Cases That Test Your Skills

HISTORY: Treatment-refractory depression

Mr. S, age 78, has a history of depression that has not responded to selective serotonin reuptake inhibitors and electroconvulsive therapy (ECT).

According to his niece, Mr. S had become withdrawn, suspicious, and forgetful. Several times over the past year, police found him wandering the streets and brought him to the community hospital’s emergency room.

During one emergency room visit, he complained of decreased appetite, poor sleep, and depressed mood. He was subsequently admitted to the psychiatric unit, where he was treated with ECT and discharged on citalopram, 20 mg/d. His symptoms did not improve and he became ataxic and incontinent of urine.

Mr. S’ family placed him in a nursing home, where he became increasingly paranoid. The attending physician prescribed risperidone, 3 mg/d, with no effect. He was then transferred to our psychiatric facility.

At admission, Mr. S told us that a group of men disguised in toupees and mustaches were out to kill him. He said these men had recently killed his niece—with whom he had just spoken on the phone and had seen at the hospital. He suspected that these men were after his money, hired a woman to impersonate his niece and spy on him, and planned to bury his body and his niece’s in a remote place.

On evaluation, Mr. S was suspicious, guarded, and uncooperative, and often ended conversations abruptly. He denied auditory and visual hallucinations, was not suicidal or homicidal, and denied abusing drugs or alcohol. He said constant fear of his imminent murder left him feeling depressed.

Physical and neurologic exams were unremarkable except for mild ataxia. Mr. S’ Folstein Mini-Mental State Examination score was 19/30, indicating moderate cognitive impairment.

Mr. S’ history and behavior suggest depression with psychotic features. Do we have enough information for a diagnosis?

Dr. Greenberg’s and Tampi’s observations

Mr. S is displaying mood symptoms consistent with his prior diagnosis of depression, but with new-onset psychosis as well.

Because of Mr. S’ neurobiologic symptoms, it is improper to diagnose depression with psychotic features without first performing a full medical and neurologic workup. The differential diagnosis needs to include medical and neurologic diagnoses, including:

• delirium secondary to urinary tract infection
• Alzheimer’s and/or vascular dementia
• normal-pressure hydrocephalus
• substance abuse.

A complete dementia and delirium workup and detailed medical history are imperative.

FURTHER HISTORY: Risky behavior

Further history reveals that Mr. S had been having sexual intercourse with prostitutes since his early teens and that this habit continued into his 70s. He had been diagnosed with syphilis in his teens and again in his 50s. Both times he refused to complete the recommended penicillin regimen because he was embarrassed by the diagnosis and had falsely believed that a single penicillin injection would cure him.

Lab tests showed a white blood cell count of 3.5 and a weakly reactive serum venereal disease research laboratory (VDRL) reading.

Box 1

Could Mr. S’ syphilis—inadequately treated in his youth—be causing his depression and paranoia decades later? If so, how would you confirm this finding?

Dr. Greenberg’s and Tampi’s observations

Mr. S has a longstanding history of syphilis secondary to high-risk sexual activity. This, combined with the lab findings and his worsening depression and paranoia, points to possible neurosyphilis.

Syphilis, caused by the spirochete Treponema pallidum., can traverse mucous membranes and abraded skin. Transmission is most common during sexual activity but also occurs through blood transfusions and nonsexual lesion contact and from mother to fetus.

Box 2

 

Because syphilis and its psychiatric effects are relatively uncommon (Box 1), many psychiatrists do not consider neurosyphilis in high-risk patients who present with depression, dementia, or psychosis (Box 2).

HOW SYPHILIS BECOMES NEUROSYPHILIS

Primary syphilis incubates for 10 to 90 days following infection. After this period, an infectious chancre appears along with regional adenopathy. If untreated, the chancre will disappear but the infection will progress.

Secondary syphilis is characterized by skin manifestations and occasionally affects the joints, eyes, bones, kidneys, liver, and CNS. Common effects include condylomata—highly infectious warty lesions—and a diffuse maculopapular rash on the palms and soles. These lesions disappear if left untreated, but most patients then either enter syphilis’ latent stage or experience a potentially fatal relapse of secondary syphilis.⁵

Latent syphilis usually remains latent or resolves, but about one-third of patients with latent syphilis slowly progress to tertiary syphilis. Neurosyphilis, one of the main forms of tertiary syphilis, can surface 5 to 35 years after an untreated primary infection.⁷

There are four categories of neurosyphilis:

• General paresis results in dementia, changes in personality, transient hemiparesis, depression, and psychosis.
• Tabes dorsalis degenerates the posterior columns and dorsal root ganglia of the spinal cord. This results in ataxia, parasthesias, decreased proprioception and vibratory sense, Argyll Robertson pupil (an optical disorder in which the pupil does not react normally to light), neurogenic bladder, and sharp shooting pains throughout the body.
• Meningovascular neurosyphilis can result in cranial nerve abnormalities, symptoms of meningitis, and cerebral infarctions.
• Asymptomatic but with CSF positive for syphilis.

Neurosyphilis is fatal if untreated, and treatment usually does not eliminate symptoms but prevents further progression. Approximately 8% of patients with untreated primary syphilis develop neurosyphilis.^5,7

Standard nontreponemal tests, such as the VDRL or rapid plasmin reagin, can be used to screen for syphilis. Because these tests often produce false positives, confirm positive results with a syphilis-specific test, such as the fluorescent treponemal antibody absorption (FTA-ABS) test, microhemagglutination assay for antibodies to T pallidum., and the T pallidum. hemagglutination assay.

If neurosyphilis is suspected, CSF testing is strongly recommended. Diagnostic findings include elevated white blood cell and protein counts and a positive VDRL. If the CSF is negative, refer the patient for treatment anyway because false negatives are common. Patients with consistent neurologic symptoms, positive VDRL and/or FTA-ABS, and negative CSF are diagnosed with neurosyphilis and warrant treatment.⁷

How would you manage Mr. S’ psychiatric symptoms concomitant with medical treatment of late-stage syphilis?

Dr. Greenberg’s and Tampi’s observations

Although no specific guidelines exist for treating psychosis secondary to neurosyphilis, atypical antipsychotics remain the first-line treatment. Atypicals do not interact significantly with penicillin and can be given safely with syphilis treatment. Atypicals also are better tolerated than typical antipsychotics and produce fewer extrapyramidal symptoms, which are common among older patients and those with neurologic diseases.

Screening for syphilis. Every patient with a history of high-risk sexual behavior who presents with new-onset dementia or psychosis should be screened for syphilis. Sexual history can be difficult to obtain from some patients and family members, so communication between providers becomes crucial. Obtain lab test results from other care team members to monitor compliance, and coordinate patient education with other doctors on safe sexual practices.

TREATMENT: Taking his medicine

Mr. S refused further testing and emergency conservatorship was sought. Citalopram was discontinued and risperidone was gradually increased to 6 mg at bedtime. He remained paranoid and delusional.

A brain MRI showed chronic ischemic small-vessel disease. HIV testing was negative, and serum FTA-ABS was reactive. CSF showed elevated protein and white blood cell count with a nonreactive VDRL and a reactive FTA-ABS. A diagnosis of neurosyphilis was made, and treatment was initiated with aqueous crystalline penicillin G, 4 million units every 4 hours for 2 weeks.

Mr. S was discharged back to the nursing home where his penicillin injections were continued. His paranoia diminished slightly but he remained ataxic, incontinent, and confused. He was discharged from the nursing home but needed confirmative HIV screening and repeated CSF testing to determine if syphilis treatment was effective.

Six months after treatment, Mr. S’ niece reports that his paranoia has decreased. He has not needed additional psychiatric hospitalizations.

Related resources

• Merck Manual. www.merck.com. Search: “syphilis”
• U.S. Centers for Disease Control and Prevention—Syphilis elimination: History in the making. www.cdc.gov. Click on “Health Topics A-Z,” then click on “S” and find “syphilis.”
• National Institute of Allergy and Infectious Disease. www.niaid.nih.gov. Search: “syphilis”

Drug brand names

• Citalopram • Celexa
• Risperidone • Risperdal

Disclosure

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

HISTORY: Treatment-refractory depression

Mr. S, age 78, has a history of depression that has not responded to selective serotonin reuptake inhibitors and electroconvulsive therapy (ECT).

According to his niece, Mr. S had become withdrawn, suspicious, and forgetful. Several times over the past year, police found him wandering the streets and brought him to the community hospital’s emergency room.

During one emergency room visit, he complained of decreased appetite, poor sleep, and depressed mood. He was subsequently admitted to the psychiatric unit, where he was treated with ECT and discharged on citalopram, 20 mg/d. His symptoms did not improve and he became ataxic and incontinent of urine.

Mr. S’ family placed him in a nursing home, where he became increasingly paranoid. The attending physician prescribed risperidone, 3 mg/d, with no effect. He was then transferred to our psychiatric facility.

At admission, Mr. S told us that a group of men disguised in toupees and mustaches were out to kill him. He said these men had recently killed his niece—with whom he had just spoken on the phone and had seen at the hospital. He suspected that these men were after his money, hired a woman to impersonate his niece and spy on him, and planned to bury his body and his niece’s in a remote place.

On evaluation, Mr. S was suspicious, guarded, and uncooperative, and often ended conversations abruptly. He denied auditory and visual hallucinations, was not suicidal or homicidal, and denied abusing drugs or alcohol. He said constant fear of his imminent murder left him feeling depressed.

Physical and neurologic exams were unremarkable except for mild ataxia. Mr. S’ Folstein Mini-Mental State Examination score was 19/30, indicating moderate cognitive impairment.

Mr. S’ history and behavior suggest depression with psychotic features. Do we have enough information for a diagnosis?

Dr. Greenberg’s and Tampi’s observations

Mr. S is displaying mood symptoms consistent with his prior diagnosis of depression, but with new-onset psychosis as well.

Because of Mr. S’ neurobiologic symptoms, it is improper to diagnose depression with psychotic features without first performing a full medical and neurologic workup. The differential diagnosis needs to include medical and neurologic diagnoses, including:

• delirium secondary to urinary tract infection
• Alzheimer’s and/or vascular dementia
• normal-pressure hydrocephalus
• substance abuse.

A complete dementia and delirium workup and detailed medical history are imperative.

FURTHER HISTORY: Risky behavior

Further history reveals that Mr. S had been having sexual intercourse with prostitutes since his early teens and that this habit continued into his 70s. He had been diagnosed with syphilis in his teens and again in his 50s. Both times he refused to complete the recommended penicillin regimen because he was embarrassed by the diagnosis and had falsely believed that a single penicillin injection would cure him.

Lab tests showed a white blood cell count of 3.5 and a weakly reactive serum venereal disease research laboratory (VDRL) reading.

Box 1

Could Mr. S’ syphilis—inadequately treated in his youth—be causing his depression and paranoia decades later? If so, how would you confirm this finding?

Dr. Greenberg’s and Tampi’s observations

Mr. S has a longstanding history of syphilis secondary to high-risk sexual activity. This, combined with the lab findings and his worsening depression and paranoia, points to possible neurosyphilis.

Syphilis, caused by the spirochete Treponema pallidum., can traverse mucous membranes and abraded skin. Transmission is most common during sexual activity but also occurs through blood transfusions and nonsexual lesion contact and from mother to fetus.

Box 2

 

Because syphilis and its psychiatric effects are relatively uncommon (Box 1), many psychiatrists do not consider neurosyphilis in high-risk patients who present with depression, dementia, or psychosis (Box 2).

HOW SYPHILIS BECOMES NEUROSYPHILIS

Primary syphilis incubates for 10 to 90 days following infection. After this period, an infectious chancre appears along with regional adenopathy. If untreated, the chancre will disappear but the infection will progress.

Secondary syphilis is characterized by skin manifestations and occasionally affects the joints, eyes, bones, kidneys, liver, and CNS. Common effects include condylomata—highly infectious warty lesions—and a diffuse maculopapular rash on the palms and soles. These lesions disappear if left untreated, but most patients then either enter syphilis’ latent stage or experience a potentially fatal relapse of secondary syphilis.⁵

Latent syphilis usually remains latent or resolves, but about one-third of patients with latent syphilis slowly progress to tertiary syphilis. Neurosyphilis, one of the main forms of tertiary syphilis, can surface 5 to 35 years after an untreated primary infection.⁷

There are four categories of neurosyphilis:

• General paresis results in dementia, changes in personality, transient hemiparesis, depression, and psychosis.
• Tabes dorsalis degenerates the posterior columns and dorsal root ganglia of the spinal cord. This results in ataxia, parasthesias, decreased proprioception and vibratory sense, Argyll Robertson pupil (an optical disorder in which the pupil does not react normally to light), neurogenic bladder, and sharp shooting pains throughout the body.
• Meningovascular neurosyphilis can result in cranial nerve abnormalities, symptoms of meningitis, and cerebral infarctions.
• Asymptomatic but with CSF positive for syphilis.

Neurosyphilis is fatal if untreated, and treatment usually does not eliminate symptoms but prevents further progression. Approximately 8% of patients with untreated primary syphilis develop neurosyphilis.^5,7

Standard nontreponemal tests, such as the VDRL or rapid plasmin reagin, can be used to screen for syphilis. Because these tests often produce false positives, confirm positive results with a syphilis-specific test, such as the fluorescent treponemal antibody absorption (FTA-ABS) test, microhemagglutination assay for antibodies to T pallidum., and the T pallidum. hemagglutination assay.

If neurosyphilis is suspected, CSF testing is strongly recommended. Diagnostic findings include elevated white blood cell and protein counts and a positive VDRL. If the CSF is negative, refer the patient for treatment anyway because false negatives are common. Patients with consistent neurologic symptoms, positive VDRL and/or FTA-ABS, and negative CSF are diagnosed with neurosyphilis and warrant treatment.⁷

How would you manage Mr. S’ psychiatric symptoms concomitant with medical treatment of late-stage syphilis?

Dr. Greenberg’s and Tampi’s observations

Although no specific guidelines exist for treating psychosis secondary to neurosyphilis, atypical antipsychotics remain the first-line treatment. Atypicals do not interact significantly with penicillin and can be given safely with syphilis treatment. Atypicals also are better tolerated than typical antipsychotics and produce fewer extrapyramidal symptoms, which are common among older patients and those with neurologic diseases.

Screening for syphilis. Every patient with a history of high-risk sexual behavior who presents with new-onset dementia or psychosis should be screened for syphilis. Sexual history can be difficult to obtain from some patients and family members, so communication between providers becomes crucial. Obtain lab test results from other care team members to monitor compliance, and coordinate patient education with other doctors on safe sexual practices.

TREATMENT: Taking his medicine

Mr. S refused further testing and emergency conservatorship was sought. Citalopram was discontinued and risperidone was gradually increased to 6 mg at bedtime. He remained paranoid and delusional.

A brain MRI showed chronic ischemic small-vessel disease. HIV testing was negative, and serum FTA-ABS was reactive. CSF showed elevated protein and white blood cell count with a nonreactive VDRL and a reactive FTA-ABS. A diagnosis of neurosyphilis was made, and treatment was initiated with aqueous crystalline penicillin G, 4 million units every 4 hours for 2 weeks.

Mr. S was discharged back to the nursing home where his penicillin injections were continued. His paranoia diminished slightly but he remained ataxic, incontinent, and confused. He was discharged from the nursing home but needed confirmative HIV screening and repeated CSF testing to determine if syphilis treatment was effective.

Six months after treatment, Mr. S’ niece reports that his paranoia has decreased. He has not needed additional psychiatric hospitalizations.

Related resources

• Merck Manual. www.merck.com. Search: “syphilis”
• U.S. Centers for Disease Control and Prevention—Syphilis elimination: History in the making. www.cdc.gov. Click on “Health Topics A-Z,” then click on “S” and find “syphilis.”
• National Institute of Allergy and Infectious Disease. www.niaid.nih.gov. Search: “syphilis”

Drug brand names

• Citalopram • Celexa
• Risperidone • Risperdal

Disclosure

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

HISTORY: Treatment-refractory depression

Mr. S, age 78, has a history of depression that has not responded to selective serotonin reuptake inhibitors and electroconvulsive therapy (ECT).

According to his niece, Mr. S had become withdrawn, suspicious, and forgetful. Several times over the past year, police found him wandering the streets and brought him to the community hospital’s emergency room.

During one emergency room visit, he complained of decreased appetite, poor sleep, and depressed mood. He was subsequently admitted to the psychiatric unit, where he was treated with ECT and discharged on citalopram, 20 mg/d. His symptoms did not improve and he became ataxic and incontinent of urine.

Mr. S’ family placed him in a nursing home, where he became increasingly paranoid. The attending physician prescribed risperidone, 3 mg/d, with no effect. He was then transferred to our psychiatric facility.

At admission, Mr. S told us that a group of men disguised in toupees and mustaches were out to kill him. He said these men had recently killed his niece—with whom he had just spoken on the phone and had seen at the hospital. He suspected that these men were after his money, hired a woman to impersonate his niece and spy on him, and planned to bury his body and his niece’s in a remote place.

On evaluation, Mr. S was suspicious, guarded, and uncooperative, and often ended conversations abruptly. He denied auditory and visual hallucinations, was not suicidal or homicidal, and denied abusing drugs or alcohol. He said constant fear of his imminent murder left him feeling depressed.

Physical and neurologic exams were unremarkable except for mild ataxia. Mr. S’ Folstein Mini-Mental State Examination score was 19/30, indicating moderate cognitive impairment.

Mr. S’ history and behavior suggest depression with psychotic features. Do we have enough information for a diagnosis?

Dr. Greenberg’s and Tampi’s observations

Mr. S is displaying mood symptoms consistent with his prior diagnosis of depression, but with new-onset psychosis as well.

Because of Mr. S’ neurobiologic symptoms, it is improper to diagnose depression with psychotic features without first performing a full medical and neurologic workup. The differential diagnosis needs to include medical and neurologic diagnoses, including:

• delirium secondary to urinary tract infection
• Alzheimer’s and/or vascular dementia
• normal-pressure hydrocephalus
• substance abuse.

A complete dementia and delirium workup and detailed medical history are imperative.

FURTHER HISTORY: Risky behavior

Further history reveals that Mr. S had been having sexual intercourse with prostitutes since his early teens and that this habit continued into his 70s. He had been diagnosed with syphilis in his teens and again in his 50s. Both times he refused to complete the recommended penicillin regimen because he was embarrassed by the diagnosis and had falsely believed that a single penicillin injection would cure him.

Lab tests showed a white blood cell count of 3.5 and a weakly reactive serum venereal disease research laboratory (VDRL) reading.

Box 1

Could Mr. S’ syphilis—inadequately treated in his youth—be causing his depression and paranoia decades later? If so, how would you confirm this finding?

Dr. Greenberg’s and Tampi’s observations

Mr. S has a longstanding history of syphilis secondary to high-risk sexual activity. This, combined with the lab findings and his worsening depression and paranoia, points to possible neurosyphilis.

Syphilis, caused by the spirochete Treponema pallidum., can traverse mucous membranes and abraded skin. Transmission is most common during sexual activity but also occurs through blood transfusions and nonsexual lesion contact and from mother to fetus.

Box 2

 

Because syphilis and its psychiatric effects are relatively uncommon (Box 1), many psychiatrists do not consider neurosyphilis in high-risk patients who present with depression, dementia, or psychosis (Box 2).

HOW SYPHILIS BECOMES NEUROSYPHILIS

Primary syphilis incubates for 10 to 90 days following infection. After this period, an infectious chancre appears along with regional adenopathy. If untreated, the chancre will disappear but the infection will progress.

Secondary syphilis is characterized by skin manifestations and occasionally affects the joints, eyes, bones, kidneys, liver, and CNS. Common effects include condylomata—highly infectious warty lesions—and a diffuse maculopapular rash on the palms and soles. These lesions disappear if left untreated, but most patients then either enter syphilis’ latent stage or experience a potentially fatal relapse of secondary syphilis.⁵

Latent syphilis usually remains latent or resolves, but about one-third of patients with latent syphilis slowly progress to tertiary syphilis. Neurosyphilis, one of the main forms of tertiary syphilis, can surface 5 to 35 years after an untreated primary infection.⁷

There are four categories of neurosyphilis:

• General paresis results in dementia, changes in personality, transient hemiparesis, depression, and psychosis.
• Tabes dorsalis degenerates the posterior columns and dorsal root ganglia of the spinal cord. This results in ataxia, parasthesias, decreased proprioception and vibratory sense, Argyll Robertson pupil (an optical disorder in which the pupil does not react normally to light), neurogenic bladder, and sharp shooting pains throughout the body.
• Meningovascular neurosyphilis can result in cranial nerve abnormalities, symptoms of meningitis, and cerebral infarctions.
• Asymptomatic but with CSF positive for syphilis.

Neurosyphilis is fatal if untreated, and treatment usually does not eliminate symptoms but prevents further progression. Approximately 8% of patients with untreated primary syphilis develop neurosyphilis.^5,7

Standard nontreponemal tests, such as the VDRL or rapid plasmin reagin, can be used to screen for syphilis. Because these tests often produce false positives, confirm positive results with a syphilis-specific test, such as the fluorescent treponemal antibody absorption (FTA-ABS) test, microhemagglutination assay for antibodies to T pallidum., and the T pallidum. hemagglutination assay.

If neurosyphilis is suspected, CSF testing is strongly recommended. Diagnostic findings include elevated white blood cell and protein counts and a positive VDRL. If the CSF is negative, refer the patient for treatment anyway because false negatives are common. Patients with consistent neurologic symptoms, positive VDRL and/or FTA-ABS, and negative CSF are diagnosed with neurosyphilis and warrant treatment.⁷

How would you manage Mr. S’ psychiatric symptoms concomitant with medical treatment of late-stage syphilis?

Dr. Greenberg’s and Tampi’s observations

Although no specific guidelines exist for treating psychosis secondary to neurosyphilis, atypical antipsychotics remain the first-line treatment. Atypicals do not interact significantly with penicillin and can be given safely with syphilis treatment. Atypicals also are better tolerated than typical antipsychotics and produce fewer extrapyramidal symptoms, which are common among older patients and those with neurologic diseases.

Screening for syphilis. Every patient with a history of high-risk sexual behavior who presents with new-onset dementia or psychosis should be screened for syphilis. Sexual history can be difficult to obtain from some patients and family members, so communication between providers becomes crucial. Obtain lab test results from other care team members to monitor compliance, and coordinate patient education with other doctors on safe sexual practices.

TREATMENT: Taking his medicine

Mr. S refused further testing and emergency conservatorship was sought. Citalopram was discontinued and risperidone was gradually increased to 6 mg at bedtime. He remained paranoid and delusional.

A brain MRI showed chronic ischemic small-vessel disease. HIV testing was negative, and serum FTA-ABS was reactive. CSF showed elevated protein and white blood cell count with a nonreactive VDRL and a reactive FTA-ABS. A diagnosis of neurosyphilis was made, and treatment was initiated with aqueous crystalline penicillin G, 4 million units every 4 hours for 2 weeks.

Mr. S was discharged back to the nursing home where his penicillin injections were continued. His paranoia diminished slightly but he remained ataxic, incontinent, and confused. He was discharged from the nursing home but needed confirmative HIV screening and repeated CSF testing to determine if syphilis treatment was effective.

Six months after treatment, Mr. S’ niece reports that his paranoia has decreased. He has not needed additional psychiatric hospitalizations.

Related resources

• Merck Manual. www.merck.com. Search: “syphilis”
• U.S. Centers for Disease Control and Prevention—Syphilis elimination: History in the making. www.cdc.gov. Click on “Health Topics A-Z,” then click on “S” and find “syphilis.”
• National Institute of Allergy and Infectious Disease. www.niaid.nih.gov. Search: “syphilis”

Drug brand names

• Citalopram • Celexa
• Risperidone • Risperdal

Disclosure

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

INITIAL PRESENTATION: A sickly child

Ms. J, age 35, was referred to a psychiatrist after she was observed endangering her daughter. The child’s pediatrician provided the following history.

The 4-year-old has frequently required medical attention. As a baby, she wore a breathing monitor at home for almost 1 year after her mother expressed fear that she would die of apnea. Throughout her early years, the child was treated for asthma and abdominal pain and for bruises her parents said were caused when she fell out of her crib.

Recently, the child has suffered with recurring skin infections over her arm and shoulders. Her mother treated those with prescribed topical and oral antibiotics and dressings. The wounds would heal briefly, then become inflamed again.

The pediatrician consulted with a child psychiatrist, who suggested that the girl be hospitalized for a day so that doctors could examine the wound. Despite the mother’s protests, her daughter was hospitalized.

That day, Ms. J visited her daughter, unaware that the hospital room was equipped with a concealed video camera. As she was leaving late that evening, she lifted her daughter’s bandages as if to check them, then applied irritants to the wounds.

When the staff confronted her about this destructive behavior toward her daughter, Ms. J denied it had occurred. Upon seeing the videotape, however, she wept profusely, exclaiming, “I didn’t mean any harm.”

Ms. J does not fit the profile of a child abuser. Aside from part-time clerical work at home, she is a full-time mother who is intensely involved in every aspect of her daughter’s life. Before the videotaped incident, her pediatrician’s office staff had described her as caring and loving, and she had brought them thank-you gifts.

On psychiatric evaluation, Ms. J’s speech is coherent and logical, and she has no delusions or hallucinations. In describing her childhood, she recalls her parents arguing constantly. Her father, with whom she had little contact, traveled extensively on business. At home, her mother ruled with an iron fist. Any show of rebellion by Ms. J or her siblings led to a sharp slap on the shoulders.

Ms. J had few friends in grade school. In college, she earned good grades but often visited the infirmary with nonspecific complaints. She was hospitalized twice without a conclusive diagnosis. She twice saw a psychiatrist to address her medical symptoms and feelings of emptiness.

Table

Defining symptoms, features of Munchausen’s syndrome

Major symptoms Simulated illness, usually recurrent Pathological lying (pseudologia fantastica) Peregrination (wandering, often with name and identity changes)
Secondary features Medical knowledge or training Multiple doctor visits or hospitalizations Several scars (usually abdominal) Unusual willingness to undergo diagnostic or treatment procedures History of rejection or abuse during childhood, with feeling of comfort while receiving medical care Borderline or antisocial personality Ostentatious presentation at emergency room or doctor’s office

After college, Ms. J worked as a teacher’s aide. At age 30 she married a teacher, and their daughter was born 1 year later. The marriage ended in divorce after 3 years. After divorce the husband tried to visit the daughter but Ms. J interfered, insisting, “I’m enough.”

Ms. J told the psychiatrist that her ex-husband at times accused her of being “too clingy.” If he went to a sporting event, she would repeatedly ask what time he would come home. If she had to go shopping and he was home, she would ask him to drop everything and accompany her.

Does Ms. J’s behavior suggest a straightforward personality disorder, or would you consider a factitious disorder?

Dr. Messer’s observations

Ms. J recalled a childhood fraught with rejection and abuse. This finding, plus the deliberate injury to her daughter, points to a diagnosis of Munchausen’s syndrome by proxy.

Although not listed in DSM-IV-TR, Munchausen’s is the most severe form of factitious disorder (Table). First described in 1951, the disorder is named for Baron Karl von Munchausen, an 18th-century German nobleman known for telling tall tales about his life and exploits.¹

In 1977, British pediatrician Roy Meadow described Munchausen’s syndrome by proxy, in which parents induce symptoms in their children—such as by injuring them with drugs or bacterial contaminants—then have doctors treat them.² Because persons with Munchausen’s tend to frequently change their names and locales, the incidence of Munchausen’s and Munchausen’s by proxy has never been accurately gauged.

Munchausen’s occurs in both sexes, although men tend to exhibit more-dramatic symptoms such as self-induced fevers, bleeding, and seizures. Antisocial behavior is common among men with Munchausen’s, and many are jailed at some point. One man flying from New York to London feigned a heart attack so convincingly that he forced an emergency landing in Halifax, Nova Scotia, where he was hospitalized and released with a referral to his cardiologist.

 

By contrast, women with Munchausen’s or Munchausen’s by proxy—often nurses or hospital personnel—are more difficult to diagnose because they usually are agreeable and compliant with medical staff. Staff members tend to ask themselves, “Could such a caring person be putting us on?”

Some persons with Munchausen’s visit disease-specific support groups and draw attention or sympathy by faking illness. Having amassed significant medical knowledge through Web searches and frequent doctor visits, they present themselves as both patient and lofty advisor. Their antisocial tendencies can negatively alter group discussions, and the revelation that a fellow group member is an impostor can distress legitimate participants.³

Ms. J exhibited no evidence of a delusional disorder, which occurs rarely among parents with Munchausen’s by proxy. Her allegedly “clingy” (dependent) behavior toward her daughter and ex-husband, however, indicates borderline personality disorder or antisocial personality disorder, which are common in both forms of Munchausen’s. Like Ms. J, these patients

• have strong fears of rejection and abandonment
• are often impulsive
• exhibit damaging behavior to self or others
• have an unstable sense of self
• are unusually willing to comply with clinical tests or procedures
• and describe feelings of emptiness.

How would you confirm a diagnosis of Munchausen’s? What features in Ms J’s case distinguish Munchausen’s from other factitious disorders?Box

Dr. Messer’s observations

When taking the patient history, look for:

• a pattern of rejection or abuse in youth. In women who have been sexually molested, Munchausen’s by proxy may manifest as allegations that their children have been touched inappropriately (Box).⁴
• history of multiple surgeries.⁵ Because Munchausen’s can coexist with genuine physical illness, the psychiatrist and other doctors need to carefully review the findings to determine the existence of medical symptoms or Munchausen’s. Doctors usually choose to operate if there is any suspicion that medical symptoms exist.
• memories of sympathetic and nurturing medical care early in life. A severe emotional crisis can awaken these memories. For example, emotional pain after a divorce or break-up can trigger a Munchausen’s episode in a subconscious attempt to repair this hurt.

Carefully reviewing the history will turn up glaring discrepancies in the patient’s account of his or her illness. Patients with Munchausen’s or Munchausen’s by proxy usually present to numerous clinicians and do not describe their “illness” the same way twice. Sharing information with other members of the care team—many of whom may feel anger after learning that a patient has been feigning illness—is crucial to confirming the diagnosis.

DIFFERENTIAL DIAGNOSIS

Munchausen’s should not be confused with symptoms of other lookalike disorders:

• Hypochondriasis applies to patients who are convinced they have a serious illness despite lack of a medical basis. The person may misinterpret normal bodily functions and suffer severe distress. The symptoms may express inner psychic conflict.
• Somatoform disorder is a physical complaint that cannot be explained as a known medical condition. This may include preoccupation with an imagined defect in appearance or loss of physical capacity. The deficit usually coincides with emotional conflict and—unlike Munchausen’s—there is no fabrication of illness.
• Malingerers purposely fake physical symptoms for specific gain, such as money, hospital care, disability, drugs, or avoiding military duty.

Persons with Munchausen’s have no external incentive for their behavior. Aside from the medical staff’s admiration, Ms. J had nothing to gain from injuring her daughter or portraying her as sickly.

TREATMENT: Coming home

Ms. J’s daughter responded well after being placed in the home of a relative who had a 3-year-old daughter of her own. Ms. J was allowed to see her daughter for 2 hours each day under strict supervision by a retired schoolteacher hired by the family. If Ms. J. violated the agreement, such as by leaving the house with her daughter, she was prohibited from seeing her child the next day.

 

Ms. J agreed to long-term therapy; in exchange, judicial proceedings were deferred. In most cases, the mother is referred to police and charged with child abuse/endangerment. However, the medical staff in this case felt treatment and supervision would provide ample rehabilitation.

The mother was referred to a psychiatrist trained in psychoanalysis. By making her aware of her unconscious responses, the doctor sought to improve Ms. J’s ability to cope with stress. Patients with a borderline personality disorder seldom respond in psychoanalysis, but Ms. J exhibited significant ego strengths and intelligence—and was motivated to regain custody of her daughter.

Ms. J’s transference response was predictable: She tried to please the doctor in everything she said or did. This reaction was analyzed and the insight helped Ms. J understand why she exaggerated or exacerbated normal childhood illnesses in her daughter. She discovered that she had hungered for approval since childhood and went as far as injuring her daughter to achieve this fulfillment. Early in treatment she developed a mantra: “I have behaved toward my daughter as my mother behaved toward me.”

After 8 months of therapy 3 times a week, Ms. J regained custody. She continued to receive once-weekly psychotherapy for 1 year.

Two years after regaining custody, Ms. J developed a stable, loving relationship with her daughter. She works full-time while her daughter is in high school and participates in many activities. The relative who assumed temporary custody stays in touch, as does her pediatrician.

The girl is seen by her father on alternate weekends. She tells friends she wants to become a nurse.

How can psychiatrists facilitate early diagnosis and treatment of Munchausen’s?

Dr. Messer’s observations

Although primary care physicians or general surgeons treat most patients with Munchausen’s, the disorder is psychiatric in nature.

For that reason, psychiatrists should participate when possible in the early medical workup of a patient who presents with an apparently severe illness. This way, the psychiatrist can:

• help detect Munchausen’s or another factitious disorder sooner
• establish a rapport with the patient early on. If Munchausen’s is subsequently diagnosed, the patient may be less likely to resist treatment or bolt when confronted.

When confronting someone suspected of fabricating or inducing symptoms, tell the patient that he or she might have Munchausen’s syndrome. Describe the disorder and cite cases, then challenge the patient to find a more appropriate way to cope with stress.

Related resources

• Adshead G, Brooke D (eds). Munchausen's syndrome by proxy. Current issues in assessment, treatment and research. Singapore: World Scientific Publishing, 2001.
• Munchausen’s syndrome by proxy. www.gktscientific.com

INITIAL PRESENTATION: A sickly child

Ms. J, age 35, was referred to a psychiatrist after she was observed endangering her daughter. The child’s pediatrician provided the following history.

The 4-year-old has frequently required medical attention. As a baby, she wore a breathing monitor at home for almost 1 year after her mother expressed fear that she would die of apnea. Throughout her early years, the child was treated for asthma and abdominal pain and for bruises her parents said were caused when she fell out of her crib.

Recently, the child has suffered with recurring skin infections over her arm and shoulders. Her mother treated those with prescribed topical and oral antibiotics and dressings. The wounds would heal briefly, then become inflamed again.

The pediatrician consulted with a child psychiatrist, who suggested that the girl be hospitalized for a day so that doctors could examine the wound. Despite the mother’s protests, her daughter was hospitalized.

That day, Ms. J visited her daughter, unaware that the hospital room was equipped with a concealed video camera. As she was leaving late that evening, she lifted her daughter’s bandages as if to check them, then applied irritants to the wounds.

When the staff confronted her about this destructive behavior toward her daughter, Ms. J denied it had occurred. Upon seeing the videotape, however, she wept profusely, exclaiming, “I didn’t mean any harm.”

Ms. J does not fit the profile of a child abuser. Aside from part-time clerical work at home, she is a full-time mother who is intensely involved in every aspect of her daughter’s life. Before the videotaped incident, her pediatrician’s office staff had described her as caring and loving, and she had brought them thank-you gifts.

On psychiatric evaluation, Ms. J’s speech is coherent and logical, and she has no delusions or hallucinations. In describing her childhood, she recalls her parents arguing constantly. Her father, with whom she had little contact, traveled extensively on business. At home, her mother ruled with an iron fist. Any show of rebellion by Ms. J or her siblings led to a sharp slap on the shoulders.

Ms. J had few friends in grade school. In college, she earned good grades but often visited the infirmary with nonspecific complaints. She was hospitalized twice without a conclusive diagnosis. She twice saw a psychiatrist to address her medical symptoms and feelings of emptiness.

Table

Defining symptoms, features of Munchausen’s syndrome

Major symptoms Simulated illness, usually recurrent Pathological lying (pseudologia fantastica) Peregrination (wandering, often with name and identity changes)
Secondary features Medical knowledge or training Multiple doctor visits or hospitalizations Several scars (usually abdominal) Unusual willingness to undergo diagnostic or treatment procedures History of rejection or abuse during childhood, with feeling of comfort while receiving medical care Borderline or antisocial personality Ostentatious presentation at emergency room or doctor’s office

After college, Ms. J worked as a teacher’s aide. At age 30 she married a teacher, and their daughter was born 1 year later. The marriage ended in divorce after 3 years. After divorce the husband tried to visit the daughter but Ms. J interfered, insisting, “I’m enough.”

Ms. J told the psychiatrist that her ex-husband at times accused her of being “too clingy.” If he went to a sporting event, she would repeatedly ask what time he would come home. If she had to go shopping and he was home, she would ask him to drop everything and accompany her.

Does Ms. J’s behavior suggest a straightforward personality disorder, or would you consider a factitious disorder?

Dr. Messer’s observations

Ms. J recalled a childhood fraught with rejection and abuse. This finding, plus the deliberate injury to her daughter, points to a diagnosis of Munchausen’s syndrome by proxy.

Although not listed in DSM-IV-TR, Munchausen’s is the most severe form of factitious disorder (Table). First described in 1951, the disorder is named for Baron Karl von Munchausen, an 18th-century German nobleman known for telling tall tales about his life and exploits.¹

In 1977, British pediatrician Roy Meadow described Munchausen’s syndrome by proxy, in which parents induce symptoms in their children—such as by injuring them with drugs or bacterial contaminants—then have doctors treat them.² Because persons with Munchausen’s tend to frequently change their names and locales, the incidence of Munchausen’s and Munchausen’s by proxy has never been accurately gauged.

Munchausen’s occurs in both sexes, although men tend to exhibit more-dramatic symptoms such as self-induced fevers, bleeding, and seizures. Antisocial behavior is common among men with Munchausen’s, and many are jailed at some point. One man flying from New York to London feigned a heart attack so convincingly that he forced an emergency landing in Halifax, Nova Scotia, where he was hospitalized and released with a referral to his cardiologist.

 

By contrast, women with Munchausen’s or Munchausen’s by proxy—often nurses or hospital personnel—are more difficult to diagnose because they usually are agreeable and compliant with medical staff. Staff members tend to ask themselves, “Could such a caring person be putting us on?”

Some persons with Munchausen’s visit disease-specific support groups and draw attention or sympathy by faking illness. Having amassed significant medical knowledge through Web searches and frequent doctor visits, they present themselves as both patient and lofty advisor. Their antisocial tendencies can negatively alter group discussions, and the revelation that a fellow group member is an impostor can distress legitimate participants.³

Ms. J exhibited no evidence of a delusional disorder, which occurs rarely among parents with Munchausen’s by proxy. Her allegedly “clingy” (dependent) behavior toward her daughter and ex-husband, however, indicates borderline personality disorder or antisocial personality disorder, which are common in both forms of Munchausen’s. Like Ms. J, these patients

• have strong fears of rejection and abandonment
• are often impulsive
• exhibit damaging behavior to self or others
• have an unstable sense of self
• are unusually willing to comply with clinical tests or procedures
• and describe feelings of emptiness.

How would you confirm a diagnosis of Munchausen’s? What features in Ms J’s case distinguish Munchausen’s from other factitious disorders?Box

Dr. Messer’s observations

When taking the patient history, look for:

• a pattern of rejection or abuse in youth. In women who have been sexually molested, Munchausen’s by proxy may manifest as allegations that their children have been touched inappropriately (Box).⁴
• history of multiple surgeries.⁵ Because Munchausen’s can coexist with genuine physical illness, the psychiatrist and other doctors need to carefully review the findings to determine the existence of medical symptoms or Munchausen’s. Doctors usually choose to operate if there is any suspicion that medical symptoms exist.
• memories of sympathetic and nurturing medical care early in life. A severe emotional crisis can awaken these memories. For example, emotional pain after a divorce or break-up can trigger a Munchausen’s episode in a subconscious attempt to repair this hurt.

Carefully reviewing the history will turn up glaring discrepancies in the patient’s account of his or her illness. Patients with Munchausen’s or Munchausen’s by proxy usually present to numerous clinicians and do not describe their “illness” the same way twice. Sharing information with other members of the care team—many of whom may feel anger after learning that a patient has been feigning illness—is crucial to confirming the diagnosis.

DIFFERENTIAL DIAGNOSIS

Munchausen’s should not be confused with symptoms of other lookalike disorders:

• Hypochondriasis applies to patients who are convinced they have a serious illness despite lack of a medical basis. The person may misinterpret normal bodily functions and suffer severe distress. The symptoms may express inner psychic conflict.
• Somatoform disorder is a physical complaint that cannot be explained as a known medical condition. This may include preoccupation with an imagined defect in appearance or loss of physical capacity. The deficit usually coincides with emotional conflict and—unlike Munchausen’s—there is no fabrication of illness.
• Malingerers purposely fake physical symptoms for specific gain, such as money, hospital care, disability, drugs, or avoiding military duty.

Persons with Munchausen’s have no external incentive for their behavior. Aside from the medical staff’s admiration, Ms. J had nothing to gain from injuring her daughter or portraying her as sickly.

TREATMENT: Coming home

Ms. J’s daughter responded well after being placed in the home of a relative who had a 3-year-old daughter of her own. Ms. J was allowed to see her daughter for 2 hours each day under strict supervision by a retired schoolteacher hired by the family. If Ms. J. violated the agreement, such as by leaving the house with her daughter, she was prohibited from seeing her child the next day.

 

Ms. J agreed to long-term therapy; in exchange, judicial proceedings were deferred. In most cases, the mother is referred to police and charged with child abuse/endangerment. However, the medical staff in this case felt treatment and supervision would provide ample rehabilitation.

The mother was referred to a psychiatrist trained in psychoanalysis. By making her aware of her unconscious responses, the doctor sought to improve Ms. J’s ability to cope with stress. Patients with a borderline personality disorder seldom respond in psychoanalysis, but Ms. J exhibited significant ego strengths and intelligence—and was motivated to regain custody of her daughter.

Ms. J’s transference response was predictable: She tried to please the doctor in everything she said or did. This reaction was analyzed and the insight helped Ms. J understand why she exaggerated or exacerbated normal childhood illnesses in her daughter. She discovered that she had hungered for approval since childhood and went as far as injuring her daughter to achieve this fulfillment. Early in treatment she developed a mantra: “I have behaved toward my daughter as my mother behaved toward me.”

After 8 months of therapy 3 times a week, Ms. J regained custody. She continued to receive once-weekly psychotherapy for 1 year.

Two years after regaining custody, Ms. J developed a stable, loving relationship with her daughter. She works full-time while her daughter is in high school and participates in many activities. The relative who assumed temporary custody stays in touch, as does her pediatrician.

The girl is seen by her father on alternate weekends. She tells friends she wants to become a nurse.

How can psychiatrists facilitate early diagnosis and treatment of Munchausen’s?

Dr. Messer’s observations

Although primary care physicians or general surgeons treat most patients with Munchausen’s, the disorder is psychiatric in nature.

For that reason, psychiatrists should participate when possible in the early medical workup of a patient who presents with an apparently severe illness. This way, the psychiatrist can:

• help detect Munchausen’s or another factitious disorder sooner
• establish a rapport with the patient early on. If Munchausen’s is subsequently diagnosed, the patient may be less likely to resist treatment or bolt when confronted.

When confronting someone suspected of fabricating or inducing symptoms, tell the patient that he or she might have Munchausen’s syndrome. Describe the disorder and cite cases, then challenge the patient to find a more appropriate way to cope with stress.

Related resources

• Adshead G, Brooke D (eds). Munchausen's syndrome by proxy. Current issues in assessment, treatment and research. Singapore: World Scientific Publishing, 2001.
• Munchausen’s syndrome by proxy. www.gktscientific.com

INITIAL PRESENTATION: A sickly child

Ms. J, age 35, was referred to a psychiatrist after she was observed endangering her daughter. The child’s pediatrician provided the following history.

The 4-year-old has frequently required medical attention. As a baby, she wore a breathing monitor at home for almost 1 year after her mother expressed fear that she would die of apnea. Throughout her early years, the child was treated for asthma and abdominal pain and for bruises her parents said were caused when she fell out of her crib.

Recently, the child has suffered with recurring skin infections over her arm and shoulders. Her mother treated those with prescribed topical and oral antibiotics and dressings. The wounds would heal briefly, then become inflamed again.

The pediatrician consulted with a child psychiatrist, who suggested that the girl be hospitalized for a day so that doctors could examine the wound. Despite the mother’s protests, her daughter was hospitalized.

That day, Ms. J visited her daughter, unaware that the hospital room was equipped with a concealed video camera. As she was leaving late that evening, she lifted her daughter’s bandages as if to check them, then applied irritants to the wounds.

When the staff confronted her about this destructive behavior toward her daughter, Ms. J denied it had occurred. Upon seeing the videotape, however, she wept profusely, exclaiming, “I didn’t mean any harm.”

Ms. J does not fit the profile of a child abuser. Aside from part-time clerical work at home, she is a full-time mother who is intensely involved in every aspect of her daughter’s life. Before the videotaped incident, her pediatrician’s office staff had described her as caring and loving, and she had brought them thank-you gifts.

On psychiatric evaluation, Ms. J’s speech is coherent and logical, and she has no delusions or hallucinations. In describing her childhood, she recalls her parents arguing constantly. Her father, with whom she had little contact, traveled extensively on business. At home, her mother ruled with an iron fist. Any show of rebellion by Ms. J or her siblings led to a sharp slap on the shoulders.

Ms. J had few friends in grade school. In college, she earned good grades but often visited the infirmary with nonspecific complaints. She was hospitalized twice without a conclusive diagnosis. She twice saw a psychiatrist to address her medical symptoms and feelings of emptiness.

Table

Defining symptoms, features of Munchausen’s syndrome

Major symptoms Simulated illness, usually recurrent Pathological lying (pseudologia fantastica) Peregrination (wandering, often with name and identity changes)
Secondary features Medical knowledge or training Multiple doctor visits or hospitalizations Several scars (usually abdominal) Unusual willingness to undergo diagnostic or treatment procedures History of rejection or abuse during childhood, with feeling of comfort while receiving medical care Borderline or antisocial personality Ostentatious presentation at emergency room or doctor’s office

After college, Ms. J worked as a teacher’s aide. At age 30 she married a teacher, and their daughter was born 1 year later. The marriage ended in divorce after 3 years. After divorce the husband tried to visit the daughter but Ms. J interfered, insisting, “I’m enough.”

Ms. J told the psychiatrist that her ex-husband at times accused her of being “too clingy.” If he went to a sporting event, she would repeatedly ask what time he would come home. If she had to go shopping and he was home, she would ask him to drop everything and accompany her.

Does Ms. J’s behavior suggest a straightforward personality disorder, or would you consider a factitious disorder?

Dr. Messer’s observations

Ms. J recalled a childhood fraught with rejection and abuse. This finding, plus the deliberate injury to her daughter, points to a diagnosis of Munchausen’s syndrome by proxy.

Although not listed in DSM-IV-TR, Munchausen’s is the most severe form of factitious disorder (Table). First described in 1951, the disorder is named for Baron Karl von Munchausen, an 18th-century German nobleman known for telling tall tales about his life and exploits.¹

In 1977, British pediatrician Roy Meadow described Munchausen’s syndrome by proxy, in which parents induce symptoms in their children—such as by injuring them with drugs or bacterial contaminants—then have doctors treat them.² Because persons with Munchausen’s tend to frequently change their names and locales, the incidence of Munchausen’s and Munchausen’s by proxy has never been accurately gauged.

Munchausen’s occurs in both sexes, although men tend to exhibit more-dramatic symptoms such as self-induced fevers, bleeding, and seizures. Antisocial behavior is common among men with Munchausen’s, and many are jailed at some point. One man flying from New York to London feigned a heart attack so convincingly that he forced an emergency landing in Halifax, Nova Scotia, where he was hospitalized and released with a referral to his cardiologist.

 

By contrast, women with Munchausen’s or Munchausen’s by proxy—often nurses or hospital personnel—are more difficult to diagnose because they usually are agreeable and compliant with medical staff. Staff members tend to ask themselves, “Could such a caring person be putting us on?”

Some persons with Munchausen’s visit disease-specific support groups and draw attention or sympathy by faking illness. Having amassed significant medical knowledge through Web searches and frequent doctor visits, they present themselves as both patient and lofty advisor. Their antisocial tendencies can negatively alter group discussions, and the revelation that a fellow group member is an impostor can distress legitimate participants.³

Ms. J exhibited no evidence of a delusional disorder, which occurs rarely among parents with Munchausen’s by proxy. Her allegedly “clingy” (dependent) behavior toward her daughter and ex-husband, however, indicates borderline personality disorder or antisocial personality disorder, which are common in both forms of Munchausen’s. Like Ms. J, these patients

• have strong fears of rejection and abandonment
• are often impulsive
• exhibit damaging behavior to self or others
• have an unstable sense of self
• are unusually willing to comply with clinical tests or procedures
• and describe feelings of emptiness.

How would you confirm a diagnosis of Munchausen’s? What features in Ms J’s case distinguish Munchausen’s from other factitious disorders?Box

Dr. Messer’s observations

When taking the patient history, look for:

• a pattern of rejection or abuse in youth. In women who have been sexually molested, Munchausen’s by proxy may manifest as allegations that their children have been touched inappropriately (Box).⁴
• history of multiple surgeries.⁵ Because Munchausen’s can coexist with genuine physical illness, the psychiatrist and other doctors need to carefully review the findings to determine the existence of medical symptoms or Munchausen’s. Doctors usually choose to operate if there is any suspicion that medical symptoms exist.
• memories of sympathetic and nurturing medical care early in life. A severe emotional crisis can awaken these memories. For example, emotional pain after a divorce or break-up can trigger a Munchausen’s episode in a subconscious attempt to repair this hurt.

Carefully reviewing the history will turn up glaring discrepancies in the patient’s account of his or her illness. Patients with Munchausen’s or Munchausen’s by proxy usually present to numerous clinicians and do not describe their “illness” the same way twice. Sharing information with other members of the care team—many of whom may feel anger after learning that a patient has been feigning illness—is crucial to confirming the diagnosis.

DIFFERENTIAL DIAGNOSIS

Munchausen’s should not be confused with symptoms of other lookalike disorders:

• Hypochondriasis applies to patients who are convinced they have a serious illness despite lack of a medical basis. The person may misinterpret normal bodily functions and suffer severe distress. The symptoms may express inner psychic conflict.
• Somatoform disorder is a physical complaint that cannot be explained as a known medical condition. This may include preoccupation with an imagined defect in appearance or loss of physical capacity. The deficit usually coincides with emotional conflict and—unlike Munchausen’s—there is no fabrication of illness.
• Malingerers purposely fake physical symptoms for specific gain, such as money, hospital care, disability, drugs, or avoiding military duty.

Persons with Munchausen’s have no external incentive for their behavior. Aside from the medical staff’s admiration, Ms. J had nothing to gain from injuring her daughter or portraying her as sickly.

TREATMENT: Coming home

Ms. J’s daughter responded well after being placed in the home of a relative who had a 3-year-old daughter of her own. Ms. J was allowed to see her daughter for 2 hours each day under strict supervision by a retired schoolteacher hired by the family. If Ms. J. violated the agreement, such as by leaving the house with her daughter, she was prohibited from seeing her child the next day.

 

Ms. J agreed to long-term therapy; in exchange, judicial proceedings were deferred. In most cases, the mother is referred to police and charged with child abuse/endangerment. However, the medical staff in this case felt treatment and supervision would provide ample rehabilitation.

The mother was referred to a psychiatrist trained in psychoanalysis. By making her aware of her unconscious responses, the doctor sought to improve Ms. J’s ability to cope with stress. Patients with a borderline personality disorder seldom respond in psychoanalysis, but Ms. J exhibited significant ego strengths and intelligence—and was motivated to regain custody of her daughter.

Ms. J’s transference response was predictable: She tried to please the doctor in everything she said or did. This reaction was analyzed and the insight helped Ms. J understand why she exaggerated or exacerbated normal childhood illnesses in her daughter. She discovered that she had hungered for approval since childhood and went as far as injuring her daughter to achieve this fulfillment. Early in treatment she developed a mantra: “I have behaved toward my daughter as my mother behaved toward me.”

After 8 months of therapy 3 times a week, Ms. J regained custody. She continued to receive once-weekly psychotherapy for 1 year.

Two years after regaining custody, Ms. J developed a stable, loving relationship with her daughter. She works full-time while her daughter is in high school and participates in many activities. The relative who assumed temporary custody stays in touch, as does her pediatrician.

The girl is seen by her father on alternate weekends. She tells friends she wants to become a nurse.

How can psychiatrists facilitate early diagnosis and treatment of Munchausen’s?

Dr. Messer’s observations

Although primary care physicians or general surgeons treat most patients with Munchausen’s, the disorder is psychiatric in nature.

For that reason, psychiatrists should participate when possible in the early medical workup of a patient who presents with an apparently severe illness. This way, the psychiatrist can:

• help detect Munchausen’s or another factitious disorder sooner
• establish a rapport with the patient early on. If Munchausen’s is subsequently diagnosed, the patient may be less likely to resist treatment or bolt when confronted.

When confronting someone suspected of fabricating or inducing symptoms, tell the patient that he or she might have Munchausen’s syndrome. Describe the disorder and cite cases, then challenge the patient to find a more appropriate way to cope with stress.

Related resources

• Adshead G, Brooke D (eds). Munchausen's syndrome by proxy. Current issues in assessment, treatment and research. Singapore: World Scientific Publishing, 2001.
• Munchausen’s syndrome by proxy. www.gktscientific.com

Culture-related anxiety and paranoia can be difficult to treat because they are reinforced by socially normative practices and beliefs.¹ As in the two cases described below, psychiatric patients with deep underlying mistrust may view a therapist from another culture—even though well-meaning—as a racist oppressor.

The clinician’s approach to therapy can help prevent cultural misunderstandings and—most important—misdiagnosis (Box).

MR. A’S CASE: ‘She’s out to get me’

Mr. A, age 38 and African-American, was admitted to the inpatient psychiatry service with neurovegetative depressive symptoms and apparent delusional thinking.

His wife of 20 years, also African-American, was concerned that he was becoming increasingly irrational. She said he accused her of conspiring with his predominantly white supervisors to “bring about my destruction.”

Mr. A consented to admission, acknowledging to the psychiatrist that he had felt depressed and at times considered suicide. He complained that he had recently experienced several unusual “happenings:”

• Pointing to recent weight loss, Mr. A feared someone was poisoning his food or that he had swallowed a “tracking” device.
• Mr. A feared that workers who were repairing flood damage in his home were sent to kill him. He remained home during the project, but the fear drove him to a panic attack.
• After more than 18 years working for the same employer with no notable interpersonal difficulties, Mr. A suddenly could not get along with his coworkers. He accused one colleague of following him to a restaurant.

Mr. A had no previous psychiatric disorder, but some distant relatives had schizophrenia. He was diagnosed as having major depressive disorder, severe with psychotic features; delusional disorder was ruled out. He was prescribed olanzapine, 10 mg at bedtime, and fluoxetine, 20 mg/d.

In the hospital, Mr. A spoke normally with no agitation, increased activity, or evidence of racing thoughts. In group therapy, he explained that he felt “confused.” He also disclosed that a recent extramarital affair left him feeling extremely guilty.

Box

A few days later, Mr. A’s suicidal and paranoid ideations disappeared. He expressed anger only while discussing his diagnosis with the attending psychiatrist, who is white. The patient feared that being diagnosed with a psychotic illness would hurt his career. He admitted he felt depressed, but insisted that he now realized his paranoid thoughts were irrational.

Mr. A was discharged after 6 days. He remained on fluoxetine, 20 mg/d; olanzapine was discontinued due to excessive sedation.

The patient also entered insight-oriented psychotherapy to address his depression. Mr. A and the therapist, who is white, spent most of the initial sessions discussing their racial differences. At one point, Mr. A complained to the therapist that white physicians were trying to “railroad” him because of his race.

After nine sessions, Mr. A revealed that he felt isolated at an early age, thinking that others “will use what they know about me against me.” He described growing up in a predominantly black community where most of his neighbors felt oppressed by white people. As therapy progressed, Mr. A realized that this experience influenced his attitudes about race, and that his extramarital affair destroyed his sense of self-trust, which may have fueled his mistrust of others.

After 20 sessions, his marriage and work relationships were stable and his overall mood was much improved. His Outcome Questionnaire 45.2 score decreased across 12 months from 88 (moderate to severe distress) to 55 (level of distress similar to that of non-patients). Delusional behavior has not re-emerged, although his comments continue to reflect mistrust of his supervisors and of white people in general.

What would your diagnosis be? What clues would you gather from Mr. A’s pretreatment behavior and from his progress in therapy?

Dr. Benzick’s observations

Mr. A’s diagnosis upon admission reflected the psychiatrist’s belief that he suffered fixed delusions. By definition, however, a delusion is a false belief that is not “ordinarily accepted by other members of the person’s culture or subculture.”²

 

Growing up, Mr. A shared his neighbors’ suspicion of white people. Further, his overvalued conspiracy theory involving his wife might have projected his own guilt over his infidelity onto a pre-existing paranoid personality.

Based on his psychosocial history, rapid progress in psychotherapy, and marked improvement in Outcome Questionnaire 45.2 scores, Mr. A does not have a personality disorder. What’s more, paranoid ideation is not uncommon in African-Americans with depressive symptoms, as demonstrated by Bazargan et al. ³

Mr. A’s diagnosis was changed to major depressive disorder, moderate, in partial remission. He is still seen approximately every 6 weeks for medication maintenance; he continues taking fluoxetine, 20 mg/d.

MR. B’S CASE: ‘Singled’ out

Mr. B, age 42 and African-American, was referred from an alcohol rehabilitation program to the psychiatry unit after exhibiting depressive and paranoid symptoms.

After 17 years with his employer, he started clashing with his supervisors and coworkers—most of whom are white. He claimed his colleagues were talking behind his back, jealous that he is single and spends his evenings at nightclubs. He alleged that his bosses were singling him out after he was transferred to another department and reprimanded for arriving late to work. Resultant worry about job security brought on panic symptoms (shortness of breath, lightheadedness, dissociative feelings, and palpitations).

Upon further questioning, Mr. B said he felt depressed and isolated. He had been prescribed nortriptyline 2 years ago but discontinued it after a few weeks because of side effects.

Mr. B said that not having a steady companion contributed to his depression and alcohol use. He had been drinking heavily for about 3 years, consuming at least a six-pack daily. He acknowledged that his suspicion of his white coworkers long preceded his alcoholism. Still, he did not see this mistrust as a problem.

Mr. B was diagnosed with major depressive disorder, severe with psychotic features. Treatment consisted of:

• paroxetine, 20 mg/d
• attendance at Alcoholics Anonymous meetings (at least three meetings per week were recommended)
• and 12 sessions of interpersonal psychotherapy. During these sessions, the therapist began to uncover the roots of Mr. B’s symptoms.

School days. Mr. B described how, as a little boy, he once watched his mother being beaten by his drunken father. He told the therapist that the beatings occurred frequently.

When he was age 5, Mr. B’s parents divorced and he and his mother moved to a mostly white Midwest neighborhood so that he could attend a high school with an advanced music program (he was honored for exceptional talent on several instruments).

In his youth, Mr. B’s mother repeatedly told him that teachers and students would treat him “differently” because of his color, though she never explained what she meant. While in high school, he began to worry about his social functioning, appearance, work performance, and future accomplishments.

After four psychotherapy sessions, Mr. B revealed that while in grade school, he was sexually assaulted by an older white boy. For more than 30 years, he had told no one. He denied hyperautonomic and re-experiencing symptoms but realized that this incident may have kept him from starting a romantic relationship.

After psychotherapy, Mr. B reported reduced depression and increased social interaction. His Beck Depression Inventory score dropped from 23 (moderate depression) to 4 (normal mood), and his Beck Anxiety Inventory score improved from 33 (moderate anxiety) to 3 (very low anxiety). He has been sober for 6 months and handles stress more effectively, although his mistrust toward coworkers is still apparent.

How would you diagnose Mr. B? Do his symptoms characterize “psychotic features” or an anxiety or alcohol-related disorder?

Dr. Benzick’s observations

Mr. B’s case illustrates how deep-seated cultural perceptions and past trauma together can cause severe anxiety—and how that anxiety can be misperceived as psychosis.⁴ Anxiety also can manifest as paranoia in “psychotically vulnerable” individuals.^5-7

Chronic anxiety seemed to cause Mr. B’s depressed mood and social withdrawal. Several anxiety disorder diagnoses were considered, including:

• panic disorder
• posttraumatic stress disorder
• social phobia
• alcohol-induced anxiety disorder
• and generalized anxiety disorder.

Mr. B, however, exhibited no evidence of repeated episodic anxiety, nor did he describe reexperiencing phenomena. His anxiety extended beyond social situations and preceded his heavy alcohol consumption. Paranoid personality disorder was also considered, but Mr. B sought relationships and lacked the angry, unforgiving qualities associated with this pathology. Finally, a battery of psychological tests did not reveal frank psychosis but suggested an avoidant personality style.

Mr. B’s diagnosis was changed to generalized anxiety disorder. He requested a trial off medications during the latter stages of therapy, but his severe anxiety returned. He was then prescribed venlafaxine, 37.5 mg/d titrated to 225 mg/d across 3 weeks. His anxiety symptoms again abated.

 

How could Mr A’s and Mr. B’s doctors have avoided their initial misdiagnoses?

Dr. Benzick’s observations

“Cultural paranoia” describes adaptive or healthy responses by African-Americans living in a society they perceive as racially prejudiced.⁸ Several researchers have studied this concept of protecting self-esteem by blaming an external source for negative events. Women who plausibly attribute unflattering feedback to prejudice exhibit higher self-esteem.⁹ A person who believes he or she is a target of discrimination identifies more strongly with his or her racial or ethnic group, leading to reduced depression, higher self-esteem, and improved psychological adjustment.⁹

Perceived discrimination, however, can also elicit feelings of hopelessness and resignation when it leads to widespread bias against the alleged oppressing racial or ethnic group. The resulting sense of social exclusion has been linked to lower self-esteem and higher rates of anxiety and depression.⁹ Thus, the individual’s environment and ability to develop relationships will determine whether “cultural paranoia” is “adaptive.”

Paranoia or prejudice? Distinguishing culturally sanctioned “paranoia” from “prejudice” can be difficult. “Prejudice” is defined as the negative evaluation of a group or individual based on group membership.¹⁰ “Paranoia” (using the DSM-IV definition of “paranoid ideation”) is a belief of less than delusional intensity “involving suspiciousness or the belief that one is being harassed, persecuted, or unfairly treated.”²

So while an individual may be prejudiced toward a group, cultural paranoia would exist only if other family members or acquaintances believe the other group is conspiring against them. Additionally, while prejudice tends to be ego-syntonic,¹¹ paranoia is more distressing because it produces heightened vigilance and possibly fear.

Both cases describe how a lack of cultural understanding between African-American patients and physicians of other ethnicities or races can lead to misdiagnosis of psychosis.¹² They also illustrate that while prejudice may be tightly focused (eg, hatred of anyone from a specific racial or ethnic group), paranoid ideation can be generalized. For example, Mr. A believed that his wife, an African-American, conspired with his white supervisors against him.

Mr. A’s and Mr. B’s depressive and anxiety symptoms unmasked longstanding, deeply rooted beliefs. Both patients’ neurovegetative symptoms responded to medication and brief psychotherapy, and both returned to prior levels of functioning. The underlying mistrust remained, however.

Related resources

• Lu FG. Annotated bibliography on cultural psychiatry and related topics-June 2003. Available at: http://www.admsep.org/culture.html. Accessed July 18, 2003.
• Forsell Y, Henderson S. Epidemiology of paranoid disorders in an elderly population. Br J Psychiatry 1998; 172:429-32.

Drug brand names

• Fluoxetine • Prozac
• Olanzapine • Zyprexa
• Nortriptyline • Aventyl, Pamelor
• Paroxetine • Paxil
• Venlafaxine • Effexor

Disclosure

Dr. Benzick reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Culture-related anxiety and paranoia can be difficult to treat because they are reinforced by socially normative practices and beliefs.¹ As in the two cases described below, psychiatric patients with deep underlying mistrust may view a therapist from another culture—even though well-meaning—as a racist oppressor.

The clinician’s approach to therapy can help prevent cultural misunderstandings and—most important—misdiagnosis (Box).

MR. A’S CASE: ‘She’s out to get me’

Mr. A, age 38 and African-American, was admitted to the inpatient psychiatry service with neurovegetative depressive symptoms and apparent delusional thinking.

His wife of 20 years, also African-American, was concerned that he was becoming increasingly irrational. She said he accused her of conspiring with his predominantly white supervisors to “bring about my destruction.”

Mr. A consented to admission, acknowledging to the psychiatrist that he had felt depressed and at times considered suicide. He complained that he had recently experienced several unusual “happenings:”

• Pointing to recent weight loss, Mr. A feared someone was poisoning his food or that he had swallowed a “tracking” device.
• Mr. A feared that workers who were repairing flood damage in his home were sent to kill him. He remained home during the project, but the fear drove him to a panic attack.
• After more than 18 years working for the same employer with no notable interpersonal difficulties, Mr. A suddenly could not get along with his coworkers. He accused one colleague of following him to a restaurant.

Mr. A had no previous psychiatric disorder, but some distant relatives had schizophrenia. He was diagnosed as having major depressive disorder, severe with psychotic features; delusional disorder was ruled out. He was prescribed olanzapine, 10 mg at bedtime, and fluoxetine, 20 mg/d.

In the hospital, Mr. A spoke normally with no agitation, increased activity, or evidence of racing thoughts. In group therapy, he explained that he felt “confused.” He also disclosed that a recent extramarital affair left him feeling extremely guilty.

Box

A few days later, Mr. A’s suicidal and paranoid ideations disappeared. He expressed anger only while discussing his diagnosis with the attending psychiatrist, who is white. The patient feared that being diagnosed with a psychotic illness would hurt his career. He admitted he felt depressed, but insisted that he now realized his paranoid thoughts were irrational.

Mr. A was discharged after 6 days. He remained on fluoxetine, 20 mg/d; olanzapine was discontinued due to excessive sedation.

The patient also entered insight-oriented psychotherapy to address his depression. Mr. A and the therapist, who is white, spent most of the initial sessions discussing their racial differences. At one point, Mr. A complained to the therapist that white physicians were trying to “railroad” him because of his race.

After nine sessions, Mr. A revealed that he felt isolated at an early age, thinking that others “will use what they know about me against me.” He described growing up in a predominantly black community where most of his neighbors felt oppressed by white people. As therapy progressed, Mr. A realized that this experience influenced his attitudes about race, and that his extramarital affair destroyed his sense of self-trust, which may have fueled his mistrust of others.

After 20 sessions, his marriage and work relationships were stable and his overall mood was much improved. His Outcome Questionnaire 45.2 score decreased across 12 months from 88 (moderate to severe distress) to 55 (level of distress similar to that of non-patients). Delusional behavior has not re-emerged, although his comments continue to reflect mistrust of his supervisors and of white people in general.

What would your diagnosis be? What clues would you gather from Mr. A’s pretreatment behavior and from his progress in therapy?

Dr. Benzick’s observations

Mr. A’s diagnosis upon admission reflected the psychiatrist’s belief that he suffered fixed delusions. By definition, however, a delusion is a false belief that is not “ordinarily accepted by other members of the person’s culture or subculture.”²

 

Growing up, Mr. A shared his neighbors’ suspicion of white people. Further, his overvalued conspiracy theory involving his wife might have projected his own guilt over his infidelity onto a pre-existing paranoid personality.

Based on his psychosocial history, rapid progress in psychotherapy, and marked improvement in Outcome Questionnaire 45.2 scores, Mr. A does not have a personality disorder. What’s more, paranoid ideation is not uncommon in African-Americans with depressive symptoms, as demonstrated by Bazargan et al. ³

Mr. A’s diagnosis was changed to major depressive disorder, moderate, in partial remission. He is still seen approximately every 6 weeks for medication maintenance; he continues taking fluoxetine, 20 mg/d.

MR. B’S CASE: ‘Singled’ out

Mr. B, age 42 and African-American, was referred from an alcohol rehabilitation program to the psychiatry unit after exhibiting depressive and paranoid symptoms.

After 17 years with his employer, he started clashing with his supervisors and coworkers—most of whom are white. He claimed his colleagues were talking behind his back, jealous that he is single and spends his evenings at nightclubs. He alleged that his bosses were singling him out after he was transferred to another department and reprimanded for arriving late to work. Resultant worry about job security brought on panic symptoms (shortness of breath, lightheadedness, dissociative feelings, and palpitations).

Upon further questioning, Mr. B said he felt depressed and isolated. He had been prescribed nortriptyline 2 years ago but discontinued it after a few weeks because of side effects.

Mr. B said that not having a steady companion contributed to his depression and alcohol use. He had been drinking heavily for about 3 years, consuming at least a six-pack daily. He acknowledged that his suspicion of his white coworkers long preceded his alcoholism. Still, he did not see this mistrust as a problem.

Mr. B was diagnosed with major depressive disorder, severe with psychotic features. Treatment consisted of:

• paroxetine, 20 mg/d
• attendance at Alcoholics Anonymous meetings (at least three meetings per week were recommended)
• and 12 sessions of interpersonal psychotherapy. During these sessions, the therapist began to uncover the roots of Mr. B’s symptoms.

School days. Mr. B described how, as a little boy, he once watched his mother being beaten by his drunken father. He told the therapist that the beatings occurred frequently.

When he was age 5, Mr. B’s parents divorced and he and his mother moved to a mostly white Midwest neighborhood so that he could attend a high school with an advanced music program (he was honored for exceptional talent on several instruments).

In his youth, Mr. B’s mother repeatedly told him that teachers and students would treat him “differently” because of his color, though she never explained what she meant. While in high school, he began to worry about his social functioning, appearance, work performance, and future accomplishments.

After four psychotherapy sessions, Mr. B revealed that while in grade school, he was sexually assaulted by an older white boy. For more than 30 years, he had told no one. He denied hyperautonomic and re-experiencing symptoms but realized that this incident may have kept him from starting a romantic relationship.

After psychotherapy, Mr. B reported reduced depression and increased social interaction. His Beck Depression Inventory score dropped from 23 (moderate depression) to 4 (normal mood), and his Beck Anxiety Inventory score improved from 33 (moderate anxiety) to 3 (very low anxiety). He has been sober for 6 months and handles stress more effectively, although his mistrust toward coworkers is still apparent.

How would you diagnose Mr. B? Do his symptoms characterize “psychotic features” or an anxiety or alcohol-related disorder?

Dr. Benzick’s observations

Mr. B’s case illustrates how deep-seated cultural perceptions and past trauma together can cause severe anxiety—and how that anxiety can be misperceived as psychosis.⁴ Anxiety also can manifest as paranoia in “psychotically vulnerable” individuals.^5-7

Chronic anxiety seemed to cause Mr. B’s depressed mood and social withdrawal. Several anxiety disorder diagnoses were considered, including:

• panic disorder
• posttraumatic stress disorder
• social phobia
• alcohol-induced anxiety disorder
• and generalized anxiety disorder.

Mr. B, however, exhibited no evidence of repeated episodic anxiety, nor did he describe reexperiencing phenomena. His anxiety extended beyond social situations and preceded his heavy alcohol consumption. Paranoid personality disorder was also considered, but Mr. B sought relationships and lacked the angry, unforgiving qualities associated with this pathology. Finally, a battery of psychological tests did not reveal frank psychosis but suggested an avoidant personality style.

Mr. B’s diagnosis was changed to generalized anxiety disorder. He requested a trial off medications during the latter stages of therapy, but his severe anxiety returned. He was then prescribed venlafaxine, 37.5 mg/d titrated to 225 mg/d across 3 weeks. His anxiety symptoms again abated.

 

How could Mr A’s and Mr. B’s doctors have avoided their initial misdiagnoses?

Dr. Benzick’s observations

“Cultural paranoia” describes adaptive or healthy responses by African-Americans living in a society they perceive as racially prejudiced.⁸ Several researchers have studied this concept of protecting self-esteem by blaming an external source for negative events. Women who plausibly attribute unflattering feedback to prejudice exhibit higher self-esteem.⁹ A person who believes he or she is a target of discrimination identifies more strongly with his or her racial or ethnic group, leading to reduced depression, higher self-esteem, and improved psychological adjustment.⁹

Perceived discrimination, however, can also elicit feelings of hopelessness and resignation when it leads to widespread bias against the alleged oppressing racial or ethnic group. The resulting sense of social exclusion has been linked to lower self-esteem and higher rates of anxiety and depression.⁹ Thus, the individual’s environment and ability to develop relationships will determine whether “cultural paranoia” is “adaptive.”

Paranoia or prejudice? Distinguishing culturally sanctioned “paranoia” from “prejudice” can be difficult. “Prejudice” is defined as the negative evaluation of a group or individual based on group membership.¹⁰ “Paranoia” (using the DSM-IV definition of “paranoid ideation”) is a belief of less than delusional intensity “involving suspiciousness or the belief that one is being harassed, persecuted, or unfairly treated.”²

So while an individual may be prejudiced toward a group, cultural paranoia would exist only if other family members or acquaintances believe the other group is conspiring against them. Additionally, while prejudice tends to be ego-syntonic,¹¹ paranoia is more distressing because it produces heightened vigilance and possibly fear.

Both cases describe how a lack of cultural understanding between African-American patients and physicians of other ethnicities or races can lead to misdiagnosis of psychosis.¹² They also illustrate that while prejudice may be tightly focused (eg, hatred of anyone from a specific racial or ethnic group), paranoid ideation can be generalized. For example, Mr. A believed that his wife, an African-American, conspired with his white supervisors against him.

Mr. A’s and Mr. B’s depressive and anxiety symptoms unmasked longstanding, deeply rooted beliefs. Both patients’ neurovegetative symptoms responded to medication and brief psychotherapy, and both returned to prior levels of functioning. The underlying mistrust remained, however.

Related resources

• Lu FG. Annotated bibliography on cultural psychiatry and related topics-June 2003. Available at: http://www.admsep.org/culture.html. Accessed July 18, 2003.
• Forsell Y, Henderson S. Epidemiology of paranoid disorders in an elderly population. Br J Psychiatry 1998; 172:429-32.

Drug brand names

• Fluoxetine • Prozac
• Olanzapine • Zyprexa
• Nortriptyline • Aventyl, Pamelor
• Paroxetine • Paxil
• Venlafaxine • Effexor

Disclosure

Dr. Benzick reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

Culture-related anxiety and paranoia can be difficult to treat because they are reinforced by socially normative practices and beliefs.¹ As in the two cases described below, psychiatric patients with deep underlying mistrust may view a therapist from another culture—even though well-meaning—as a racist oppressor.

The clinician’s approach to therapy can help prevent cultural misunderstandings and—most important—misdiagnosis (Box).

MR. A’S CASE: ‘She’s out to get me’

Mr. A, age 38 and African-American, was admitted to the inpatient psychiatry service with neurovegetative depressive symptoms and apparent delusional thinking.

His wife of 20 years, also African-American, was concerned that he was becoming increasingly irrational. She said he accused her of conspiring with his predominantly white supervisors to “bring about my destruction.”

Mr. A consented to admission, acknowledging to the psychiatrist that he had felt depressed and at times considered suicide. He complained that he had recently experienced several unusual “happenings:”

• Pointing to recent weight loss, Mr. A feared someone was poisoning his food or that he had swallowed a “tracking” device.
• Mr. A feared that workers who were repairing flood damage in his home were sent to kill him. He remained home during the project, but the fear drove him to a panic attack.
• After more than 18 years working for the same employer with no notable interpersonal difficulties, Mr. A suddenly could not get along with his coworkers. He accused one colleague of following him to a restaurant.

Mr. A had no previous psychiatric disorder, but some distant relatives had schizophrenia. He was diagnosed as having major depressive disorder, severe with psychotic features; delusional disorder was ruled out. He was prescribed olanzapine, 10 mg at bedtime, and fluoxetine, 20 mg/d.

In the hospital, Mr. A spoke normally with no agitation, increased activity, or evidence of racing thoughts. In group therapy, he explained that he felt “confused.” He also disclosed that a recent extramarital affair left him feeling extremely guilty.

Box

A few days later, Mr. A’s suicidal and paranoid ideations disappeared. He expressed anger only while discussing his diagnosis with the attending psychiatrist, who is white. The patient feared that being diagnosed with a psychotic illness would hurt his career. He admitted he felt depressed, but insisted that he now realized his paranoid thoughts were irrational.

Mr. A was discharged after 6 days. He remained on fluoxetine, 20 mg/d; olanzapine was discontinued due to excessive sedation.

The patient also entered insight-oriented psychotherapy to address his depression. Mr. A and the therapist, who is white, spent most of the initial sessions discussing their racial differences. At one point, Mr. A complained to the therapist that white physicians were trying to “railroad” him because of his race.

After nine sessions, Mr. A revealed that he felt isolated at an early age, thinking that others “will use what they know about me against me.” He described growing up in a predominantly black community where most of his neighbors felt oppressed by white people. As therapy progressed, Mr. A realized that this experience influenced his attitudes about race, and that his extramarital affair destroyed his sense of self-trust, which may have fueled his mistrust of others.

After 20 sessions, his marriage and work relationships were stable and his overall mood was much improved. His Outcome Questionnaire 45.2 score decreased across 12 months from 88 (moderate to severe distress) to 55 (level of distress similar to that of non-patients). Delusional behavior has not re-emerged, although his comments continue to reflect mistrust of his supervisors and of white people in general.

What would your diagnosis be? What clues would you gather from Mr. A’s pretreatment behavior and from his progress in therapy?

Dr. Benzick’s observations

Mr. A’s diagnosis upon admission reflected the psychiatrist’s belief that he suffered fixed delusions. By definition, however, a delusion is a false belief that is not “ordinarily accepted by other members of the person’s culture or subculture.”²

 

Growing up, Mr. A shared his neighbors’ suspicion of white people. Further, his overvalued conspiracy theory involving his wife might have projected his own guilt over his infidelity onto a pre-existing paranoid personality.

Based on his psychosocial history, rapid progress in psychotherapy, and marked improvement in Outcome Questionnaire 45.2 scores, Mr. A does not have a personality disorder. What’s more, paranoid ideation is not uncommon in African-Americans with depressive symptoms, as demonstrated by Bazargan et al. ³

Mr. A’s diagnosis was changed to major depressive disorder, moderate, in partial remission. He is still seen approximately every 6 weeks for medication maintenance; he continues taking fluoxetine, 20 mg/d.

MR. B’S CASE: ‘Singled’ out

Mr. B, age 42 and African-American, was referred from an alcohol rehabilitation program to the psychiatry unit after exhibiting depressive and paranoid symptoms.

After 17 years with his employer, he started clashing with his supervisors and coworkers—most of whom are white. He claimed his colleagues were talking behind his back, jealous that he is single and spends his evenings at nightclubs. He alleged that his bosses were singling him out after he was transferred to another department and reprimanded for arriving late to work. Resultant worry about job security brought on panic symptoms (shortness of breath, lightheadedness, dissociative feelings, and palpitations).

Upon further questioning, Mr. B said he felt depressed and isolated. He had been prescribed nortriptyline 2 years ago but discontinued it after a few weeks because of side effects.

Mr. B said that not having a steady companion contributed to his depression and alcohol use. He had been drinking heavily for about 3 years, consuming at least a six-pack daily. He acknowledged that his suspicion of his white coworkers long preceded his alcoholism. Still, he did not see this mistrust as a problem.

Mr. B was diagnosed with major depressive disorder, severe with psychotic features. Treatment consisted of:

• paroxetine, 20 mg/d
• attendance at Alcoholics Anonymous meetings (at least three meetings per week were recommended)
• and 12 sessions of interpersonal psychotherapy. During these sessions, the therapist began to uncover the roots of Mr. B’s symptoms.

School days. Mr. B described how, as a little boy, he once watched his mother being beaten by his drunken father. He told the therapist that the beatings occurred frequently.

When he was age 5, Mr. B’s parents divorced and he and his mother moved to a mostly white Midwest neighborhood so that he could attend a high school with an advanced music program (he was honored for exceptional talent on several instruments).

In his youth, Mr. B’s mother repeatedly told him that teachers and students would treat him “differently” because of his color, though she never explained what she meant. While in high school, he began to worry about his social functioning, appearance, work performance, and future accomplishments.

After four psychotherapy sessions, Mr. B revealed that while in grade school, he was sexually assaulted by an older white boy. For more than 30 years, he had told no one. He denied hyperautonomic and re-experiencing symptoms but realized that this incident may have kept him from starting a romantic relationship.

After psychotherapy, Mr. B reported reduced depression and increased social interaction. His Beck Depression Inventory score dropped from 23 (moderate depression) to 4 (normal mood), and his Beck Anxiety Inventory score improved from 33 (moderate anxiety) to 3 (very low anxiety). He has been sober for 6 months and handles stress more effectively, although his mistrust toward coworkers is still apparent.

How would you diagnose Mr. B? Do his symptoms characterize “psychotic features” or an anxiety or alcohol-related disorder?

Dr. Benzick’s observations

Mr. B’s case illustrates how deep-seated cultural perceptions and past trauma together can cause severe anxiety—and how that anxiety can be misperceived as psychosis.⁴ Anxiety also can manifest as paranoia in “psychotically vulnerable” individuals.^5-7

Chronic anxiety seemed to cause Mr. B’s depressed mood and social withdrawal. Several anxiety disorder diagnoses were considered, including:

• panic disorder
• posttraumatic stress disorder
• social phobia
• alcohol-induced anxiety disorder
• and generalized anxiety disorder.

Mr. B, however, exhibited no evidence of repeated episodic anxiety, nor did he describe reexperiencing phenomena. His anxiety extended beyond social situations and preceded his heavy alcohol consumption. Paranoid personality disorder was also considered, but Mr. B sought relationships and lacked the angry, unforgiving qualities associated with this pathology. Finally, a battery of psychological tests did not reveal frank psychosis but suggested an avoidant personality style.

Mr. B’s diagnosis was changed to generalized anxiety disorder. He requested a trial off medications during the latter stages of therapy, but his severe anxiety returned. He was then prescribed venlafaxine, 37.5 mg/d titrated to 225 mg/d across 3 weeks. His anxiety symptoms again abated.

 

How could Mr A’s and Mr. B’s doctors have avoided their initial misdiagnoses?

Dr. Benzick’s observations

“Cultural paranoia” describes adaptive or healthy responses by African-Americans living in a society they perceive as racially prejudiced.⁸ Several researchers have studied this concept of protecting self-esteem by blaming an external source for negative events. Women who plausibly attribute unflattering feedback to prejudice exhibit higher self-esteem.⁹ A person who believes he or she is a target of discrimination identifies more strongly with his or her racial or ethnic group, leading to reduced depression, higher self-esteem, and improved psychological adjustment.⁹

Perceived discrimination, however, can also elicit feelings of hopelessness and resignation when it leads to widespread bias against the alleged oppressing racial or ethnic group. The resulting sense of social exclusion has been linked to lower self-esteem and higher rates of anxiety and depression.⁹ Thus, the individual’s environment and ability to develop relationships will determine whether “cultural paranoia” is “adaptive.”

Paranoia or prejudice? Distinguishing culturally sanctioned “paranoia” from “prejudice” can be difficult. “Prejudice” is defined as the negative evaluation of a group or individual based on group membership.¹⁰ “Paranoia” (using the DSM-IV definition of “paranoid ideation”) is a belief of less than delusional intensity “involving suspiciousness or the belief that one is being harassed, persecuted, or unfairly treated.”²

So while an individual may be prejudiced toward a group, cultural paranoia would exist only if other family members or acquaintances believe the other group is conspiring against them. Additionally, while prejudice tends to be ego-syntonic,¹¹ paranoia is more distressing because it produces heightened vigilance and possibly fear.

Both cases describe how a lack of cultural understanding between African-American patients and physicians of other ethnicities or races can lead to misdiagnosis of psychosis.¹² They also illustrate that while prejudice may be tightly focused (eg, hatred of anyone from a specific racial or ethnic group), paranoid ideation can be generalized. For example, Mr. A believed that his wife, an African-American, conspired with his white supervisors against him.

Mr. A’s and Mr. B’s depressive and anxiety symptoms unmasked longstanding, deeply rooted beliefs. Both patients’ neurovegetative symptoms responded to medication and brief psychotherapy, and both returned to prior levels of functioning. The underlying mistrust remained, however.

Related resources

• Lu FG. Annotated bibliography on cultural psychiatry and related topics-June 2003. Available at: http://www.admsep.org/culture.html. Accessed July 18, 2003.
• Forsell Y, Henderson S. Epidemiology of paranoid disorders in an elderly population. Br J Psychiatry 1998; 172:429-32.

Drug brand names

• Fluoxetine • Prozac
• Olanzapine • Zyprexa
• Nortriptyline • Aventyl, Pamelor
• Paroxetine • Paxil
• Venlafaxine • Effexor

Disclosure

Dr. Benzick reports no financial relationship with any company whose products are mentioned in this article, or with manufacturers of competing products.

HISTORY: Six years of psychosis

Ms. G, age 37, has had paranoid schizophrenia f or 6 years, resulting in numerous hospitalizations and continuous outpatient follow-up. Her family is supportive and supervises her when she’s not hospitalized.

Though fluent in English, Ms. G—a Polish immigrant—speaks primarily in her native tongue during psychotic episodes and becomes increasingly paranoid toward neighbors. As her condition degenerates, she hears her late father’s voice criticizing her. Because of marked social withdrawal and isolation, she cannot maintain basic interpersonal skills or live independently. Her psychosis, apathy, avolition, withdrawal, and lack of focus have persisted despite trials of numerous antipsychotics, including olanzapine, 25 mg nightly for 1 month, and quetiapine, 300 mg bid for 3 weeks.

What are the drug therapy options for this patient?

The authors’ observations

“Treatment-refractory” schizophrenia has numerous definitions. One that is widely accepted but cumbersome—used in the multicenter clozapine trial¹ —requires a 5-year absence of periods of good functioning in patients taking an antipsychotic at dosages equivalent to chlorpromazine, 1,000 mg/d. In that time, the patient must have received two or more antipsychotic classes for at least 6 weeks each without achieving significant relief. The Brief Psychiatric Rating Scale (BPRS) score must be at least 45, with item scores of moderate severity for two or more of the following:

• disorganization
• suspiciousness
• hallucinatory behavior
• unusual thought content.

The Clinical Global Impression (CGI) Scale score must be at least 4 (moderately ill). Also, a 6-week trial of haloperidol, with a mean dosage of 60 mg/d:

• must fail to decrease the BPRS score by 20% or to below 35
• or must fail to decrease the CGI severity score to 3 (mildly ill).¹

In 1990, an international study group defined treatment-refractory schizophrenia as “the presence of ongoing psychotic symptoms with substantial functional disability and/or behavioral deviances that persist in well-diagnosed persons with schizophrenia despite reasonable and customary pharmacological and psychosocial treatment that has been provided for an adequate period.”² This definition is far more useful to clinical practice and also considers psychosocial function. Seven levels of treatment response and resistance were suggested, based on presence of positive and negative symptoms, personal and social functioning, and CGI scores.²

Meltzer³ proposed that any person not returning to his or her highest premorbid level of functioning with a tolerable antipsychotic be considered refractory and thus a possible candidate for clozapine therapy.

Ms. G’s illness meets the definition of treatment-refractory schizophrenia. Her CGI score at baseline was 5—severely ill—and several medication trials at sufficient dosages failed to control her positive or negative symptoms. Upon psychotic decompensation, she required prolonged hospitalization and could no longer live independently or work. At this point, she is a possible candidate for clozapine therapy.

TREATMENT: Starting clozapine

Ms. G was started on clozapine, 25 mg at night, titrated to 300 mg at bedtime.

Two weeks later, her paranoia and auditory hallucinations diminished, her interpersonal relationships improved, she was less withdrawn, her thoughts became more organized, and her range of affect expanded. She functioned at her highest level since her initial presentation based on clinical observation and family reports. Her CGI Global Improvement score at this point was 2 (much improved).

Ms. G. continued to take clozapine, 300 mg/d, for 2 years while undergoing weekly blood tests for white blood cell counts (WBC) with differentials. She did not require hospitalization for schizophrenia during this time, and her WBC count averaged between 4,000 and 4,500/mm³, well within the normal range of 3,500 to 12,000/mm³.

Then one day—after maintaining a relatively stable WBC for several weeks—a blood test revealed a WBC of 2,700/mm³. Ms. G exhibited no objective signs of immunosuppression, such as fever or infection. Still, the psychiatrist immediately discontinued clozapine.

Was the treating psychiatrist justified in immediately stopping clozapine after one low WBC reading?

The authors’ observations

Leukopenia, defined as a WBC <3,000/mm³, and agranulocytosis, defined as an absolute neutrophil count <500/mm³, are well-documented adverse reactions to clozapine. Early data on clozapine-associated agranulocytosis cases prior to 1989 suggest that up to 32% were fatal,⁴ but relatively few cases have occurred since the Clozaril National Registry was instituted in 1977.^4,5 Between 1977 and 1997, 585 clozapine-associated agranulocytosis cases were reported in the United States; 19 of these were fatal, suggesting a mortality rate of 3.2% and attesting to the effectiveness of FDA-mandated WBC testing. During this period, 150,409 patients received clozapine.⁴

The agranulocytosis risk does not appear to be dose-related but declines substantially after the 10th week. Three out of 1,000 patients who take clozapine for 1 year are likely to develop agranulocytosis at the 3- to 6-month mark.⁴ Although the incidence continues to drop after month 6, it never reaches zero.^4-6

 

Table

Life-threatening effects of clozapine and their reported frequency of occurrence

Adverse effect	Incidence rate among clozapine users
Agranulocytosis	3/1000 person years* at 6 months
Hepatitis	Less than 1%
Hyperglycemia with ketoacidosis	Unknown, case reports
Myocarditis	5.0-96.6 cases/100,000 patient years
Neuroleptic malignant syndrome	Unknown, several case reports
Orthostasis with cardiac collapse	1/3,000 cases
Pulmonary embolism	1/3,450 person years
Seizures	5% after 1 year of therapy
* Person year = 1 person taking medication for 1 year
Source: Clozaril prescribing information. In: Physicians’ Desk Reference (57th ed). Montvale, NJ: Thomson Healthcare, 2003.

Other severe adverse effects of clozapine include myocarditis associated with cardiac failure, orthostatic hypotension with circulatory collapse, and rhabdomyolysis (Table).^4,7 Leukocytosis and eosinophilia are generally transient and self-limited but may predict agranulocytosis.^8,9 The risk of seizure occurs most commonly at dosages greater than 500 mg/d.⁴

Given these potentially fatal effects, the authors’ treatment guidelines call for potential suspension of clozapine therapy when the WBC is consistently <3,000 mm³ (Algorithm).

CONTINUED TREATMENT: A difficult decision

Ms. G was switched to quetiapine, 100 mg nightly, titrated to 800 mg/d in divided doses.

Approximately 3 weeks later, Ms. G was hospitalized for renewed severe paranoia and command-type auditory hallucinations accompanied by prominent mood lability, avolition, and thought disorganization. During her 7-week hospitalization, she underwent sequential and sometimes overlapping trials of:

• ziprasidone, 160 mg bid
• risperidone, 3 mg bid
• trifluoperazine, 3 mg bid
• haloperidol, 10 mg bid
• divalproex sodium, 500 mg bid
• and carbamazepine, 400 mg bid.

None of these trials significantly improved her psychosis or mood.

At this point, the treating psychiatrists faced a difficult but clear decision: Ms. G was rechallenged on clozapine, 25 mg nightly, titrated again to 300 mg nightly. After she provided informed consent, her WBC was monitored twice daily—morning and evening—for agranulocytosis and to examine WBC patterns. Her average daily WBC counts were 4,200/mm³ in the morning and 5,500/mm³ at night. No physical signs of agranulocytosis emerged.

One week after restarting clozapine, Ms. G became less paranoid and socially more appropriate. Her thought process became increasingly organized, and after 4 weeks she reached her baseline status based upon family reports and the clinician’s CGI Global Improvement rating of 2 (much improved). Her auditory hallucinations resolved, and she was discharged to her family’s care.

Twice-daily blood testing was stopped at discharge. Ms. G continues to take clozapine and receives blood tests every 2 weeks, with no apparent signs of agranulocytosis.

Algorithm Suggested guidelines for managing WBC counts during clozapine therapy

Box

How could Ms. G’s doctors have avoided stopping her clozapine therapy and her subsequent decompensation?

The authors’ observations

Aggressive blood testing and cessation of clozapine therapy are indicated when onset of granulocytopenia and agranulocytosis are suspected. Even with early detection and discontinuation, the chance of infectious disease poses a danger for up to 4 weeks until WBC levels return to normal.⁴

Given Ms. G’s lack of response to other antipsychotics, however, we had to consider resuming clozapine therapy. Studies have described agranulocytosis management strategies that may allow patients to keep taking clozapine despite low WBC counts (Box).

We also considered the timing of Ms. G’s blood test that showed a WBC count <2,700/mm³. Ahokas¹⁶ suggests that evening WBC counts are significantly higher than those taken in the morning and that granulocytes fluctuate in a diurnal pattern. Ms. G’s evening WBC counts were on average 1,300/mm³ higher than morning levels. Allowing for this diurnal variation and comparing evening blood samples could have averted the interruption in Ms. G’s clozapine therapy and prevented relapse in a patient with highly treatment-refractory schizophrenia.

Related resources

• Chong SA, Remington G. Clozapine augmentation: safety and efficacy. Schizophr Bull 2000;26:421-40.
• Emsley R, Oosthuizen P. The new and evolving pharmacotherapy of schizophrenia. Psychiatr Clin North Am 2003;26:141-63.
• Barnas C, Zwierzina H, Hummer M, Sperner-Unterweger B, Stern A, Fleischhacker WW. Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment of clozapine-induced agranulocytosis: a case report. J Clin Psychiatry 1992;53:245-7.

Drug brand names

 

• Carbamazepine • Tegretol
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Divalproex sodium • Depakote
• GM-CSF—Filgrastim • Neupogen
• Haloperidol • Haldol
• Lithium • Eskalith, Lithobid, others
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Trifluoperazine • Stelazine
• Ziprasidone • Geodon

Disclosure

Dr. Rao is a speaker for Pfizer Inc.

Drs. Goforth, Raval, and Sharma report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

HISTORY: Six years of psychosis

Ms. G, age 37, has had paranoid schizophrenia f or 6 years, resulting in numerous hospitalizations and continuous outpatient follow-up. Her family is supportive and supervises her when she’s not hospitalized.

Though fluent in English, Ms. G—a Polish immigrant—speaks primarily in her native tongue during psychotic episodes and becomes increasingly paranoid toward neighbors. As her condition degenerates, she hears her late father’s voice criticizing her. Because of marked social withdrawal and isolation, she cannot maintain basic interpersonal skills or live independently. Her psychosis, apathy, avolition, withdrawal, and lack of focus have persisted despite trials of numerous antipsychotics, including olanzapine, 25 mg nightly for 1 month, and quetiapine, 300 mg bid for 3 weeks.

What are the drug therapy options for this patient?

The authors’ observations

“Treatment-refractory” schizophrenia has numerous definitions. One that is widely accepted but cumbersome—used in the multicenter clozapine trial¹ —requires a 5-year absence of periods of good functioning in patients taking an antipsychotic at dosages equivalent to chlorpromazine, 1,000 mg/d. In that time, the patient must have received two or more antipsychotic classes for at least 6 weeks each without achieving significant relief. The Brief Psychiatric Rating Scale (BPRS) score must be at least 45, with item scores of moderate severity for two or more of the following:

• disorganization
• suspiciousness
• hallucinatory behavior
• unusual thought content.

The Clinical Global Impression (CGI) Scale score must be at least 4 (moderately ill). Also, a 6-week trial of haloperidol, with a mean dosage of 60 mg/d:

• must fail to decrease the BPRS score by 20% or to below 35
• or must fail to decrease the CGI severity score to 3 (mildly ill).¹

In 1990, an international study group defined treatment-refractory schizophrenia as “the presence of ongoing psychotic symptoms with substantial functional disability and/or behavioral deviances that persist in well-diagnosed persons with schizophrenia despite reasonable and customary pharmacological and psychosocial treatment that has been provided for an adequate period.”² This definition is far more useful to clinical practice and also considers psychosocial function. Seven levels of treatment response and resistance were suggested, based on presence of positive and negative symptoms, personal and social functioning, and CGI scores.²

Meltzer³ proposed that any person not returning to his or her highest premorbid level of functioning with a tolerable antipsychotic be considered refractory and thus a possible candidate for clozapine therapy.

Ms. G’s illness meets the definition of treatment-refractory schizophrenia. Her CGI score at baseline was 5—severely ill—and several medication trials at sufficient dosages failed to control her positive or negative symptoms. Upon psychotic decompensation, she required prolonged hospitalization and could no longer live independently or work. At this point, she is a possible candidate for clozapine therapy.

TREATMENT: Starting clozapine

Ms. G was started on clozapine, 25 mg at night, titrated to 300 mg at bedtime.

Two weeks later, her paranoia and auditory hallucinations diminished, her interpersonal relationships improved, she was less withdrawn, her thoughts became more organized, and her range of affect expanded. She functioned at her highest level since her initial presentation based on clinical observation and family reports. Her CGI Global Improvement score at this point was 2 (much improved).

Ms. G. continued to take clozapine, 300 mg/d, for 2 years while undergoing weekly blood tests for white blood cell counts (WBC) with differentials. She did not require hospitalization for schizophrenia during this time, and her WBC count averaged between 4,000 and 4,500/mm³, well within the normal range of 3,500 to 12,000/mm³.

Then one day—after maintaining a relatively stable WBC for several weeks—a blood test revealed a WBC of 2,700/mm³. Ms. G exhibited no objective signs of immunosuppression, such as fever or infection. Still, the psychiatrist immediately discontinued clozapine.

Was the treating psychiatrist justified in immediately stopping clozapine after one low WBC reading?

The authors’ observations

Leukopenia, defined as a WBC <3,000/mm³, and agranulocytosis, defined as an absolute neutrophil count <500/mm³, are well-documented adverse reactions to clozapine. Early data on clozapine-associated agranulocytosis cases prior to 1989 suggest that up to 32% were fatal,⁴ but relatively few cases have occurred since the Clozaril National Registry was instituted in 1977.^4,5 Between 1977 and 1997, 585 clozapine-associated agranulocytosis cases were reported in the United States; 19 of these were fatal, suggesting a mortality rate of 3.2% and attesting to the effectiveness of FDA-mandated WBC testing. During this period, 150,409 patients received clozapine.⁴

The agranulocytosis risk does not appear to be dose-related but declines substantially after the 10th week. Three out of 1,000 patients who take clozapine for 1 year are likely to develop agranulocytosis at the 3- to 6-month mark.⁴ Although the incidence continues to drop after month 6, it never reaches zero.^4-6

 

Table

Life-threatening effects of clozapine and their reported frequency of occurrence

Adverse effect	Incidence rate among clozapine users
Agranulocytosis	3/1000 person years* at 6 months
Hepatitis	Less than 1%
Hyperglycemia with ketoacidosis	Unknown, case reports
Myocarditis	5.0-96.6 cases/100,000 patient years
Neuroleptic malignant syndrome	Unknown, several case reports
Orthostasis with cardiac collapse	1/3,000 cases
Pulmonary embolism	1/3,450 person years
Seizures	5% after 1 year of therapy
* Person year = 1 person taking medication for 1 year
Source: Clozaril prescribing information. In: Physicians’ Desk Reference (57th ed). Montvale, NJ: Thomson Healthcare, 2003.

Other severe adverse effects of clozapine include myocarditis associated with cardiac failure, orthostatic hypotension with circulatory collapse, and rhabdomyolysis (Table).^4,7 Leukocytosis and eosinophilia are generally transient and self-limited but may predict agranulocytosis.^8,9 The risk of seizure occurs most commonly at dosages greater than 500 mg/d.⁴

Given these potentially fatal effects, the authors’ treatment guidelines call for potential suspension of clozapine therapy when the WBC is consistently <3,000 mm³ (Algorithm).

CONTINUED TREATMENT: A difficult decision

Ms. G was switched to quetiapine, 100 mg nightly, titrated to 800 mg/d in divided doses.

Approximately 3 weeks later, Ms. G was hospitalized for renewed severe paranoia and command-type auditory hallucinations accompanied by prominent mood lability, avolition, and thought disorganization. During her 7-week hospitalization, she underwent sequential and sometimes overlapping trials of:

• ziprasidone, 160 mg bid
• risperidone, 3 mg bid
• trifluoperazine, 3 mg bid
• haloperidol, 10 mg bid
• divalproex sodium, 500 mg bid
• and carbamazepine, 400 mg bid.

None of these trials significantly improved her psychosis or mood.

At this point, the treating psychiatrists faced a difficult but clear decision: Ms. G was rechallenged on clozapine, 25 mg nightly, titrated again to 300 mg nightly. After she provided informed consent, her WBC was monitored twice daily—morning and evening—for agranulocytosis and to examine WBC patterns. Her average daily WBC counts were 4,200/mm³ in the morning and 5,500/mm³ at night. No physical signs of agranulocytosis emerged.

One week after restarting clozapine, Ms. G became less paranoid and socially more appropriate. Her thought process became increasingly organized, and after 4 weeks she reached her baseline status based upon family reports and the clinician’s CGI Global Improvement rating of 2 (much improved). Her auditory hallucinations resolved, and she was discharged to her family’s care.

Twice-daily blood testing was stopped at discharge. Ms. G continues to take clozapine and receives blood tests every 2 weeks, with no apparent signs of agranulocytosis.

Algorithm Suggested guidelines for managing WBC counts during clozapine therapy

Box

How could Ms. G’s doctors have avoided stopping her clozapine therapy and her subsequent decompensation?

The authors’ observations

Aggressive blood testing and cessation of clozapine therapy are indicated when onset of granulocytopenia and agranulocytosis are suspected. Even with early detection and discontinuation, the chance of infectious disease poses a danger for up to 4 weeks until WBC levels return to normal.⁴

Given Ms. G’s lack of response to other antipsychotics, however, we had to consider resuming clozapine therapy. Studies have described agranulocytosis management strategies that may allow patients to keep taking clozapine despite low WBC counts (Box).

We also considered the timing of Ms. G’s blood test that showed a WBC count <2,700/mm³. Ahokas¹⁶ suggests that evening WBC counts are significantly higher than those taken in the morning and that granulocytes fluctuate in a diurnal pattern. Ms. G’s evening WBC counts were on average 1,300/mm³ higher than morning levels. Allowing for this diurnal variation and comparing evening blood samples could have averted the interruption in Ms. G’s clozapine therapy and prevented relapse in a patient with highly treatment-refractory schizophrenia.

Related resources

• Chong SA, Remington G. Clozapine augmentation: safety and efficacy. Schizophr Bull 2000;26:421-40.
• Emsley R, Oosthuizen P. The new and evolving pharmacotherapy of schizophrenia. Psychiatr Clin North Am 2003;26:141-63.
• Barnas C, Zwierzina H, Hummer M, Sperner-Unterweger B, Stern A, Fleischhacker WW. Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment of clozapine-induced agranulocytosis: a case report. J Clin Psychiatry 1992;53:245-7.

Drug brand names

 

• Carbamazepine • Tegretol
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Divalproex sodium • Depakote
• GM-CSF—Filgrastim • Neupogen
• Haloperidol • Haldol
• Lithium • Eskalith, Lithobid, others
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Trifluoperazine • Stelazine
• Ziprasidone • Geodon

Disclosure

Dr. Rao is a speaker for Pfizer Inc.

Drs. Goforth, Raval, and Sharma report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

HISTORY: Six years of psychosis

Ms. G, age 37, has had paranoid schizophrenia f or 6 years, resulting in numerous hospitalizations and continuous outpatient follow-up. Her family is supportive and supervises her when she’s not hospitalized.

Though fluent in English, Ms. G—a Polish immigrant—speaks primarily in her native tongue during psychotic episodes and becomes increasingly paranoid toward neighbors. As her condition degenerates, she hears her late father’s voice criticizing her. Because of marked social withdrawal and isolation, she cannot maintain basic interpersonal skills or live independently. Her psychosis, apathy, avolition, withdrawal, and lack of focus have persisted despite trials of numerous antipsychotics, including olanzapine, 25 mg nightly for 1 month, and quetiapine, 300 mg bid for 3 weeks.

What are the drug therapy options for this patient?

The authors’ observations

“Treatment-refractory” schizophrenia has numerous definitions. One that is widely accepted but cumbersome—used in the multicenter clozapine trial¹ —requires a 5-year absence of periods of good functioning in patients taking an antipsychotic at dosages equivalent to chlorpromazine, 1,000 mg/d. In that time, the patient must have received two or more antipsychotic classes for at least 6 weeks each without achieving significant relief. The Brief Psychiatric Rating Scale (BPRS) score must be at least 45, with item scores of moderate severity for two or more of the following:

• disorganization
• suspiciousness
• hallucinatory behavior
• unusual thought content.

The Clinical Global Impression (CGI) Scale score must be at least 4 (moderately ill). Also, a 6-week trial of haloperidol, with a mean dosage of 60 mg/d:

• must fail to decrease the BPRS score by 20% or to below 35
• or must fail to decrease the CGI severity score to 3 (mildly ill).¹

In 1990, an international study group defined treatment-refractory schizophrenia as “the presence of ongoing psychotic symptoms with substantial functional disability and/or behavioral deviances that persist in well-diagnosed persons with schizophrenia despite reasonable and customary pharmacological and psychosocial treatment that has been provided for an adequate period.”² This definition is far more useful to clinical practice and also considers psychosocial function. Seven levels of treatment response and resistance were suggested, based on presence of positive and negative symptoms, personal and social functioning, and CGI scores.²

Meltzer³ proposed that any person not returning to his or her highest premorbid level of functioning with a tolerable antipsychotic be considered refractory and thus a possible candidate for clozapine therapy.

Ms. G’s illness meets the definition of treatment-refractory schizophrenia. Her CGI score at baseline was 5—severely ill—and several medication trials at sufficient dosages failed to control her positive or negative symptoms. Upon psychotic decompensation, she required prolonged hospitalization and could no longer live independently or work. At this point, she is a possible candidate for clozapine therapy.

TREATMENT: Starting clozapine

Ms. G was started on clozapine, 25 mg at night, titrated to 300 mg at bedtime.

Two weeks later, her paranoia and auditory hallucinations diminished, her interpersonal relationships improved, she was less withdrawn, her thoughts became more organized, and her range of affect expanded. She functioned at her highest level since her initial presentation based on clinical observation and family reports. Her CGI Global Improvement score at this point was 2 (much improved).

Ms. G. continued to take clozapine, 300 mg/d, for 2 years while undergoing weekly blood tests for white blood cell counts (WBC) with differentials. She did not require hospitalization for schizophrenia during this time, and her WBC count averaged between 4,000 and 4,500/mm³, well within the normal range of 3,500 to 12,000/mm³.

Then one day—after maintaining a relatively stable WBC for several weeks—a blood test revealed a WBC of 2,700/mm³. Ms. G exhibited no objective signs of immunosuppression, such as fever or infection. Still, the psychiatrist immediately discontinued clozapine.

Was the treating psychiatrist justified in immediately stopping clozapine after one low WBC reading?

The authors’ observations

Leukopenia, defined as a WBC <3,000/mm³, and agranulocytosis, defined as an absolute neutrophil count <500/mm³, are well-documented adverse reactions to clozapine. Early data on clozapine-associated agranulocytosis cases prior to 1989 suggest that up to 32% were fatal,⁴ but relatively few cases have occurred since the Clozaril National Registry was instituted in 1977.^4,5 Between 1977 and 1997, 585 clozapine-associated agranulocytosis cases were reported in the United States; 19 of these were fatal, suggesting a mortality rate of 3.2% and attesting to the effectiveness of FDA-mandated WBC testing. During this period, 150,409 patients received clozapine.⁴

The agranulocytosis risk does not appear to be dose-related but declines substantially after the 10th week. Three out of 1,000 patients who take clozapine for 1 year are likely to develop agranulocytosis at the 3- to 6-month mark.⁴ Although the incidence continues to drop after month 6, it never reaches zero.^4-6

 

Table

Life-threatening effects of clozapine and their reported frequency of occurrence

Adverse effect	Incidence rate among clozapine users
Agranulocytosis	3/1000 person years* at 6 months
Hepatitis	Less than 1%
Hyperglycemia with ketoacidosis	Unknown, case reports
Myocarditis	5.0-96.6 cases/100,000 patient years
Neuroleptic malignant syndrome	Unknown, several case reports
Orthostasis with cardiac collapse	1/3,000 cases
Pulmonary embolism	1/3,450 person years
Seizures	5% after 1 year of therapy
* Person year = 1 person taking medication for 1 year
Source: Clozaril prescribing information. In: Physicians’ Desk Reference (57th ed). Montvale, NJ: Thomson Healthcare, 2003.

Other severe adverse effects of clozapine include myocarditis associated with cardiac failure, orthostatic hypotension with circulatory collapse, and rhabdomyolysis (Table).^4,7 Leukocytosis and eosinophilia are generally transient and self-limited but may predict agranulocytosis.^8,9 The risk of seizure occurs most commonly at dosages greater than 500 mg/d.⁴

Given these potentially fatal effects, the authors’ treatment guidelines call for potential suspension of clozapine therapy when the WBC is consistently <3,000 mm³ (Algorithm).

CONTINUED TREATMENT: A difficult decision

Ms. G was switched to quetiapine, 100 mg nightly, titrated to 800 mg/d in divided doses.

Approximately 3 weeks later, Ms. G was hospitalized for renewed severe paranoia and command-type auditory hallucinations accompanied by prominent mood lability, avolition, and thought disorganization. During her 7-week hospitalization, she underwent sequential and sometimes overlapping trials of:

• ziprasidone, 160 mg bid
• risperidone, 3 mg bid
• trifluoperazine, 3 mg bid
• haloperidol, 10 mg bid
• divalproex sodium, 500 mg bid
• and carbamazepine, 400 mg bid.

None of these trials significantly improved her psychosis or mood.

At this point, the treating psychiatrists faced a difficult but clear decision: Ms. G was rechallenged on clozapine, 25 mg nightly, titrated again to 300 mg nightly. After she provided informed consent, her WBC was monitored twice daily—morning and evening—for agranulocytosis and to examine WBC patterns. Her average daily WBC counts were 4,200/mm³ in the morning and 5,500/mm³ at night. No physical signs of agranulocytosis emerged.

One week after restarting clozapine, Ms. G became less paranoid and socially more appropriate. Her thought process became increasingly organized, and after 4 weeks she reached her baseline status based upon family reports and the clinician’s CGI Global Improvement rating of 2 (much improved). Her auditory hallucinations resolved, and she was discharged to her family’s care.

Twice-daily blood testing was stopped at discharge. Ms. G continues to take clozapine and receives blood tests every 2 weeks, with no apparent signs of agranulocytosis.

Algorithm Suggested guidelines for managing WBC counts during clozapine therapy

Box

How could Ms. G’s doctors have avoided stopping her clozapine therapy and her subsequent decompensation?

The authors’ observations

Aggressive blood testing and cessation of clozapine therapy are indicated when onset of granulocytopenia and agranulocytosis are suspected. Even with early detection and discontinuation, the chance of infectious disease poses a danger for up to 4 weeks until WBC levels return to normal.⁴

Given Ms. G’s lack of response to other antipsychotics, however, we had to consider resuming clozapine therapy. Studies have described agranulocytosis management strategies that may allow patients to keep taking clozapine despite low WBC counts (Box).

We also considered the timing of Ms. G’s blood test that showed a WBC count <2,700/mm³. Ahokas¹⁶ suggests that evening WBC counts are significantly higher than those taken in the morning and that granulocytes fluctuate in a diurnal pattern. Ms. G’s evening WBC counts were on average 1,300/mm³ higher than morning levels. Allowing for this diurnal variation and comparing evening blood samples could have averted the interruption in Ms. G’s clozapine therapy and prevented relapse in a patient with highly treatment-refractory schizophrenia.

Related resources

• Chong SA, Remington G. Clozapine augmentation: safety and efficacy. Schizophr Bull 2000;26:421-40.
• Emsley R, Oosthuizen P. The new and evolving pharmacotherapy of schizophrenia. Psychiatr Clin North Am 2003;26:141-63.
• Barnas C, Zwierzina H, Hummer M, Sperner-Unterweger B, Stern A, Fleischhacker WW. Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment of clozapine-induced agranulocytosis: a case report. J Clin Psychiatry 1992;53:245-7.

Drug brand names

 

• Carbamazepine • Tegretol
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Divalproex sodium • Depakote
• GM-CSF—Filgrastim • Neupogen
• Haloperidol • Haldol
• Lithium • Eskalith, Lithobid, others
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Trifluoperazine • Stelazine
• Ziprasidone • Geodon

Disclosure

Dr. Rao is a speaker for Pfizer Inc.

Drs. Goforth, Raval, and Sharma report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CHIEF COMPLAINT: Anxiety and disordered sleep

Mr. Q, a college sophomore, reported symptoms of insomnia, anxiety, and sadness to the university health service. When in bed, he said, he would ruminate about whether he had studied adequately and would ultimately qualify for a graduate program. He exhibited no pervasive sadness, loss of interest or motivation, suicidal ideation, or loss of self-esteem. His medical history revealed no serious illness.

The student health psychiatrist diagnosed Mr. Q as having generalized anxiety disorder. She prescribed trazodone, up to 100 mg/d as needed, for the insomnia. For the next 3 weeks, he took one 25 mg dose each night. After that time, Mr. Q reported that the trazodone alleviated the insomnia and that he felt more rested and could study more effectively. He had stopped taking the medication.

Mr. Q, however, did not tell the health service psychiatrist that he had also experienced an uncomfortable erection that lasted about 4 hours and was not precipitated or accompanied by sexual activity. He finally experienced detumescence after several cold showers. He did not inform her of the episode because he felt embarrassed to discuss “such a thing” with a female physician.

After his anxiety and insomnia resurfaced, Mr. Q was referred to one of the authors.

Why did Mr. Q. develop priapism? How would you counsel him at this point?

Dr. Freed’s and Dr. Muskin’s observations

Priapism refers to a prolonged and painful erection that results from sustained blood flow into the corpora cavernosa. In contrast to a normal erection, both the corpus spongiosum and glans penis remain flaccid. Medical complications and reactions to drugs are well-documented causes.

Table 1

Drugs reported to cause priapism

Antidepressants
Trazodone and, in rare cases, phenelzine and sertraline; bupropion has been associated with clitoral priapism3
Antihypertensives that act via alpha blockade Labetalol, prazosin3-5
Metoclopramide when taken with thioridazine3,4
Sildenafil citrate6 (rare case reports)
Substances of abuse
Alcohol, marijuana, crack cocaine
Typical and atypical antipsychotics
Chlorpromazine, clozapine, fluphenazine, haloperidol, mesoridazine, molindone, levomepromazine, perphenazine, promazine, risperidone, thioridazine, thiothixene3-5

An erection in priapism may result from sexual stimulation/activity, although this is not typical. Sexually stimulated erections in priapism persist hours after the stimulation ceases.

High-flow priapism is rare, painless, and occurs when well-oxygenated blood stays in the corpora cavernosa. It may result from perineal trauma creating a fistula between an artery and the cavernosa. Because the blood is oxygenated, there is no tissue damage, intervention is not urgent, and the prognosis usually is good.

Low-flow priapism, the more prevalent type, is painful and occurs when venous blood remains in the corpora, resulting in hypoxia and ischemia. Approximately 50% of low-flow priapism cases can result in impotence.¹

Because men often are embarrassed by priapism, they may not seek medical attention or mention a prior episode to their physicians. This neglect can be dangerous: Painful erections that persist for more than 4 hours can lead to impotence if left untreated.

The physician must surmount the patient’s reluctance to discuss the symptom. Inquiring about past priapism episodes as part of a complete patient history is essential. We suggest routinely asking patients taking priapism-causing psychotropics (Table 1) if they’ve had a recent erectile problem. Mentioning that a medication can cause uncomfortable and serious sexual side effects may prompt the patient to discuss such problems.

Above all, be direct. A straightforward inquiry about a sensitive medical condition usually draws an honest answer; the patient then realizes the subject is important and should not be embarrassed about it.

After the patient discloses a priapism episode, ask him:

• Was the erection related to sexual activity or desire?
• Were you using any other medications or illicit drugs when the erection occurred?
• Do you have a systemic blood disorder?
• Did you feel any pain during your erection? If so, how long did it persist?

Men who present during a priapism episode should immediately be sent to the ER for urologic treatment. Patients reporting a recent sustained erection should be referred to a urologist if they need to keep taking the priapism-causing drug. Urologic treatment is not necessary if the patient stops the medication and the priapism resolves.

Men who have had at least one past priapism episode and those taking alpha-adrenergic blockers should be instructed to visit the ER immediately if a painful, persistent erection develops. Patients also should be warned not to induce detumescence (such as by taking cold showers, drinking alcohol, or engaging in sexual activity) if the erection persists for more than 2 hours. Any delay in emergency care could lead to impotence.

HISTORY: A probable side effect

 

Because Mr. Q had no other past erectile problems, we strongly suspected his priapism was medication-induced. He reported he had neither been drinking nor taking illicit drugs or other medications when the erection occurred.

Mr. Q also was convinced that the trazodone had caused the sustained erection. He said, however, he was never informed that priapism was a potential side effect of that medication.

Would you resume trazodone, switch to another sleep-promoting or antianxiety medication, or consider other therapy?

Dr. Freed’s and Dr. Muskin’s observations

The prevalence of priapism is not known, although yearly estimates range from 1/1,000 to 1/10,000 patients who take trazodone.²

Trazodone, an alpha-adrenergic blocker, is most commonly implicated among psychotropics in causing priapism.² Blockade of alpha-adrenergic receptors in the corpora cavernosa creates a parasympathetic imbalance favoring erection and prevents sympathetic-mediated detumescence. Histaminic, beta-adrenergic, and adrenergic/cholinergic components may also contribute to priapism.

Other medications associated with priapism include antipsychotics, antihypertensives, anticoagulants, some antidepressants, and antiimpotence medications injected into the penis.

Low-flow priapism can also be caused by systemic disorders (Table 2), including malignancies—particularly when a tumor has infiltrated the penis—and carcinoma of the bladder or prostate. Prostatitis has been implicated in some cases.

Table 2

Systemic illnesses and conditions that can cause priapism

Carcinoma of the bladder or prostate Diabetic neuropathy Fabray’s disease (genetic disorder that causes heart, kidney, and brain damage) Blood disorders, including leukemia, thrombocytopenia, sickle cell disease, thalassemia, polycythemia Lymphomas Malignancies, particularly when a tumor has infiltrated the penis Mumps Spinal cord trauma Prostatitis Rocky Mountain spotted fever

Because Mr. Q has had at least one priapism episode, we would avoid prescribing any agent with alpha-adrenergic blocking properties.

Could Mr. Q’s response to trazodone have been dose-related? How would you ensure that the patient understands a medication’s risks?

Dr. Freed’s and Dr. Muskin’s observations

No findings indicate that trazodone-related priapism is dose-related. Several cases of men developing sustained priapism—resulting in permanent injury and impotence—have been reported after initial dosages of 25 and 50 mg/d.^1,4,7 In a study using the FDA Spontaneous Reporting System, Warner et al found that priapism with trazodone was most likely to occur within the first month of treatment and at dosages 150 mg/d.7 Still other reports indicate that new-onset priapism may occur after years of treatment.³

Box 1

Box 2

Despite its association with priapism, trazodone is used frequently in men and is a popular medication for disordered sleep. Nierenberg et al demonstrated improved sleep in 67% of depressed patients with insomnia who received trazodone either for depression or disordered sleep.⁸

When prescribing a priapism-causing agent, make sure the patient understands that erectile effects—though rare—can occur. Consider giving patients an informed consent form explaining the association between psychotropics and priapism and the potential long-term health implications (Box 1). Include the form in the patient’s record for documentation in the event of a malpractice lawsuit (Box 2).

FURTHER TREATMENT: Learning how to cope

Self-hypnosis/relaxation therapy was initiated to address Mr. Q’s anxiety and insomnia. The patient quickly learned the hypnosis techniques and his anxiety/insomnia symptoms began to resolve almost immediately.

 

Mr. Q’s priapism resolved spontaneously with no apparent erectile dysfunction. He was referred back to the university health service and has been in apparent good health since.

Related resources

• Sleepnet.com. Information on sleep disorders and sleep hygiene. http://www.sleepnet.com/
• National Center on Sleep Disorders Research http://www.nhlbi.nih.gov/about/ncsdr/

Drug brand names

• Bupropion • Wellbutrin
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Labetalol • Trandate
• Levomepromazine • Nozinan
• Mesoridazine • Serentil
• Metoclopramide • Reglan
• Molindone • Lidone
• Perphenazine • Trilafon
• Phenelzine • Nardil
• Prazosin • Minipress
• Promazine • Sparine
• Risperidone • Risperdal
• Sertraline • Zoloft
• Sildenafil citrate • Viagra
• Thioridazine • Mellaril
• Thiothixene • Navane
• Trazodone • Desyrel

Disclosure

Dr. Freed reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Muskin receives research/grant support from Bristol-Myers Squibb Co., is a speaker for and consultant to Bristol-Myers Squibb Co., Forest Laboratories, GlaxoSmithKline, Janssen Pharmaceutica, and Pfizer Inc.; and is a speaker for Cephalon Inc. and Eli Lilly and Co.

CHIEF COMPLAINT: Anxiety and disordered sleep

Mr. Q, a college sophomore, reported symptoms of insomnia, anxiety, and sadness to the university health service. When in bed, he said, he would ruminate about whether he had studied adequately and would ultimately qualify for a graduate program. He exhibited no pervasive sadness, loss of interest or motivation, suicidal ideation, or loss of self-esteem. His medical history revealed no serious illness.

The student health psychiatrist diagnosed Mr. Q as having generalized anxiety disorder. She prescribed trazodone, up to 100 mg/d as needed, for the insomnia. For the next 3 weeks, he took one 25 mg dose each night. After that time, Mr. Q reported that the trazodone alleviated the insomnia and that he felt more rested and could study more effectively. He had stopped taking the medication.

Mr. Q, however, did not tell the health service psychiatrist that he had also experienced an uncomfortable erection that lasted about 4 hours and was not precipitated or accompanied by sexual activity. He finally experienced detumescence after several cold showers. He did not inform her of the episode because he felt embarrassed to discuss “such a thing” with a female physician.

After his anxiety and insomnia resurfaced, Mr. Q was referred to one of the authors.

Why did Mr. Q. develop priapism? How would you counsel him at this point?

Dr. Freed’s and Dr. Muskin’s observations

Priapism refers to a prolonged and painful erection that results from sustained blood flow into the corpora cavernosa. In contrast to a normal erection, both the corpus spongiosum and glans penis remain flaccid. Medical complications and reactions to drugs are well-documented causes.

Table 1

Drugs reported to cause priapism

Antidepressants
Trazodone and, in rare cases, phenelzine and sertraline; bupropion has been associated with clitoral priapism3
Antihypertensives that act via alpha blockade Labetalol, prazosin3-5
Metoclopramide when taken with thioridazine3,4
Sildenafil citrate6 (rare case reports)
Substances of abuse
Alcohol, marijuana, crack cocaine
Typical and atypical antipsychotics
Chlorpromazine, clozapine, fluphenazine, haloperidol, mesoridazine, molindone, levomepromazine, perphenazine, promazine, risperidone, thioridazine, thiothixene3-5

An erection in priapism may result from sexual stimulation/activity, although this is not typical. Sexually stimulated erections in priapism persist hours after the stimulation ceases.

High-flow priapism is rare, painless, and occurs when well-oxygenated blood stays in the corpora cavernosa. It may result from perineal trauma creating a fistula between an artery and the cavernosa. Because the blood is oxygenated, there is no tissue damage, intervention is not urgent, and the prognosis usually is good.

Low-flow priapism, the more prevalent type, is painful and occurs when venous blood remains in the corpora, resulting in hypoxia and ischemia. Approximately 50% of low-flow priapism cases can result in impotence.¹

Because men often are embarrassed by priapism, they may not seek medical attention or mention a prior episode to their physicians. This neglect can be dangerous: Painful erections that persist for more than 4 hours can lead to impotence if left untreated.

The physician must surmount the patient’s reluctance to discuss the symptom. Inquiring about past priapism episodes as part of a complete patient history is essential. We suggest routinely asking patients taking priapism-causing psychotropics (Table 1) if they’ve had a recent erectile problem. Mentioning that a medication can cause uncomfortable and serious sexual side effects may prompt the patient to discuss such problems.

Above all, be direct. A straightforward inquiry about a sensitive medical condition usually draws an honest answer; the patient then realizes the subject is important and should not be embarrassed about it.

After the patient discloses a priapism episode, ask him:

• Was the erection related to sexual activity or desire?
• Were you using any other medications or illicit drugs when the erection occurred?
• Do you have a systemic blood disorder?
• Did you feel any pain during your erection? If so, how long did it persist?

Men who present during a priapism episode should immediately be sent to the ER for urologic treatment. Patients reporting a recent sustained erection should be referred to a urologist if they need to keep taking the priapism-causing drug. Urologic treatment is not necessary if the patient stops the medication and the priapism resolves.

Men who have had at least one past priapism episode and those taking alpha-adrenergic blockers should be instructed to visit the ER immediately if a painful, persistent erection develops. Patients also should be warned not to induce detumescence (such as by taking cold showers, drinking alcohol, or engaging in sexual activity) if the erection persists for more than 2 hours. Any delay in emergency care could lead to impotence.

HISTORY: A probable side effect

 

Because Mr. Q had no other past erectile problems, we strongly suspected his priapism was medication-induced. He reported he had neither been drinking nor taking illicit drugs or other medications when the erection occurred.

Mr. Q also was convinced that the trazodone had caused the sustained erection. He said, however, he was never informed that priapism was a potential side effect of that medication.

Would you resume trazodone, switch to another sleep-promoting or antianxiety medication, or consider other therapy?

Dr. Freed’s and Dr. Muskin’s observations

The prevalence of priapism is not known, although yearly estimates range from 1/1,000 to 1/10,000 patients who take trazodone.²

Trazodone, an alpha-adrenergic blocker, is most commonly implicated among psychotropics in causing priapism.² Blockade of alpha-adrenergic receptors in the corpora cavernosa creates a parasympathetic imbalance favoring erection and prevents sympathetic-mediated detumescence. Histaminic, beta-adrenergic, and adrenergic/cholinergic components may also contribute to priapism.

Other medications associated with priapism include antipsychotics, antihypertensives, anticoagulants, some antidepressants, and antiimpotence medications injected into the penis.

Low-flow priapism can also be caused by systemic disorders (Table 2), including malignancies—particularly when a tumor has infiltrated the penis—and carcinoma of the bladder or prostate. Prostatitis has been implicated in some cases.

Table 2

Systemic illnesses and conditions that can cause priapism

Carcinoma of the bladder or prostate Diabetic neuropathy Fabray’s disease (genetic disorder that causes heart, kidney, and brain damage) Blood disorders, including leukemia, thrombocytopenia, sickle cell disease, thalassemia, polycythemia Lymphomas Malignancies, particularly when a tumor has infiltrated the penis Mumps Spinal cord trauma Prostatitis Rocky Mountain spotted fever

Because Mr. Q has had at least one priapism episode, we would avoid prescribing any agent with alpha-adrenergic blocking properties.

Could Mr. Q’s response to trazodone have been dose-related? How would you ensure that the patient understands a medication’s risks?

Dr. Freed’s and Dr. Muskin’s observations

No findings indicate that trazodone-related priapism is dose-related. Several cases of men developing sustained priapism—resulting in permanent injury and impotence—have been reported after initial dosages of 25 and 50 mg/d.^1,4,7 In a study using the FDA Spontaneous Reporting System, Warner et al found that priapism with trazodone was most likely to occur within the first month of treatment and at dosages 150 mg/d.7 Still other reports indicate that new-onset priapism may occur after years of treatment.³

Box 1

Box 2

Despite its association with priapism, trazodone is used frequently in men and is a popular medication for disordered sleep. Nierenberg et al demonstrated improved sleep in 67% of depressed patients with insomnia who received trazodone either for depression or disordered sleep.⁸

When prescribing a priapism-causing agent, make sure the patient understands that erectile effects—though rare—can occur. Consider giving patients an informed consent form explaining the association between psychotropics and priapism and the potential long-term health implications (Box 1). Include the form in the patient’s record for documentation in the event of a malpractice lawsuit (Box 2).

FURTHER TREATMENT: Learning how to cope

Self-hypnosis/relaxation therapy was initiated to address Mr. Q’s anxiety and insomnia. The patient quickly learned the hypnosis techniques and his anxiety/insomnia symptoms began to resolve almost immediately.

 

Mr. Q’s priapism resolved spontaneously with no apparent erectile dysfunction. He was referred back to the university health service and has been in apparent good health since.

Related resources

• Sleepnet.com. Information on sleep disorders and sleep hygiene. http://www.sleepnet.com/
• National Center on Sleep Disorders Research http://www.nhlbi.nih.gov/about/ncsdr/

Drug brand names

• Bupropion • Wellbutrin
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Labetalol • Trandate
• Levomepromazine • Nozinan
• Mesoridazine • Serentil
• Metoclopramide • Reglan
• Molindone • Lidone
• Perphenazine • Trilafon
• Phenelzine • Nardil
• Prazosin • Minipress
• Promazine • Sparine
• Risperidone • Risperdal
• Sertraline • Zoloft
• Sildenafil citrate • Viagra
• Thioridazine • Mellaril
• Thiothixene • Navane
• Trazodone • Desyrel

Disclosure

Dr. Freed reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Muskin receives research/grant support from Bristol-Myers Squibb Co., is a speaker for and consultant to Bristol-Myers Squibb Co., Forest Laboratories, GlaxoSmithKline, Janssen Pharmaceutica, and Pfizer Inc.; and is a speaker for Cephalon Inc. and Eli Lilly and Co.

CHIEF COMPLAINT: Anxiety and disordered sleep

Mr. Q, a college sophomore, reported symptoms of insomnia, anxiety, and sadness to the university health service. When in bed, he said, he would ruminate about whether he had studied adequately and would ultimately qualify for a graduate program. He exhibited no pervasive sadness, loss of interest or motivation, suicidal ideation, or loss of self-esteem. His medical history revealed no serious illness.

The student health psychiatrist diagnosed Mr. Q as having generalized anxiety disorder. She prescribed trazodone, up to 100 mg/d as needed, for the insomnia. For the next 3 weeks, he took one 25 mg dose each night. After that time, Mr. Q reported that the trazodone alleviated the insomnia and that he felt more rested and could study more effectively. He had stopped taking the medication.

Mr. Q, however, did not tell the health service psychiatrist that he had also experienced an uncomfortable erection that lasted about 4 hours and was not precipitated or accompanied by sexual activity. He finally experienced detumescence after several cold showers. He did not inform her of the episode because he felt embarrassed to discuss “such a thing” with a female physician.

After his anxiety and insomnia resurfaced, Mr. Q was referred to one of the authors.

Why did Mr. Q. develop priapism? How would you counsel him at this point?

Dr. Freed’s and Dr. Muskin’s observations

Priapism refers to a prolonged and painful erection that results from sustained blood flow into the corpora cavernosa. In contrast to a normal erection, both the corpus spongiosum and glans penis remain flaccid. Medical complications and reactions to drugs are well-documented causes.

Table 1

Drugs reported to cause priapism

Antidepressants
Trazodone and, in rare cases, phenelzine and sertraline; bupropion has been associated with clitoral priapism3
Antihypertensives that act via alpha blockade Labetalol, prazosin3-5
Metoclopramide when taken with thioridazine3,4
Sildenafil citrate6 (rare case reports)
Substances of abuse
Alcohol, marijuana, crack cocaine
Typical and atypical antipsychotics
Chlorpromazine, clozapine, fluphenazine, haloperidol, mesoridazine, molindone, levomepromazine, perphenazine, promazine, risperidone, thioridazine, thiothixene3-5

An erection in priapism may result from sexual stimulation/activity, although this is not typical. Sexually stimulated erections in priapism persist hours after the stimulation ceases.

High-flow priapism is rare, painless, and occurs when well-oxygenated blood stays in the corpora cavernosa. It may result from perineal trauma creating a fistula between an artery and the cavernosa. Because the blood is oxygenated, there is no tissue damage, intervention is not urgent, and the prognosis usually is good.

Low-flow priapism, the more prevalent type, is painful and occurs when venous blood remains in the corpora, resulting in hypoxia and ischemia. Approximately 50% of low-flow priapism cases can result in impotence.¹

Because men often are embarrassed by priapism, they may not seek medical attention or mention a prior episode to their physicians. This neglect can be dangerous: Painful erections that persist for more than 4 hours can lead to impotence if left untreated.

The physician must surmount the patient’s reluctance to discuss the symptom. Inquiring about past priapism episodes as part of a complete patient history is essential. We suggest routinely asking patients taking priapism-causing psychotropics (Table 1) if they’ve had a recent erectile problem. Mentioning that a medication can cause uncomfortable and serious sexual side effects may prompt the patient to discuss such problems.

Above all, be direct. A straightforward inquiry about a sensitive medical condition usually draws an honest answer; the patient then realizes the subject is important and should not be embarrassed about it.

After the patient discloses a priapism episode, ask him:

• Was the erection related to sexual activity or desire?
• Were you using any other medications or illicit drugs when the erection occurred?
• Do you have a systemic blood disorder?
• Did you feel any pain during your erection? If so, how long did it persist?

Men who present during a priapism episode should immediately be sent to the ER for urologic treatment. Patients reporting a recent sustained erection should be referred to a urologist if they need to keep taking the priapism-causing drug. Urologic treatment is not necessary if the patient stops the medication and the priapism resolves.

Men who have had at least one past priapism episode and those taking alpha-adrenergic blockers should be instructed to visit the ER immediately if a painful, persistent erection develops. Patients also should be warned not to induce detumescence (such as by taking cold showers, drinking alcohol, or engaging in sexual activity) if the erection persists for more than 2 hours. Any delay in emergency care could lead to impotence.

HISTORY: A probable side effect

 

Because Mr. Q had no other past erectile problems, we strongly suspected his priapism was medication-induced. He reported he had neither been drinking nor taking illicit drugs or other medications when the erection occurred.

Mr. Q also was convinced that the trazodone had caused the sustained erection. He said, however, he was never informed that priapism was a potential side effect of that medication.

Would you resume trazodone, switch to another sleep-promoting or antianxiety medication, or consider other therapy?

Dr. Freed’s and Dr. Muskin’s observations

The prevalence of priapism is not known, although yearly estimates range from 1/1,000 to 1/10,000 patients who take trazodone.²

Trazodone, an alpha-adrenergic blocker, is most commonly implicated among psychotropics in causing priapism.² Blockade of alpha-adrenergic receptors in the corpora cavernosa creates a parasympathetic imbalance favoring erection and prevents sympathetic-mediated detumescence. Histaminic, beta-adrenergic, and adrenergic/cholinergic components may also contribute to priapism.

Other medications associated with priapism include antipsychotics, antihypertensives, anticoagulants, some antidepressants, and antiimpotence medications injected into the penis.

Low-flow priapism can also be caused by systemic disorders (Table 2), including malignancies—particularly when a tumor has infiltrated the penis—and carcinoma of the bladder or prostate. Prostatitis has been implicated in some cases.

Table 2

Systemic illnesses and conditions that can cause priapism

Carcinoma of the bladder or prostate Diabetic neuropathy Fabray’s disease (genetic disorder that causes heart, kidney, and brain damage) Blood disorders, including leukemia, thrombocytopenia, sickle cell disease, thalassemia, polycythemia Lymphomas Malignancies, particularly when a tumor has infiltrated the penis Mumps Spinal cord trauma Prostatitis Rocky Mountain spotted fever

Because Mr. Q has had at least one priapism episode, we would avoid prescribing any agent with alpha-adrenergic blocking properties.

Could Mr. Q’s response to trazodone have been dose-related? How would you ensure that the patient understands a medication’s risks?

Dr. Freed’s and Dr. Muskin’s observations

No findings indicate that trazodone-related priapism is dose-related. Several cases of men developing sustained priapism—resulting in permanent injury and impotence—have been reported after initial dosages of 25 and 50 mg/d.^1,4,7 In a study using the FDA Spontaneous Reporting System, Warner et al found that priapism with trazodone was most likely to occur within the first month of treatment and at dosages 150 mg/d.7 Still other reports indicate that new-onset priapism may occur after years of treatment.³

Box 1

Box 2

Despite its association with priapism, trazodone is used frequently in men and is a popular medication for disordered sleep. Nierenberg et al demonstrated improved sleep in 67% of depressed patients with insomnia who received trazodone either for depression or disordered sleep.⁸

When prescribing a priapism-causing agent, make sure the patient understands that erectile effects—though rare—can occur. Consider giving patients an informed consent form explaining the association between psychotropics and priapism and the potential long-term health implications (Box 1). Include the form in the patient’s record for documentation in the event of a malpractice lawsuit (Box 2).

FURTHER TREATMENT: Learning how to cope

Self-hypnosis/relaxation therapy was initiated to address Mr. Q’s anxiety and insomnia. The patient quickly learned the hypnosis techniques and his anxiety/insomnia symptoms began to resolve almost immediately.

 

Mr. Q’s priapism resolved spontaneously with no apparent erectile dysfunction. He was referred back to the university health service and has been in apparent good health since.

Related resources

• Sleepnet.com. Information on sleep disorders and sleep hygiene. http://www.sleepnet.com/
• National Center on Sleep Disorders Research http://www.nhlbi.nih.gov/about/ncsdr/

Drug brand names

• Bupropion • Wellbutrin
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Labetalol • Trandate
• Levomepromazine • Nozinan
• Mesoridazine • Serentil
• Metoclopramide • Reglan
• Molindone • Lidone
• Perphenazine • Trilafon
• Phenelzine • Nardil
• Prazosin • Minipress
• Promazine • Sparine
• Risperidone • Risperdal
• Sertraline • Zoloft
• Sildenafil citrate • Viagra
• Thioridazine • Mellaril
• Thiothixene • Navane
• Trazodone • Desyrel

Disclosure

Dr. Freed reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Muskin receives research/grant support from Bristol-Myers Squibb Co., is a speaker for and consultant to Bristol-Myers Squibb Co., Forest Laboratories, GlaxoSmithKline, Janssen Pharmaceutica, and Pfizer Inc.; and is a speaker for Cephalon Inc. and Eli Lilly and Co.

HISTORY: Jesus’ ‘cousin’

Mr. F, age 60, was hospitalized in May 1995 after expressing fear he would hurt—or kill—himself or someone else. He cooperated with admission procedures but refused to participate in ward activities or meetings. His hygiene was poor, he made little eye contact, and reportedly heard voices. Two days after admission, he emphatically denied suicidal or homicidal ideation and was discharged against medical advice.

Two weeks later, Mr. F was readmitted after his symptoms worsened. He said voices told him that he was a cousin to Jesus Christ and that he had telepathic abilities. He also reported visual hallucinations.

Twice divorced, Mr. F has three uncles who have been diagnosed with schizophrenia. His late father had a history of alcohol abuse, and his late mother suffered from Alzheimer’s disease.

Mr. F lived a normal life until 1975, when he began drinking heavily. Three years later, he quit his job of 11 years at the local airport. At that time, he told a psychiatrist that “people are out to get me. I feel nervous a lot.” He was diagnosed as having generalized anxiety disorder and treated with diazepam, 20 mg/d.

Four months later he complained of severe insomnia, was diagnosed with depression, and was prescribed amitriptyline, 100 mg at bedtime. He was hospitalized 1 week later after he complained of chest pain and expressed paranoid thoughts. During the 3-week hospitalization, he experienced persecutory delusions and heard voices telling him he was “damned.” He was diagnosed with paranoid schizophrenia and alcohol dependence. The amitriptyline was stopped, and Mr. F was discharged on chlorpromazine, 300 mg/d.

From 1978 to 1995, Mr. F was hospitalized 35 times, often at his family’s urging after he made threats or became violent at home. He once kicked his elderly father and another time was jailed after a domestic violence incident. Religious delusions characterized his thought content. Thought blocking, flight of ideas, and somatic and sexual delusions were also apparent.

Was Mr. F’s diagnosis accurate, or do his frequent psychotic episodes meet criteria for a type of mania?

Dr. Canive’s observations

Diagnoses of mania or mood disorder with psychotic features were not considered because Mr. F never experienced a distinct period of persistently expansive or depressed mood.

Mr. F’s initial complaints of increased anxiety and depression were considered prodromal symptoms of schizophrenia and may have reflected his inability to discuss or cope with his delusions and hallucinations during the initial evaluation. What’s more, his occupational functioning gradually deteriorated months before his initial mental health assessment.

TREATMENT: Many medications, no progress

At different times from 1978 to 1995, Mr. F had taken chlorpromazine, 100 to 300 mg/d; thioridazine, 50 to 200 mg/d; loxapine, 25 mg/d; fluphenazine, 5 to 10 mg/d; haloperidol, 2 to 4 mg/d, and fluphenazine decanoate, 3.125 to 6.25 mg biweekly, as well as concomitant anticholinergics, benzodiazepines, or other hypnotics.

A closer look at Mr. F’s chart revealed that medication noncompliance often preceded hospitalization. He was extremely prone to antipsychotic-related extrapyramidal symptoms (EPS), even at low dosages. Whenever motor symptoms surfaced, he would stop taking his antipsychotics.

Buccolingual tardive dyskinesia (TD) was first noticed in 1987. Four years later, an Abnormal Involuntary Movement Scale (AIMS) exam revealed mild TD that was managed with vitamin E, 400 IU/d.

While hospitalized, Mr. F many times received injectable antipsychotics and benzodiazepines, mostly to control violence. Depot antipsychotics also were tried in an effort to promote compliance, but recurrent alcohol abuse often triggered a relapse.

How would you confront Mr. F’s history of noncompliance? Can his delusions be controlled without prompting severe motor effects?

Dr. Canive’s observations

For Mr. F, poor tolerability, incomplete efficacy, and variable compliance have repeatedly led to symptom exacerbation and hospitalization. Low dosing because of sensitivity to EPS may partially explain his insufficient response to antipsychotics.

In 1995, after numerous unsuccessful drug treatments, we considered entering Mr. F into a phase II clinical trial of the atypical antipsychotic aripiprazole.

Now FDA-approved for treatment of schizophrenia, aripiprazole decreases dopaminergic transmission in the nigrostriatal and tuberoinfundibular pathways, thus reducing the likelihood of EPS.^1,2 Also, aripiprazole’s dopamine-serotonin stabilization effects have been reported in clinical trials to improve tolerability, compliance, and overall effectiveness in patients with schizophrenia.³

Common side effects of aripiprazole are mild nausea, insomnia, and restlessness, although data indicate that these effects have a low prevalence and disappear within 2 weeks. If insomnia and restlessness are prominent, a low-dose, short-acting benzodiazepine may be added, tapered after 1 week, and discontinued at week 2.

Table

Mr. F’s progress while taking aripiprazole, 1995-2003

 

Visit	CGI-S	CGI-G	PANSS Positive	PANSS Negative	PANSS total	Clinical correlates
Baseline	4	5	24	21	94	—-
Week 2	3	2	N/A	N/A	N/A	Positive, negative symptoms much improved
Week 12	3	2	11	16	56	Mr. F’s understanding about his illness, life, socioeconomic issues much improved
Week 76	3	2	11	18	56	Activity level increased; starts doing yard work to supplement disability income
Week 88	3	2	12	14	52	Volunteers as courier at local hospital; continues to do yard work
Week 226	2	2	9	12	42	Starts steady work as a janitor and security aid
Week 284	2	2	9	14	45	Concerned about losing Social Security benefits, since he is working 40 hours a week.
Week 328	3	1	11	15	52	Discharged from hospital after psychotic relapse. Looking for apartment.
Week 384 (Final visit)	3	1	9	12	45	Father died the previous week. Mr. F accepted his father’s passing well. Open-label study terminated. Patient continued on aripiprazole, 20 mg/d.

What the scores mean

Clinical Global Impression-Severity of Illness (CGI-S)—Scores range from 1 to 7, with 1 meaning normal (normal, minimal, mild, moderate, moderately severe, severe, among the most extreme).

Clinical Global Impression-Global Improvement (CGI-G)—Scores range from 1 to 7, with 1 meaning very much improved (very much improved, much improved, improved, unchanged, little worse, much worse, very much worse).

Positive and Negative Syndrome Scale (PANSS) Positive—consists of 7 items (delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, hostility); scores range from 7 to 49 and decrease as patients improve.

PANSS Negative—consists of 7 items (blunted affect, emotional withdrawal, poor rapport, passive pathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking); scores range from 7 to 49 and decrease as patients improve.

PANSS General—consists of 16 items (somatic concern, anxiety, guilt feelings, tension, mannerism and posturing, depression, motor retardation, uncooperativeness, unusual thought content, disorientation, poor attention, lack of judgment and insight, disturbance of volition, poor impulse control, preoccupation, active social avoidance). Scores range from 16 to 112 and decrease as patients improve.

CONTINUED TREATMENT: A new trial

Mr. F participated in a 4-week, double-blind, placebo-controlled trial of aripiprazole, 2, 10, or 30 mg/d, versus haloperidol, 10 mg/d.

One month later, he entered a second aripiprazole trial: a 4-day, open-label study starting at 5 mg/d with titration to 20 mg/d. In the interval between the two trials, Mr. F was prescribed thiothixene, 10 mg/d, and benztropine, 2 mg at bedtime.

During the 4-day trial, he complained of insomnia and was given chloral hydrate, 500 to 1,000 mg at bedtime. He also complained of anxiety and was started on lorazepam, 2 mg bid.

After completing the open-label aripiprazole trial, Mr. F exhibited no behavioral problems and complied with ward routine. He was discharged after 17 days, at which time he denied auditory or visual hallucinations. His thinking seemed clear and his insight improved. His Global Assessment of Functioning (GAF) score at discharge was 55, suggesting moderate symptoms and difficulty in social and occupational functioning.

For the next 5 1/2 years, Mr. F was maintained on aripiprazole, 20 mg/d, as part of the same ongoing open-label trial. During that period he also took lorazepam, 1 mg bid prn; oxazepam, 15 mg bid; or clonazepam, 0.5 mg bid, for anxiety.

Mr. F. exhibited significant sustained improvement as measured with the Positive and Negative Symptom Scale (PANSS), Clinical Global Impression scale (CGI), and GAF (Table). His TD remained mild throughout the trial, as determined through AIMS scores. He also reported no EPS, akathisia, or other adverse events.

About 18 months after starting aripiprazole, Mr. F resumed working part time. In September 2001, he stopped receiving disability benefits and started supporting himself again.

FOLLOW-UP: ‘The voices were ugly’

In December 2001, after 6 years without hospitalization, Mr. F was back in the psychiatric ward. One week before admission, he reported that he had been having panic attacks because “the voices were ugly.” He only slept 4 to 5 hours per night.

He then revealed that he had stopped taking aripiprazole for 2 weeks because he had no longer felt ill. He was still taking his lorazepam, however.

Mr. F appeared mildly anxious upon presentation and his affect was blunted. On examination, his thought processes were linear; he was once again hearing voices and experiencing delusions of telepathic control.

The patient was placed back on aripiprazole, 20 mg/d. His behavior on the ward improved dramatically, and the frequency and severity of his delusions and auditory hallucinations decreased gradually.

At discharge, Mr. F’s insight was good, his delusions had disappeared, and auditory hallucinations were rare. He was instructed to continue the aripiprazole and was prescribed clonazepam, 0.5 mg bid, for his anxiety and trazodone, 50 mg at bed-time, to help his sleep.

Since then, Mr. F has lived on his own, is working steadily, and has not required hospitalization. He stopped taking trazodone soon after discharge, but continues taking aripiprazole and clonazepam as prescribed. His hygiene is good, and he is making amends with family members. He attends church every Sunday—free of the messianic delusions that once tormented him. He also stopped abusing alcohol on his own in 1995 and has remained abstinent since.

 

How can we ensure that patients with schizophrenia keep taking their medications—regardless of whether symptoms are present?

Dr. Canive’s observations

Clinical trials measure a drug’s efficacy under highly controlled circumstances. In the “real world,” however, noncompliance due to intolerability can undermine a medication’s effectiveness.

Too often noncompliance—stemming from abatement of symptoms or the emergence of side effects—derails treatment of schizophrenia. Misdrahi et al found that medication noncompliance accounts for 40% of schizophrenia relapses occurring more than 1 year after patients’ first hospitalization.⁴

Given aripiprazole’s 75-hour half-life, one might not expect to see symptoms emerge so soon after discontinuation. It is possible that:

• Mr. F. abstained from aripiprazole longer than he realized—or admitted
• Unidentified stressful life events also exacerbated symptoms and precipitated hospitalization.

When Mr. F consistently followed his regimen, his positive symptoms abated and he could attempt to live a normal life.

Our patients must understand that schizophrenia is a lifelong illness and that continued adherence to medication—even when symptoms do not exist—is crucial. A strong therapeutic alliance,⁵ increased social support, adjunctive cognitive-behavioral therapy, psychosocial interventions,⁶ and medications with fewer and less-severe side effects may help patients embrace this message.

Related resources

• Tamminga CA. Partial dopamine agonists in the treatment of psychosis. J Neural Transm 2002;109:411-20.

Drug brand names

• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Benztropine • Cogentin
• Chlorpromazine • Thorazine
• Clonazepam • Klonopin
• Diazepam • Valium
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Lorazepam • Ativan
• Loxapine • Loxitane
• Oxazepam • Serax
• Thiothixene • Navane
• Trazodone • Desyrel

Disclosure

The author receives research/grant support from and is a speaker for and consultant to Bristol-Myers Squibb Co. He also receives research/grant support from and/or is a speaker for AstraZeneca Pharmaceuticals, Janssen Pharmaceutica, and Eli Lilly and Co.

HISTORY: Jesus’ ‘cousin’

Mr. F, age 60, was hospitalized in May 1995 after expressing fear he would hurt—or kill—himself or someone else. He cooperated with admission procedures but refused to participate in ward activities or meetings. His hygiene was poor, he made little eye contact, and reportedly heard voices. Two days after admission, he emphatically denied suicidal or homicidal ideation and was discharged against medical advice.

Two weeks later, Mr. F was readmitted after his symptoms worsened. He said voices told him that he was a cousin to Jesus Christ and that he had telepathic abilities. He also reported visual hallucinations.

Twice divorced, Mr. F has three uncles who have been diagnosed with schizophrenia. His late father had a history of alcohol abuse, and his late mother suffered from Alzheimer’s disease.

Mr. F lived a normal life until 1975, when he began drinking heavily. Three years later, he quit his job of 11 years at the local airport. At that time, he told a psychiatrist that “people are out to get me. I feel nervous a lot.” He was diagnosed as having generalized anxiety disorder and treated with diazepam, 20 mg/d.

Four months later he complained of severe insomnia, was diagnosed with depression, and was prescribed amitriptyline, 100 mg at bedtime. He was hospitalized 1 week later after he complained of chest pain and expressed paranoid thoughts. During the 3-week hospitalization, he experienced persecutory delusions and heard voices telling him he was “damned.” He was diagnosed with paranoid schizophrenia and alcohol dependence. The amitriptyline was stopped, and Mr. F was discharged on chlorpromazine, 300 mg/d.

From 1978 to 1995, Mr. F was hospitalized 35 times, often at his family’s urging after he made threats or became violent at home. He once kicked his elderly father and another time was jailed after a domestic violence incident. Religious delusions characterized his thought content. Thought blocking, flight of ideas, and somatic and sexual delusions were also apparent.

Was Mr. F’s diagnosis accurate, or do his frequent psychotic episodes meet criteria for a type of mania?

Dr. Canive’s observations

Diagnoses of mania or mood disorder with psychotic features were not considered because Mr. F never experienced a distinct period of persistently expansive or depressed mood.

Mr. F’s initial complaints of increased anxiety and depression were considered prodromal symptoms of schizophrenia and may have reflected his inability to discuss or cope with his delusions and hallucinations during the initial evaluation. What’s more, his occupational functioning gradually deteriorated months before his initial mental health assessment.

TREATMENT: Many medications, no progress

At different times from 1978 to 1995, Mr. F had taken chlorpromazine, 100 to 300 mg/d; thioridazine, 50 to 200 mg/d; loxapine, 25 mg/d; fluphenazine, 5 to 10 mg/d; haloperidol, 2 to 4 mg/d, and fluphenazine decanoate, 3.125 to 6.25 mg biweekly, as well as concomitant anticholinergics, benzodiazepines, or other hypnotics.

A closer look at Mr. F’s chart revealed that medication noncompliance often preceded hospitalization. He was extremely prone to antipsychotic-related extrapyramidal symptoms (EPS), even at low dosages. Whenever motor symptoms surfaced, he would stop taking his antipsychotics.

Buccolingual tardive dyskinesia (TD) was first noticed in 1987. Four years later, an Abnormal Involuntary Movement Scale (AIMS) exam revealed mild TD that was managed with vitamin E, 400 IU/d.

While hospitalized, Mr. F many times received injectable antipsychotics and benzodiazepines, mostly to control violence. Depot antipsychotics also were tried in an effort to promote compliance, but recurrent alcohol abuse often triggered a relapse.

How would you confront Mr. F’s history of noncompliance? Can his delusions be controlled without prompting severe motor effects?

Dr. Canive’s observations

For Mr. F, poor tolerability, incomplete efficacy, and variable compliance have repeatedly led to symptom exacerbation and hospitalization. Low dosing because of sensitivity to EPS may partially explain his insufficient response to antipsychotics.

In 1995, after numerous unsuccessful drug treatments, we considered entering Mr. F into a phase II clinical trial of the atypical antipsychotic aripiprazole.

Now FDA-approved for treatment of schizophrenia, aripiprazole decreases dopaminergic transmission in the nigrostriatal and tuberoinfundibular pathways, thus reducing the likelihood of EPS.^1,2 Also, aripiprazole’s dopamine-serotonin stabilization effects have been reported in clinical trials to improve tolerability, compliance, and overall effectiveness in patients with schizophrenia.³

Common side effects of aripiprazole are mild nausea, insomnia, and restlessness, although data indicate that these effects have a low prevalence and disappear within 2 weeks. If insomnia and restlessness are prominent, a low-dose, short-acting benzodiazepine may be added, tapered after 1 week, and discontinued at week 2.

Table

Mr. F’s progress while taking aripiprazole, 1995-2003

 

Visit	CGI-S	CGI-G	PANSS Positive	PANSS Negative	PANSS total	Clinical correlates
Baseline	4	5	24	21	94	—-
Week 2	3	2	N/A	N/A	N/A	Positive, negative symptoms much improved
Week 12	3	2	11	16	56	Mr. F’s understanding about his illness, life, socioeconomic issues much improved
Week 76	3	2	11	18	56	Activity level increased; starts doing yard work to supplement disability income
Week 88	3	2	12	14	52	Volunteers as courier at local hospital; continues to do yard work
Week 226	2	2	9	12	42	Starts steady work as a janitor and security aid
Week 284	2	2	9	14	45	Concerned about losing Social Security benefits, since he is working 40 hours a week.
Week 328	3	1	11	15	52	Discharged from hospital after psychotic relapse. Looking for apartment.
Week 384 (Final visit)	3	1	9	12	45	Father died the previous week. Mr. F accepted his father’s passing well. Open-label study terminated. Patient continued on aripiprazole, 20 mg/d.

What the scores mean

Clinical Global Impression-Severity of Illness (CGI-S)—Scores range from 1 to 7, with 1 meaning normal (normal, minimal, mild, moderate, moderately severe, severe, among the most extreme).

Clinical Global Impression-Global Improvement (CGI-G)—Scores range from 1 to 7, with 1 meaning very much improved (very much improved, much improved, improved, unchanged, little worse, much worse, very much worse).

Positive and Negative Syndrome Scale (PANSS) Positive—consists of 7 items (delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, hostility); scores range from 7 to 49 and decrease as patients improve.

PANSS Negative—consists of 7 items (blunted affect, emotional withdrawal, poor rapport, passive pathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking); scores range from 7 to 49 and decrease as patients improve.

PANSS General—consists of 16 items (somatic concern, anxiety, guilt feelings, tension, mannerism and posturing, depression, motor retardation, uncooperativeness, unusual thought content, disorientation, poor attention, lack of judgment and insight, disturbance of volition, poor impulse control, preoccupation, active social avoidance). Scores range from 16 to 112 and decrease as patients improve.

CONTINUED TREATMENT: A new trial

Mr. F participated in a 4-week, double-blind, placebo-controlled trial of aripiprazole, 2, 10, or 30 mg/d, versus haloperidol, 10 mg/d.

One month later, he entered a second aripiprazole trial: a 4-day, open-label study starting at 5 mg/d with titration to 20 mg/d. In the interval between the two trials, Mr. F was prescribed thiothixene, 10 mg/d, and benztropine, 2 mg at bedtime.

During the 4-day trial, he complained of insomnia and was given chloral hydrate, 500 to 1,000 mg at bedtime. He also complained of anxiety and was started on lorazepam, 2 mg bid.

After completing the open-label aripiprazole trial, Mr. F exhibited no behavioral problems and complied with ward routine. He was discharged after 17 days, at which time he denied auditory or visual hallucinations. His thinking seemed clear and his insight improved. His Global Assessment of Functioning (GAF) score at discharge was 55, suggesting moderate symptoms and difficulty in social and occupational functioning.

For the next 5 1/2 years, Mr. F was maintained on aripiprazole, 20 mg/d, as part of the same ongoing open-label trial. During that period he also took lorazepam, 1 mg bid prn; oxazepam, 15 mg bid; or clonazepam, 0.5 mg bid, for anxiety.

Mr. F. exhibited significant sustained improvement as measured with the Positive and Negative Symptom Scale (PANSS), Clinical Global Impression scale (CGI), and GAF (Table). His TD remained mild throughout the trial, as determined through AIMS scores. He also reported no EPS, akathisia, or other adverse events.

About 18 months after starting aripiprazole, Mr. F resumed working part time. In September 2001, he stopped receiving disability benefits and started supporting himself again.

FOLLOW-UP: ‘The voices were ugly’

In December 2001, after 6 years without hospitalization, Mr. F was back in the psychiatric ward. One week before admission, he reported that he had been having panic attacks because “the voices were ugly.” He only slept 4 to 5 hours per night.

He then revealed that he had stopped taking aripiprazole for 2 weeks because he had no longer felt ill. He was still taking his lorazepam, however.

Mr. F appeared mildly anxious upon presentation and his affect was blunted. On examination, his thought processes were linear; he was once again hearing voices and experiencing delusions of telepathic control.

The patient was placed back on aripiprazole, 20 mg/d. His behavior on the ward improved dramatically, and the frequency and severity of his delusions and auditory hallucinations decreased gradually.

At discharge, Mr. F’s insight was good, his delusions had disappeared, and auditory hallucinations were rare. He was instructed to continue the aripiprazole and was prescribed clonazepam, 0.5 mg bid, for his anxiety and trazodone, 50 mg at bed-time, to help his sleep.

Since then, Mr. F has lived on his own, is working steadily, and has not required hospitalization. He stopped taking trazodone soon after discharge, but continues taking aripiprazole and clonazepam as prescribed. His hygiene is good, and he is making amends with family members. He attends church every Sunday—free of the messianic delusions that once tormented him. He also stopped abusing alcohol on his own in 1995 and has remained abstinent since.

 

How can we ensure that patients with schizophrenia keep taking their medications—regardless of whether symptoms are present?

Dr. Canive’s observations

Clinical trials measure a drug’s efficacy under highly controlled circumstances. In the “real world,” however, noncompliance due to intolerability can undermine a medication’s effectiveness.

Too often noncompliance—stemming from abatement of symptoms or the emergence of side effects—derails treatment of schizophrenia. Misdrahi et al found that medication noncompliance accounts for 40% of schizophrenia relapses occurring more than 1 year after patients’ first hospitalization.⁴

Given aripiprazole’s 75-hour half-life, one might not expect to see symptoms emerge so soon after discontinuation. It is possible that:

• Mr. F. abstained from aripiprazole longer than he realized—or admitted
• Unidentified stressful life events also exacerbated symptoms and precipitated hospitalization.

When Mr. F consistently followed his regimen, his positive symptoms abated and he could attempt to live a normal life.

Our patients must understand that schizophrenia is a lifelong illness and that continued adherence to medication—even when symptoms do not exist—is crucial. A strong therapeutic alliance,⁵ increased social support, adjunctive cognitive-behavioral therapy, psychosocial interventions,⁶ and medications with fewer and less-severe side effects may help patients embrace this message.

Related resources

• Tamminga CA. Partial dopamine agonists in the treatment of psychosis. J Neural Transm 2002;109:411-20.

Drug brand names

• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Benztropine • Cogentin
• Chlorpromazine • Thorazine
• Clonazepam • Klonopin
• Diazepam • Valium
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Lorazepam • Ativan
• Loxapine • Loxitane
• Oxazepam • Serax
• Thiothixene • Navane
• Trazodone • Desyrel

Disclosure

The author receives research/grant support from and is a speaker for and consultant to Bristol-Myers Squibb Co. He also receives research/grant support from and/or is a speaker for AstraZeneca Pharmaceuticals, Janssen Pharmaceutica, and Eli Lilly and Co.

HISTORY: Jesus’ ‘cousin’

Mr. F, age 60, was hospitalized in May 1995 after expressing fear he would hurt—or kill—himself or someone else. He cooperated with admission procedures but refused to participate in ward activities or meetings. His hygiene was poor, he made little eye contact, and reportedly heard voices. Two days after admission, he emphatically denied suicidal or homicidal ideation and was discharged against medical advice.

Two weeks later, Mr. F was readmitted after his symptoms worsened. He said voices told him that he was a cousin to Jesus Christ and that he had telepathic abilities. He also reported visual hallucinations.

Twice divorced, Mr. F has three uncles who have been diagnosed with schizophrenia. His late father had a history of alcohol abuse, and his late mother suffered from Alzheimer’s disease.

Mr. F lived a normal life until 1975, when he began drinking heavily. Three years later, he quit his job of 11 years at the local airport. At that time, he told a psychiatrist that “people are out to get me. I feel nervous a lot.” He was diagnosed as having generalized anxiety disorder and treated with diazepam, 20 mg/d.

Four months later he complained of severe insomnia, was diagnosed with depression, and was prescribed amitriptyline, 100 mg at bedtime. He was hospitalized 1 week later after he complained of chest pain and expressed paranoid thoughts. During the 3-week hospitalization, he experienced persecutory delusions and heard voices telling him he was “damned.” He was diagnosed with paranoid schizophrenia and alcohol dependence. The amitriptyline was stopped, and Mr. F was discharged on chlorpromazine, 300 mg/d.

From 1978 to 1995, Mr. F was hospitalized 35 times, often at his family’s urging after he made threats or became violent at home. He once kicked his elderly father and another time was jailed after a domestic violence incident. Religious delusions characterized his thought content. Thought blocking, flight of ideas, and somatic and sexual delusions were also apparent.

Was Mr. F’s diagnosis accurate, or do his frequent psychotic episodes meet criteria for a type of mania?

Dr. Canive’s observations

Diagnoses of mania or mood disorder with psychotic features were not considered because Mr. F never experienced a distinct period of persistently expansive or depressed mood.

Mr. F’s initial complaints of increased anxiety and depression were considered prodromal symptoms of schizophrenia and may have reflected his inability to discuss or cope with his delusions and hallucinations during the initial evaluation. What’s more, his occupational functioning gradually deteriorated months before his initial mental health assessment.

TREATMENT: Many medications, no progress

At different times from 1978 to 1995, Mr. F had taken chlorpromazine, 100 to 300 mg/d; thioridazine, 50 to 200 mg/d; loxapine, 25 mg/d; fluphenazine, 5 to 10 mg/d; haloperidol, 2 to 4 mg/d, and fluphenazine decanoate, 3.125 to 6.25 mg biweekly, as well as concomitant anticholinergics, benzodiazepines, or other hypnotics.

A closer look at Mr. F’s chart revealed that medication noncompliance often preceded hospitalization. He was extremely prone to antipsychotic-related extrapyramidal symptoms (EPS), even at low dosages. Whenever motor symptoms surfaced, he would stop taking his antipsychotics.

Buccolingual tardive dyskinesia (TD) was first noticed in 1987. Four years later, an Abnormal Involuntary Movement Scale (AIMS) exam revealed mild TD that was managed with vitamin E, 400 IU/d.

While hospitalized, Mr. F many times received injectable antipsychotics and benzodiazepines, mostly to control violence. Depot antipsychotics also were tried in an effort to promote compliance, but recurrent alcohol abuse often triggered a relapse.

How would you confront Mr. F’s history of noncompliance? Can his delusions be controlled without prompting severe motor effects?

Dr. Canive’s observations

For Mr. F, poor tolerability, incomplete efficacy, and variable compliance have repeatedly led to symptom exacerbation and hospitalization. Low dosing because of sensitivity to EPS may partially explain his insufficient response to antipsychotics.

In 1995, after numerous unsuccessful drug treatments, we considered entering Mr. F into a phase II clinical trial of the atypical antipsychotic aripiprazole.

Now FDA-approved for treatment of schizophrenia, aripiprazole decreases dopaminergic transmission in the nigrostriatal and tuberoinfundibular pathways, thus reducing the likelihood of EPS.^1,2 Also, aripiprazole’s dopamine-serotonin stabilization effects have been reported in clinical trials to improve tolerability, compliance, and overall effectiveness in patients with schizophrenia.³

Common side effects of aripiprazole are mild nausea, insomnia, and restlessness, although data indicate that these effects have a low prevalence and disappear within 2 weeks. If insomnia and restlessness are prominent, a low-dose, short-acting benzodiazepine may be added, tapered after 1 week, and discontinued at week 2.

Table

Mr. F’s progress while taking aripiprazole, 1995-2003

 

Visit	CGI-S	CGI-G	PANSS Positive	PANSS Negative	PANSS total	Clinical correlates
Baseline	4	5	24	21	94	—-
Week 2	3	2	N/A	N/A	N/A	Positive, negative symptoms much improved
Week 12	3	2	11	16	56	Mr. F’s understanding about his illness, life, socioeconomic issues much improved
Week 76	3	2	11	18	56	Activity level increased; starts doing yard work to supplement disability income
Week 88	3	2	12	14	52	Volunteers as courier at local hospital; continues to do yard work
Week 226	2	2	9	12	42	Starts steady work as a janitor and security aid
Week 284	2	2	9	14	45	Concerned about losing Social Security benefits, since he is working 40 hours a week.
Week 328	3	1	11	15	52	Discharged from hospital after psychotic relapse. Looking for apartment.
Week 384 (Final visit)	3	1	9	12	45	Father died the previous week. Mr. F accepted his father’s passing well. Open-label study terminated. Patient continued on aripiprazole, 20 mg/d.

What the scores mean

Clinical Global Impression-Severity of Illness (CGI-S)—Scores range from 1 to 7, with 1 meaning normal (normal, minimal, mild, moderate, moderately severe, severe, among the most extreme).

Clinical Global Impression-Global Improvement (CGI-G)—Scores range from 1 to 7, with 1 meaning very much improved (very much improved, much improved, improved, unchanged, little worse, much worse, very much worse).

Positive and Negative Syndrome Scale (PANSS) Positive—consists of 7 items (delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, hostility); scores range from 7 to 49 and decrease as patients improve.

PANSS Negative—consists of 7 items (blunted affect, emotional withdrawal, poor rapport, passive pathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking); scores range from 7 to 49 and decrease as patients improve.

PANSS General—consists of 16 items (somatic concern, anxiety, guilt feelings, tension, mannerism and posturing, depression, motor retardation, uncooperativeness, unusual thought content, disorientation, poor attention, lack of judgment and insight, disturbance of volition, poor impulse control, preoccupation, active social avoidance). Scores range from 16 to 112 and decrease as patients improve.

CONTINUED TREATMENT: A new trial

Mr. F participated in a 4-week, double-blind, placebo-controlled trial of aripiprazole, 2, 10, or 30 mg/d, versus haloperidol, 10 mg/d.

One month later, he entered a second aripiprazole trial: a 4-day, open-label study starting at 5 mg/d with titration to 20 mg/d. In the interval between the two trials, Mr. F was prescribed thiothixene, 10 mg/d, and benztropine, 2 mg at bedtime.

During the 4-day trial, he complained of insomnia and was given chloral hydrate, 500 to 1,000 mg at bedtime. He also complained of anxiety and was started on lorazepam, 2 mg bid.

After completing the open-label aripiprazole trial, Mr. F exhibited no behavioral problems and complied with ward routine. He was discharged after 17 days, at which time he denied auditory or visual hallucinations. His thinking seemed clear and his insight improved. His Global Assessment of Functioning (GAF) score at discharge was 55, suggesting moderate symptoms and difficulty in social and occupational functioning.

For the next 5 1/2 years, Mr. F was maintained on aripiprazole, 20 mg/d, as part of the same ongoing open-label trial. During that period he also took lorazepam, 1 mg bid prn; oxazepam, 15 mg bid; or clonazepam, 0.5 mg bid, for anxiety.

Mr. F. exhibited significant sustained improvement as measured with the Positive and Negative Symptom Scale (PANSS), Clinical Global Impression scale (CGI), and GAF (Table). His TD remained mild throughout the trial, as determined through AIMS scores. He also reported no EPS, akathisia, or other adverse events.

About 18 months after starting aripiprazole, Mr. F resumed working part time. In September 2001, he stopped receiving disability benefits and started supporting himself again.

FOLLOW-UP: ‘The voices were ugly’

In December 2001, after 6 years without hospitalization, Mr. F was back in the psychiatric ward. One week before admission, he reported that he had been having panic attacks because “the voices were ugly.” He only slept 4 to 5 hours per night.

He then revealed that he had stopped taking aripiprazole for 2 weeks because he had no longer felt ill. He was still taking his lorazepam, however.

Mr. F appeared mildly anxious upon presentation and his affect was blunted. On examination, his thought processes were linear; he was once again hearing voices and experiencing delusions of telepathic control.

The patient was placed back on aripiprazole, 20 mg/d. His behavior on the ward improved dramatically, and the frequency and severity of his delusions and auditory hallucinations decreased gradually.

At discharge, Mr. F’s insight was good, his delusions had disappeared, and auditory hallucinations were rare. He was instructed to continue the aripiprazole and was prescribed clonazepam, 0.5 mg bid, for his anxiety and trazodone, 50 mg at bed-time, to help his sleep.

Since then, Mr. F has lived on his own, is working steadily, and has not required hospitalization. He stopped taking trazodone soon after discharge, but continues taking aripiprazole and clonazepam as prescribed. His hygiene is good, and he is making amends with family members. He attends church every Sunday—free of the messianic delusions that once tormented him. He also stopped abusing alcohol on his own in 1995 and has remained abstinent since.

 

How can we ensure that patients with schizophrenia keep taking their medications—regardless of whether symptoms are present?

Dr. Canive’s observations

Clinical trials measure a drug’s efficacy under highly controlled circumstances. In the “real world,” however, noncompliance due to intolerability can undermine a medication’s effectiveness.

Too often noncompliance—stemming from abatement of symptoms or the emergence of side effects—derails treatment of schizophrenia. Misdrahi et al found that medication noncompliance accounts for 40% of schizophrenia relapses occurring more than 1 year after patients’ first hospitalization.⁴

Given aripiprazole’s 75-hour half-life, one might not expect to see symptoms emerge so soon after discontinuation. It is possible that:

• Mr. F. abstained from aripiprazole longer than he realized—or admitted
• Unidentified stressful life events also exacerbated symptoms and precipitated hospitalization.

When Mr. F consistently followed his regimen, his positive symptoms abated and he could attempt to live a normal life.

Our patients must understand that schizophrenia is a lifelong illness and that continued adherence to medication—even when symptoms do not exist—is crucial. A strong therapeutic alliance,⁵ increased social support, adjunctive cognitive-behavioral therapy, psychosocial interventions,⁶ and medications with fewer and less-severe side effects may help patients embrace this message.

Related resources

• Tamminga CA. Partial dopamine agonists in the treatment of psychosis. J Neural Transm 2002;109:411-20.

Drug brand names

• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Benztropine • Cogentin
• Chlorpromazine • Thorazine
• Clonazepam • Klonopin
• Diazepam • Valium
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Lorazepam • Ativan
• Loxapine • Loxitane
• Oxazepam • Serax
• Thiothixene • Navane
• Trazodone • Desyrel

Disclosure

The author receives research/grant support from and is a speaker for and consultant to Bristol-Myers Squibb Co. He also receives research/grant support from and/or is a speaker for AstraZeneca Pharmaceuticals, Janssen Pharmaceutica, and Eli Lilly and Co.

HISTORY: A sudden vision

Ms. K, 73, was in reasonably good health when one day she suddenly noticed red, green, and yellow birds and butterflies covering her wall.

Ms. K, who lives alone, was frightened at first, but she did not immediately alert anyone because she thought she “was just seeing things, and they’ll go away.”

Instead, she saw more visions over the next 3 months. She once “watched” as two doctors and a nun carried a middle-aged burn victim into her apartment. She remembers seeing the doctors put a “patch” over the woman’s body. To Ms. K, this experience seemed so shockingly real that she called 911, reporting, “That woman should have been in the hospital!”

She reports that a pack of butterflies once “followed” her to the market. She vividly recalls how they crawled about her shoes and legs as she entered the store. When asked if anyone noticed her insect-covered extremities, she replied matter-of-factly, “Maybe it’s not for them to see, maybe it’s just for me,” as if her hallucinations were a divine gift.

Ms. K’s hallucinations usually occur at home, where she spends most of her time. She says that the images are fleeting, lasting from a few seconds to several minutes, and that the creatures fly silently around her room.

Ms. K’s daughter grew concerned that the hallucinations were increasingly diminishing her mother’s ability to care for herself. She brought Ms. K into our emergency department, from which the patient was admitted.

On admission, Ms. K said she had lost 20 lbs within 6 months, and that “concentrating on those things in the house” was impairing her sleep. She denied recent illness, trauma, loss of conscious ness, changes in medications, seizures, drug or alcohol use, suicidal or homicidal ideation, or specific stress in her life. She added that she often cooks for herself—only to lose her appetite after seeing bugs and other creatures crawl into her food.

Her medical history includes hypertension, type 2 diabetes mellitus, peripheral vascular disease, urinary incontinence, gastroesophageal reflux, glaucoma in her left eye, and bilateral cataracts. She denies any psychiatric history and adds that she had never experienced hallucinations until about 3 months before hospitalization. She also denies any history of auditory, tactile, or olfactory hallucinations.

Would you suspect a primary psychotic illness? What clinical tests might help us understand Ms. K’s progressively debilitating visual hallucinations?

The authors’ observations

Ms. K’s case places us at the crossroads of psychiatric disturbances and medical conditions that can present as or precipitate apparent psychiatric symptoms. Delirium, dementia, psychosis, endocrinopathies, encephalitis, electrolyte disturbances, drug abuse/withdrawal, and occipital or temporal lobe seizures are all possible differential diagnoses (Table 1).

A cognitive function screening and a battery of laboratory tests, imaging scans, and neurologic and vision exams are needed to uncover the cause of her hallucinations.

EVALUATION: Looking for clues

Ms. K’s left pupil was fixed at 6 mm and did not respond to light, while the right pupil was regular and reactive to light at 3 mm. Using a Snellen eye chart, her visual acuity was poor: 20/100 to 20/200 in her right eye and less than 20/200 in the left eye. She scored a 29 out of 30 on the Folstein Mini-Mental State Examination (MMSE), indicating her cognition was intact. The remainder of the neurologic exam was unremarkable.

At admission, Ms. K’s medications included metoprolol, 100 mg qd, for hypertension; lansoprazole, 30 mg qd, for gastroesophageal reflux; tolterodine, 2 mg bid, and oxybutynin, 10 mg qd, for urinary incontinence; repaglinide, 2 mg bid, for type 2 diabetes; and three ophthalmic agents: brimonidine, prednisolone, and dorzolamide/timolol. The patient had been maintained on these medications for more than 2 years with no recent changes in dosing.

Results of Ms. K’s lab studies were normal, including a basic metabolic panel, CBC, liver function tests, urinalysis, B12, thyroid panel, rapid plasma reagin test, and urine drug screen.

A head CT without contrast revealed chronic small-vessel ischemic white matter disease and a chronic infarct of the left cerebellar hemisphere. No acute intracranial hemorrhages, masses, or other abnormalities were noted. No seizures were seen on EEG.

Table 1

Common causes of visual hallucinations

Schizophrenia
Delirium
Dementias
Substance-induced psychosis
Electrolyte disturbances
Occipital and temporal lobe epilepsy
Charles Bonnet syndrome

What do the laboratory and imaging tests reveal about Ms. K’s hallucinations? Is her diagnosis delirium? Alzheimer’s or other type of dementia? Schizophrenia?

The authors’ observations

Visual hallucinations—often of deceased parents or siblings, unknown intruders, and animals—can occur in up to 25% of patients with Alzheimer’s-type dementia.¹ Also, patients with Lewy body dementia often present with well-formed visual hallucinations, which are thought to result from temporal lobe involvement by the characteristic Lewy bodies.

 

To diagnose dementia, DSM-IV requires the presence of multiple cognitive deficits manifested by memory impairment and one or more of the following:

• aphasia
• apraxia
• agnosia
• disturbance of executive functioning.²

Ms. K exhibited none of these characteristics, and she retained full executive function—she could balance her checkbook, buy groceries, and cook for herself. Also, her MMSE score was high.

Ms. K showed no consciousness fluctuations or attention deficits, two features commonly seen in delirium. She was alert and oriented throughout the interview, and her flow of thought, speech, language, and attention were appropriate. Therefore, delirium can be reasonably excluded.

The hallucinations probably do not signal onset of schizophrenia because of Ms. K’s age at presentation, lack of family history of psychotic disorder, and paucity of negative symptoms. Auditory hallucinations are much more common in psychosis, and isolated visual hallucinations rarely occur in schizophrenia.

Finally, Ms. K’s electrophysiologic, laboratory, and imaging studies revealed isolated systolic hypertension, low visual acuity, and a mild gait disturbance. Severe left lens opacification accounted for the patient’s discordant pupillary light reflex. None of these findings explained her visual hallucinations, however.

Is a non-psychiatric disorder causing Ms. K’s hallucinations? What type of medication might alleviate her symptoms?

The authors’ observations

Given Ms. K’s strong cognitive function and poor visual acuity, we concluded that her hallucinations may fit the criteria for Charles Bonnet syndrome (CBS), a poorly understood medical phenomenon.

CBS is characterized by complex visual hallucinations in visually impaired elderly patients without cognitive deficits (Table 2).^3,4 Swiss philosopher Charles Bonnet first described the disorder in 1760 to explain the vivid visual hallucinations of his 89-year-old grandfather, who had severe cataracts but no cognitive deficits.³ Bonnet’s grandfather claimed to have visions of men, women, birds, buildings, and tapestries.³

CBS is increasingly recognized and reported, but the medical community has never formed a universally accepted definition for this phenomenon. Persons with CBS react positively or negatively to their hallucinations, and the images may stimulate anxiety, anger, or mild paranoia. Research has focused on prevalence, risk indicators, and treatment.

Table 2

Charles Bonnet syndrome: fast facts

Visual hallucinations in older, visually impaired persons Gross cognitive deficits not present Prevalence of up to 14% of visually handicapped patients. Images disappear upon eye closure Social isolation may be a risk factor Treatment includes support and reassurance, typical and atypical antipsychotics, anticonvulsants, and 5-HT3 receptor antagonists

Teunisse et al determined that visual hallucinations plague up to 14% of sight-impaired persons.^4,5 The hallucinations vary widely: people, animals, flowers, vehicles, buildings, and sometimes complete scenes.^4,5 Significant risk factors for CBS include advanced age and low visual acuity.^4,5 Loneliness, introversion, and shyness are additional risk indicators in older, visually handicapped persons.⁶ Therefore, social isolation may be a predisposing factor.

Drug treatment of visual hallucinations in CBS currently includes antipsychotics, such as quetiapine (25 to 100 mg/d) and risperidone (0.25 to 1.0 mg/d).⁷ However, mixed results have been reported after use of antipsychotics in CBS; one patient’s visual hallucinations were exacerbated after risperidone was initiated.⁸ Case reports have also described the use of valproate, carbamazepine, and ondansetron in CBS.^9-11

Empathy and patient education are the cornerstones of CBS treatment.³ Patients need to be reassured that their visions are benign. For many, simply increasing the amount of ambient light in the home can reduce hallucinations.

TREATMENT A frog in the toilet

Ms. K was started on quetiapine, 25 mg bid, to try to promote restorative sleep and resolve her hallucinations. Up to 18% of persons treated with quetiapine report somnolence as an adverse effect, vs. 3 to 8% of those treated with risperidone.¹²

During her hospital stay, Ms. K experienced no visual hallucinations during the day but reported seeing a grayish-brown bullfrog in the toilet at night. This hallucination did not frighten her; she would simply close the bathroom door and wait until the bullfrog “disappeared.”

Her sleep improved, as did her appetite. She participated in daily group sessions and socialized with other patients.

After 12 days, Ms. K was discharged. To decrease her social isolation, we encouraged her to participate in a day program for seniors. We also continued her on quetiapine, 25 mg bid.

Five months later, her primary care physician reports that Ms. K remains symptom free while maintaining her quetiapine dosage.

Related resources

• Royal National Institute of the Blind: Fact sheet for Charles Bonnet syndrome. Available at: http://www.rnib.org.uk/info/cbsfin.htm
• Verstraten PFJ. The Charles Bonnet syndrome: Development of a protocol for clinical practice in a multidisciplinary approach from assessment to intervention. Available at: http://www.rehab-syn.enter.iris.se/kc-syn/cb.htm
• Adamczyk DT. Optometric educators. Am I seeing things? Optometry Today June 18, 1999:37-9. Available at: http://www.optometry.co.uk/articles/19990618/Adamczyk.pdf

 

Drug brand names

• Brimonidine Ophthalmic • Alphagan
• Carbamazepine • Tegretol
• Dorzolamide/Timolol • Cosopt
• Lansoprazole • Prevacid
• Metoprolol • Toprol XL
• Ondansetron • Zofran
• Oxybutynin • Ditropan XL
• Quetiapine • Seroquel
• Repaglinide • Prandin
• Risperidone • Risperdal
• Tolterodine • Detrol
• Valproate • Depakote

Disclosure

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

HISTORY: A sudden vision

Ms. K, 73, was in reasonably good health when one day she suddenly noticed red, green, and yellow birds and butterflies covering her wall.

Ms. K, who lives alone, was frightened at first, but she did not immediately alert anyone because she thought she “was just seeing things, and they’ll go away.”

Instead, she saw more visions over the next 3 months. She once “watched” as two doctors and a nun carried a middle-aged burn victim into her apartment. She remembers seeing the doctors put a “patch” over the woman’s body. To Ms. K, this experience seemed so shockingly real that she called 911, reporting, “That woman should have been in the hospital!”

She reports that a pack of butterflies once “followed” her to the market. She vividly recalls how they crawled about her shoes and legs as she entered the store. When asked if anyone noticed her insect-covered extremities, she replied matter-of-factly, “Maybe it’s not for them to see, maybe it’s just for me,” as if her hallucinations were a divine gift.

Ms. K’s hallucinations usually occur at home, where she spends most of her time. She says that the images are fleeting, lasting from a few seconds to several minutes, and that the creatures fly silently around her room.

Ms. K’s daughter grew concerned that the hallucinations were increasingly diminishing her mother’s ability to care for herself. She brought Ms. K into our emergency department, from which the patient was admitted.

On admission, Ms. K said she had lost 20 lbs within 6 months, and that “concentrating on those things in the house” was impairing her sleep. She denied recent illness, trauma, loss of conscious ness, changes in medications, seizures, drug or alcohol use, suicidal or homicidal ideation, or specific stress in her life. She added that she often cooks for herself—only to lose her appetite after seeing bugs and other creatures crawl into her food.

Her medical history includes hypertension, type 2 diabetes mellitus, peripheral vascular disease, urinary incontinence, gastroesophageal reflux, glaucoma in her left eye, and bilateral cataracts. She denies any psychiatric history and adds that she had never experienced hallucinations until about 3 months before hospitalization. She also denies any history of auditory, tactile, or olfactory hallucinations.

Would you suspect a primary psychotic illness? What clinical tests might help us understand Ms. K’s progressively debilitating visual hallucinations?

The authors’ observations

Ms. K’s case places us at the crossroads of psychiatric disturbances and medical conditions that can present as or precipitate apparent psychiatric symptoms. Delirium, dementia, psychosis, endocrinopathies, encephalitis, electrolyte disturbances, drug abuse/withdrawal, and occipital or temporal lobe seizures are all possible differential diagnoses (Table 1).

A cognitive function screening and a battery of laboratory tests, imaging scans, and neurologic and vision exams are needed to uncover the cause of her hallucinations.

EVALUATION: Looking for clues

Ms. K’s left pupil was fixed at 6 mm and did not respond to light, while the right pupil was regular and reactive to light at 3 mm. Using a Snellen eye chart, her visual acuity was poor: 20/100 to 20/200 in her right eye and less than 20/200 in the left eye. She scored a 29 out of 30 on the Folstein Mini-Mental State Examination (MMSE), indicating her cognition was intact. The remainder of the neurologic exam was unremarkable.

At admission, Ms. K’s medications included metoprolol, 100 mg qd, for hypertension; lansoprazole, 30 mg qd, for gastroesophageal reflux; tolterodine, 2 mg bid, and oxybutynin, 10 mg qd, for urinary incontinence; repaglinide, 2 mg bid, for type 2 diabetes; and three ophthalmic agents: brimonidine, prednisolone, and dorzolamide/timolol. The patient had been maintained on these medications for more than 2 years with no recent changes in dosing.

Results of Ms. K’s lab studies were normal, including a basic metabolic panel, CBC, liver function tests, urinalysis, B12, thyroid panel, rapid plasma reagin test, and urine drug screen.

A head CT without contrast revealed chronic small-vessel ischemic white matter disease and a chronic infarct of the left cerebellar hemisphere. No acute intracranial hemorrhages, masses, or other abnormalities were noted. No seizures were seen on EEG.

Table 1

Common causes of visual hallucinations

Schizophrenia
Delirium
Dementias
Substance-induced psychosis
Electrolyte disturbances
Occipital and temporal lobe epilepsy
Charles Bonnet syndrome

What do the laboratory and imaging tests reveal about Ms. K’s hallucinations? Is her diagnosis delirium? Alzheimer’s or other type of dementia? Schizophrenia?

The authors’ observations

Visual hallucinations—often of deceased parents or siblings, unknown intruders, and animals—can occur in up to 25% of patients with Alzheimer’s-type dementia.¹ Also, patients with Lewy body dementia often present with well-formed visual hallucinations, which are thought to result from temporal lobe involvement by the characteristic Lewy bodies.

 

To diagnose dementia, DSM-IV requires the presence of multiple cognitive deficits manifested by memory impairment and one or more of the following:

• aphasia
• apraxia
• agnosia
• disturbance of executive functioning.²

Ms. K exhibited none of these characteristics, and she retained full executive function—she could balance her checkbook, buy groceries, and cook for herself. Also, her MMSE score was high.

Ms. K showed no consciousness fluctuations or attention deficits, two features commonly seen in delirium. She was alert and oriented throughout the interview, and her flow of thought, speech, language, and attention were appropriate. Therefore, delirium can be reasonably excluded.

The hallucinations probably do not signal onset of schizophrenia because of Ms. K’s age at presentation, lack of family history of psychotic disorder, and paucity of negative symptoms. Auditory hallucinations are much more common in psychosis, and isolated visual hallucinations rarely occur in schizophrenia.

Finally, Ms. K’s electrophysiologic, laboratory, and imaging studies revealed isolated systolic hypertension, low visual acuity, and a mild gait disturbance. Severe left lens opacification accounted for the patient’s discordant pupillary light reflex. None of these findings explained her visual hallucinations, however.

Is a non-psychiatric disorder causing Ms. K’s hallucinations? What type of medication might alleviate her symptoms?

The authors’ observations

Given Ms. K’s strong cognitive function and poor visual acuity, we concluded that her hallucinations may fit the criteria for Charles Bonnet syndrome (CBS), a poorly understood medical phenomenon.

CBS is characterized by complex visual hallucinations in visually impaired elderly patients without cognitive deficits (Table 2).^3,4 Swiss philosopher Charles Bonnet first described the disorder in 1760 to explain the vivid visual hallucinations of his 89-year-old grandfather, who had severe cataracts but no cognitive deficits.³ Bonnet’s grandfather claimed to have visions of men, women, birds, buildings, and tapestries.³

CBS is increasingly recognized and reported, but the medical community has never formed a universally accepted definition for this phenomenon. Persons with CBS react positively or negatively to their hallucinations, and the images may stimulate anxiety, anger, or mild paranoia. Research has focused on prevalence, risk indicators, and treatment.

Table 2

Charles Bonnet syndrome: fast facts

Visual hallucinations in older, visually impaired persons Gross cognitive deficits not present Prevalence of up to 14% of visually handicapped patients. Images disappear upon eye closure Social isolation may be a risk factor Treatment includes support and reassurance, typical and atypical antipsychotics, anticonvulsants, and 5-HT3 receptor antagonists

Teunisse et al determined that visual hallucinations plague up to 14% of sight-impaired persons.^4,5 The hallucinations vary widely: people, animals, flowers, vehicles, buildings, and sometimes complete scenes.^4,5 Significant risk factors for CBS include advanced age and low visual acuity.^4,5 Loneliness, introversion, and shyness are additional risk indicators in older, visually handicapped persons.⁶ Therefore, social isolation may be a predisposing factor.

Drug treatment of visual hallucinations in CBS currently includes antipsychotics, such as quetiapine (25 to 100 mg/d) and risperidone (0.25 to 1.0 mg/d).⁷ However, mixed results have been reported after use of antipsychotics in CBS; one patient’s visual hallucinations were exacerbated after risperidone was initiated.⁸ Case reports have also described the use of valproate, carbamazepine, and ondansetron in CBS.^9-11

Empathy and patient education are the cornerstones of CBS treatment.³ Patients need to be reassured that their visions are benign. For many, simply increasing the amount of ambient light in the home can reduce hallucinations.

TREATMENT A frog in the toilet

Ms. K was started on quetiapine, 25 mg bid, to try to promote restorative sleep and resolve her hallucinations. Up to 18% of persons treated with quetiapine report somnolence as an adverse effect, vs. 3 to 8% of those treated with risperidone.¹²

During her hospital stay, Ms. K experienced no visual hallucinations during the day but reported seeing a grayish-brown bullfrog in the toilet at night. This hallucination did not frighten her; she would simply close the bathroom door and wait until the bullfrog “disappeared.”

Her sleep improved, as did her appetite. She participated in daily group sessions and socialized with other patients.

After 12 days, Ms. K was discharged. To decrease her social isolation, we encouraged her to participate in a day program for seniors. We also continued her on quetiapine, 25 mg bid.

Five months later, her primary care physician reports that Ms. K remains symptom free while maintaining her quetiapine dosage.

Related resources

• Royal National Institute of the Blind: Fact sheet for Charles Bonnet syndrome. Available at: http://www.rnib.org.uk/info/cbsfin.htm
• Verstraten PFJ. The Charles Bonnet syndrome: Development of a protocol for clinical practice in a multidisciplinary approach from assessment to intervention. Available at: http://www.rehab-syn.enter.iris.se/kc-syn/cb.htm
• Adamczyk DT. Optometric educators. Am I seeing things? Optometry Today June 18, 1999:37-9. Available at: http://www.optometry.co.uk/articles/19990618/Adamczyk.pdf

 

Drug brand names

• Brimonidine Ophthalmic • Alphagan
• Carbamazepine • Tegretol
• Dorzolamide/Timolol • Cosopt
• Lansoprazole • Prevacid
• Metoprolol • Toprol XL
• Ondansetron • Zofran
• Oxybutynin • Ditropan XL
• Quetiapine • Seroquel
• Repaglinide • Prandin
• Risperidone • Risperdal
• Tolterodine • Detrol
• Valproate • Depakote

Disclosure

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

HISTORY: A sudden vision

Ms. K, 73, was in reasonably good health when one day she suddenly noticed red, green, and yellow birds and butterflies covering her wall.

Ms. K, who lives alone, was frightened at first, but she did not immediately alert anyone because she thought she “was just seeing things, and they’ll go away.”

Instead, she saw more visions over the next 3 months. She once “watched” as two doctors and a nun carried a middle-aged burn victim into her apartment. She remembers seeing the doctors put a “patch” over the woman’s body. To Ms. K, this experience seemed so shockingly real that she called 911, reporting, “That woman should have been in the hospital!”

She reports that a pack of butterflies once “followed” her to the market. She vividly recalls how they crawled about her shoes and legs as she entered the store. When asked if anyone noticed her insect-covered extremities, she replied matter-of-factly, “Maybe it’s not for them to see, maybe it’s just for me,” as if her hallucinations were a divine gift.

Ms. K’s hallucinations usually occur at home, where she spends most of her time. She says that the images are fleeting, lasting from a few seconds to several minutes, and that the creatures fly silently around her room.

Ms. K’s daughter grew concerned that the hallucinations were increasingly diminishing her mother’s ability to care for herself. She brought Ms. K into our emergency department, from which the patient was admitted.

On admission, Ms. K said she had lost 20 lbs within 6 months, and that “concentrating on those things in the house” was impairing her sleep. She denied recent illness, trauma, loss of conscious ness, changes in medications, seizures, drug or alcohol use, suicidal or homicidal ideation, or specific stress in her life. She added that she often cooks for herself—only to lose her appetite after seeing bugs and other creatures crawl into her food.

Her medical history includes hypertension, type 2 diabetes mellitus, peripheral vascular disease, urinary incontinence, gastroesophageal reflux, glaucoma in her left eye, and bilateral cataracts. She denies any psychiatric history and adds that she had never experienced hallucinations until about 3 months before hospitalization. She also denies any history of auditory, tactile, or olfactory hallucinations.

Would you suspect a primary psychotic illness? What clinical tests might help us understand Ms. K’s progressively debilitating visual hallucinations?

The authors’ observations

Ms. K’s case places us at the crossroads of psychiatric disturbances and medical conditions that can present as or precipitate apparent psychiatric symptoms. Delirium, dementia, psychosis, endocrinopathies, encephalitis, electrolyte disturbances, drug abuse/withdrawal, and occipital or temporal lobe seizures are all possible differential diagnoses (Table 1).

A cognitive function screening and a battery of laboratory tests, imaging scans, and neurologic and vision exams are needed to uncover the cause of her hallucinations.

EVALUATION: Looking for clues

Ms. K’s left pupil was fixed at 6 mm and did not respond to light, while the right pupil was regular and reactive to light at 3 mm. Using a Snellen eye chart, her visual acuity was poor: 20/100 to 20/200 in her right eye and less than 20/200 in the left eye. She scored a 29 out of 30 on the Folstein Mini-Mental State Examination (MMSE), indicating her cognition was intact. The remainder of the neurologic exam was unremarkable.

At admission, Ms. K’s medications included metoprolol, 100 mg qd, for hypertension; lansoprazole, 30 mg qd, for gastroesophageal reflux; tolterodine, 2 mg bid, and oxybutynin, 10 mg qd, for urinary incontinence; repaglinide, 2 mg bid, for type 2 diabetes; and three ophthalmic agents: brimonidine, prednisolone, and dorzolamide/timolol. The patient had been maintained on these medications for more than 2 years with no recent changes in dosing.

Results of Ms. K’s lab studies were normal, including a basic metabolic panel, CBC, liver function tests, urinalysis, B12, thyroid panel, rapid plasma reagin test, and urine drug screen.

A head CT without contrast revealed chronic small-vessel ischemic white matter disease and a chronic infarct of the left cerebellar hemisphere. No acute intracranial hemorrhages, masses, or other abnormalities were noted. No seizures were seen on EEG.

Table 1

Common causes of visual hallucinations

Schizophrenia
Delirium
Dementias
Substance-induced psychosis
Electrolyte disturbances
Occipital and temporal lobe epilepsy
Charles Bonnet syndrome

What do the laboratory and imaging tests reveal about Ms. K’s hallucinations? Is her diagnosis delirium? Alzheimer’s or other type of dementia? Schizophrenia?

The authors’ observations

Visual hallucinations—often of deceased parents or siblings, unknown intruders, and animals—can occur in up to 25% of patients with Alzheimer’s-type dementia.¹ Also, patients with Lewy body dementia often present with well-formed visual hallucinations, which are thought to result from temporal lobe involvement by the characteristic Lewy bodies.

 

To diagnose dementia, DSM-IV requires the presence of multiple cognitive deficits manifested by memory impairment and one or more of the following:

• aphasia
• apraxia
• agnosia
• disturbance of executive functioning.²

Ms. K exhibited none of these characteristics, and she retained full executive function—she could balance her checkbook, buy groceries, and cook for herself. Also, her MMSE score was high.

Ms. K showed no consciousness fluctuations or attention deficits, two features commonly seen in delirium. She was alert and oriented throughout the interview, and her flow of thought, speech, language, and attention were appropriate. Therefore, delirium can be reasonably excluded.

The hallucinations probably do not signal onset of schizophrenia because of Ms. K’s age at presentation, lack of family history of psychotic disorder, and paucity of negative symptoms. Auditory hallucinations are much more common in psychosis, and isolated visual hallucinations rarely occur in schizophrenia.

Finally, Ms. K’s electrophysiologic, laboratory, and imaging studies revealed isolated systolic hypertension, low visual acuity, and a mild gait disturbance. Severe left lens opacification accounted for the patient’s discordant pupillary light reflex. None of these findings explained her visual hallucinations, however.

Is a non-psychiatric disorder causing Ms. K’s hallucinations? What type of medication might alleviate her symptoms?

The authors’ observations

Given Ms. K’s strong cognitive function and poor visual acuity, we concluded that her hallucinations may fit the criteria for Charles Bonnet syndrome (CBS), a poorly understood medical phenomenon.

CBS is characterized by complex visual hallucinations in visually impaired elderly patients without cognitive deficits (Table 2).^3,4 Swiss philosopher Charles Bonnet first described the disorder in 1760 to explain the vivid visual hallucinations of his 89-year-old grandfather, who had severe cataracts but no cognitive deficits.³ Bonnet’s grandfather claimed to have visions of men, women, birds, buildings, and tapestries.³

CBS is increasingly recognized and reported, but the medical community has never formed a universally accepted definition for this phenomenon. Persons with CBS react positively or negatively to their hallucinations, and the images may stimulate anxiety, anger, or mild paranoia. Research has focused on prevalence, risk indicators, and treatment.

Table 2

Charles Bonnet syndrome: fast facts

Visual hallucinations in older, visually impaired persons Gross cognitive deficits not present Prevalence of up to 14% of visually handicapped patients. Images disappear upon eye closure Social isolation may be a risk factor Treatment includes support and reassurance, typical and atypical antipsychotics, anticonvulsants, and 5-HT3 receptor antagonists

Teunisse et al determined that visual hallucinations plague up to 14% of sight-impaired persons.^4,5 The hallucinations vary widely: people, animals, flowers, vehicles, buildings, and sometimes complete scenes.^4,5 Significant risk factors for CBS include advanced age and low visual acuity.^4,5 Loneliness, introversion, and shyness are additional risk indicators in older, visually handicapped persons.⁶ Therefore, social isolation may be a predisposing factor.

Drug treatment of visual hallucinations in CBS currently includes antipsychotics, such as quetiapine (25 to 100 mg/d) and risperidone (0.25 to 1.0 mg/d).⁷ However, mixed results have been reported after use of antipsychotics in CBS; one patient’s visual hallucinations were exacerbated after risperidone was initiated.⁸ Case reports have also described the use of valproate, carbamazepine, and ondansetron in CBS.^9-11

Empathy and patient education are the cornerstones of CBS treatment.³ Patients need to be reassured that their visions are benign. For many, simply increasing the amount of ambient light in the home can reduce hallucinations.

TREATMENT A frog in the toilet

Ms. K was started on quetiapine, 25 mg bid, to try to promote restorative sleep and resolve her hallucinations. Up to 18% of persons treated with quetiapine report somnolence as an adverse effect, vs. 3 to 8% of those treated with risperidone.¹²

During her hospital stay, Ms. K experienced no visual hallucinations during the day but reported seeing a grayish-brown bullfrog in the toilet at night. This hallucination did not frighten her; she would simply close the bathroom door and wait until the bullfrog “disappeared.”

Her sleep improved, as did her appetite. She participated in daily group sessions and socialized with other patients.

After 12 days, Ms. K was discharged. To decrease her social isolation, we encouraged her to participate in a day program for seniors. We also continued her on quetiapine, 25 mg bid.

Five months later, her primary care physician reports that Ms. K remains symptom free while maintaining her quetiapine dosage.

Related resources

• Royal National Institute of the Blind: Fact sheet for Charles Bonnet syndrome. Available at: http://www.rnib.org.uk/info/cbsfin.htm
• Verstraten PFJ. The Charles Bonnet syndrome: Development of a protocol for clinical practice in a multidisciplinary approach from assessment to intervention. Available at: http://www.rehab-syn.enter.iris.se/kc-syn/cb.htm
• Adamczyk DT. Optometric educators. Am I seeing things? Optometry Today June 18, 1999:37-9. Available at: http://www.optometry.co.uk/articles/19990618/Adamczyk.pdf

 

Drug brand names

• Brimonidine Ophthalmic • Alphagan
• Carbamazepine • Tegretol
• Dorzolamide/Timolol • Cosopt
• Lansoprazole • Prevacid
• Metoprolol • Toprol XL
• Ondansetron • Zofran
• Oxybutynin • Ditropan XL
• Quetiapine • Seroquel
• Repaglinide • Prandin
• Risperidone • Risperdal
• Tolterodine • Detrol
• Valproate • Depakote

Disclosure

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

History: Initial symptoms

Ms. G, 17, has battled attention-deficit/hyperactivity disorder (ADHD) since age 6, and within the past 2 years was also diagnosed as having schizoaffective disorder, bipolar type. An outpatient child psychiatrist and a therapist have helped keep her symptoms in control through much of her life.

During one recent visit to her psychiatrist, however, she complained of decreased energy, increased crying spells, broken sleep, and a depressed mood. She reported that these symptoms began approximately 2 months before the visit, and neither she nor her parents could identify a clear-cut cause.

Throughout her life she has complied with her drug regimens. For 2 years she has been taking divalproex sodium, 500 mg twice daily to manage her manic and depressive episodes, dextroamphetamine sulfate, 30 mg in the morning for her ADHD; risperidone, 2 mg at bedtime for her psychotic symptoms; and mestranol, 60 mcg/d, plus norethindrone, 1 mg/d, for contraception. A recent valproic acid reading of 62 μg/ml is consistent with levels over the last 2 years.

During previous psychotic episodes, Ms. G often became delusional and paranoid with command-type hallucinations. She destroyed her room during her most recent episode.

Ms. G’s adoptive mother accompanied her during this visit. She is concerned for her daughter, especially with the start of school about 1 month away.

Which would you address first: the depression or the psychosis? Would you change Ms. G’s medication and if so, how?

Figure 1 DEPRESSION IN SCHIZOPHRENIA: IMPROVING OUTCOMES

Drs. Yu’s and Maguire’s observations

Complaints of depression in a patient with schizoaffective disorder are especially concerning because multiple domains could be affected (Figure 1). For patients with schizophrenia, the 60% lifetime incidence of major depressive disorder substantially exceeds the 8 to 26% risk in the general population. Ms. G’s comorbid depression also may predispose her to an increased rate of relapse into schizoaffective psychosis, poor treatment response, and a longer duration of psychotic illness that could require hospitalization.¹

Although Ms. G’s divalproex level was therapeutic (between 50 and 100 μg/ml), some data indicate that valproic acid may be less effective in schizoaffective disorder than in bipolar I disorder. Still, treatment of schizoaffective disorder often follows antimanic and antidepressant protocols.²

Treatment: An agent is added

The outpatient psychiatrist adds fluoxetine, 20 mg each morning, to address Ms. G’s depressive symptoms. She reports no improvement after 1 month, and her fluoxetine is increased to 30 mg/d.

Three weeks later, Ms. G’s parents bring her to the psychiatrist for an emergency visit. She reports suicidal ideation over the previous month. Rolling up both sleeves, she reveals several superficial cuts on her forearms and wrists that she inflicted after breaking up with her boyfriend.

Her mother, appearing anxious and overwhelmed, reports that her daughter pushed her because she had refused to give Ms. G her calling card. She had told her mother that she wanted to call a boy in Utah that she had met over the Internet.

Ms. G’s speech is noticeably pressured and she is extremely distractible. Her mother notes that her daughter is sleeping only 2 to 3 hours a night, yet exhibits no decrease in energy. Still depressed, her affect is markedly labile, crying at one moment when discussing her suicidality, then railing at her mother when she tries to explain Ms. G’s aggressiveness. When the psychiatrist recommends hospitalization to stabilize her symptoms, she vehemently demands to be let out so that she can run in front of a moving car. The police are called, and she is restrained and brought into the hospital.

What caused Ms. G’s sudden decline? How would you address it?

Drs. Yu’s and Maguire’s observations

Although antidepressants can effectively treat depression in schizoaffective disorder, many of these medications can trigger a manic episode,³ which can include mania, mixed mania with depression, or rapid cycling every few days or hours. In Ms. G’s case, an increase in serotonin due to the fluoxetine may have caused her mania.

We would stop the fluoxetine and see if her manic symptoms resolve. Fluoxetine’s long half-life (4 to 16 days) cuts down the odds of a serotonin-discontinuation syndrome, making immediate discontinuation feasible.

Still, the cause of Ms. G’s depressive symptoms remains unknown. At this stage, observation in the adolescent inpatient ward holds our best hope of reaching a definitive diagnosis.

Treatment: A diagnostic clue surfaces

Blood tests on admission (including a negative drug screen for narcotics or other depressogenic substances) are normal, and her valproic acid level is 61 μg/ml. Her divalproex is increased to 500 mg in the morning and 750 mg at bedtime, and she is tapered off fluoxetine. Her symptoms gradually improve with the change in the medications and her attendance in milieu and group therapy on the ward. A second valproic acid reading on day three of hospitalization is 67 μg/ml.

 

That day, a nurse informs the inpatient child/adolescent psychiatrist that Ms. G has requested extra hospital gowns. Ms. G later reveals that for about 4 months she has been producing a milky discharge from both breasts, and that the flow has been increasing in frequency and quantity. She adds that she has not menstruated for almost 5 months and complains of breast tenderness.

What do Ms. G’s latest symptoms suggest? How will your response to these symptoms affect treatment?

Drs. Yu’s and Maguire’s observations

Complaints of menstrual irregularities, breast tenderness, and galactorrhea should arouse suspicions of hyperprolactinemia. Because tumors that raise prolactin levels are rare, medications are the most likely culprit in Ms. G’s case. Dopamine blockade within the tuberoinfundibular tract is the mechanism of action behind prolactin elevation.⁴

Prolactin levels in patients with schizophrenia are generally normal (1 to 25 mg/L) prior to treatment,⁵ but have been known to increase with use of typical antipsychotics. The atypical antipsychotic risperidone has been associated with dose-related increases in plasma prolactin concentration, although Kleinberg et al found no correlation between risperidone-induced plasma prolactin concentrations and adverse events.⁶

Figure 2 POSSIBLE ADVERSE EFFECTS OF HYPERPROLACTINEMIA⁸

Prolactin-sparing atypical antipsychotics such as olanzapine, quetiapine, ziprasidone, and aripiprazole may cause a transient prolactin increase in the first few weeks of use. These levels tend to remain within the normal range before decreasing to baseline levels or lower.^7,8

Prolactin elevation in women may lead to an estrogen deficiency, causing changes in mood and cognition and psychopathology⁹ that can manifest as increased depression, anxiety, and hostility.¹⁰ Hyperprolactinemia can also cause depression in men, though the mechanism of action is unknown.

Prolactin elevation can lead to numerous other health disturbances (Figure 2). When screening women who are taking antipsychotics, ask about menstrual irregularities, sexual dysfunction, breast tenderness, and galactorrhea. Ask male patients about a loss of libido, erectile dysfunction, ejaculatory dysfunction, and gynecomastia.

When hyperprolactinemia becomes apparent, we suggest discontinuing the offending drug and, if necessary:

• switching to a prolactin-sparing atypical antipsychotic
• or trying another agent, such as bromocriptine or pergolide, if switching to another antipsychotic is infeasible.^10,11

Baseline prolactin levels should be measured before starting any prolactin-elevating antipsychotic. Because prolactin levels may not correlate with severity of clinical symptoms, the net change in these levels may be a better indicator.⁴ If prolactin levels exceed 100 mg/L, consider an MRI with fine cuts though the sellae to check for a primary adenoma.⁴

Conclusion: A cause is found

An MRI of Ms. G’s head is normal, but her serum prolactin level is 125 μg/L. Her risperidone is tapered off, and olanzapine, 10 mg at bedtime, is started with her mother’s consent. Two days later, her prolactin level drops to 85 μg/L. Notable improvement is reported on day seven of hospitalization; she is sleeping and eating well with no suicidal or homicidal ideations and notes no psychotic symptoms. She is discharged that day.

Two weeks later, Ms. G’s improvement continues. Lab tests reveal normal prolactin levels. Over the next few months, she remains stable, attends school, and takes her medications with no adverse effects.

Related resources

• Maguire GA. Prolactin elevation with antipsychotic medications: mechanisms of action and clinical consequences. J Clin Psychiatry 2002; 63(suppl 4):56-62. Available at: www.psychiatrist.com/supplenet/v63s04/v63s0408.pdf. Accessed March 11, 2003.

Drug brand names

• Aripiprazole • Abilify
• Dextroamphetamine sulfate • Dexadrine
• Divalproex sodium • Depakote
• Fluoxetine • Prozac
• Mestranol • Necon 1/50
• Norethindrone • Activella
• Pergolide • Permax
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

Dr. Yu receives research/grant support from, is a consultant to, and/or is a speaker for Cephalon Inc., Eli Lilly and Co., Novartis Pharmaceuticals Corp., and Pfizer Inc.

Dr. Maguire receives research/grant support from, is a consultant to, and/or is a speaker for Eli Lilly and Co., Pfizer Inc., Forest Laboratories, and GlaxoSmithKline.

History: Initial symptoms

Ms. G, 17, has battled attention-deficit/hyperactivity disorder (ADHD) since age 6, and within the past 2 years was also diagnosed as having schizoaffective disorder, bipolar type. An outpatient child psychiatrist and a therapist have helped keep her symptoms in control through much of her life.

During one recent visit to her psychiatrist, however, she complained of decreased energy, increased crying spells, broken sleep, and a depressed mood. She reported that these symptoms began approximately 2 months before the visit, and neither she nor her parents could identify a clear-cut cause.

Throughout her life she has complied with her drug regimens. For 2 years she has been taking divalproex sodium, 500 mg twice daily to manage her manic and depressive episodes, dextroamphetamine sulfate, 30 mg in the morning for her ADHD; risperidone, 2 mg at bedtime for her psychotic symptoms; and mestranol, 60 mcg/d, plus norethindrone, 1 mg/d, for contraception. A recent valproic acid reading of 62 μg/ml is consistent with levels over the last 2 years.

During previous psychotic episodes, Ms. G often became delusional and paranoid with command-type hallucinations. She destroyed her room during her most recent episode.

Ms. G’s adoptive mother accompanied her during this visit. She is concerned for her daughter, especially with the start of school about 1 month away.

Which would you address first: the depression or the psychosis? Would you change Ms. G’s medication and if so, how?

Figure 1 DEPRESSION IN SCHIZOPHRENIA: IMPROVING OUTCOMES

Drs. Yu’s and Maguire’s observations

Complaints of depression in a patient with schizoaffective disorder are especially concerning because multiple domains could be affected (Figure 1). For patients with schizophrenia, the 60% lifetime incidence of major depressive disorder substantially exceeds the 8 to 26% risk in the general population. Ms. G’s comorbid depression also may predispose her to an increased rate of relapse into schizoaffective psychosis, poor treatment response, and a longer duration of psychotic illness that could require hospitalization.¹

Although Ms. G’s divalproex level was therapeutic (between 50 and 100 μg/ml), some data indicate that valproic acid may be less effective in schizoaffective disorder than in bipolar I disorder. Still, treatment of schizoaffective disorder often follows antimanic and antidepressant protocols.²

Treatment: An agent is added

The outpatient psychiatrist adds fluoxetine, 20 mg each morning, to address Ms. G’s depressive symptoms. She reports no improvement after 1 month, and her fluoxetine is increased to 30 mg/d.

Three weeks later, Ms. G’s parents bring her to the psychiatrist for an emergency visit. She reports suicidal ideation over the previous month. Rolling up both sleeves, she reveals several superficial cuts on her forearms and wrists that she inflicted after breaking up with her boyfriend.

Her mother, appearing anxious and overwhelmed, reports that her daughter pushed her because she had refused to give Ms. G her calling card. She had told her mother that she wanted to call a boy in Utah that she had met over the Internet.

Ms. G’s speech is noticeably pressured and she is extremely distractible. Her mother notes that her daughter is sleeping only 2 to 3 hours a night, yet exhibits no decrease in energy. Still depressed, her affect is markedly labile, crying at one moment when discussing her suicidality, then railing at her mother when she tries to explain Ms. G’s aggressiveness. When the psychiatrist recommends hospitalization to stabilize her symptoms, she vehemently demands to be let out so that she can run in front of a moving car. The police are called, and she is restrained and brought into the hospital.

What caused Ms. G’s sudden decline? How would you address it?

Drs. Yu’s and Maguire’s observations

Although antidepressants can effectively treat depression in schizoaffective disorder, many of these medications can trigger a manic episode,³ which can include mania, mixed mania with depression, or rapid cycling every few days or hours. In Ms. G’s case, an increase in serotonin due to the fluoxetine may have caused her mania.

We would stop the fluoxetine and see if her manic symptoms resolve. Fluoxetine’s long half-life (4 to 16 days) cuts down the odds of a serotonin-discontinuation syndrome, making immediate discontinuation feasible.

Still, the cause of Ms. G’s depressive symptoms remains unknown. At this stage, observation in the adolescent inpatient ward holds our best hope of reaching a definitive diagnosis.

Treatment: A diagnostic clue surfaces

Blood tests on admission (including a negative drug screen for narcotics or other depressogenic substances) are normal, and her valproic acid level is 61 μg/ml. Her divalproex is increased to 500 mg in the morning and 750 mg at bedtime, and she is tapered off fluoxetine. Her symptoms gradually improve with the change in the medications and her attendance in milieu and group therapy on the ward. A second valproic acid reading on day three of hospitalization is 67 μg/ml.

 

That day, a nurse informs the inpatient child/adolescent psychiatrist that Ms. G has requested extra hospital gowns. Ms. G later reveals that for about 4 months she has been producing a milky discharge from both breasts, and that the flow has been increasing in frequency and quantity. She adds that she has not menstruated for almost 5 months and complains of breast tenderness.

What do Ms. G’s latest symptoms suggest? How will your response to these symptoms affect treatment?

Drs. Yu’s and Maguire’s observations

Complaints of menstrual irregularities, breast tenderness, and galactorrhea should arouse suspicions of hyperprolactinemia. Because tumors that raise prolactin levels are rare, medications are the most likely culprit in Ms. G’s case. Dopamine blockade within the tuberoinfundibular tract is the mechanism of action behind prolactin elevation.⁴

Prolactin levels in patients with schizophrenia are generally normal (1 to 25 mg/L) prior to treatment,⁵ but have been known to increase with use of typical antipsychotics. The atypical antipsychotic risperidone has been associated with dose-related increases in plasma prolactin concentration, although Kleinberg et al found no correlation between risperidone-induced plasma prolactin concentrations and adverse events.⁶

Figure 2 POSSIBLE ADVERSE EFFECTS OF HYPERPROLACTINEMIA⁸

Prolactin-sparing atypical antipsychotics such as olanzapine, quetiapine, ziprasidone, and aripiprazole may cause a transient prolactin increase in the first few weeks of use. These levels tend to remain within the normal range before decreasing to baseline levels or lower.^7,8

Prolactin elevation in women may lead to an estrogen deficiency, causing changes in mood and cognition and psychopathology⁹ that can manifest as increased depression, anxiety, and hostility.¹⁰ Hyperprolactinemia can also cause depression in men, though the mechanism of action is unknown.

Prolactin elevation can lead to numerous other health disturbances (Figure 2). When screening women who are taking antipsychotics, ask about menstrual irregularities, sexual dysfunction, breast tenderness, and galactorrhea. Ask male patients about a loss of libido, erectile dysfunction, ejaculatory dysfunction, and gynecomastia.

When hyperprolactinemia becomes apparent, we suggest discontinuing the offending drug and, if necessary:

• switching to a prolactin-sparing atypical antipsychotic
• or trying another agent, such as bromocriptine or pergolide, if switching to another antipsychotic is infeasible.^10,11

Baseline prolactin levels should be measured before starting any prolactin-elevating antipsychotic. Because prolactin levels may not correlate with severity of clinical symptoms, the net change in these levels may be a better indicator.⁴ If prolactin levels exceed 100 mg/L, consider an MRI with fine cuts though the sellae to check for a primary adenoma.⁴

Conclusion: A cause is found

An MRI of Ms. G’s head is normal, but her serum prolactin level is 125 μg/L. Her risperidone is tapered off, and olanzapine, 10 mg at bedtime, is started with her mother’s consent. Two days later, her prolactin level drops to 85 μg/L. Notable improvement is reported on day seven of hospitalization; she is sleeping and eating well with no suicidal or homicidal ideations and notes no psychotic symptoms. She is discharged that day.

Two weeks later, Ms. G’s improvement continues. Lab tests reveal normal prolactin levels. Over the next few months, she remains stable, attends school, and takes her medications with no adverse effects.

Related resources

• Maguire GA. Prolactin elevation with antipsychotic medications: mechanisms of action and clinical consequences. J Clin Psychiatry 2002; 63(suppl 4):56-62. Available at: www.psychiatrist.com/supplenet/v63s04/v63s0408.pdf. Accessed March 11, 2003.

Drug brand names

• Aripiprazole • Abilify
• Dextroamphetamine sulfate • Dexadrine
• Divalproex sodium • Depakote
• Fluoxetine • Prozac
• Mestranol • Necon 1/50
• Norethindrone • Activella
• Pergolide • Permax
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

Dr. Yu receives research/grant support from, is a consultant to, and/or is a speaker for Cephalon Inc., Eli Lilly and Co., Novartis Pharmaceuticals Corp., and Pfizer Inc.

Dr. Maguire receives research/grant support from, is a consultant to, and/or is a speaker for Eli Lilly and Co., Pfizer Inc., Forest Laboratories, and GlaxoSmithKline.

History: Initial symptoms

Ms. G, 17, has battled attention-deficit/hyperactivity disorder (ADHD) since age 6, and within the past 2 years was also diagnosed as having schizoaffective disorder, bipolar type. An outpatient child psychiatrist and a therapist have helped keep her symptoms in control through much of her life.

During one recent visit to her psychiatrist, however, she complained of decreased energy, increased crying spells, broken sleep, and a depressed mood. She reported that these symptoms began approximately 2 months before the visit, and neither she nor her parents could identify a clear-cut cause.

Throughout her life she has complied with her drug regimens. For 2 years she has been taking divalproex sodium, 500 mg twice daily to manage her manic and depressive episodes, dextroamphetamine sulfate, 30 mg in the morning for her ADHD; risperidone, 2 mg at bedtime for her psychotic symptoms; and mestranol, 60 mcg/d, plus norethindrone, 1 mg/d, for contraception. A recent valproic acid reading of 62 μg/ml is consistent with levels over the last 2 years.

During previous psychotic episodes, Ms. G often became delusional and paranoid with command-type hallucinations. She destroyed her room during her most recent episode.

Ms. G’s adoptive mother accompanied her during this visit. She is concerned for her daughter, especially with the start of school about 1 month away.

Which would you address first: the depression or the psychosis? Would you change Ms. G’s medication and if so, how?

Figure 1 DEPRESSION IN SCHIZOPHRENIA: IMPROVING OUTCOMES

Drs. Yu’s and Maguire’s observations

Complaints of depression in a patient with schizoaffective disorder are especially concerning because multiple domains could be affected (Figure 1). For patients with schizophrenia, the 60% lifetime incidence of major depressive disorder substantially exceeds the 8 to 26% risk in the general population. Ms. G’s comorbid depression also may predispose her to an increased rate of relapse into schizoaffective psychosis, poor treatment response, and a longer duration of psychotic illness that could require hospitalization.¹

Although Ms. G’s divalproex level was therapeutic (between 50 and 100 μg/ml), some data indicate that valproic acid may be less effective in schizoaffective disorder than in bipolar I disorder. Still, treatment of schizoaffective disorder often follows antimanic and antidepressant protocols.²

Treatment: An agent is added

The outpatient psychiatrist adds fluoxetine, 20 mg each morning, to address Ms. G’s depressive symptoms. She reports no improvement after 1 month, and her fluoxetine is increased to 30 mg/d.

Three weeks later, Ms. G’s parents bring her to the psychiatrist for an emergency visit. She reports suicidal ideation over the previous month. Rolling up both sleeves, she reveals several superficial cuts on her forearms and wrists that she inflicted after breaking up with her boyfriend.

Her mother, appearing anxious and overwhelmed, reports that her daughter pushed her because she had refused to give Ms. G her calling card. She had told her mother that she wanted to call a boy in Utah that she had met over the Internet.

Ms. G’s speech is noticeably pressured and she is extremely distractible. Her mother notes that her daughter is sleeping only 2 to 3 hours a night, yet exhibits no decrease in energy. Still depressed, her affect is markedly labile, crying at one moment when discussing her suicidality, then railing at her mother when she tries to explain Ms. G’s aggressiveness. When the psychiatrist recommends hospitalization to stabilize her symptoms, she vehemently demands to be let out so that she can run in front of a moving car. The police are called, and she is restrained and brought into the hospital.

What caused Ms. G’s sudden decline? How would you address it?

Drs. Yu’s and Maguire’s observations

Although antidepressants can effectively treat depression in schizoaffective disorder, many of these medications can trigger a manic episode,³ which can include mania, mixed mania with depression, or rapid cycling every few days or hours. In Ms. G’s case, an increase in serotonin due to the fluoxetine may have caused her mania.

We would stop the fluoxetine and see if her manic symptoms resolve. Fluoxetine’s long half-life (4 to 16 days) cuts down the odds of a serotonin-discontinuation syndrome, making immediate discontinuation feasible.

Still, the cause of Ms. G’s depressive symptoms remains unknown. At this stage, observation in the adolescent inpatient ward holds our best hope of reaching a definitive diagnosis.

Treatment: A diagnostic clue surfaces

Blood tests on admission (including a negative drug screen for narcotics or other depressogenic substances) are normal, and her valproic acid level is 61 μg/ml. Her divalproex is increased to 500 mg in the morning and 750 mg at bedtime, and she is tapered off fluoxetine. Her symptoms gradually improve with the change in the medications and her attendance in milieu and group therapy on the ward. A second valproic acid reading on day three of hospitalization is 67 μg/ml.

 

That day, a nurse informs the inpatient child/adolescent psychiatrist that Ms. G has requested extra hospital gowns. Ms. G later reveals that for about 4 months she has been producing a milky discharge from both breasts, and that the flow has been increasing in frequency and quantity. She adds that she has not menstruated for almost 5 months and complains of breast tenderness.

What do Ms. G’s latest symptoms suggest? How will your response to these symptoms affect treatment?

Drs. Yu’s and Maguire’s observations

Complaints of menstrual irregularities, breast tenderness, and galactorrhea should arouse suspicions of hyperprolactinemia. Because tumors that raise prolactin levels are rare, medications are the most likely culprit in Ms. G’s case. Dopamine blockade within the tuberoinfundibular tract is the mechanism of action behind prolactin elevation.⁴

Prolactin levels in patients with schizophrenia are generally normal (1 to 25 mg/L) prior to treatment,⁵ but have been known to increase with use of typical antipsychotics. The atypical antipsychotic risperidone has been associated with dose-related increases in plasma prolactin concentration, although Kleinberg et al found no correlation between risperidone-induced plasma prolactin concentrations and adverse events.⁶

Figure 2 POSSIBLE ADVERSE EFFECTS OF HYPERPROLACTINEMIA⁸

Prolactin-sparing atypical antipsychotics such as olanzapine, quetiapine, ziprasidone, and aripiprazole may cause a transient prolactin increase in the first few weeks of use. These levels tend to remain within the normal range before decreasing to baseline levels or lower.^7,8

Prolactin elevation in women may lead to an estrogen deficiency, causing changes in mood and cognition and psychopathology⁹ that can manifest as increased depression, anxiety, and hostility.¹⁰ Hyperprolactinemia can also cause depression in men, though the mechanism of action is unknown.

Prolactin elevation can lead to numerous other health disturbances (Figure 2). When screening women who are taking antipsychotics, ask about menstrual irregularities, sexual dysfunction, breast tenderness, and galactorrhea. Ask male patients about a loss of libido, erectile dysfunction, ejaculatory dysfunction, and gynecomastia.

When hyperprolactinemia becomes apparent, we suggest discontinuing the offending drug and, if necessary:

• switching to a prolactin-sparing atypical antipsychotic
• or trying another agent, such as bromocriptine or pergolide, if switching to another antipsychotic is infeasible.^10,11

Baseline prolactin levels should be measured before starting any prolactin-elevating antipsychotic. Because prolactin levels may not correlate with severity of clinical symptoms, the net change in these levels may be a better indicator.⁴ If prolactin levels exceed 100 mg/L, consider an MRI with fine cuts though the sellae to check for a primary adenoma.⁴

Conclusion: A cause is found

An MRI of Ms. G’s head is normal, but her serum prolactin level is 125 μg/L. Her risperidone is tapered off, and olanzapine, 10 mg at bedtime, is started with her mother’s consent. Two days later, her prolactin level drops to 85 μg/L. Notable improvement is reported on day seven of hospitalization; she is sleeping and eating well with no suicidal or homicidal ideations and notes no psychotic symptoms. She is discharged that day.

Two weeks later, Ms. G’s improvement continues. Lab tests reveal normal prolactin levels. Over the next few months, she remains stable, attends school, and takes her medications with no adverse effects.

Related resources

• Maguire GA. Prolactin elevation with antipsychotic medications: mechanisms of action and clinical consequences. J Clin Psychiatry 2002; 63(suppl 4):56-62. Available at: www.psychiatrist.com/supplenet/v63s04/v63s0408.pdf. Accessed March 11, 2003.

Drug brand names

• Aripiprazole • Abilify
• Dextroamphetamine sulfate • Dexadrine
• Divalproex sodium • Depakote
• Fluoxetine • Prozac
• Mestranol • Necon 1/50
• Norethindrone • Activella
• Pergolide • Permax
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

Dr. Yu receives research/grant support from, is a consultant to, and/or is a speaker for Cephalon Inc., Eli Lilly and Co., Novartis Pharmaceuticals Corp., and Pfizer Inc.

Dr. Maguire receives research/grant support from, is a consultant to, and/or is a speaker for Eli Lilly and Co., Pfizer Inc., Forest Laboratories, and GlaxoSmithKline.