucinations. The medical team requests a psychiatric consultation. Although Mr. S initially reported he had no psychiatric history, he later reveals he had visual hallucinations and stopped eating an undetermined time prior to being admitted because he believed his food was poisoned. The patient’s father reports that for the past 3 to 4 months, Mr. S has had poor sleep, poor concentration, and pain in his back, stomach, and feet.

The psychiatrist decides the patient’s symptoms are the result of a long course of delirium secondary to his medical condition. He starts oral risperidone, 1 mg bid. Mr. S’ temperature at this time is 36.8°C. Mr. S fails to improve, so the psychiatrist initiates quetiapine, 100 mg qhs. Two days after starting the combination of risperidone and quetiapine, Mr. S’ temperature is 35.2°C.

The author’s observations

Body temperature dysregulation as a result of antipsychotic use can manifest as hyperthermia in the case of neuroleptic malignant syndrome or, less commonly, hypothermia.¹ Symptoms of hypothermia—defined as a core body temperature of Table 1).² However, a hypothermic patient can be asymptomatic.

A recent literature review³ evaluated hypothermia cases following antipsychotic use reported in the PubMed and Embase databases (43 case reports) and the World Health Organization’s database of adverse drug reactions (480 reports). In this sample:

• More than one-half of patients had schizophrenia, 41% were male, and the mean age was 49.
  
• The reported mean body temperature was 32.6°C, with a range of 20°C to 36.1°C.
  
• 80% of hypothermia episodes occurred during an antipsychotic start, change, or dosage increase.
  
• 57% occurred within 2 days of a start, change, or dosage increase, and 16% occurred between days 2 to 7.
  

Table 1

Hypothermia symptoms

Delirium
Slurred speech
Ataxia
Fatigue
Incoordination
Subjective coldness
Shivering
Bradycardia
Source: Reference 2

TREATMENT: Antipsychotic changes

Mr. S’ disorganized behavior continues, but a workup for delirium is negative. Because the patient experiences cogwheel rigidity, the psychiatrist decreases risperidone and titrates quetiapine to 150 mg bid. Mr. S’ temperature rises to 36.8°C, and risperidone is stopped. Because of Mr. S’ continued disorganized behavior and low blood pressure, the psychiatrist changes the antipsychotic to ziprasidone, 40 mg bid. Within 5 days of this switch, Mr. S’ temperature drops from 36.4°C to 35.4°C, and then slowly returns to normal.

Mr. S’ mental status continues to wax and wane. He is not eating and is losing weight. Because the psychiatrist feels that ziprasidone is causing sedation, he switches to aripiprazole, 10 mg/d, approximately 1 week later. On aripiprazole Mr. S exhibits low temperatures (35.7°C), hypotension, and a pulse of 106. Although his medical condition is stabilized, Mr. S reports hearing male voices mumbling to him and is paranoid, stating he believes people are out to get him.

The psychiatrist increases aripiprazole to 15 mg/d. Within 2 days Mr. S’ temperature drops to 34.7°C, then gradually normalizes over the next 7 days. Aripiprazole is increased to 20 mg. Mr. S’ mental status improves and he is fully oriented, but his temperature drops to 34.1°C. His blood glucose continues to fluctuate despite normal dietary intake.

The author’s observations

Antipsychotics can influence thermoregulation by effects on the anterior preoptic hypothalamus. One possible mechanism is related to effects on the serotonin system. Atypical antipsychotics—which have a strong affinity for 5-HT2A—seem to be implicated in this reaction.

Another possible mechanism is action on alpha-2 adrenergic receptors, which may increase the hypothermic effects by inhibiting peripheral responses to cooling such as vasoconstriction and shivering. In addition, mixing atypical antipsychotics with mood stabilizers and benzodiazepines contributes to this reaction.⁴

 

GABA may have a role in hypothermia. Experiments with rats have shown that L-methionine-DL-sulfoximine infusions into the dorsal raphe nucleus of rats slows serotonin turnover, which decreases the release of GABA synthesis, and both induce hypothermia.⁵

Other neurotransmitter systems involved include dopamine and norepinephrine and their increased metabolism. One study compared clozapine with risperidone, quetiapine, and olanzapine with regard to dopamine receptor affinity in rats.⁵ Clozapine had a greater affinity for D1 compared with D2 receptors. Researchers used antipsychotic-induced hypothermia to measure this. Clozapine, olanzapine, and risperidone produced dose-dependent hypothermia, which researchers were able to prevent by blocking the D1 receptor.

Other factors can contribute to hypothermia in patients taking antipsychotics, including:

• pre-existing brain damage
  
• lesions of the preoptic anterior hypothalamic region
  
• neurotensin, a thermoregulatory neuropeptide
  
• ambient temperature
  
• apathy and indifference resulting from antipsychotic use, which may dampen behavior aimed toward thermoregulation, such as using blankets when sleeping.
  

Some cases have suggested coexisting infections may play a role in temperature dysregulation.¹ Other compounding factors may include elevated thyroid-stimulating hormone and hypothyroidism at the time of temperature drop.¹

OUTCOME: Multiple infections

Mr. S remains hospitalized because of complications related to his diabetes, which contribute to fluctuations in mental status consistent with delirium. Two months into Mr. S’ hospital stay, the psychiatrist decides to address these symptoms by restarting risperidone, 0.5 mg in the morning and 1 mg in the evening. Within several days of restarting risperidone, Mr. S’ temperature drops from 37°C to 35.1°C. One day after another dose of risperidone, 0.5 mg, is added at noon, the patient’s temperature drops to 33.1°C. Mr. S continues to be lethargic and confused and is hypoglycemic.

Earlier that month, a blood culture from Mr. S was found to be positive for Clostridium difficile and Staphylococcus aureus. Both infections were treated and resolved, seemingly independent from the times Mr. S’ temperature dropped with addition of antipsychotics.

Mr. S eventually decompensates and is admitted to the ICU, where he is intubated. There, the patient has positive cultures for methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. While in the ICU Mr. S continues to receive risperidone, and his temperature drops to 30.5°C.

Mr. S improves and he is subsequently sent to the medical floor, then he is discharged to a long-term acute care facility. His temperature continues to range between 33°C and 34°C for 2 weeks, then returns to normal after all antipsychotics are discontinued.

The author’s observations

This case report documents periods of hypothermia in a male patient who received various antipsychotics during treatment. It appears that his hypothermia occurred in conjunction with starting and changing antipsychotics and increasing dosages (Table 2).

Mr. S’ case is unique in that it involves hypothermia apparently in response to multiple atypical antipsychotics in 1 patient over a prolonged time; to our knowledge, no other such cases exist. This was a complicated case of a patient with multiple serious comorbidities. We feel, however, that antipsychotics were the major contributor to Mr. S’ hypothermia because the drops in temperature occurred as discrete periods tied to times of antipsychotic use.

Close monitoring of drug serum levels—particularly when starting, changing, or increasing a dosage—may help prevent antipsychotic-induced hypothermia. Be vigilant for behavioral changes and problems that could contribute to hypothermia, such as social isolation and inappropriate dress, as well as comorbidities such as infection. It is unclear at what core body temperature to consider stopping an antipsychotic or decreasing the dosage.

Table 2

Mr. S’ temperature during hospitalization

Hospitalized day	Core body temperature (°C)*	Antipsychotic
Admission	35.5	None
8	36.8	Started risperidone, 1 mg bid
11	35.2	Added quetiapine, 100 mg po qhs
14	36.8	Stopped risperidone, increased quetiapine to 150 mg bid
18	35.4	Switched to ziprasidone, 40 mg bid
23	35.7	Switched to aripiprazole, 10 mg/d
30	34.7	Increased aripiprazole to 15 mg/d
38	34.1	Increased aripiprazole to 20 mg/d
76	33.1	Switched to risperidone, 0.5 mg am and noon and 1 mg qhs
107	37.0	None
*Normal core body temperature is 37°C (98.6°F)

Related resources

• Gibbons GM, Wein DA, Paula R. Profound hypothermia secondary to normal ziprasidone use. Am J Emerg Med. 2008;26(6):737.
  

Drug brand names

• Aripiprazole • Abilify
  
• Clozapine • Clozaril
  
• Olanzapine • Zyprexa
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Vancomycin • Vancocin
  
• Ziprasidone • Geodon
  

Disclosure

The authors report no financial relationship with an company whose products are mentioned in this article or with manufacturers of competing products.