Cases That Test Your Skills

HISTORY: TOO MUCH FOR TOO LONG

Mrs. B, age 73, has been alcohol-dependent for 20 years. Since her husband’s death 5 years ago, she has been drinking 1 to 2 liters of vodka a week. At her family’s insistence, she checks into a tertiary-care hospital for worsening alcohol use, memory problems, and increasing confusion.

Mrs. B’s family removed her car because of her alcohol and cognitive problems, but she walks half a mile to buy alcohol. She lives alone in an assisted-living facility and has been hospitalized for detoxification 3 times within 2 years.

At intake, her judgment and abstract thinking are impaired. She has poor insight into her condition. Physical examination reveals fine hand tremors. Lab test results and vital signs are normal. Mrs. B was previously diagnosed with bipolar disorder and takes divalproex, 250 each morning and 500 mg at bedtime, and paroxetine, 20 mg/d.

Mrs. B’s Folstein Mini-Mental State Examination (MMSE) score 1 week after admission was 5/30, indicating severe cognitive deficits. Her mood was euthymic, speech and motor activity were normal, and thought process was logical with intact associations. She exhibited no delusions or hallucinations but was disoriented, with a short attention span and poor concentration.

The authors’ observations

Mrs. B’s confusion has increased in recent weeks. Hand tremors could signal a neurologic problem triggered by a vascular event or alcohol use. Include dementia in the differential diagnosis.

Distinguishing between vascular dementia and alcohol-induced persisting dementia requires a thorough history, neurologic exam, and lab testing.

Vascular dementia. Cognition deteriorates step by step. Patients with this dementia have multiple vascular risk factors and display evidence of cerebrovascular events on physical examination or imaging studies. Watch for high blood pressure, high cholesterol, or obesity; history of diabetes, cardiac arrythmias, or strokes; or other vascular changes in the brain.

Alcohol-induced persisting dementia. Patients usually have abused alcohol for years, and memory slowly deteriorates. Vascular events that would explain cognitive deficits are not found. Such patients usually do not have vascular and cerebrovascular risk factors, but may exhibit worsening cognition in the context of alcohol use. Watch for mean corpuscular volume >100 femtoliters, gamma glutamyl transferase >50 U/L, and elevated liver function tests.

For Mrs. B, both dementia types were ruled out. Her memory problems were mild, and she had been functioning independently at the assisted-living facility. Dementia is not characterized by clouding of consciousness, and her disorder’s progression was fast. Mrs. B’s bipolar disorder was not a factor because she did not have significant depressive or manic symptoms.

Amnestic disorder. Mrs. B’s worsening mental status and neurologic signs after admission suggest amnestic disorder. Patients with amnestic disorder have trouble learning or recalling new information and forming new memories, although they can talk coherently and appropriately.

Injury to the diencephalic and medial temporal lobe structures triggers amnestic disorder. Head trauma, cerebral infections, and infarctions can damage these structures, but alcoholism is the most common cause.

ADMISSION: INCREASING CONFUSION

Mrs. B was admitted to the dual diagnosis unit for patients with substance use and psychiatric disorders. Although confused, she could eat and walk.

For 2 days, Mrs. B received chlordiazepoxide, 200 mg/d, for detoxification; a multivitamin tablet; and oral vitamin B1 (thiamine), 100 mg once daily. She also continued her divalproex/paroxetine regimen. Chlordiazepoxide was tapered and discontinued over 4 days. Vital signs remained normal.

Two days after starting detox, Mrs. B’s condition began to worsen. She became incontinent of urine and feces, had trouble eating, and required extensive assistance with activities of daily living.

On examination by the geriatric psychiatry team, Mrs. B appeared very confused. She was confabulating, had hand tremors, and was ataxic, with nystagmus on lateral gaze. Coordination was poor. Because she reported visual hallucinations and appeared delirious, divalproex sodium and paroxetine—which can worsen delirium—were stopped.

Head MRI with contrast revealed sulcal space prominence in the cerebral and cerebellar hemispheres, suggesting minimal volume loss, and nonspecific bilateral periventricular punctuate flairs and T2 hypodensities, indicating small-vessel ischemic disease. EEG showed moderate rhythm slowing. Blood and urine tests showed no infectious disease or metabolic abnormalities.

Box

 

The authors’ observations

Mrs. B’s presentation suggests Wernicke’s encephalopathy (WE), an acute amnestic disorder caused by thiamine deficiency.

WE lesions are seen on autopsy in approximately 12.5% of alcohol abusers.¹ Although alcoholism is more prevalent in men age 65, women are more likely to develop WE and cognitive dysfunction secondary to alcohol use.²

Alcoholism accounts for 77% of WE cases,³ although malnutrition caused by infection, cancer, gastric surgery, hemodialysis, hyperemesis, or starvation is another cause.

Clinical features of WE include confusion and disorientation (80% of cases, with stupor in 5%), ataxia (23%), and ocular abnormalities (29%). Nystagmus, especially to lateral gaze but also in vertical and other forms, is most common.⁴ Because less than one-third of patients with WE exhibit all 3 symptoms,⁵ the diagnosis is often missed. In studies, 15% of WE cases were diagnosed antemortem.^1,6

Imaging studies. Brain MRI is more sensitive than computed tomography (CT) in detecting diencephalic, periventricular, and periaqueductal lesions (Box).⁷ Because of costs, physicians tend to order CT more often than MRI. CT can help rule out gross structural and vascular defects but is less adequate for evaluating specific lesions. In detecting WE lesions, MRI’s sensitivity is 53% and its specificity is 93%.⁷

Thiamine deficiency can occur when the liver can no longer absorb or store thiamine. Enzyme systems involved in the citric acid cycle and pentose phosphate pathway malfunction, and lactic acid production is increased. The associated pH change damages the apoenzymes. Glutamate accumulates, leading to production of free radicals, which cause cellular damage.¹¹

Circulating thiamine levels are low (<50 ng/mL) in 30% to 80% of persons with alcoholism, putting them at risk for WE.¹² Malnutrition secondary to alcoholism reduces thiamine absorption from the gut by 70%. Alcohol alone can reduce thiamine absorption by nearly 50%.¹³

WE lesions usually shrink within 48 to 72 hours of treatment with parenteral thiamine. Lactate <3.3 mg/dL or >14.9 mg/dL, and pyruvate <0.37 mg/dL or >0.75 mg/dL, indicate abnormal thiamine levels.¹⁴

Mrs. B’s confusion, hallucinations, and clouding of consciousness suggested DT, but this was ruled out because she had normal vital signs, classic eye signs of WE, no autonomic instability, and had been adequately tapered off alcohol.

TREATMENT: SHAKING ALCOHOL’S GRIP

A consulting neurologist confirmed a tentative diagnosis of WE.

Mrs. B’s oral thiamine was increased to 100 mg tid. She also received IM thiamine, 100 mg once daily for 5 days; risperidone, 0.5 mg every 4 hours as needed; and trazodone, 50 mg at bedtime as needed for irritability, agitation, and poor sleep. Multivitamins and folic acid were continued.

One week after starting IM thiamine, Mrs. B’s gait steadied, her coordination improved, and tremors and nystagmus stopped. She became more adept at eating. Cognitive impairment continued, but she confabulated less frequently. Her insight into her condition was improving.

Over the next 10 days, Mrs. B continued to improve, although neuropsychological assessment revealed major deficits in visuospatial function, attention, concentration, and memory. Repeat EEG showed diffuse slowing with frontal intermittent rhythmic delta activity, consistent with diffuse toxic metabolic encephalopathy.

Three weeks after admission, Mrs. B was discharged to her assisted-living facility, where she receives follow-up medical and psychiatric care. Her MMSE score at discharge was 12/30, indicating moderately severe cognitive impairment. Motor function has improved, although Mrs. B remains confused and needs help with daily living.

One month after discharge, Mrs. B’s diet was much improved; thiamine was reduced to 100 mg once daily. She has stayed sober but has repeatedly tried to drink. She was referred to a 12-step program but has not complied.

Table 1

Clinical features of WE, Korsakoff’s psychosis

Wernicke’s encephalopathy	Korsakoff’s psychosis
Acute onset	Subacute or chronic onset
Clouding of conciousness common	Consciousness usually clear
Ataxia, nystagmus, ophthalmoplegiao usually present	Ataxia, nystagmus, ophthalmoplegia not common
Impaired anterograde, retrograde memory; confabulation is rare	Impaired anterograde, retrograde memory with prominent confabulation
Without adequate treatment, >80% progress to Korsakoff’s psychosis; death rate is 20%	>80% progress to alcohol induced persisting dementia; nursing home admission rate is 25%
Source: Reference 14.

The authors’ observations

Suspect WE in all patients with alcohol abuse disorder who are malnourished and/or elderly and whose dietary history is unclear. Early detection and treatment are crucial to preventing WE from becoming chronic. WE progresses to Korsakoff’s psychosis—a form of permanent short-term memory loss—in up to 80% of patients.⁵

Because Korsakoff’s psychosis carries an 8% death rate, consider the disorder in the differential diagnosis (Table). The disorder was ruled out in Mrs. B because of clouding of consciousness, ataxia, nystagmus, and shorter symptom duration.

Thiamine should be given IV, but can be given IM if unit nurses are not certified to give IV injections. Oral thiamine cannot generate the high thiamine blood concentrations (>50 ng/mL within the first 12 hours of treatment) needed to prevent irreversible damage.

 

Parenteral thiamine, 100 mg/d for 5 to 7 days, is given for acute WE. Some patients who are genetically predisposed to thiamine deficiency may need up to 1,000 mg/d. Continue oral thiamine, 100 mg/d, after parenteral dosing.

Although anaphylaxis risk during a 10-minute thiamine infusion is less than 1 in 1 million, make sure cardiopulmonary resuscitation is available during treatment. Glucose load can precipitate or worsen WE in a thiamine-deficient patient, so give thiamine before giving glucose in any form, including everyday foods.

Watch for other vitamin and magnesium deficiencies common to patients with alcoholism, as these might compromise response to IV/IM thiamine.¹⁵ Also rule out stroke in men age >65 who present with signs of hemiparesis.

Related resources

• Stern Y, Sackheim HA. Neuropsychiatric aspects of memory and amnesia. In: Yudofsky SC, Hales RE, (eds). Essentials of neuropsychiatry and clinical neurosciences. Washington, DC: American Psychiatric Publishing, 2004:201-38.
• National Institute of Neurological Disorders and Stroke. http://www.ninds.nih.gov/health_and_medical/disorders/wernicke-korsakoff.htm

Drug brand names

• Chlordiazepoxide • Libritabs, Lithium
• Divalproex sodium • Depakote
• Paroxetine • Paxil
• Risperidone • Risperdal
• Trazodone • Desyrel

Disclosure

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

Acknowledgment

Dr. Tampi’s efforts were supported by funds from the Division of State, Community, and Public Health, Bureau of Health Professions, Health Resources and Services Administration, Department of Health and Human Services, under grant number 1 K01 HP 00071-01, and the Geriatric Academic Career Award ($57,007). The information is that of Dr. Tampi and should not be construed as the official position or policy of, nor should any endorsements be inferred by, the aforementioned departments or the United States government.

HISTORY: TOO MUCH FOR TOO LONG

Mrs. B, age 73, has been alcohol-dependent for 20 years. Since her husband’s death 5 years ago, she has been drinking 1 to 2 liters of vodka a week. At her family’s insistence, she checks into a tertiary-care hospital for worsening alcohol use, memory problems, and increasing confusion.

Mrs. B’s family removed her car because of her alcohol and cognitive problems, but she walks half a mile to buy alcohol. She lives alone in an assisted-living facility and has been hospitalized for detoxification 3 times within 2 years.

At intake, her judgment and abstract thinking are impaired. She has poor insight into her condition. Physical examination reveals fine hand tremors. Lab test results and vital signs are normal. Mrs. B was previously diagnosed with bipolar disorder and takes divalproex, 250 each morning and 500 mg at bedtime, and paroxetine, 20 mg/d.

Mrs. B’s Folstein Mini-Mental State Examination (MMSE) score 1 week after admission was 5/30, indicating severe cognitive deficits. Her mood was euthymic, speech and motor activity were normal, and thought process was logical with intact associations. She exhibited no delusions or hallucinations but was disoriented, with a short attention span and poor concentration.

The authors’ observations

Mrs. B’s confusion has increased in recent weeks. Hand tremors could signal a neurologic problem triggered by a vascular event or alcohol use. Include dementia in the differential diagnosis.

Distinguishing between vascular dementia and alcohol-induced persisting dementia requires a thorough history, neurologic exam, and lab testing.

Vascular dementia. Cognition deteriorates step by step. Patients with this dementia have multiple vascular risk factors and display evidence of cerebrovascular events on physical examination or imaging studies. Watch for high blood pressure, high cholesterol, or obesity; history of diabetes, cardiac arrythmias, or strokes; or other vascular changes in the brain.

Alcohol-induced persisting dementia. Patients usually have abused alcohol for years, and memory slowly deteriorates. Vascular events that would explain cognitive deficits are not found. Such patients usually do not have vascular and cerebrovascular risk factors, but may exhibit worsening cognition in the context of alcohol use. Watch for mean corpuscular volume >100 femtoliters, gamma glutamyl transferase >50 U/L, and elevated liver function tests.

For Mrs. B, both dementia types were ruled out. Her memory problems were mild, and she had been functioning independently at the assisted-living facility. Dementia is not characterized by clouding of consciousness, and her disorder’s progression was fast. Mrs. B’s bipolar disorder was not a factor because she did not have significant depressive or manic symptoms.

Amnestic disorder. Mrs. B’s worsening mental status and neurologic signs after admission suggest amnestic disorder. Patients with amnestic disorder have trouble learning or recalling new information and forming new memories, although they can talk coherently and appropriately.

Injury to the diencephalic and medial temporal lobe structures triggers amnestic disorder. Head trauma, cerebral infections, and infarctions can damage these structures, but alcoholism is the most common cause.

ADMISSION: INCREASING CONFUSION

Mrs. B was admitted to the dual diagnosis unit for patients with substance use and psychiatric disorders. Although confused, she could eat and walk.

For 2 days, Mrs. B received chlordiazepoxide, 200 mg/d, for detoxification; a multivitamin tablet; and oral vitamin B1 (thiamine), 100 mg once daily. She also continued her divalproex/paroxetine regimen. Chlordiazepoxide was tapered and discontinued over 4 days. Vital signs remained normal.

Two days after starting detox, Mrs. B’s condition began to worsen. She became incontinent of urine and feces, had trouble eating, and required extensive assistance with activities of daily living.

On examination by the geriatric psychiatry team, Mrs. B appeared very confused. She was confabulating, had hand tremors, and was ataxic, with nystagmus on lateral gaze. Coordination was poor. Because she reported visual hallucinations and appeared delirious, divalproex sodium and paroxetine—which can worsen delirium—were stopped.

Head MRI with contrast revealed sulcal space prominence in the cerebral and cerebellar hemispheres, suggesting minimal volume loss, and nonspecific bilateral periventricular punctuate flairs and T2 hypodensities, indicating small-vessel ischemic disease. EEG showed moderate rhythm slowing. Blood and urine tests showed no infectious disease or metabolic abnormalities.

Box

 

The authors’ observations

Mrs. B’s presentation suggests Wernicke’s encephalopathy (WE), an acute amnestic disorder caused by thiamine deficiency.

WE lesions are seen on autopsy in approximately 12.5% of alcohol abusers.¹ Although alcoholism is more prevalent in men age 65, women are more likely to develop WE and cognitive dysfunction secondary to alcohol use.²

Alcoholism accounts for 77% of WE cases,³ although malnutrition caused by infection, cancer, gastric surgery, hemodialysis, hyperemesis, or starvation is another cause.

Clinical features of WE include confusion and disorientation (80% of cases, with stupor in 5%), ataxia (23%), and ocular abnormalities (29%). Nystagmus, especially to lateral gaze but also in vertical and other forms, is most common.⁴ Because less than one-third of patients with WE exhibit all 3 symptoms,⁵ the diagnosis is often missed. In studies, 15% of WE cases were diagnosed antemortem.^1,6

Imaging studies. Brain MRI is more sensitive than computed tomography (CT) in detecting diencephalic, periventricular, and periaqueductal lesions (Box).⁷ Because of costs, physicians tend to order CT more often than MRI. CT can help rule out gross structural and vascular defects but is less adequate for evaluating specific lesions. In detecting WE lesions, MRI’s sensitivity is 53% and its specificity is 93%.⁷

Thiamine deficiency can occur when the liver can no longer absorb or store thiamine. Enzyme systems involved in the citric acid cycle and pentose phosphate pathway malfunction, and lactic acid production is increased. The associated pH change damages the apoenzymes. Glutamate accumulates, leading to production of free radicals, which cause cellular damage.¹¹

Circulating thiamine levels are low (<50 ng/mL) in 30% to 80% of persons with alcoholism, putting them at risk for WE.¹² Malnutrition secondary to alcoholism reduces thiamine absorption from the gut by 70%. Alcohol alone can reduce thiamine absorption by nearly 50%.¹³

WE lesions usually shrink within 48 to 72 hours of treatment with parenteral thiamine. Lactate <3.3 mg/dL or >14.9 mg/dL, and pyruvate <0.37 mg/dL or >0.75 mg/dL, indicate abnormal thiamine levels.¹⁴

Mrs. B’s confusion, hallucinations, and clouding of consciousness suggested DT, but this was ruled out because she had normal vital signs, classic eye signs of WE, no autonomic instability, and had been adequately tapered off alcohol.

TREATMENT: SHAKING ALCOHOL’S GRIP

A consulting neurologist confirmed a tentative diagnosis of WE.

Mrs. B’s oral thiamine was increased to 100 mg tid. She also received IM thiamine, 100 mg once daily for 5 days; risperidone, 0.5 mg every 4 hours as needed; and trazodone, 50 mg at bedtime as needed for irritability, agitation, and poor sleep. Multivitamins and folic acid were continued.

One week after starting IM thiamine, Mrs. B’s gait steadied, her coordination improved, and tremors and nystagmus stopped. She became more adept at eating. Cognitive impairment continued, but she confabulated less frequently. Her insight into her condition was improving.

Over the next 10 days, Mrs. B continued to improve, although neuropsychological assessment revealed major deficits in visuospatial function, attention, concentration, and memory. Repeat EEG showed diffuse slowing with frontal intermittent rhythmic delta activity, consistent with diffuse toxic metabolic encephalopathy.

Three weeks after admission, Mrs. B was discharged to her assisted-living facility, where she receives follow-up medical and psychiatric care. Her MMSE score at discharge was 12/30, indicating moderately severe cognitive impairment. Motor function has improved, although Mrs. B remains confused and needs help with daily living.

One month after discharge, Mrs. B’s diet was much improved; thiamine was reduced to 100 mg once daily. She has stayed sober but has repeatedly tried to drink. She was referred to a 12-step program but has not complied.

Table 1

Clinical features of WE, Korsakoff’s psychosis

Wernicke’s encephalopathy	Korsakoff’s psychosis
Acute onset	Subacute or chronic onset
Clouding of conciousness common	Consciousness usually clear
Ataxia, nystagmus, ophthalmoplegiao usually present	Ataxia, nystagmus, ophthalmoplegia not common
Impaired anterograde, retrograde memory; confabulation is rare	Impaired anterograde, retrograde memory with prominent confabulation
Without adequate treatment, >80% progress to Korsakoff’s psychosis; death rate is 20%	>80% progress to alcohol induced persisting dementia; nursing home admission rate is 25%
Source: Reference 14.

The authors’ observations

Suspect WE in all patients with alcohol abuse disorder who are malnourished and/or elderly and whose dietary history is unclear. Early detection and treatment are crucial to preventing WE from becoming chronic. WE progresses to Korsakoff’s psychosis—a form of permanent short-term memory loss—in up to 80% of patients.⁵

Because Korsakoff’s psychosis carries an 8% death rate, consider the disorder in the differential diagnosis (Table). The disorder was ruled out in Mrs. B because of clouding of consciousness, ataxia, nystagmus, and shorter symptom duration.

Thiamine should be given IV, but can be given IM if unit nurses are not certified to give IV injections. Oral thiamine cannot generate the high thiamine blood concentrations (>50 ng/mL within the first 12 hours of treatment) needed to prevent irreversible damage.

 

Parenteral thiamine, 100 mg/d for 5 to 7 days, is given for acute WE. Some patients who are genetically predisposed to thiamine deficiency may need up to 1,000 mg/d. Continue oral thiamine, 100 mg/d, after parenteral dosing.

Although anaphylaxis risk during a 10-minute thiamine infusion is less than 1 in 1 million, make sure cardiopulmonary resuscitation is available during treatment. Glucose load can precipitate or worsen WE in a thiamine-deficient patient, so give thiamine before giving glucose in any form, including everyday foods.

Watch for other vitamin and magnesium deficiencies common to patients with alcoholism, as these might compromise response to IV/IM thiamine.¹⁵ Also rule out stroke in men age >65 who present with signs of hemiparesis.

Related resources

• Stern Y, Sackheim HA. Neuropsychiatric aspects of memory and amnesia. In: Yudofsky SC, Hales RE, (eds). Essentials of neuropsychiatry and clinical neurosciences. Washington, DC: American Psychiatric Publishing, 2004:201-38.
• National Institute of Neurological Disorders and Stroke. http://www.ninds.nih.gov/health_and_medical/disorders/wernicke-korsakoff.htm

Drug brand names

• Chlordiazepoxide • Libritabs, Lithium
• Divalproex sodium • Depakote
• Paroxetine • Paxil
• Risperidone • Risperdal
• Trazodone • Desyrel

Disclosure

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

Acknowledgment

Dr. Tampi’s efforts were supported by funds from the Division of State, Community, and Public Health, Bureau of Health Professions, Health Resources and Services Administration, Department of Health and Human Services, under grant number 1 K01 HP 00071-01, and the Geriatric Academic Career Award ($57,007). The information is that of Dr. Tampi and should not be construed as the official position or policy of, nor should any endorsements be inferred by, the aforementioned departments or the United States government.

HISTORY: TOO MUCH FOR TOO LONG

Mrs. B, age 73, has been alcohol-dependent for 20 years. Since her husband’s death 5 years ago, she has been drinking 1 to 2 liters of vodka a week. At her family’s insistence, she checks into a tertiary-care hospital for worsening alcohol use, memory problems, and increasing confusion.

Mrs. B’s family removed her car because of her alcohol and cognitive problems, but she walks half a mile to buy alcohol. She lives alone in an assisted-living facility and has been hospitalized for detoxification 3 times within 2 years.

At intake, her judgment and abstract thinking are impaired. She has poor insight into her condition. Physical examination reveals fine hand tremors. Lab test results and vital signs are normal. Mrs. B was previously diagnosed with bipolar disorder and takes divalproex, 250 each morning and 500 mg at bedtime, and paroxetine, 20 mg/d.

Mrs. B’s Folstein Mini-Mental State Examination (MMSE) score 1 week after admission was 5/30, indicating severe cognitive deficits. Her mood was euthymic, speech and motor activity were normal, and thought process was logical with intact associations. She exhibited no delusions or hallucinations but was disoriented, with a short attention span and poor concentration.

The authors’ observations

Mrs. B’s confusion has increased in recent weeks. Hand tremors could signal a neurologic problem triggered by a vascular event or alcohol use. Include dementia in the differential diagnosis.

Distinguishing between vascular dementia and alcohol-induced persisting dementia requires a thorough history, neurologic exam, and lab testing.

Vascular dementia. Cognition deteriorates step by step. Patients with this dementia have multiple vascular risk factors and display evidence of cerebrovascular events on physical examination or imaging studies. Watch for high blood pressure, high cholesterol, or obesity; history of diabetes, cardiac arrythmias, or strokes; or other vascular changes in the brain.

Alcohol-induced persisting dementia. Patients usually have abused alcohol for years, and memory slowly deteriorates. Vascular events that would explain cognitive deficits are not found. Such patients usually do not have vascular and cerebrovascular risk factors, but may exhibit worsening cognition in the context of alcohol use. Watch for mean corpuscular volume >100 femtoliters, gamma glutamyl transferase >50 U/L, and elevated liver function tests.

For Mrs. B, both dementia types were ruled out. Her memory problems were mild, and she had been functioning independently at the assisted-living facility. Dementia is not characterized by clouding of consciousness, and her disorder’s progression was fast. Mrs. B’s bipolar disorder was not a factor because she did not have significant depressive or manic symptoms.

Amnestic disorder. Mrs. B’s worsening mental status and neurologic signs after admission suggest amnestic disorder. Patients with amnestic disorder have trouble learning or recalling new information and forming new memories, although they can talk coherently and appropriately.

Injury to the diencephalic and medial temporal lobe structures triggers amnestic disorder. Head trauma, cerebral infections, and infarctions can damage these structures, but alcoholism is the most common cause.

ADMISSION: INCREASING CONFUSION

Mrs. B was admitted to the dual diagnosis unit for patients with substance use and psychiatric disorders. Although confused, she could eat and walk.

For 2 days, Mrs. B received chlordiazepoxide, 200 mg/d, for detoxification; a multivitamin tablet; and oral vitamin B1 (thiamine), 100 mg once daily. She also continued her divalproex/paroxetine regimen. Chlordiazepoxide was tapered and discontinued over 4 days. Vital signs remained normal.

Two days after starting detox, Mrs. B’s condition began to worsen. She became incontinent of urine and feces, had trouble eating, and required extensive assistance with activities of daily living.

On examination by the geriatric psychiatry team, Mrs. B appeared very confused. She was confabulating, had hand tremors, and was ataxic, with nystagmus on lateral gaze. Coordination was poor. Because she reported visual hallucinations and appeared delirious, divalproex sodium and paroxetine—which can worsen delirium—were stopped.

Head MRI with contrast revealed sulcal space prominence in the cerebral and cerebellar hemispheres, suggesting minimal volume loss, and nonspecific bilateral periventricular punctuate flairs and T2 hypodensities, indicating small-vessel ischemic disease. EEG showed moderate rhythm slowing. Blood and urine tests showed no infectious disease or metabolic abnormalities.

Box

 

The authors’ observations

Mrs. B’s presentation suggests Wernicke’s encephalopathy (WE), an acute amnestic disorder caused by thiamine deficiency.

WE lesions are seen on autopsy in approximately 12.5% of alcohol abusers.¹ Although alcoholism is more prevalent in men age 65, women are more likely to develop WE and cognitive dysfunction secondary to alcohol use.²

Alcoholism accounts for 77% of WE cases,³ although malnutrition caused by infection, cancer, gastric surgery, hemodialysis, hyperemesis, or starvation is another cause.

Clinical features of WE include confusion and disorientation (80% of cases, with stupor in 5%), ataxia (23%), and ocular abnormalities (29%). Nystagmus, especially to lateral gaze but also in vertical and other forms, is most common.⁴ Because less than one-third of patients with WE exhibit all 3 symptoms,⁵ the diagnosis is often missed. In studies, 15% of WE cases were diagnosed antemortem.^1,6

Imaging studies. Brain MRI is more sensitive than computed tomography (CT) in detecting diencephalic, periventricular, and periaqueductal lesions (Box).⁷ Because of costs, physicians tend to order CT more often than MRI. CT can help rule out gross structural and vascular defects but is less adequate for evaluating specific lesions. In detecting WE lesions, MRI’s sensitivity is 53% and its specificity is 93%.⁷

Thiamine deficiency can occur when the liver can no longer absorb or store thiamine. Enzyme systems involved in the citric acid cycle and pentose phosphate pathway malfunction, and lactic acid production is increased. The associated pH change damages the apoenzymes. Glutamate accumulates, leading to production of free radicals, which cause cellular damage.¹¹

Circulating thiamine levels are low (<50 ng/mL) in 30% to 80% of persons with alcoholism, putting them at risk for WE.¹² Malnutrition secondary to alcoholism reduces thiamine absorption from the gut by 70%. Alcohol alone can reduce thiamine absorption by nearly 50%.¹³

WE lesions usually shrink within 48 to 72 hours of treatment with parenteral thiamine. Lactate <3.3 mg/dL or >14.9 mg/dL, and pyruvate <0.37 mg/dL or >0.75 mg/dL, indicate abnormal thiamine levels.¹⁴

Mrs. B’s confusion, hallucinations, and clouding of consciousness suggested DT, but this was ruled out because she had normal vital signs, classic eye signs of WE, no autonomic instability, and had been adequately tapered off alcohol.

TREATMENT: SHAKING ALCOHOL’S GRIP

A consulting neurologist confirmed a tentative diagnosis of WE.

Mrs. B’s oral thiamine was increased to 100 mg tid. She also received IM thiamine, 100 mg once daily for 5 days; risperidone, 0.5 mg every 4 hours as needed; and trazodone, 50 mg at bedtime as needed for irritability, agitation, and poor sleep. Multivitamins and folic acid were continued.

One week after starting IM thiamine, Mrs. B’s gait steadied, her coordination improved, and tremors and nystagmus stopped. She became more adept at eating. Cognitive impairment continued, but she confabulated less frequently. Her insight into her condition was improving.

Over the next 10 days, Mrs. B continued to improve, although neuropsychological assessment revealed major deficits in visuospatial function, attention, concentration, and memory. Repeat EEG showed diffuse slowing with frontal intermittent rhythmic delta activity, consistent with diffuse toxic metabolic encephalopathy.

Three weeks after admission, Mrs. B was discharged to her assisted-living facility, where she receives follow-up medical and psychiatric care. Her MMSE score at discharge was 12/30, indicating moderately severe cognitive impairment. Motor function has improved, although Mrs. B remains confused and needs help with daily living.

One month after discharge, Mrs. B’s diet was much improved; thiamine was reduced to 100 mg once daily. She has stayed sober but has repeatedly tried to drink. She was referred to a 12-step program but has not complied.

Table 1

Clinical features of WE, Korsakoff’s psychosis

Wernicke’s encephalopathy	Korsakoff’s psychosis
Acute onset	Subacute or chronic onset
Clouding of conciousness common	Consciousness usually clear
Ataxia, nystagmus, ophthalmoplegiao usually present	Ataxia, nystagmus, ophthalmoplegia not common
Impaired anterograde, retrograde memory; confabulation is rare	Impaired anterograde, retrograde memory with prominent confabulation
Without adequate treatment, >80% progress to Korsakoff’s psychosis; death rate is 20%	>80% progress to alcohol induced persisting dementia; nursing home admission rate is 25%
Source: Reference 14.

The authors’ observations

Suspect WE in all patients with alcohol abuse disorder who are malnourished and/or elderly and whose dietary history is unclear. Early detection and treatment are crucial to preventing WE from becoming chronic. WE progresses to Korsakoff’s psychosis—a form of permanent short-term memory loss—in up to 80% of patients.⁵

Because Korsakoff’s psychosis carries an 8% death rate, consider the disorder in the differential diagnosis (Table). The disorder was ruled out in Mrs. B because of clouding of consciousness, ataxia, nystagmus, and shorter symptom duration.

Thiamine should be given IV, but can be given IM if unit nurses are not certified to give IV injections. Oral thiamine cannot generate the high thiamine blood concentrations (>50 ng/mL within the first 12 hours of treatment) needed to prevent irreversible damage.

 

Parenteral thiamine, 100 mg/d for 5 to 7 days, is given for acute WE. Some patients who are genetically predisposed to thiamine deficiency may need up to 1,000 mg/d. Continue oral thiamine, 100 mg/d, after parenteral dosing.

Although anaphylaxis risk during a 10-minute thiamine infusion is less than 1 in 1 million, make sure cardiopulmonary resuscitation is available during treatment. Glucose load can precipitate or worsen WE in a thiamine-deficient patient, so give thiamine before giving glucose in any form, including everyday foods.

Watch for other vitamin and magnesium deficiencies common to patients with alcoholism, as these might compromise response to IV/IM thiamine.¹⁵ Also rule out stroke in men age >65 who present with signs of hemiparesis.

Related resources

• Stern Y, Sackheim HA. Neuropsychiatric aspects of memory and amnesia. In: Yudofsky SC, Hales RE, (eds). Essentials of neuropsychiatry and clinical neurosciences. Washington, DC: American Psychiatric Publishing, 2004:201-38.
• National Institute of Neurological Disorders and Stroke. http://www.ninds.nih.gov/health_and_medical/disorders/wernicke-korsakoff.htm

Drug brand names

• Chlordiazepoxide • Libritabs, Lithium
• Divalproex sodium • Depakote
• Paroxetine • Paxil
• Risperidone • Risperdal
• Trazodone • Desyrel

Disclosure

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

Acknowledgment

Dr. Tampi’s efforts were supported by funds from the Division of State, Community, and Public Health, Bureau of Health Professions, Health Resources and Services Administration, Department of Health and Human Services, under grant number 1 K01 HP 00071-01, and the Geriatric Academic Career Award ($57,007). The information is that of Dr. Tampi and should not be construed as the official position or policy of, nor should any endorsements be inferred by, the aforementioned departments or the United States government.

CASE 1: BEWARE ‘OLD MAN KIPLING’

Mrs. A, age 87, has Alzheimer’s disease. About 1 month before presentation, she entered a nursing home because of increasing agitation, paranoia, auditory and visual hallucinations, and decreased ability to care for herself. Her doctor started risperidone, 0.5 mg bid, to treat her agitation and psychosis.

Two days later, Mrs. A barricaded herself in her room. She told staff that “Old Man Kipling” was trying to break in, steal her money, and kill her and her son. She was sent to the emergency room; psychiatric consultation was ordered.

Mrs. A also has hypertension, renal cell carcinoma, anemia, and chronic renal failure. She had seen a psychiatrist for worsening cognitive function but has no other psychiatric history. Brain CT without contrast revealed generalized atrophy with no acute cerebral events. Workup showed decreased potassium (3.1 mEq/L), which returned to normal after Mrs. A was given potassium chloride, 20 mEq/d for 5 days. Other lab results were normal. Hydrochlorothiazide, 25 mg/d for hypertension, was stopped to prevent potassium depletion. No neurologic deficits were found.

Upon admission to the geriatric psychiatry unit, Mrs. A was paranoid and agitated. She talked to an imaginary person, continued to fear “Old Man Kipling,” and again tried to barricade herself.

ECG at admission—done because of Mrs. A’s age, cardiac history, and hydrochlorothiazide use—showed a corrected QT (QTc) interval of 494 msec, nearly 50 msec above the high-normal range for women. The interval was 460 msec at baseline (before risperidone treatment). Mrs. A was switched to olanzapine, 5 mg at bedtime, but her QTc intervals stayed between 494 and 495 msec, and her psychotic symptoms continued unabated.

Table 1

Mean antipsychotic-induced QTc interval change from baseline to steady state

Antipsychotic	Mean QTc interval change
Haloperidol	4.7 msec
Olanzapine	6.4 msec
Risperidone	10.0 msec
Quetiapine	14.5 msec
Ziprasidone	20.6 msec
Thioridazine	35.8 msec
Source: reference 2.

The authors’ observations

Antipsychotics, used to treat behavioral disturbances in older patients, can prolong QTc intervals. Although often asymptomatic, a prolonged interval can lead to torsade de pointes, a polymorphic ventricular arrhythmia that can progress to ventricular fibrillation and cause sudden death.

Reilly et al¹ suggest that antipsychotic-induced QTc prolongation may be dose-dependent. Age >65 is also a risk factor.

Start low and go slow when prescribing antipsychotics to patients with QTc intervals 450 msec. If prolonged intervals persist, switch antipsychotics and consult a cardiologist to help manage the patient’s care.

Switching agents will not entirely eliminate the risk, however. Mrs. A’s QTc interval remained elevated despite the switch to olanzapine, which is less likely than most antipsychotics to increase the interval.

Among mostly healthy men, haloperidol was shown to cause a lower mean QTc interval increase than other antipsychotics (Table 1), although QTc prolongations >60 msec were reported in 4% of those who took haloperidol.² The agent also may cause tardive dyskinesia, and that risk is multiplied in patients >age 65.³ For Mrs. A, however, persistent psychosis and declining function outweighed the risks.

With haloperidol, start low and titrate slowly to reduce the risk of extrapyramidal symptoms (EPS). Decrease the dosage if involuntary movements develop. If a haloperidol decrease would lead to decompensation, add an anticholinergic agent such as benztropine, but be careful because anticholinergics can worsen cognitive function.

Test for involuntary movements before starting an antipsychotic. Retest every 4 to 6 months, when changing dosages or switching antipsychotics, and when patients complain of EPS.

CASE 1 CONTINUED: GOODBYE MR. KIPLING

Mrs. A was switched to haloperidol, 0.5 mg bid titrated over 3 weeks to 2 mg every morning and 3 mg nightly. Daily ECGs across 10 days showed QTc intervals 467 msec. Abnormal Involuntary Movement Scale testing showed no EPS. Her blood pressure was stable, ranging from 110 to 130 mm Hg (systolic) and 70 to 80 mm Hg (diastolic).

The patient became calmer and her paranoid delusions and hallucinations disappeared. Her Folstein Mini-Mental Status Examination score during her third and final week of hospitalization was 16, indicating moderate dementia. She was discharged to her son’s care; outpatient psychiatric care was also arranged. The psychiatrist started donepezil, 5 mg/d titrated to 10 mg/d after 6 weeks, to treat her memory impairments.

More than 1 year later, Mrs. A lives at home with her son. She has not needed psychiatric hospitalization. Her primary care physician monitors her cardiac health.

CASE 2: SUICIDALITY AND SEXUAL BEHAVIOR

Mr. B, age 50, has battled schizoaffective disorder for more than 30 years. Upon presenting to the ER, he told clinicians he planned to jump from his seventh-floor apartment after arguing with his neighbor.

The patient had been taking gabapentin, 300 mg bid; olanzapine, 10 mg at bedtime; citalopram, 20 mg/d; clonazepam, 1 mg at bedtime for panic symptoms; atorvastatin, 10 mg/d for hyperlipidemia; and esomeprazole, 40 mg/d, for ongoing GI problems. He also has bradycardia.

 

Electrolyte and magnesium levels, thyroid function, and liver function tests were normal. Potassium was 3.9 mEq/L, indicating possible deficiency. Toxicity screen was negative, ruling out substance abuse or medication overdose. Baseline ECG—ordered because of Mr. B’s bradycardia—showed a QTc interval of 519 msec (almost 80 msec above high-normal for men) and a heart rate of 50 bpm.

The cardiology team found that 1 year before, while being examined for suspected syncope, Mr. B had a prolonged QTc interval that resolved after olanzapine was stopped. Acting on cardiology’s advice, the psychiatrist stopped olanzapine and clonazepam, continued gabapentin, 300 mg/d, and added lorazepam, 1 mg as needed for agitation.

Within 48 hours, Mr. B’s QTc interval decreased to 400 msec. Gabapentin and lorazepam were continued. He received potassium chloride, 40 mEq qid for 4 days, and within 2 days potassium was normal (4.4 to 4.8 mEq/L). Magnesium also was monitored.

Over the next few days, Mr. B decompensated. He exposed himself, requested sexual favors from staff, and became agitated. Staff reported that he was responding to internal stimuli and had pressured speech and flight of ideas.

After consulting cardiology, the psychiatrist restarted olanzapine, 10 mg/d, and lorazepam, 1 mg bid. Daily ECGs were ordered. After two olanzapine doses, Mr. B’s QTc interval rose to 550 msec. The psychiatrist stopped all psychotropics except lorazepam, which was increased to 2 mg bid. When Mr. B became more agitated, throwing himself to the floor and hitting himself, he was isolated for his safety.

The authors’ observations

For years, olanzapine abated Mr. B’s mood and psychotic symptoms, and until the previous year significant QTc prolongation had not been detected. Other risk factors—such as electrolyte imbalance and change in olanzapine metabolism—were ruled out.

Mr. B’s chart indicated that he had responded well to haloperidol during a prior hospitalization. Divalproex, which has little effect on QTc interval, was also considered to control his mood.

CASE 2 CONTINUED: DRUG TRIALS

Eight days after Mr. B was hospitalized, the psychiatrist added divalproex, 250 mg tid titrated over 4 days to 1,000 mg/d. Mr. B became less manic but remained psychotic and disorganized. Lorazepam was increased to 2 mg tid and 3 mg at bedtime. His QTc interval now averaged 400 msec.

Loxapine, 10 mg tid, was added but then quickly discontinued after Mr. B’s QTc interval approached 500 msec.

Table 2

QTc interval ranges in men and women

Range	Men (msec)	Women (msec)
Normal	<430	<450
Borderline	431-450	451-470
Source: reference 8.

The following week, after consulting cardiology, the psychiatrist started haloperidol, 2 mg tid, and added benztropine, 1 mg for dystonia as needed. The next day, Mr. B’s QTc interval was 402 msec.

Medications were readjusted gradually. Gabapentin was restarted and increased to 600 mg tid, lorazepam was decreased to 1 mg tid, and divalproex was increased to 500 mg tid with no major QTc change.

Haloperidol was titrated to 5 mg bid, but the interval increased to 549 msec, then fell below 500 msec after haloperidol was readjusted to 2 mg bid.

Over the next 2 weeks, Mr. B’s mood and psychotic symptoms gradually improved. He was discharged after 27 days, at which point his QTc interval ranged between 360 and 409 msec. He was told to continue his medications.

The authors’ observations

Many factors other than antipsychotic use can lengthen QTc interval. Patients with major psychiatric disorders tend to have more risk factors compared with the general population.⁴

Serial or signal-averaged ECGs are the most accurate ways to monitor QTc intervals.⁵ Obtain a baseline ECG before starting an antipsychotic for patients with one or more risk factors:

Age >65. Older persons without coronary artery disease (CAD) have longer QTc intervals than do younger patients in similar health.⁶

Drug-drug interactions—common among the elderly—can further prolong the interval. Decreased drug metabolism also raises drug plasma levels and increases QTc prolongation risk.

Cardiac diseases. CAD, cardiac arrhythmias, and congestive heart failure are serious risk factors, particularly for older patients. Watch for pre-existing heart disease—which heightens risk of conduction defects—and family history of cardiac disease, syncope, or sudden death.

CNS diseases. Stroke, tumors, and brain infections can cause autonomic dysfunction and electrolyte imbalances.

Electrolyte imbalance. Hypokalemia and hypomagnesemia can prolong the interval.⁷ Take complaints of diarrhea or frequent vomiting seriously, and refer patients with renal disease or who are using diuretics for an ECG. Regularly test for electrolytes, especially potassium and magnesium.

Endocrine diseases. Diabetes, hypothyroidism, and pituitary insufficiency can cause electrolyte abnormalities.

Female sex. QTc intervals are on average 20 msec longer in women <age>Table 2)⁸ and are prolonged during the first half of the menstrual cycle. Androgen may shorten intervals in men. Women account for about 70% of drug-induced torsade de pointes cases.⁹
</age>

 

Medications. Antipsychotics, tricyclics, and antihistamines can prolong the interval alone or when combined with drugs that inhibit their metabolism. Concomitant use of agents that inhibit cytochrome P-450 enzyme systems may elevate serum concentrations of the interval-prolonging medication,⁴ as can decreased CYP 2D6 activity.¹⁰ Check plasma drug levels in patients who exhibit side effects.

Also check for congenital long QTc interval, autonomic CNS abnormalities, and overdose of a prescribed psychotropic.

Check ECGs every 2 days for inpatients and at every visit for outpatients taking antipsychotics. Frequent testing is crucial for elderly patients with multiple cardiac risk factors who are taking medications likely to increase the interval. Repeat ECGs if the patient reports lightheadedness or palpitations.

QTc interval prolongation is minimal in healthy young adults taking antipsychotics, so order ECGs only when symptoms arise. A baseline ECG is advisable but not necessary.

Order a cardiology consult and immediate ECG when the QTc interval exceeds 500 msec¹¹ or if the patient exhibits arrhythmia symptoms (palpitation chest pain, dizziness, presyncope, syncope). Work with the cardiologist to manage medication.

Related resources

• University of Arizona Center for Education and Research on Therapeutics. Drugs that prolong the QT interval. http://www.qtdrugs.org/medical-pros/drug-lists/drug-lists.htm
• Glassman AH, Bigger JT Jr. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry 2001;158:1774-82.

Drug brand names

• Atorvastatin • Lipitor
• Benztropine • Cogentin
• Citalopram • Celexa
• Clonazepam • Klonopin
• Divalproex • Depakote
• Donepezil • Aricept
• Esomeprazole • Nexium
• Gabapentin • Neurontin
• Haloperidol • Haldol
• Hydrochlorothiazide • Atacand, others
• Lorazepam • Ativan
• Loxapine • Loxitane
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Ziprasidone •Geodon

Disclosure

Dr. Tampi receives research support from the division of state, community, and public health, bureau of health professions, Health Resources and Services Administration, Department of Health and Human Services.

Dr. Ruedrich receives grants from Pfizer Inc. and Eisai Inc., and is a consultant to Abbott Laboratories.

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

CASE 1: BEWARE ‘OLD MAN KIPLING’

Mrs. A, age 87, has Alzheimer’s disease. About 1 month before presentation, she entered a nursing home because of increasing agitation, paranoia, auditory and visual hallucinations, and decreased ability to care for herself. Her doctor started risperidone, 0.5 mg bid, to treat her agitation and psychosis.

Two days later, Mrs. A barricaded herself in her room. She told staff that “Old Man Kipling” was trying to break in, steal her money, and kill her and her son. She was sent to the emergency room; psychiatric consultation was ordered.

Mrs. A also has hypertension, renal cell carcinoma, anemia, and chronic renal failure. She had seen a psychiatrist for worsening cognitive function but has no other psychiatric history. Brain CT without contrast revealed generalized atrophy with no acute cerebral events. Workup showed decreased potassium (3.1 mEq/L), which returned to normal after Mrs. A was given potassium chloride, 20 mEq/d for 5 days. Other lab results were normal. Hydrochlorothiazide, 25 mg/d for hypertension, was stopped to prevent potassium depletion. No neurologic deficits were found.

Upon admission to the geriatric psychiatry unit, Mrs. A was paranoid and agitated. She talked to an imaginary person, continued to fear “Old Man Kipling,” and again tried to barricade herself.

ECG at admission—done because of Mrs. A’s age, cardiac history, and hydrochlorothiazide use—showed a corrected QT (QTc) interval of 494 msec, nearly 50 msec above the high-normal range for women. The interval was 460 msec at baseline (before risperidone treatment). Mrs. A was switched to olanzapine, 5 mg at bedtime, but her QTc intervals stayed between 494 and 495 msec, and her psychotic symptoms continued unabated.

Table 1

Mean antipsychotic-induced QTc interval change from baseline to steady state

Antipsychotic	Mean QTc interval change
Haloperidol	4.7 msec
Olanzapine	6.4 msec
Risperidone	10.0 msec
Quetiapine	14.5 msec
Ziprasidone	20.6 msec
Thioridazine	35.8 msec
Source: reference 2.

The authors’ observations

Antipsychotics, used to treat behavioral disturbances in older patients, can prolong QTc intervals. Although often asymptomatic, a prolonged interval can lead to torsade de pointes, a polymorphic ventricular arrhythmia that can progress to ventricular fibrillation and cause sudden death.

Reilly et al¹ suggest that antipsychotic-induced QTc prolongation may be dose-dependent. Age >65 is also a risk factor.

Start low and go slow when prescribing antipsychotics to patients with QTc intervals 450 msec. If prolonged intervals persist, switch antipsychotics and consult a cardiologist to help manage the patient’s care.

Switching agents will not entirely eliminate the risk, however. Mrs. A’s QTc interval remained elevated despite the switch to olanzapine, which is less likely than most antipsychotics to increase the interval.

Among mostly healthy men, haloperidol was shown to cause a lower mean QTc interval increase than other antipsychotics (Table 1), although QTc prolongations >60 msec were reported in 4% of those who took haloperidol.² The agent also may cause tardive dyskinesia, and that risk is multiplied in patients >age 65.³ For Mrs. A, however, persistent psychosis and declining function outweighed the risks.

With haloperidol, start low and titrate slowly to reduce the risk of extrapyramidal symptoms (EPS). Decrease the dosage if involuntary movements develop. If a haloperidol decrease would lead to decompensation, add an anticholinergic agent such as benztropine, but be careful because anticholinergics can worsen cognitive function.

Test for involuntary movements before starting an antipsychotic. Retest every 4 to 6 months, when changing dosages or switching antipsychotics, and when patients complain of EPS.

CASE 1 CONTINUED: GOODBYE MR. KIPLING

Mrs. A was switched to haloperidol, 0.5 mg bid titrated over 3 weeks to 2 mg every morning and 3 mg nightly. Daily ECGs across 10 days showed QTc intervals 467 msec. Abnormal Involuntary Movement Scale testing showed no EPS. Her blood pressure was stable, ranging from 110 to 130 mm Hg (systolic) and 70 to 80 mm Hg (diastolic).

The patient became calmer and her paranoid delusions and hallucinations disappeared. Her Folstein Mini-Mental Status Examination score during her third and final week of hospitalization was 16, indicating moderate dementia. She was discharged to her son’s care; outpatient psychiatric care was also arranged. The psychiatrist started donepezil, 5 mg/d titrated to 10 mg/d after 6 weeks, to treat her memory impairments.

More than 1 year later, Mrs. A lives at home with her son. She has not needed psychiatric hospitalization. Her primary care physician monitors her cardiac health.

CASE 2: SUICIDALITY AND SEXUAL BEHAVIOR

Mr. B, age 50, has battled schizoaffective disorder for more than 30 years. Upon presenting to the ER, he told clinicians he planned to jump from his seventh-floor apartment after arguing with his neighbor.

The patient had been taking gabapentin, 300 mg bid; olanzapine, 10 mg at bedtime; citalopram, 20 mg/d; clonazepam, 1 mg at bedtime for panic symptoms; atorvastatin, 10 mg/d for hyperlipidemia; and esomeprazole, 40 mg/d, for ongoing GI problems. He also has bradycardia.

 

Electrolyte and magnesium levels, thyroid function, and liver function tests were normal. Potassium was 3.9 mEq/L, indicating possible deficiency. Toxicity screen was negative, ruling out substance abuse or medication overdose. Baseline ECG—ordered because of Mr. B’s bradycardia—showed a QTc interval of 519 msec (almost 80 msec above high-normal for men) and a heart rate of 50 bpm.

The cardiology team found that 1 year before, while being examined for suspected syncope, Mr. B had a prolonged QTc interval that resolved after olanzapine was stopped. Acting on cardiology’s advice, the psychiatrist stopped olanzapine and clonazepam, continued gabapentin, 300 mg/d, and added lorazepam, 1 mg as needed for agitation.

Within 48 hours, Mr. B’s QTc interval decreased to 400 msec. Gabapentin and lorazepam were continued. He received potassium chloride, 40 mEq qid for 4 days, and within 2 days potassium was normal (4.4 to 4.8 mEq/L). Magnesium also was monitored.

Over the next few days, Mr. B decompensated. He exposed himself, requested sexual favors from staff, and became agitated. Staff reported that he was responding to internal stimuli and had pressured speech and flight of ideas.

After consulting cardiology, the psychiatrist restarted olanzapine, 10 mg/d, and lorazepam, 1 mg bid. Daily ECGs were ordered. After two olanzapine doses, Mr. B’s QTc interval rose to 550 msec. The psychiatrist stopped all psychotropics except lorazepam, which was increased to 2 mg bid. When Mr. B became more agitated, throwing himself to the floor and hitting himself, he was isolated for his safety.

The authors’ observations

For years, olanzapine abated Mr. B’s mood and psychotic symptoms, and until the previous year significant QTc prolongation had not been detected. Other risk factors—such as electrolyte imbalance and change in olanzapine metabolism—were ruled out.

Mr. B’s chart indicated that he had responded well to haloperidol during a prior hospitalization. Divalproex, which has little effect on QTc interval, was also considered to control his mood.

CASE 2 CONTINUED: DRUG TRIALS

Eight days after Mr. B was hospitalized, the psychiatrist added divalproex, 250 mg tid titrated over 4 days to 1,000 mg/d. Mr. B became less manic but remained psychotic and disorganized. Lorazepam was increased to 2 mg tid and 3 mg at bedtime. His QTc interval now averaged 400 msec.

Loxapine, 10 mg tid, was added but then quickly discontinued after Mr. B’s QTc interval approached 500 msec.

Table 2

QTc interval ranges in men and women

Range	Men (msec)	Women (msec)
Normal	<430	<450
Borderline	431-450	451-470
Source: reference 8.

The following week, after consulting cardiology, the psychiatrist started haloperidol, 2 mg tid, and added benztropine, 1 mg for dystonia as needed. The next day, Mr. B’s QTc interval was 402 msec.

Medications were readjusted gradually. Gabapentin was restarted and increased to 600 mg tid, lorazepam was decreased to 1 mg tid, and divalproex was increased to 500 mg tid with no major QTc change.

Haloperidol was titrated to 5 mg bid, but the interval increased to 549 msec, then fell below 500 msec after haloperidol was readjusted to 2 mg bid.

Over the next 2 weeks, Mr. B’s mood and psychotic symptoms gradually improved. He was discharged after 27 days, at which point his QTc interval ranged between 360 and 409 msec. He was told to continue his medications.

The authors’ observations

Many factors other than antipsychotic use can lengthen QTc interval. Patients with major psychiatric disorders tend to have more risk factors compared with the general population.⁴

Serial or signal-averaged ECGs are the most accurate ways to monitor QTc intervals.⁵ Obtain a baseline ECG before starting an antipsychotic for patients with one or more risk factors:

Age >65. Older persons without coronary artery disease (CAD) have longer QTc intervals than do younger patients in similar health.⁶

Drug-drug interactions—common among the elderly—can further prolong the interval. Decreased drug metabolism also raises drug plasma levels and increases QTc prolongation risk.

Cardiac diseases. CAD, cardiac arrhythmias, and congestive heart failure are serious risk factors, particularly for older patients. Watch for pre-existing heart disease—which heightens risk of conduction defects—and family history of cardiac disease, syncope, or sudden death.

CNS diseases. Stroke, tumors, and brain infections can cause autonomic dysfunction and electrolyte imbalances.

Electrolyte imbalance. Hypokalemia and hypomagnesemia can prolong the interval.⁷ Take complaints of diarrhea or frequent vomiting seriously, and refer patients with renal disease or who are using diuretics for an ECG. Regularly test for electrolytes, especially potassium and magnesium.

Endocrine diseases. Diabetes, hypothyroidism, and pituitary insufficiency can cause electrolyte abnormalities.

Female sex. QTc intervals are on average 20 msec longer in women <age>Table 2)⁸ and are prolonged during the first half of the menstrual cycle. Androgen may shorten intervals in men. Women account for about 70% of drug-induced torsade de pointes cases.⁹
</age>

 

Medications. Antipsychotics, tricyclics, and antihistamines can prolong the interval alone or when combined with drugs that inhibit their metabolism. Concomitant use of agents that inhibit cytochrome P-450 enzyme systems may elevate serum concentrations of the interval-prolonging medication,⁴ as can decreased CYP 2D6 activity.¹⁰ Check plasma drug levels in patients who exhibit side effects.

Also check for congenital long QTc interval, autonomic CNS abnormalities, and overdose of a prescribed psychotropic.

Check ECGs every 2 days for inpatients and at every visit for outpatients taking antipsychotics. Frequent testing is crucial for elderly patients with multiple cardiac risk factors who are taking medications likely to increase the interval. Repeat ECGs if the patient reports lightheadedness or palpitations.

QTc interval prolongation is minimal in healthy young adults taking antipsychotics, so order ECGs only when symptoms arise. A baseline ECG is advisable but not necessary.

Order a cardiology consult and immediate ECG when the QTc interval exceeds 500 msec¹¹ or if the patient exhibits arrhythmia symptoms (palpitation chest pain, dizziness, presyncope, syncope). Work with the cardiologist to manage medication.

Related resources

• University of Arizona Center for Education and Research on Therapeutics. Drugs that prolong the QT interval. http://www.qtdrugs.org/medical-pros/drug-lists/drug-lists.htm
• Glassman AH, Bigger JT Jr. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry 2001;158:1774-82.

Drug brand names

• Atorvastatin • Lipitor
• Benztropine • Cogentin
• Citalopram • Celexa
• Clonazepam • Klonopin
• Divalproex • Depakote
• Donepezil • Aricept
• Esomeprazole • Nexium
• Gabapentin • Neurontin
• Haloperidol • Haldol
• Hydrochlorothiazide • Atacand, others
• Lorazepam • Ativan
• Loxapine • Loxitane
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Ziprasidone •Geodon

Disclosure

Dr. Tampi receives research support from the division of state, community, and public health, bureau of health professions, Health Resources and Services Administration, Department of Health and Human Services.

Dr. Ruedrich receives grants from Pfizer Inc. and Eisai Inc., and is a consultant to Abbott Laboratories.

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

CASE 1: BEWARE ‘OLD MAN KIPLING’

Mrs. A, age 87, has Alzheimer’s disease. About 1 month before presentation, she entered a nursing home because of increasing agitation, paranoia, auditory and visual hallucinations, and decreased ability to care for herself. Her doctor started risperidone, 0.5 mg bid, to treat her agitation and psychosis.

Two days later, Mrs. A barricaded herself in her room. She told staff that “Old Man Kipling” was trying to break in, steal her money, and kill her and her son. She was sent to the emergency room; psychiatric consultation was ordered.

Mrs. A also has hypertension, renal cell carcinoma, anemia, and chronic renal failure. She had seen a psychiatrist for worsening cognitive function but has no other psychiatric history. Brain CT without contrast revealed generalized atrophy with no acute cerebral events. Workup showed decreased potassium (3.1 mEq/L), which returned to normal after Mrs. A was given potassium chloride, 20 mEq/d for 5 days. Other lab results were normal. Hydrochlorothiazide, 25 mg/d for hypertension, was stopped to prevent potassium depletion. No neurologic deficits were found.

Upon admission to the geriatric psychiatry unit, Mrs. A was paranoid and agitated. She talked to an imaginary person, continued to fear “Old Man Kipling,” and again tried to barricade herself.

ECG at admission—done because of Mrs. A’s age, cardiac history, and hydrochlorothiazide use—showed a corrected QT (QTc) interval of 494 msec, nearly 50 msec above the high-normal range for women. The interval was 460 msec at baseline (before risperidone treatment). Mrs. A was switched to olanzapine, 5 mg at bedtime, but her QTc intervals stayed between 494 and 495 msec, and her psychotic symptoms continued unabated.

Table 1

Mean antipsychotic-induced QTc interval change from baseline to steady state

Antipsychotic	Mean QTc interval change
Haloperidol	4.7 msec
Olanzapine	6.4 msec
Risperidone	10.0 msec
Quetiapine	14.5 msec
Ziprasidone	20.6 msec
Thioridazine	35.8 msec
Source: reference 2.

The authors’ observations

Antipsychotics, used to treat behavioral disturbances in older patients, can prolong QTc intervals. Although often asymptomatic, a prolonged interval can lead to torsade de pointes, a polymorphic ventricular arrhythmia that can progress to ventricular fibrillation and cause sudden death.

Reilly et al¹ suggest that antipsychotic-induced QTc prolongation may be dose-dependent. Age >65 is also a risk factor.

Start low and go slow when prescribing antipsychotics to patients with QTc intervals 450 msec. If prolonged intervals persist, switch antipsychotics and consult a cardiologist to help manage the patient’s care.

Switching agents will not entirely eliminate the risk, however. Mrs. A’s QTc interval remained elevated despite the switch to olanzapine, which is less likely than most antipsychotics to increase the interval.

Among mostly healthy men, haloperidol was shown to cause a lower mean QTc interval increase than other antipsychotics (Table 1), although QTc prolongations >60 msec were reported in 4% of those who took haloperidol.² The agent also may cause tardive dyskinesia, and that risk is multiplied in patients >age 65.³ For Mrs. A, however, persistent psychosis and declining function outweighed the risks.

With haloperidol, start low and titrate slowly to reduce the risk of extrapyramidal symptoms (EPS). Decrease the dosage if involuntary movements develop. If a haloperidol decrease would lead to decompensation, add an anticholinergic agent such as benztropine, but be careful because anticholinergics can worsen cognitive function.

Test for involuntary movements before starting an antipsychotic. Retest every 4 to 6 months, when changing dosages or switching antipsychotics, and when patients complain of EPS.

CASE 1 CONTINUED: GOODBYE MR. KIPLING

Mrs. A was switched to haloperidol, 0.5 mg bid titrated over 3 weeks to 2 mg every morning and 3 mg nightly. Daily ECGs across 10 days showed QTc intervals 467 msec. Abnormal Involuntary Movement Scale testing showed no EPS. Her blood pressure was stable, ranging from 110 to 130 mm Hg (systolic) and 70 to 80 mm Hg (diastolic).

The patient became calmer and her paranoid delusions and hallucinations disappeared. Her Folstein Mini-Mental Status Examination score during her third and final week of hospitalization was 16, indicating moderate dementia. She was discharged to her son’s care; outpatient psychiatric care was also arranged. The psychiatrist started donepezil, 5 mg/d titrated to 10 mg/d after 6 weeks, to treat her memory impairments.

More than 1 year later, Mrs. A lives at home with her son. She has not needed psychiatric hospitalization. Her primary care physician monitors her cardiac health.

CASE 2: SUICIDALITY AND SEXUAL BEHAVIOR

Mr. B, age 50, has battled schizoaffective disorder for more than 30 years. Upon presenting to the ER, he told clinicians he planned to jump from his seventh-floor apartment after arguing with his neighbor.

The patient had been taking gabapentin, 300 mg bid; olanzapine, 10 mg at bedtime; citalopram, 20 mg/d; clonazepam, 1 mg at bedtime for panic symptoms; atorvastatin, 10 mg/d for hyperlipidemia; and esomeprazole, 40 mg/d, for ongoing GI problems. He also has bradycardia.

 

Electrolyte and magnesium levels, thyroid function, and liver function tests were normal. Potassium was 3.9 mEq/L, indicating possible deficiency. Toxicity screen was negative, ruling out substance abuse or medication overdose. Baseline ECG—ordered because of Mr. B’s bradycardia—showed a QTc interval of 519 msec (almost 80 msec above high-normal for men) and a heart rate of 50 bpm.

The cardiology team found that 1 year before, while being examined for suspected syncope, Mr. B had a prolonged QTc interval that resolved after olanzapine was stopped. Acting on cardiology’s advice, the psychiatrist stopped olanzapine and clonazepam, continued gabapentin, 300 mg/d, and added lorazepam, 1 mg as needed for agitation.

Within 48 hours, Mr. B’s QTc interval decreased to 400 msec. Gabapentin and lorazepam were continued. He received potassium chloride, 40 mEq qid for 4 days, and within 2 days potassium was normal (4.4 to 4.8 mEq/L). Magnesium also was monitored.

Over the next few days, Mr. B decompensated. He exposed himself, requested sexual favors from staff, and became agitated. Staff reported that he was responding to internal stimuli and had pressured speech and flight of ideas.

After consulting cardiology, the psychiatrist restarted olanzapine, 10 mg/d, and lorazepam, 1 mg bid. Daily ECGs were ordered. After two olanzapine doses, Mr. B’s QTc interval rose to 550 msec. The psychiatrist stopped all psychotropics except lorazepam, which was increased to 2 mg bid. When Mr. B became more agitated, throwing himself to the floor and hitting himself, he was isolated for his safety.

The authors’ observations

For years, olanzapine abated Mr. B’s mood and psychotic symptoms, and until the previous year significant QTc prolongation had not been detected. Other risk factors—such as electrolyte imbalance and change in olanzapine metabolism—were ruled out.

Mr. B’s chart indicated that he had responded well to haloperidol during a prior hospitalization. Divalproex, which has little effect on QTc interval, was also considered to control his mood.

CASE 2 CONTINUED: DRUG TRIALS

Eight days after Mr. B was hospitalized, the psychiatrist added divalproex, 250 mg tid titrated over 4 days to 1,000 mg/d. Mr. B became less manic but remained psychotic and disorganized. Lorazepam was increased to 2 mg tid and 3 mg at bedtime. His QTc interval now averaged 400 msec.

Loxapine, 10 mg tid, was added but then quickly discontinued after Mr. B’s QTc interval approached 500 msec.

Table 2

QTc interval ranges in men and women

Range	Men (msec)	Women (msec)
Normal	<430	<450
Borderline	431-450	451-470
Source: reference 8.

The following week, after consulting cardiology, the psychiatrist started haloperidol, 2 mg tid, and added benztropine, 1 mg for dystonia as needed. The next day, Mr. B’s QTc interval was 402 msec.

Medications were readjusted gradually. Gabapentin was restarted and increased to 600 mg tid, lorazepam was decreased to 1 mg tid, and divalproex was increased to 500 mg tid with no major QTc change.

Haloperidol was titrated to 5 mg bid, but the interval increased to 549 msec, then fell below 500 msec after haloperidol was readjusted to 2 mg bid.

Over the next 2 weeks, Mr. B’s mood and psychotic symptoms gradually improved. He was discharged after 27 days, at which point his QTc interval ranged between 360 and 409 msec. He was told to continue his medications.

The authors’ observations

Many factors other than antipsychotic use can lengthen QTc interval. Patients with major psychiatric disorders tend to have more risk factors compared with the general population.⁴

Serial or signal-averaged ECGs are the most accurate ways to monitor QTc intervals.⁵ Obtain a baseline ECG before starting an antipsychotic for patients with one or more risk factors:

Age >65. Older persons without coronary artery disease (CAD) have longer QTc intervals than do younger patients in similar health.⁶

Drug-drug interactions—common among the elderly—can further prolong the interval. Decreased drug metabolism also raises drug plasma levels and increases QTc prolongation risk.

Cardiac diseases. CAD, cardiac arrhythmias, and congestive heart failure are serious risk factors, particularly for older patients. Watch for pre-existing heart disease—which heightens risk of conduction defects—and family history of cardiac disease, syncope, or sudden death.

CNS diseases. Stroke, tumors, and brain infections can cause autonomic dysfunction and electrolyte imbalances.

Electrolyte imbalance. Hypokalemia and hypomagnesemia can prolong the interval.⁷ Take complaints of diarrhea or frequent vomiting seriously, and refer patients with renal disease or who are using diuretics for an ECG. Regularly test for electrolytes, especially potassium and magnesium.

Endocrine diseases. Diabetes, hypothyroidism, and pituitary insufficiency can cause electrolyte abnormalities.

Female sex. QTc intervals are on average 20 msec longer in women <age>Table 2)⁸ and are prolonged during the first half of the menstrual cycle. Androgen may shorten intervals in men. Women account for about 70% of drug-induced torsade de pointes cases.⁹
</age>

 

Medications. Antipsychotics, tricyclics, and antihistamines can prolong the interval alone or when combined with drugs that inhibit their metabolism. Concomitant use of agents that inhibit cytochrome P-450 enzyme systems may elevate serum concentrations of the interval-prolonging medication,⁴ as can decreased CYP 2D6 activity.¹⁰ Check plasma drug levels in patients who exhibit side effects.

Also check for congenital long QTc interval, autonomic CNS abnormalities, and overdose of a prescribed psychotropic.

Check ECGs every 2 days for inpatients and at every visit for outpatients taking antipsychotics. Frequent testing is crucial for elderly patients with multiple cardiac risk factors who are taking medications likely to increase the interval. Repeat ECGs if the patient reports lightheadedness or palpitations.

QTc interval prolongation is minimal in healthy young adults taking antipsychotics, so order ECGs only when symptoms arise. A baseline ECG is advisable but not necessary.

Order a cardiology consult and immediate ECG when the QTc interval exceeds 500 msec¹¹ or if the patient exhibits arrhythmia symptoms (palpitation chest pain, dizziness, presyncope, syncope). Work with the cardiologist to manage medication.

Related resources

• University of Arizona Center for Education and Research on Therapeutics. Drugs that prolong the QT interval. http://www.qtdrugs.org/medical-pros/drug-lists/drug-lists.htm
• Glassman AH, Bigger JT Jr. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry 2001;158:1774-82.

Drug brand names

• Atorvastatin • Lipitor
• Benztropine • Cogentin
• Citalopram • Celexa
• Clonazepam • Klonopin
• Divalproex • Depakote
• Donepezil • Aricept
• Esomeprazole • Nexium
• Gabapentin • Neurontin
• Haloperidol • Haldol
• Hydrochlorothiazide • Atacand, others
• Lorazepam • Ativan
• Loxapine • Loxitane
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Thioridazine • Mellaril
• Ziprasidone •Geodon

Disclosure

Dr. Tampi receives research support from the division of state, community, and public health, bureau of health professions, Health Resources and Services Administration, Department of Health and Human Services.

Dr. Ruedrich receives grants from Pfizer Inc. and Eisai Inc., and is a consultant to Abbott Laboratories.

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

History: Threatened by an ‘angel’

Mr. M, age 32, began hearing voices at age 16. He had been diagnosed as having bipolar disorder with psychotic features before presenting to our hospital in 1995. He often experienced hypomania (euphoria, decreased sleep, free spending) followed by depressive periods (lack of energy, tearfulness, decreased concentration), and heard commands to kill himself or saw menacing shadows or “angels.”

Several psychiatrists tried various psychotropics across 6 years, but Mr. M’s odd behaviors persisted. One night he physically threatened his father, who tried to stop Mr. M from eating a sandwich wrapped in a plastic bag. Mr. M was hospitalized that night, and his diagnosis was changed to schizoaffective disorder based on recurrent auditory and visual hallucinations when mood symptoms were absent.

Mr. M was hospitalized nine times within 6 years for psychotic or depressive symptoms— including twice in 1 month for depression and suicidal ideation. Two months later, he attempted suicide by taking 1,200 mg of ziprasidone (about 10 times the normal daily dosage) and an unknown amount of lorazepam, after which he was treated in the ER and released. He presented to me shortly afterward, frightened by his suicide attempt.

At intake, Mr. M was taking lorazepam, 1 mg tid for anxiety, and ziprasidone, 20 mg bid.

Single and unemployed, Mr. M lived with his parents and a brother, and was collecting disability benefits because of his psychiatric problems. He told me that he had been off cocaine for 3 years but had used marijuana 2 weeks earlier. He also reported ongoing family problems but did not elaborate. He said he did not feel suicidal but described continued depressive episodes.

Dr. Fraser’s observations

Mr. M’s last six psychiatric hospitalizations and at least 5 years of outpatient notes by other psychiatrists indicated a history of schizoaffective disorder. Mr. M’s psychotic symptoms persisted for substantial periods while mood symptoms were absent, thus supporting the diagnosis. By contrast, mood and psychotic symptoms in major depression with psychotic features are almost always simultaneous.

Mr. M’s substance use should be considered. Fifty percent of persons with schizophrenia or an affective disorder have a lifetime prevalence of substance abuse disorder.¹ The rate climbs to 60% to 90% for patients with schizophrenia seen in emergency rooms, inpatient psychiatric units, and community settings.²

Mr. M’s last documented cocaine use was in 1998; subsequent urine drug screens showed only marijuana.

Cocaine abuse could have contributed to Mr. M’s psychotic symptoms, and marijuana use could have caused his inertia, lack of motivation, and difficulty concentrating. It is unclear why previous doctors attributed most of his psychotic symptoms to a major mental illness rather than cocaine use.

Ask patients about substance use along with a chronology of psychiatric symptoms. Encourage patients who are regularly using substances to stop for a trial period to see if symptoms abate during abstinence. Refer patients for substance use treatment if necessary.

Treatment: A waighty issue

I feared that Mr. M’s psychotic symptoms would recur, but he was more concerned about his depression and obesity. He said he gained 50 pounds over 3 1/2 years while taking olanzapine, 10 to 15 mg/d, and divalproex at various dosages. He stopped both agents on his own and lost 35 pounds across 6 months but was still obese (197 lbs., body mass index [BMI] 32.9).

I prescribed bupropion SR—100 mg/d titrated over several weeks to 200 mg each morning and 100 mg at night—because of its association with weight loss. I also:

• continued ziprasidone, 20 mg bid, to prevent psychosis
• continued lorazepam, 1 mg tid, to reduce anxiety stemming from his family problems. I asked Mr. M to slowly taper off the agent—which he had been taking for 8 years—across 6 to 12 months because a protracted benzodiazepine regimen can contribute to depression.
• referred him to a psychotherapist for cognitive-behavioral therapy to help reduce his depressive thinking and suicide risk
• recommended that he stop using marijuana.

At his second visit, Mr. M reported more auditory hallucinations. I increased ziprasidone to 40 mg bid.

By this time, Mr. M was becoming more comfortable in therapy. He began discussing his family problems in more detail, telling me that his brother is addicted to heroin.

I asked Mr. M if he was again threatening family members or other people. He replied that he had not been violent, but that his mother often slaps him and others in his family. I commended him for not retaliating, but warned him that his mother’s aggression was perpetuating his depression.

I encouraged Mr. M to find an apartment, but he said he could not yet afford to live on his own. I referred him to case management services to help him find affordable housing and urged him to avoid his mother’s assaults. He seemed to appreciate my concern for him.

 

Box

Twelve days later, Mr. M made an unplanned visit. He was angry because our pharmacy had not refilled his prescriptions and no one had returned his call asking about the refills. He was irritable but nonthreatening, although he planned to complain to the psychiatric center’s medical director.

I had received no phone messages, and my notes indicated the prescriptions were refilled. Nonetheless, my assuming responsibility for this problem was key to preserving our therapeutic alliance (Box). I resolved the matter and apologized for the miscommunication. Mr. M accepted my apology and scheduled a return visit.

About 1 month later, Mr. M’s self-esteem had increased. He stopped using marijuana, went on a low-calorie diet, and exercised at least 1 hour daily at a local gym. He lost 27 lbs. over 2 months, dropping his weight to 170 lbs. (BMI 28.3). He finished group (15 sessions) and individual (four sessions) psychotherapy, and avoided his mother when she became aggressive.

Before his next monthly visit, Mr. M had called the state vocational rehabilitation department to begin employment. I tapered lorazepam to 0.5 mg nightly while continuing ziprasidone and bupropion. His weight was near normal (150 lbs., BMI 25).

Six months into treatment, Mr. M. applied for a job and moved out of his parents’ home to live with another brother, who does not take drugs. He said that he “felt at peace” for the first time in years. His weight stayed in the 140s. I stopped lorazepam and he requested to see me 3 months later.

Dr. Fraser’s observations

Many patients with schizophrenia or schizoaffective disorder struggle with weight gain, substance use, employment problems, and family conflict, and some make slow progress with one or more of these issues. Mr. M’s rapid improvement on all fronts was striking, however.

Recovery from schizophrenia has been documented,³ and the prognosis for schizoaffective disorder is often more positive than for schizophrenia or severe bipolar disorder.⁴ Still, Mr. M’s apparent recovery seemed incredible.

To prevent symptom recurrence, I left the bupropion/ziprasidone regimen unchanged. Even after a chronically ill patient responds to medication, I feel dosages should be maintained unless side effects occur or a medication loses effectiveness.

Table

PTSD symptoms that suggest other diagnoses

PTSD symptoms	Similar to	Diagnosis suggested
Depersonalization, derealization, dissociation	Psychosis	Schizophrenia, schizoaffective disorder
Anxiety, hypervigilance, insomnia	Anxiety	Exacerbations of schizophrenia, schizoaffective disorder, bipolar disorder (mania)
Flashbacks, fear of trauma recurrence	Paranoia	Schizophrenia, schizoaffective disorder

Follow-up: Mr. M’s story

Since the mix-up with Mr. M’s medications, our therapeutic alliance grew stronger. He told me more about himself with each visit. Four months into treatment, he revealed that he is gay and feels “liberated” after years of keeping it secret.

Five months later, Mr. M confided that an older male partner had physically, sexually, and emotionally abused him for about 10 years, starting when Mr. M was 16—about the time his auditory hallucinations began. The abusive relationship ended when the partner died of an unspecified overdose.

Mr. M’s gay friends advised him to seek closure. He visited his ex-partner’s grave, placed a rose, said goodbye, and left vowing he’d never again become an abuse victim. He said he had never told any health professional this story.

Mr. M then asked to be tapered off medications. I was afraid his psychotic symptoms could resurface, although I now wondered whether his schizoaffective disorder diagnosis had been correct. We tapered bupropion and ziprasidone over the next month.

Twenty-four months later, his schizoaffective symptoms had not resurfaced. He worked as a security guard, maintained an apartment, and continued exercising and eating right. His weight stayed normal (140 lbs., BMI 23.3). No signs of hypomania were present, and he was finding fulfillment in nonabusive relationships.

Dr. Fraser’s observations

Some patients progress to schizophrenia’s residual “burnout” phase and become asymptomatic. Mr. M, however, was much younger than other patients with residual schizophrenia, and his mental and physical health were more robust.

 

Instead, Mr. M may have had complex PTSD secondary to 10 years of abuse by a partner and lifelong abuse by his mother, with drug-induced psychotic symptoms. PTSD can mimic schizoaffective disorder and schizophrenia (Table), and DSM-IV trains us to manage the differential diagnosis first. Mr. M’s revelation about his abusive mother could have raised suspicion of PTSD, but I was targeting apparent psychotic symptoms.

Mr. M’s shame over being gay and his inability to discuss his guilt with family and friends likely contributed to his isolation and perpetuated both the abuse and psychiatric symptoms. Although his ex-partner’s death ended an abusive relationship, his mother’s ongoing abuse prolonged its emotional effects.

If Mr. M. had not revealed his mother’s aggression—in response to a question about his abusive behavior—his psychiatric symptoms may have continued unabated. For years, despite many psychiatric consultations and hospitalizations, Mr. M kept his abusive relationships a secret.

Ask patients about ongoing physical, sexual, and emotional abuse as part of the initial evaluation. Even if the patient denies abuse at first, he or she may reveal this information as the therapeutic alliance develops. As treatment continues—particularly when the patient seems more stressed—ask again about abuse by or toward the patient. If necessary, be direct: “Is anyone hitting or hurting you in any way? Are you hurting someone else in any way?”

Building an alliance

Although clinicians often harbor low expectations for chronically ill patients, I believe that recovery from major psychiatric illness is possible.

Whatever his diagnosis, a strong therapeutic alliance hastened Mr. M’s recovery. Respecting his treatment goals, enhancing motivation to change, being his advocate, and considering alternate diagnoses helped me gain his trust (Box). Because I accepted responsibility for Mr. M’s prescription problems, for example, he sensed that I was on his side. This trust may have ultimately encouraged him to share secrets with me that he had not told other psychiatrists.

Related resources

• National Center for Post-Traumatic Stress Disorder. www.ncptsd.org
• Heim C, Meinlschmidt G, Nemeroff CB. Neurobiology of early-life stress. Psychiatric Annals 2003;33(1):18-26.
• Yehuda R. Post-traumatic stress disorder. N Engl J Med 2002;346:108-14.

Drug brand names

• Bupropion • Wellbutrin
• Divalproex • Depakote
• Lorazepam •Ativan
• Olanzapine • Zyprexa
• Ziprasidone • Geodon

Disclosure

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

Acknowledgment

The author thanks Mr. M for permission to publish this case report.

History: Threatened by an ‘angel’

Mr. M, age 32, began hearing voices at age 16. He had been diagnosed as having bipolar disorder with psychotic features before presenting to our hospital in 1995. He often experienced hypomania (euphoria, decreased sleep, free spending) followed by depressive periods (lack of energy, tearfulness, decreased concentration), and heard commands to kill himself or saw menacing shadows or “angels.”

Several psychiatrists tried various psychotropics across 6 years, but Mr. M’s odd behaviors persisted. One night he physically threatened his father, who tried to stop Mr. M from eating a sandwich wrapped in a plastic bag. Mr. M was hospitalized that night, and his diagnosis was changed to schizoaffective disorder based on recurrent auditory and visual hallucinations when mood symptoms were absent.

Mr. M was hospitalized nine times within 6 years for psychotic or depressive symptoms— including twice in 1 month for depression and suicidal ideation. Two months later, he attempted suicide by taking 1,200 mg of ziprasidone (about 10 times the normal daily dosage) and an unknown amount of lorazepam, after which he was treated in the ER and released. He presented to me shortly afterward, frightened by his suicide attempt.

At intake, Mr. M was taking lorazepam, 1 mg tid for anxiety, and ziprasidone, 20 mg bid.

Single and unemployed, Mr. M lived with his parents and a brother, and was collecting disability benefits because of his psychiatric problems. He told me that he had been off cocaine for 3 years but had used marijuana 2 weeks earlier. He also reported ongoing family problems but did not elaborate. He said he did not feel suicidal but described continued depressive episodes.

Dr. Fraser’s observations

Mr. M’s last six psychiatric hospitalizations and at least 5 years of outpatient notes by other psychiatrists indicated a history of schizoaffective disorder. Mr. M’s psychotic symptoms persisted for substantial periods while mood symptoms were absent, thus supporting the diagnosis. By contrast, mood and psychotic symptoms in major depression with psychotic features are almost always simultaneous.

Mr. M’s substance use should be considered. Fifty percent of persons with schizophrenia or an affective disorder have a lifetime prevalence of substance abuse disorder.¹ The rate climbs to 60% to 90% for patients with schizophrenia seen in emergency rooms, inpatient psychiatric units, and community settings.²

Mr. M’s last documented cocaine use was in 1998; subsequent urine drug screens showed only marijuana.

Cocaine abuse could have contributed to Mr. M’s psychotic symptoms, and marijuana use could have caused his inertia, lack of motivation, and difficulty concentrating. It is unclear why previous doctors attributed most of his psychotic symptoms to a major mental illness rather than cocaine use.

Ask patients about substance use along with a chronology of psychiatric symptoms. Encourage patients who are regularly using substances to stop for a trial period to see if symptoms abate during abstinence. Refer patients for substance use treatment if necessary.

Treatment: A waighty issue

I feared that Mr. M’s psychotic symptoms would recur, but he was more concerned about his depression and obesity. He said he gained 50 pounds over 3 1/2 years while taking olanzapine, 10 to 15 mg/d, and divalproex at various dosages. He stopped both agents on his own and lost 35 pounds across 6 months but was still obese (197 lbs., body mass index [BMI] 32.9).

I prescribed bupropion SR—100 mg/d titrated over several weeks to 200 mg each morning and 100 mg at night—because of its association with weight loss. I also:

• continued ziprasidone, 20 mg bid, to prevent psychosis
• continued lorazepam, 1 mg tid, to reduce anxiety stemming from his family problems. I asked Mr. M to slowly taper off the agent—which he had been taking for 8 years—across 6 to 12 months because a protracted benzodiazepine regimen can contribute to depression.
• referred him to a psychotherapist for cognitive-behavioral therapy to help reduce his depressive thinking and suicide risk
• recommended that he stop using marijuana.

At his second visit, Mr. M reported more auditory hallucinations. I increased ziprasidone to 40 mg bid.

By this time, Mr. M was becoming more comfortable in therapy. He began discussing his family problems in more detail, telling me that his brother is addicted to heroin.

I asked Mr. M if he was again threatening family members or other people. He replied that he had not been violent, but that his mother often slaps him and others in his family. I commended him for not retaliating, but warned him that his mother’s aggression was perpetuating his depression.

I encouraged Mr. M to find an apartment, but he said he could not yet afford to live on his own. I referred him to case management services to help him find affordable housing and urged him to avoid his mother’s assaults. He seemed to appreciate my concern for him.

 

Box

Twelve days later, Mr. M made an unplanned visit. He was angry because our pharmacy had not refilled his prescriptions and no one had returned his call asking about the refills. He was irritable but nonthreatening, although he planned to complain to the psychiatric center’s medical director.

I had received no phone messages, and my notes indicated the prescriptions were refilled. Nonetheless, my assuming responsibility for this problem was key to preserving our therapeutic alliance (Box). I resolved the matter and apologized for the miscommunication. Mr. M accepted my apology and scheduled a return visit.

About 1 month later, Mr. M’s self-esteem had increased. He stopped using marijuana, went on a low-calorie diet, and exercised at least 1 hour daily at a local gym. He lost 27 lbs. over 2 months, dropping his weight to 170 lbs. (BMI 28.3). He finished group (15 sessions) and individual (four sessions) psychotherapy, and avoided his mother when she became aggressive.

Before his next monthly visit, Mr. M had called the state vocational rehabilitation department to begin employment. I tapered lorazepam to 0.5 mg nightly while continuing ziprasidone and bupropion. His weight was near normal (150 lbs., BMI 25).

Six months into treatment, Mr. M. applied for a job and moved out of his parents’ home to live with another brother, who does not take drugs. He said that he “felt at peace” for the first time in years. His weight stayed in the 140s. I stopped lorazepam and he requested to see me 3 months later.

Dr. Fraser’s observations

Many patients with schizophrenia or schizoaffective disorder struggle with weight gain, substance use, employment problems, and family conflict, and some make slow progress with one or more of these issues. Mr. M’s rapid improvement on all fronts was striking, however.

Recovery from schizophrenia has been documented,³ and the prognosis for schizoaffective disorder is often more positive than for schizophrenia or severe bipolar disorder.⁴ Still, Mr. M’s apparent recovery seemed incredible.

To prevent symptom recurrence, I left the bupropion/ziprasidone regimen unchanged. Even after a chronically ill patient responds to medication, I feel dosages should be maintained unless side effects occur or a medication loses effectiveness.

Table

PTSD symptoms that suggest other diagnoses

PTSD symptoms	Similar to	Diagnosis suggested
Depersonalization, derealization, dissociation	Psychosis	Schizophrenia, schizoaffective disorder
Anxiety, hypervigilance, insomnia	Anxiety	Exacerbations of schizophrenia, schizoaffective disorder, bipolar disorder (mania)
Flashbacks, fear of trauma recurrence	Paranoia	Schizophrenia, schizoaffective disorder

Follow-up: Mr. M’s story

Since the mix-up with Mr. M’s medications, our therapeutic alliance grew stronger. He told me more about himself with each visit. Four months into treatment, he revealed that he is gay and feels “liberated” after years of keeping it secret.

Five months later, Mr. M confided that an older male partner had physically, sexually, and emotionally abused him for about 10 years, starting when Mr. M was 16—about the time his auditory hallucinations began. The abusive relationship ended when the partner died of an unspecified overdose.

Mr. M’s gay friends advised him to seek closure. He visited his ex-partner’s grave, placed a rose, said goodbye, and left vowing he’d never again become an abuse victim. He said he had never told any health professional this story.

Mr. M then asked to be tapered off medications. I was afraid his psychotic symptoms could resurface, although I now wondered whether his schizoaffective disorder diagnosis had been correct. We tapered bupropion and ziprasidone over the next month.

Twenty-four months later, his schizoaffective symptoms had not resurfaced. He worked as a security guard, maintained an apartment, and continued exercising and eating right. His weight stayed normal (140 lbs., BMI 23.3). No signs of hypomania were present, and he was finding fulfillment in nonabusive relationships.

Dr. Fraser’s observations

Some patients progress to schizophrenia’s residual “burnout” phase and become asymptomatic. Mr. M, however, was much younger than other patients with residual schizophrenia, and his mental and physical health were more robust.

 

Instead, Mr. M may have had complex PTSD secondary to 10 years of abuse by a partner and lifelong abuse by his mother, with drug-induced psychotic symptoms. PTSD can mimic schizoaffective disorder and schizophrenia (Table), and DSM-IV trains us to manage the differential diagnosis first. Mr. M’s revelation about his abusive mother could have raised suspicion of PTSD, but I was targeting apparent psychotic symptoms.

Mr. M’s shame over being gay and his inability to discuss his guilt with family and friends likely contributed to his isolation and perpetuated both the abuse and psychiatric symptoms. Although his ex-partner’s death ended an abusive relationship, his mother’s ongoing abuse prolonged its emotional effects.

If Mr. M. had not revealed his mother’s aggression—in response to a question about his abusive behavior—his psychiatric symptoms may have continued unabated. For years, despite many psychiatric consultations and hospitalizations, Mr. M kept his abusive relationships a secret.

Ask patients about ongoing physical, sexual, and emotional abuse as part of the initial evaluation. Even if the patient denies abuse at first, he or she may reveal this information as the therapeutic alliance develops. As treatment continues—particularly when the patient seems more stressed—ask again about abuse by or toward the patient. If necessary, be direct: “Is anyone hitting or hurting you in any way? Are you hurting someone else in any way?”

Building an alliance

Although clinicians often harbor low expectations for chronically ill patients, I believe that recovery from major psychiatric illness is possible.

Whatever his diagnosis, a strong therapeutic alliance hastened Mr. M’s recovery. Respecting his treatment goals, enhancing motivation to change, being his advocate, and considering alternate diagnoses helped me gain his trust (Box). Because I accepted responsibility for Mr. M’s prescription problems, for example, he sensed that I was on his side. This trust may have ultimately encouraged him to share secrets with me that he had not told other psychiatrists.

Related resources

• National Center for Post-Traumatic Stress Disorder. www.ncptsd.org
• Heim C, Meinlschmidt G, Nemeroff CB. Neurobiology of early-life stress. Psychiatric Annals 2003;33(1):18-26.
• Yehuda R. Post-traumatic stress disorder. N Engl J Med 2002;346:108-14.

Drug brand names

• Bupropion • Wellbutrin
• Divalproex • Depakote
• Lorazepam •Ativan
• Olanzapine • Zyprexa
• Ziprasidone • Geodon

Disclosure

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

Acknowledgment

The author thanks Mr. M for permission to publish this case report.

History: Threatened by an ‘angel’

Mr. M, age 32, began hearing voices at age 16. He had been diagnosed as having bipolar disorder with psychotic features before presenting to our hospital in 1995. He often experienced hypomania (euphoria, decreased sleep, free spending) followed by depressive periods (lack of energy, tearfulness, decreased concentration), and heard commands to kill himself or saw menacing shadows or “angels.”

Several psychiatrists tried various psychotropics across 6 years, but Mr. M’s odd behaviors persisted. One night he physically threatened his father, who tried to stop Mr. M from eating a sandwich wrapped in a plastic bag. Mr. M was hospitalized that night, and his diagnosis was changed to schizoaffective disorder based on recurrent auditory and visual hallucinations when mood symptoms were absent.

Mr. M was hospitalized nine times within 6 years for psychotic or depressive symptoms— including twice in 1 month for depression and suicidal ideation. Two months later, he attempted suicide by taking 1,200 mg of ziprasidone (about 10 times the normal daily dosage) and an unknown amount of lorazepam, after which he was treated in the ER and released. He presented to me shortly afterward, frightened by his suicide attempt.

At intake, Mr. M was taking lorazepam, 1 mg tid for anxiety, and ziprasidone, 20 mg bid.

Single and unemployed, Mr. M lived with his parents and a brother, and was collecting disability benefits because of his psychiatric problems. He told me that he had been off cocaine for 3 years but had used marijuana 2 weeks earlier. He also reported ongoing family problems but did not elaborate. He said he did not feel suicidal but described continued depressive episodes.

Dr. Fraser’s observations

Mr. M’s last six psychiatric hospitalizations and at least 5 years of outpatient notes by other psychiatrists indicated a history of schizoaffective disorder. Mr. M’s psychotic symptoms persisted for substantial periods while mood symptoms were absent, thus supporting the diagnosis. By contrast, mood and psychotic symptoms in major depression with psychotic features are almost always simultaneous.

Mr. M’s substance use should be considered. Fifty percent of persons with schizophrenia or an affective disorder have a lifetime prevalence of substance abuse disorder.¹ The rate climbs to 60% to 90% for patients with schizophrenia seen in emergency rooms, inpatient psychiatric units, and community settings.²

Mr. M’s last documented cocaine use was in 1998; subsequent urine drug screens showed only marijuana.

Cocaine abuse could have contributed to Mr. M’s psychotic symptoms, and marijuana use could have caused his inertia, lack of motivation, and difficulty concentrating. It is unclear why previous doctors attributed most of his psychotic symptoms to a major mental illness rather than cocaine use.

Ask patients about substance use along with a chronology of psychiatric symptoms. Encourage patients who are regularly using substances to stop for a trial period to see if symptoms abate during abstinence. Refer patients for substance use treatment if necessary.

Treatment: A waighty issue

I feared that Mr. M’s psychotic symptoms would recur, but he was more concerned about his depression and obesity. He said he gained 50 pounds over 3 1/2 years while taking olanzapine, 10 to 15 mg/d, and divalproex at various dosages. He stopped both agents on his own and lost 35 pounds across 6 months but was still obese (197 lbs., body mass index [BMI] 32.9).

I prescribed bupropion SR—100 mg/d titrated over several weeks to 200 mg each morning and 100 mg at night—because of its association with weight loss. I also:

• continued ziprasidone, 20 mg bid, to prevent psychosis
• continued lorazepam, 1 mg tid, to reduce anxiety stemming from his family problems. I asked Mr. M to slowly taper off the agent—which he had been taking for 8 years—across 6 to 12 months because a protracted benzodiazepine regimen can contribute to depression.
• referred him to a psychotherapist for cognitive-behavioral therapy to help reduce his depressive thinking and suicide risk
• recommended that he stop using marijuana.

At his second visit, Mr. M reported more auditory hallucinations. I increased ziprasidone to 40 mg bid.

By this time, Mr. M was becoming more comfortable in therapy. He began discussing his family problems in more detail, telling me that his brother is addicted to heroin.

I asked Mr. M if he was again threatening family members or other people. He replied that he had not been violent, but that his mother often slaps him and others in his family. I commended him for not retaliating, but warned him that his mother’s aggression was perpetuating his depression.

I encouraged Mr. M to find an apartment, but he said he could not yet afford to live on his own. I referred him to case management services to help him find affordable housing and urged him to avoid his mother’s assaults. He seemed to appreciate my concern for him.

 

Box

Twelve days later, Mr. M made an unplanned visit. He was angry because our pharmacy had not refilled his prescriptions and no one had returned his call asking about the refills. He was irritable but nonthreatening, although he planned to complain to the psychiatric center’s medical director.

I had received no phone messages, and my notes indicated the prescriptions were refilled. Nonetheless, my assuming responsibility for this problem was key to preserving our therapeutic alliance (Box). I resolved the matter and apologized for the miscommunication. Mr. M accepted my apology and scheduled a return visit.

About 1 month later, Mr. M’s self-esteem had increased. He stopped using marijuana, went on a low-calorie diet, and exercised at least 1 hour daily at a local gym. He lost 27 lbs. over 2 months, dropping his weight to 170 lbs. (BMI 28.3). He finished group (15 sessions) and individual (four sessions) psychotherapy, and avoided his mother when she became aggressive.

Before his next monthly visit, Mr. M had called the state vocational rehabilitation department to begin employment. I tapered lorazepam to 0.5 mg nightly while continuing ziprasidone and bupropion. His weight was near normal (150 lbs., BMI 25).

Six months into treatment, Mr. M. applied for a job and moved out of his parents’ home to live with another brother, who does not take drugs. He said that he “felt at peace” for the first time in years. His weight stayed in the 140s. I stopped lorazepam and he requested to see me 3 months later.

Dr. Fraser’s observations

Many patients with schizophrenia or schizoaffective disorder struggle with weight gain, substance use, employment problems, and family conflict, and some make slow progress with one or more of these issues. Mr. M’s rapid improvement on all fronts was striking, however.

Recovery from schizophrenia has been documented,³ and the prognosis for schizoaffective disorder is often more positive than for schizophrenia or severe bipolar disorder.⁴ Still, Mr. M’s apparent recovery seemed incredible.

To prevent symptom recurrence, I left the bupropion/ziprasidone regimen unchanged. Even after a chronically ill patient responds to medication, I feel dosages should be maintained unless side effects occur or a medication loses effectiveness.

Table

PTSD symptoms that suggest other diagnoses

PTSD symptoms	Similar to	Diagnosis suggested
Depersonalization, derealization, dissociation	Psychosis	Schizophrenia, schizoaffective disorder
Anxiety, hypervigilance, insomnia	Anxiety	Exacerbations of schizophrenia, schizoaffective disorder, bipolar disorder (mania)
Flashbacks, fear of trauma recurrence	Paranoia	Schizophrenia, schizoaffective disorder

Follow-up: Mr. M’s story

Since the mix-up with Mr. M’s medications, our therapeutic alliance grew stronger. He told me more about himself with each visit. Four months into treatment, he revealed that he is gay and feels “liberated” after years of keeping it secret.

Five months later, Mr. M confided that an older male partner had physically, sexually, and emotionally abused him for about 10 years, starting when Mr. M was 16—about the time his auditory hallucinations began. The abusive relationship ended when the partner died of an unspecified overdose.

Mr. M’s gay friends advised him to seek closure. He visited his ex-partner’s grave, placed a rose, said goodbye, and left vowing he’d never again become an abuse victim. He said he had never told any health professional this story.

Mr. M then asked to be tapered off medications. I was afraid his psychotic symptoms could resurface, although I now wondered whether his schizoaffective disorder diagnosis had been correct. We tapered bupropion and ziprasidone over the next month.

Twenty-four months later, his schizoaffective symptoms had not resurfaced. He worked as a security guard, maintained an apartment, and continued exercising and eating right. His weight stayed normal (140 lbs., BMI 23.3). No signs of hypomania were present, and he was finding fulfillment in nonabusive relationships.

Dr. Fraser’s observations

Some patients progress to schizophrenia’s residual “burnout” phase and become asymptomatic. Mr. M, however, was much younger than other patients with residual schizophrenia, and his mental and physical health were more robust.

 

Instead, Mr. M may have had complex PTSD secondary to 10 years of abuse by a partner and lifelong abuse by his mother, with drug-induced psychotic symptoms. PTSD can mimic schizoaffective disorder and schizophrenia (Table), and DSM-IV trains us to manage the differential diagnosis first. Mr. M’s revelation about his abusive mother could have raised suspicion of PTSD, but I was targeting apparent psychotic symptoms.

Mr. M’s shame over being gay and his inability to discuss his guilt with family and friends likely contributed to his isolation and perpetuated both the abuse and psychiatric symptoms. Although his ex-partner’s death ended an abusive relationship, his mother’s ongoing abuse prolonged its emotional effects.

If Mr. M. had not revealed his mother’s aggression—in response to a question about his abusive behavior—his psychiatric symptoms may have continued unabated. For years, despite many psychiatric consultations and hospitalizations, Mr. M kept his abusive relationships a secret.

Ask patients about ongoing physical, sexual, and emotional abuse as part of the initial evaluation. Even if the patient denies abuse at first, he or she may reveal this information as the therapeutic alliance develops. As treatment continues—particularly when the patient seems more stressed—ask again about abuse by or toward the patient. If necessary, be direct: “Is anyone hitting or hurting you in any way? Are you hurting someone else in any way?”

Building an alliance

Although clinicians often harbor low expectations for chronically ill patients, I believe that recovery from major psychiatric illness is possible.

Whatever his diagnosis, a strong therapeutic alliance hastened Mr. M’s recovery. Respecting his treatment goals, enhancing motivation to change, being his advocate, and considering alternate diagnoses helped me gain his trust (Box). Because I accepted responsibility for Mr. M’s prescription problems, for example, he sensed that I was on his side. This trust may have ultimately encouraged him to share secrets with me that he had not told other psychiatrists.

Related resources

• National Center for Post-Traumatic Stress Disorder. www.ncptsd.org
• Heim C, Meinlschmidt G, Nemeroff CB. Neurobiology of early-life stress. Psychiatric Annals 2003;33(1):18-26.
• Yehuda R. Post-traumatic stress disorder. N Engl J Med 2002;346:108-14.

Drug brand names

• Bupropion • Wellbutrin
• Divalproex • Depakote
• Lorazepam •Ativan
• Olanzapine • Zyprexa
• Ziprasidone • Geodon

Disclosure

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

Acknowledgment

The author thanks Mr. M for permission to publish this case report.

Presentation: 3 o’clock comes early

Miss T, age 9, presents with decreased sensation and motility in both legs. She cannot walk or stand.

Three days before, Miss T said she was consistently answering the teacher’s questions correctly at school. Because of this, a classmate teased her by calling her a “show off.” Soon after, Miss T began feeling weak and nauseous. The school nurse got a blood sugar reading of 68 mg/dL, slightly below the low-normal range.

Miss T’s mother arrived and convinced her to eat crackers and drink juice. Her blood sugar rose to 139 mg/dL and she began to feel better. When Miss T tried to stand, however, her legs and feet felt weak. She had trouble standing without support and needed help walking even a short distance. The mother brought Miss T home from school early.

Over the next 2 days, Miss T’s lower-extremity symptoms worsened. Her mother brought her to the pediatric emergency room.

Initial physical exam showed normal vital signs with no gross abnormalities. Neurologic exam revealed no lower-extremity masses, lesions, or deformities. Laboratory tests were normal. Cranial nerves were grossly intact. Right and left upper and lower extremities exhibited good tone, normal reflexes, and good strength against resistance. Miss T, however, said she could not feel sharp or dull objects against her lower legs.

ER pediatricians then called on the child psychiatry department to evaluate Miss T for possible psychiatric causes.

At intake, Miss T sits with her legs dangling from a stretcher. She is pleasant, articulate, and well-mannered. She spontaneously moves both legs and does not seem distressed when asked about her sudden disability. Her mood is euthymic, but she reports that constant teasing at school sometimes causes intense stress. She says that her sister sometimes “gets mean” with her but does not elaborate. She adds that she is sometimes sad because her parents recently separated, but she denies resultant emotional effects.

No suicidal/homicidal ideations or psychotic symptoms are present. Miss T’s thought process is logical and goal-directed. She is alert and oriented with good memory, language, concentration, and impulse control.

Neither Miss T nor her family has a significant psychiatric or medical history. Miss T has not been taking medications or over-the-counter supplements. Upon questioning, the mother denies that her daughter has been physically or sexually abused.

Despite a lack of positive neurologic findings, the neurology team recommends admission to rule out unseen medical problems.

The authors’ observations

Medical diagnosis.^1,2 In Guillain-Barré syndrome, an infection usually precedes symptom onset, and maximum weakness is seen within 7 to 10 days. Respiration may be compromised, and weakness tends to spread throughout the body. Miss T’s symptoms came on more rapidly, her breathing was normal, and weakness was confined to her legs and feet.

In neuromuscular junction disorders such as myasthenia gravis and Lambert-Eaton syndrome, symptoms are not as acute, fluctuate throughout the day, and usually worsen with exertion. By contrast, Miss T’s symptoms steadily worsened without provocation.

Muscular dystrophy and myopathy were ruled out because of Miss T’s rapid symptom onset and lack of prior health problems. Dystrophy usually is seen in early childhood, affects the hip and girdle muscles, and progresses slowly. Myopathy symptoms usually are chronic and progressive, and associated medical disorders overshadow the muscle disease.

Patients with intracranial lesions may present with:

• symptoms of diffuse cerebral disease, such as mental impairment, headache, or seizures
• focal neurologic signs, such as aphasia or hemiparesis
• evidence of increased intracranial pressure, such as headache, vomiting, drowsiness, or papilledema.

Miss T had none of these.

Patients with spinal cord tumors usually have radicular pain, sensory/motor involvement, sphincteric dysfunction, and percussible back tenderness. Symptoms develop over weeks to months.

Psychiatric diagnosis. Factitious disorder, malingering, somatization disorder, and conversion disorder (Box) also were considered:

• In factitious disorder, the patient exacerbates his or her symptoms to assume the sick role.
• Malingering patients have external motivations behind symptom fabrication.
• Somatization disorder involves multiple organ systems, and patients often are preoccupied with their symptoms.

Miss T’s complaints were not consciously induced, external motivations were absent, a single organ system (musculoskeletal) was involved, and she appeared largely untroubled by her deficit.

Her presentation most closely fit the diagnosis of conversion disorder. Patients with this disorder complain of symptoms or deficits affecting voluntary muscles or of sensory function deficits that suggest a neurologic or medical condition. The symptoms’ temporal relationship to a stressful event suggests psychological factors. Symptoms:

• are not intentionally produced
• cannot be attributed to an organic cause
• cause significant functional impairment
• are not limited to pain or sexual dysfunction
• cannot be explained by another mental disorder.

 

Treatment: A miraculous recovery

The pediatrics, child psychiatry, pediatric neurology, and physical medicine/rehabilitation departments treated Miss T. No organic cause of her symptoms was found; results of an MRI with contrast, EEG, and repeated lab tests were negative.

On day 3, Miss T started taking small steps on her own. Two days later, she walked without assistance; discharge was considered.

The hospital’s social services department, however, discovered that the state child welfare agency had investigated Miss T’s family for alleged child abuse/neglect years before but found no evidence.

Also, a school social worker had recently visited Miss T’s family after receiving a complaint that an older sibling was allegedly hitting the younger ones. The social worker noticed that the kitchen door was padlocked; she speculated that the family was struggling financially and did not want the children to eat all the food. No other evidence of child maltreatment was found and the investigation was stopped. None of Miss T’s lab results indicated malnutrition.

The girl was discharged after the mother agreed to allow a home health aide to monitor the children’s well-being and a psychologist to perform neuropsychological tests on Miss T. Follow-up out-patient visits with the pediatric neurology, general pediatrics, and child psychiatry departments were also required.

Box 1

The authors’ observations

Once we learned Miss T’s family had been investigated for child neglect, we had to find out if her symptoms were an expression of maltreatment or were caused by psychological stressors at school. Definitive maltreatment never surfaced, and school stress was determined to be a minor factor.

Neglected children exhibit characteristics at different ages that might contribute to conversion symptom development (Table). Most notably, such children have trouble understanding appropriate affective responses to interpersonal situations. As a result, they may express distress in unconventional ways.³

Table

Psychopathology of the neglected child

Age	Developmental difficulties
1 year	Insecure attachments
2 years	Easily frustrated
3 years	Low self-esteem/self-assertion Impaired flexibility, self-control compared with similarly aged healthy children Difficulty dealing with frustration Lack of persistence, enthusiasm when performing educational tasks
Preschool (4-6 years)	Overly dependent Lack of enthusiasm in preschool environment
Elementary school (6-12 years)	Attention problems Low self-assertion, self-esteem Withdrawal behaviors, dysphoric affect Social isolation
General	Trouble understanding appropriate affective responses to interpersonal situations Limited social problem-solving skills
Source: adapted from reference 4

Little empirical evidence supports the link between childhood maltreatment and conversion disorder. In one study:⁵

• Adults with conversion disorder (mean age 37.6) reported a higher incidence of physical and sexual abuse, more types of physical abuse, sexual abuse of longer duration, and more-frequent incestuous episodes than did adults with affective disorder.
• Among patients with conversion disorder, having a mother with recurrent illness, nervousness or depression, or who abuses alcohol or sedatives was associated with higher dissociative and somatoform scale scores.
• Physical abuse was associated with increased conversion symptoms.

The authors concluded that childhood trauma is a distinct and predictive—though not necessary—feature of conversion disorder.⁵

The authors’ observations

Psychotherapy and attention to socio-cultural beliefs may enable the patient to “give up” the conversion symptom.³ Several factors determine choices of psychotherapies, although elements of all approaches are commonly used:

• CBT and behavioral therapy have roles in treating acute symptoms.
• Supportive therapy and hypnotherapy are recommended for treating rare, longstanding conversion symptoms (4 to 6 months duration).
• Psychodynamic therapy can help patients who are introspective, can remember details about their past, and are willing to participate in longer-term therapy.

Cognitive-behavioral therapy. Behavior is shaped by what we learn from the environment. Conversion behavior can be reinforced by others who help maintain the symptoms. Behavioral therapy and CBT are aimed at modifying behaviors via desensitization and by increasing the patient’s understanding of his or her physical capacities.

Hypnosis gives patients a medium to recall experiences and feelings they cannot consciously bring up in treatment. Symptom exploration and reduction are broad goals.

Psychodynamic therapy aims to resolve unconscious conflict after a traumatic event. A patient who develops lower-extremity paralysis or sensory problems after having been chastised for running away might benefit from this model, for example.

 

Supportive psychotherapy emphasizes reassurance and education. For Miss T, that would mean reassurance that her paralysis will improve, with education about conversion disorder and how difficult life events can cause similar symptoms.

Sociocultural considerations. Cultural beliefs inhibit some people’s emotions and may predispose them to conversion symptoms.

No empirical evidence indicates that medication improves conversion disorder. Anecdotal reports cite positive response to older antipsychotics, lithium, and electroconvulsive therapy.⁶

Patients with conversion disorder, however, tend to develop mood and/or anxiety symptoms later, and psychotropics may help treat these comorbidities. Follow the patient while symptoms are present.⁷ Comorbid symptoms’ severity, response, and presentation dictate follow-up frequency.

Prognosis. Children with conversion disorder generally have good outcomes,⁵ particularly those with good premorbid function who are diagnosed early.⁷ Time from symptom onset to diagnosis ranges from weeks to 1 year, and most cases resolve within 3 months of diagnosis. Symptom recurrence is rare but may indicate emerging polysymptomatic somatization disorder.⁵

Treatment: Reassurance and support

Miss T responded well to supportive psychotherapy and reassurance from hospital staff. No psychiatric screening tests were done, but child psychiatrists saw Miss T several times daily, and she exhibited no other psychiatric symptoms. We have no information on follow-up treatment, which occurred outside the hospital.

Related resources

• Academy of Psychosomatic Medicine. www.apm.org
• Weiner J, Dulcan M. Textbook of child and adolescent psychiatry (3rd ed). Washington, DC: American Psychiatric Publishing, 2003.

Presentation: 3 o’clock comes early

Miss T, age 9, presents with decreased sensation and motility in both legs. She cannot walk or stand.

Three days before, Miss T said she was consistently answering the teacher’s questions correctly at school. Because of this, a classmate teased her by calling her a “show off.” Soon after, Miss T began feeling weak and nauseous. The school nurse got a blood sugar reading of 68 mg/dL, slightly below the low-normal range.

Miss T’s mother arrived and convinced her to eat crackers and drink juice. Her blood sugar rose to 139 mg/dL and she began to feel better. When Miss T tried to stand, however, her legs and feet felt weak. She had trouble standing without support and needed help walking even a short distance. The mother brought Miss T home from school early.

Over the next 2 days, Miss T’s lower-extremity symptoms worsened. Her mother brought her to the pediatric emergency room.

Initial physical exam showed normal vital signs with no gross abnormalities. Neurologic exam revealed no lower-extremity masses, lesions, or deformities. Laboratory tests were normal. Cranial nerves were grossly intact. Right and left upper and lower extremities exhibited good tone, normal reflexes, and good strength against resistance. Miss T, however, said she could not feel sharp or dull objects against her lower legs.

ER pediatricians then called on the child psychiatry department to evaluate Miss T for possible psychiatric causes.

At intake, Miss T sits with her legs dangling from a stretcher. She is pleasant, articulate, and well-mannered. She spontaneously moves both legs and does not seem distressed when asked about her sudden disability. Her mood is euthymic, but she reports that constant teasing at school sometimes causes intense stress. She says that her sister sometimes “gets mean” with her but does not elaborate. She adds that she is sometimes sad because her parents recently separated, but she denies resultant emotional effects.

No suicidal/homicidal ideations or psychotic symptoms are present. Miss T’s thought process is logical and goal-directed. She is alert and oriented with good memory, language, concentration, and impulse control.

Neither Miss T nor her family has a significant psychiatric or medical history. Miss T has not been taking medications or over-the-counter supplements. Upon questioning, the mother denies that her daughter has been physically or sexually abused.

Despite a lack of positive neurologic findings, the neurology team recommends admission to rule out unseen medical problems.

The authors’ observations

Medical diagnosis.^1,2 In Guillain-Barré syndrome, an infection usually precedes symptom onset, and maximum weakness is seen within 7 to 10 days. Respiration may be compromised, and weakness tends to spread throughout the body. Miss T’s symptoms came on more rapidly, her breathing was normal, and weakness was confined to her legs and feet.

In neuromuscular junction disorders such as myasthenia gravis and Lambert-Eaton syndrome, symptoms are not as acute, fluctuate throughout the day, and usually worsen with exertion. By contrast, Miss T’s symptoms steadily worsened without provocation.

Muscular dystrophy and myopathy were ruled out because of Miss T’s rapid symptom onset and lack of prior health problems. Dystrophy usually is seen in early childhood, affects the hip and girdle muscles, and progresses slowly. Myopathy symptoms usually are chronic and progressive, and associated medical disorders overshadow the muscle disease.

Patients with intracranial lesions may present with:

• symptoms of diffuse cerebral disease, such as mental impairment, headache, or seizures
• focal neurologic signs, such as aphasia or hemiparesis
• evidence of increased intracranial pressure, such as headache, vomiting, drowsiness, or papilledema.

Miss T had none of these.

Patients with spinal cord tumors usually have radicular pain, sensory/motor involvement, sphincteric dysfunction, and percussible back tenderness. Symptoms develop over weeks to months.

Psychiatric diagnosis. Factitious disorder, malingering, somatization disorder, and conversion disorder (Box) also were considered:

• In factitious disorder, the patient exacerbates his or her symptoms to assume the sick role.
• Malingering patients have external motivations behind symptom fabrication.
• Somatization disorder involves multiple organ systems, and patients often are preoccupied with their symptoms.

Miss T’s complaints were not consciously induced, external motivations were absent, a single organ system (musculoskeletal) was involved, and she appeared largely untroubled by her deficit.

Her presentation most closely fit the diagnosis of conversion disorder. Patients with this disorder complain of symptoms or deficits affecting voluntary muscles or of sensory function deficits that suggest a neurologic or medical condition. The symptoms’ temporal relationship to a stressful event suggests psychological factors. Symptoms:

• are not intentionally produced
• cannot be attributed to an organic cause
• cause significant functional impairment
• are not limited to pain or sexual dysfunction
• cannot be explained by another mental disorder.

 

Treatment: A miraculous recovery

The pediatrics, child psychiatry, pediatric neurology, and physical medicine/rehabilitation departments treated Miss T. No organic cause of her symptoms was found; results of an MRI with contrast, EEG, and repeated lab tests were negative.

On day 3, Miss T started taking small steps on her own. Two days later, she walked without assistance; discharge was considered.

The hospital’s social services department, however, discovered that the state child welfare agency had investigated Miss T’s family for alleged child abuse/neglect years before but found no evidence.

Also, a school social worker had recently visited Miss T’s family after receiving a complaint that an older sibling was allegedly hitting the younger ones. The social worker noticed that the kitchen door was padlocked; she speculated that the family was struggling financially and did not want the children to eat all the food. No other evidence of child maltreatment was found and the investigation was stopped. None of Miss T’s lab results indicated malnutrition.

The girl was discharged after the mother agreed to allow a home health aide to monitor the children’s well-being and a psychologist to perform neuropsychological tests on Miss T. Follow-up out-patient visits with the pediatric neurology, general pediatrics, and child psychiatry departments were also required.

Box 1

The authors’ observations

Once we learned Miss T’s family had been investigated for child neglect, we had to find out if her symptoms were an expression of maltreatment or were caused by psychological stressors at school. Definitive maltreatment never surfaced, and school stress was determined to be a minor factor.

Neglected children exhibit characteristics at different ages that might contribute to conversion symptom development (Table). Most notably, such children have trouble understanding appropriate affective responses to interpersonal situations. As a result, they may express distress in unconventional ways.³

Table

Psychopathology of the neglected child

Age	Developmental difficulties
1 year	Insecure attachments
2 years	Easily frustrated
3 years	Low self-esteem/self-assertion Impaired flexibility, self-control compared with similarly aged healthy children Difficulty dealing with frustration Lack of persistence, enthusiasm when performing educational tasks
Preschool (4-6 years)	Overly dependent Lack of enthusiasm in preschool environment
Elementary school (6-12 years)	Attention problems Low self-assertion, self-esteem Withdrawal behaviors, dysphoric affect Social isolation
General	Trouble understanding appropriate affective responses to interpersonal situations Limited social problem-solving skills
Source: adapted from reference 4

Little empirical evidence supports the link between childhood maltreatment and conversion disorder. In one study:⁵

• Adults with conversion disorder (mean age 37.6) reported a higher incidence of physical and sexual abuse, more types of physical abuse, sexual abuse of longer duration, and more-frequent incestuous episodes than did adults with affective disorder.
• Among patients with conversion disorder, having a mother with recurrent illness, nervousness or depression, or who abuses alcohol or sedatives was associated with higher dissociative and somatoform scale scores.
• Physical abuse was associated with increased conversion symptoms.

The authors concluded that childhood trauma is a distinct and predictive—though not necessary—feature of conversion disorder.⁵

The authors’ observations

Psychotherapy and attention to socio-cultural beliefs may enable the patient to “give up” the conversion symptom.³ Several factors determine choices of psychotherapies, although elements of all approaches are commonly used:

• CBT and behavioral therapy have roles in treating acute symptoms.
• Supportive therapy and hypnotherapy are recommended for treating rare, longstanding conversion symptoms (4 to 6 months duration).
• Psychodynamic therapy can help patients who are introspective, can remember details about their past, and are willing to participate in longer-term therapy.

Cognitive-behavioral therapy. Behavior is shaped by what we learn from the environment. Conversion behavior can be reinforced by others who help maintain the symptoms. Behavioral therapy and CBT are aimed at modifying behaviors via desensitization and by increasing the patient’s understanding of his or her physical capacities.

Hypnosis gives patients a medium to recall experiences and feelings they cannot consciously bring up in treatment. Symptom exploration and reduction are broad goals.

Psychodynamic therapy aims to resolve unconscious conflict after a traumatic event. A patient who develops lower-extremity paralysis or sensory problems after having been chastised for running away might benefit from this model, for example.

 

Supportive psychotherapy emphasizes reassurance and education. For Miss T, that would mean reassurance that her paralysis will improve, with education about conversion disorder and how difficult life events can cause similar symptoms.

Sociocultural considerations. Cultural beliefs inhibit some people’s emotions and may predispose them to conversion symptoms.

No empirical evidence indicates that medication improves conversion disorder. Anecdotal reports cite positive response to older antipsychotics, lithium, and electroconvulsive therapy.⁶

Patients with conversion disorder, however, tend to develop mood and/or anxiety symptoms later, and psychotropics may help treat these comorbidities. Follow the patient while symptoms are present.⁷ Comorbid symptoms’ severity, response, and presentation dictate follow-up frequency.

Prognosis. Children with conversion disorder generally have good outcomes,⁵ particularly those with good premorbid function who are diagnosed early.⁷ Time from symptom onset to diagnosis ranges from weeks to 1 year, and most cases resolve within 3 months of diagnosis. Symptom recurrence is rare but may indicate emerging polysymptomatic somatization disorder.⁵

Treatment: Reassurance and support

Miss T responded well to supportive psychotherapy and reassurance from hospital staff. No psychiatric screening tests were done, but child psychiatrists saw Miss T several times daily, and she exhibited no other psychiatric symptoms. We have no information on follow-up treatment, which occurred outside the hospital.

Related resources

• Academy of Psychosomatic Medicine. www.apm.org
• Weiner J, Dulcan M. Textbook of child and adolescent psychiatry (3rd ed). Washington, DC: American Psychiatric Publishing, 2003.

Presentation: 3 o’clock comes early

Miss T, age 9, presents with decreased sensation and motility in both legs. She cannot walk or stand.

Three days before, Miss T said she was consistently answering the teacher’s questions correctly at school. Because of this, a classmate teased her by calling her a “show off.” Soon after, Miss T began feeling weak and nauseous. The school nurse got a blood sugar reading of 68 mg/dL, slightly below the low-normal range.

Miss T’s mother arrived and convinced her to eat crackers and drink juice. Her blood sugar rose to 139 mg/dL and she began to feel better. When Miss T tried to stand, however, her legs and feet felt weak. She had trouble standing without support and needed help walking even a short distance. The mother brought Miss T home from school early.

Over the next 2 days, Miss T’s lower-extremity symptoms worsened. Her mother brought her to the pediatric emergency room.

Initial physical exam showed normal vital signs with no gross abnormalities. Neurologic exam revealed no lower-extremity masses, lesions, or deformities. Laboratory tests were normal. Cranial nerves were grossly intact. Right and left upper and lower extremities exhibited good tone, normal reflexes, and good strength against resistance. Miss T, however, said she could not feel sharp or dull objects against her lower legs.

ER pediatricians then called on the child psychiatry department to evaluate Miss T for possible psychiatric causes.

At intake, Miss T sits with her legs dangling from a stretcher. She is pleasant, articulate, and well-mannered. She spontaneously moves both legs and does not seem distressed when asked about her sudden disability. Her mood is euthymic, but she reports that constant teasing at school sometimes causes intense stress. She says that her sister sometimes “gets mean” with her but does not elaborate. She adds that she is sometimes sad because her parents recently separated, but she denies resultant emotional effects.

No suicidal/homicidal ideations or psychotic symptoms are present. Miss T’s thought process is logical and goal-directed. She is alert and oriented with good memory, language, concentration, and impulse control.

Neither Miss T nor her family has a significant psychiatric or medical history. Miss T has not been taking medications or over-the-counter supplements. Upon questioning, the mother denies that her daughter has been physically or sexually abused.

Despite a lack of positive neurologic findings, the neurology team recommends admission to rule out unseen medical problems.

The authors’ observations

Medical diagnosis.^1,2 In Guillain-Barré syndrome, an infection usually precedes symptom onset, and maximum weakness is seen within 7 to 10 days. Respiration may be compromised, and weakness tends to spread throughout the body. Miss T’s symptoms came on more rapidly, her breathing was normal, and weakness was confined to her legs and feet.

In neuromuscular junction disorders such as myasthenia gravis and Lambert-Eaton syndrome, symptoms are not as acute, fluctuate throughout the day, and usually worsen with exertion. By contrast, Miss T’s symptoms steadily worsened without provocation.

Muscular dystrophy and myopathy were ruled out because of Miss T’s rapid symptom onset and lack of prior health problems. Dystrophy usually is seen in early childhood, affects the hip and girdle muscles, and progresses slowly. Myopathy symptoms usually are chronic and progressive, and associated medical disorders overshadow the muscle disease.

Patients with intracranial lesions may present with:

• symptoms of diffuse cerebral disease, such as mental impairment, headache, or seizures
• focal neurologic signs, such as aphasia or hemiparesis
• evidence of increased intracranial pressure, such as headache, vomiting, drowsiness, or papilledema.

Miss T had none of these.

Patients with spinal cord tumors usually have radicular pain, sensory/motor involvement, sphincteric dysfunction, and percussible back tenderness. Symptoms develop over weeks to months.

Psychiatric diagnosis. Factitious disorder, malingering, somatization disorder, and conversion disorder (Box) also were considered:

• In factitious disorder, the patient exacerbates his or her symptoms to assume the sick role.
• Malingering patients have external motivations behind symptom fabrication.
• Somatization disorder involves multiple organ systems, and patients often are preoccupied with their symptoms.

Miss T’s complaints were not consciously induced, external motivations were absent, a single organ system (musculoskeletal) was involved, and she appeared largely untroubled by her deficit.

Her presentation most closely fit the diagnosis of conversion disorder. Patients with this disorder complain of symptoms or deficits affecting voluntary muscles or of sensory function deficits that suggest a neurologic or medical condition. The symptoms’ temporal relationship to a stressful event suggests psychological factors. Symptoms:

• are not intentionally produced
• cannot be attributed to an organic cause
• cause significant functional impairment
• are not limited to pain or sexual dysfunction
• cannot be explained by another mental disorder.

 

Treatment: A miraculous recovery

The pediatrics, child psychiatry, pediatric neurology, and physical medicine/rehabilitation departments treated Miss T. No organic cause of her symptoms was found; results of an MRI with contrast, EEG, and repeated lab tests were negative.

On day 3, Miss T started taking small steps on her own. Two days later, she walked without assistance; discharge was considered.

The hospital’s social services department, however, discovered that the state child welfare agency had investigated Miss T’s family for alleged child abuse/neglect years before but found no evidence.

Also, a school social worker had recently visited Miss T’s family after receiving a complaint that an older sibling was allegedly hitting the younger ones. The social worker noticed that the kitchen door was padlocked; she speculated that the family was struggling financially and did not want the children to eat all the food. No other evidence of child maltreatment was found and the investigation was stopped. None of Miss T’s lab results indicated malnutrition.

The girl was discharged after the mother agreed to allow a home health aide to monitor the children’s well-being and a psychologist to perform neuropsychological tests on Miss T. Follow-up out-patient visits with the pediatric neurology, general pediatrics, and child psychiatry departments were also required.

Box 1

The authors’ observations

Once we learned Miss T’s family had been investigated for child neglect, we had to find out if her symptoms were an expression of maltreatment or were caused by psychological stressors at school. Definitive maltreatment never surfaced, and school stress was determined to be a minor factor.

Neglected children exhibit characteristics at different ages that might contribute to conversion symptom development (Table). Most notably, such children have trouble understanding appropriate affective responses to interpersonal situations. As a result, they may express distress in unconventional ways.³

Table

Psychopathology of the neglected child

Age	Developmental difficulties
1 year	Insecure attachments
2 years	Easily frustrated
3 years	Low self-esteem/self-assertion Impaired flexibility, self-control compared with similarly aged healthy children Difficulty dealing with frustration Lack of persistence, enthusiasm when performing educational tasks
Preschool (4-6 years)	Overly dependent Lack of enthusiasm in preschool environment
Elementary school (6-12 years)	Attention problems Low self-assertion, self-esteem Withdrawal behaviors, dysphoric affect Social isolation
General	Trouble understanding appropriate affective responses to interpersonal situations Limited social problem-solving skills
Source: adapted from reference 4

Little empirical evidence supports the link between childhood maltreatment and conversion disorder. In one study:⁵

• Adults with conversion disorder (mean age 37.6) reported a higher incidence of physical and sexual abuse, more types of physical abuse, sexual abuse of longer duration, and more-frequent incestuous episodes than did adults with affective disorder.
• Among patients with conversion disorder, having a mother with recurrent illness, nervousness or depression, or who abuses alcohol or sedatives was associated with higher dissociative and somatoform scale scores.
• Physical abuse was associated with increased conversion symptoms.

The authors concluded that childhood trauma is a distinct and predictive—though not necessary—feature of conversion disorder.⁵

The authors’ observations

Psychotherapy and attention to socio-cultural beliefs may enable the patient to “give up” the conversion symptom.³ Several factors determine choices of psychotherapies, although elements of all approaches are commonly used:

• CBT and behavioral therapy have roles in treating acute symptoms.
• Supportive therapy and hypnotherapy are recommended for treating rare, longstanding conversion symptoms (4 to 6 months duration).
• Psychodynamic therapy can help patients who are introspective, can remember details about their past, and are willing to participate in longer-term therapy.

Cognitive-behavioral therapy. Behavior is shaped by what we learn from the environment. Conversion behavior can be reinforced by others who help maintain the symptoms. Behavioral therapy and CBT are aimed at modifying behaviors via desensitization and by increasing the patient’s understanding of his or her physical capacities.

Hypnosis gives patients a medium to recall experiences and feelings they cannot consciously bring up in treatment. Symptom exploration and reduction are broad goals.

Psychodynamic therapy aims to resolve unconscious conflict after a traumatic event. A patient who develops lower-extremity paralysis or sensory problems after having been chastised for running away might benefit from this model, for example.

 

Supportive psychotherapy emphasizes reassurance and education. For Miss T, that would mean reassurance that her paralysis will improve, with education about conversion disorder and how difficult life events can cause similar symptoms.

Sociocultural considerations. Cultural beliefs inhibit some people’s emotions and may predispose them to conversion symptoms.

No empirical evidence indicates that medication improves conversion disorder. Anecdotal reports cite positive response to older antipsychotics, lithium, and electroconvulsive therapy.⁶

Patients with conversion disorder, however, tend to develop mood and/or anxiety symptoms later, and psychotropics may help treat these comorbidities. Follow the patient while symptoms are present.⁷ Comorbid symptoms’ severity, response, and presentation dictate follow-up frequency.

Prognosis. Children with conversion disorder generally have good outcomes,⁵ particularly those with good premorbid function who are diagnosed early.⁷ Time from symptom onset to diagnosis ranges from weeks to 1 year, and most cases resolve within 3 months of diagnosis. Symptom recurrence is rare but may indicate emerging polysymptomatic somatization disorder.⁵

Treatment: Reassurance and support

Miss T responded well to supportive psychotherapy and reassurance from hospital staff. No psychiatric screening tests were done, but child psychiatrists saw Miss T several times daily, and she exhibited no other psychiatric symptoms. We have no information on follow-up treatment, which occurred outside the hospital.

Related resources

• Academy of Psychosomatic Medicine. www.apm.org
• Weiner J, Dulcan M. Textbook of child and adolescent psychiatry (3rd ed). Washington, DC: American Psychiatric Publishing, 2003.

History: Initial symptoms

Ms. F, age 39, presented with depression, severe anxiety, and disturbed sleep. She denied psychiatric or medical history, but reported that her depressive symptoms hampered her performance at work and led to work-related stress.

Ms. F’s Beck Depression Inventory (BDI) score at baseline was 21, indicating moderate depression. The psychiatrist diagnosed her as having generalized anxiety disorder and adjustment disorder with depressed mood.

The patient was started on paroxetine, 10 mg/d. Five weeks later, her anxiety had decreased significantly and her BDI score had dropped to 10, indicating normal mood. Both the patient and clinician decided at this point that Ms. F had reached remission. The patient demanded that paroxetine be stopped, saying that she “does not like medication.” The psychiatrist reluctantly agreed.

Eight weeks later, during a follow-up examination, Ms. F complained of severely depressed mood with frequent crying spells. She complained of fatigue, nausea, headaches, decreased appetite, and dizziness. Her work performance, which had improved during the paroxetine trial, was again compromised. Her BDI score was 32, indicating severe depression.

Was the psychiatrist justified in stopping paroxetine therapy after 5 weeks?

Dr. Fishbain’s observations

Premature paroxetine discontinuation cannot be ruled out as a cause for Ms. F’s relapse. Sood et al¹ found that duration of antidepressant therapy beyond treatment guidelines correlated with longer times to relapse.

By contrast, Ms. F’s initial therapy duration fell short of the 6 to 8 weeks recommended by the American Psychiatric Association.²

Patients commonly cite adverse events as a reason for wanting to stop antidepressant therapy.³ Ms. F reported no adverse effects, however; she said only that she did “not like medication.” Despite her insistence to the contrary, antidepressant therapy probably should not have been stopped.

Further history: A painful discovery

After questioning, Ms. F told the psychiatrist that she had been involved in a motor vehicle accident 2 weeks before the follow-up visit and had since been suffering lower back and neck pain.

After more questioning, Mr. F revealed that the pain was disrupting her sleep. She was getting about 4 hours of fragmented sleep per night, resulting in lack of energy during the day. The pain made it hard for her to sit, further impairing her work performance.

Ms. F was restarted on paroxetine, 10 mg/d titrated across 6 weeks to 60 mg/d for her depression, and zolpidem, 10 mg at bedtime, to help her sleep. After 6 weeks, her BDI score improved to 20, and she was less labile. Her depressive symptoms persisted, however, as did her pain, fatigue, headaches, nausea, dizziness, and sleep disturbances.

What role did Ms. F’s pain play in her relapse? How can clinicians detect somatic symptoms and gauge their effect on mood?

Dr. Fishbain’s observations

Pain most likely caused Ms. F’s depression relapse. McBeth et al⁴ have demonstrated that pain can contribute to depression’s development. In another study,⁵ 43.4% of subjects who met criteria for major depression reported painful symptoms. The presence of a chronic painful condition was also found to contribute to major depression.⁵

Nakao et al⁶ screened 2,215 outpatients who were referred with mind/body complaints. Patients who were diagnosed with major depression had significantly higher rates of fatigue (86% vs. 65%), insomnia (79% vs. 58%), nausea/vomiting (51% vs. 40%), and low-back pain (36% vs. 24%) than those who were not. Within the major depression group, somatic symptoms were more abundant in patients with severe depressive episodes than in those with mild depressive episodes (5.8 vs. 3.7, P < 0.05).

Depression prevalence appears to increase when somatic symptoms are considered in the diagnosis. Posse and Hallstrom⁷ used a two-stage design to screen for depression. In the first stage, depression prevalence was 1.8%. In the second stage, 62 patients with high somatic complaint scores were re-evaluated. Of this group, 41 were diagnosed with a major depressive disorder or dysthymia.

Patients with continued pain after depression treatment are at high risk for depression recurrence.⁸ Diffuseness of pain and extent to which it interferes with daily activities strongly predict depression.⁹

Diagnostic challenges. Patients with depression often present to their primary care physicians with somatic rather than behavioral symptoms, making it hard for the family doctor to diagnose depression.¹⁰ By contrast, when presenting to a psychiatrist, depressed patients tend to discuss their emotional symptoms but not their physical complaints.¹¹ This is because patients often:

• attribute physical symptoms to an unrelated medical illness
• consider aches and pains a normal part of aging
• or are not aware that psychiatrists can treat physical symptoms.¹¹

Psychiatrists in the past have emphasized emotional symptoms while barely addressing physical symptoms. This trend is changing, however, as the link between physical pain and depression has become clearer.

 

Be sure to include chronic pain or other somatic symptoms in the systems review. Screening tools such as the Visual Analogue Scale can measure pain intensity, while the Cornell Medical Index can uncover somatic symptoms. No all-inclusive tool exists to help detect depression-related somatic symptoms. however.

Should the psychiatrist continue to address Ms. F’s depressive symptoms, or should the focus shift to her somatic symptoms?

Dr. Fishbain’s observations

Patients who do not respond to depression treatment (ie, achieve >50% symptom reduction), or who respond without achieving remission, usually have residual physical symptoms—often fatigue, sleep disturbance, decreased appetite, anxiety, sexual dysfunction, and/or pain.^12-14 Severe pain and other somatic symptoms are likely prolonging Ms. F’s depression, despite increased paroxetine dosages.

Paykel et al⁸ have associated residual depression symptoms with early relapse of depression. In their study, 94% of depressed patients with lingering depressive symptoms had mild to moderate physical symptoms. By contrast, degree of physical symptom improvement has been shown to correlate with likelihood of depression remission.¹⁵

Although emotional symptoms improve with antidepressants,¹⁶ some evidence¹⁷ indicates that physical symptoms associated with depression may be less responsive.

Also, because many psychiatrists have been taught to track emotional symptoms and only some physical symptoms, somatic symptoms of depression often are not targeted for treatment.¹⁷ Lack of rating scales to track somatic symptoms compounds this problem.¹⁷

Psychiatrists need to target both the physical and emotional symptoms of depression. When pain prolongs depression, it should be the primary target of antidepressant drug therapy (Algorithm).

To date, several meta-analyses^18-20 have demonstrated that antidepressants have a separate analgesic effect on all forms of chronic pain. Evidence^21,22 also indicates that the dualaction antidepressants—such as amitriptyline, bupropion, venlafaxine, and (awaiting FDA approval) duloxetine—have a more-consistent analgesic effect than do the serotonin reuptake inhibitors.

The analgesic effects of bupropion, duloxetine, and venlafaxine have not been compared with those of tricyclics or other older antidepressants. If one of the newer dualaction antidepressants does not reduce somatic conditions or produce an adequate response, consider switching to a tricyclic.

Treatment: No pain, some gain

Another psychiatrist who specializes in pain medicine targeted some of Ms. F’s somatic symptoms with antidepressants. Paroxetine and zolpidem were discontinued and the patient was started on:

• venlafaxine, 37.5 mg bid, titrated to 225 mg/d across 2 weeks. Because of its activating properties, venlafaxine was chosen to address Ms. F’s pain and daytime fatigue.
• amitriptyline, 50 mg at bedtime nightly, to promote sleep
• prochlorperazine, 10 mg as needed, and meclizine, 25 mg as needed, to treat her nausea and dizziness, respectively.

Algorithm Suggested drug treatment of depression with somatic symptoms

Ms. F also was advised to take an abortive migraine compound (Midrin, 2 tablets at headache onset and 1 additional tablet every half-hour as needed, maximum 5 tablets per day). Mr. F’s primary care physician also referred her to a physical therapist to treat her neck and low-back pain; workup revealed no surgically treatable problem.

Four weeks later, Ms. F reported that her somatic symptoms significantly improved and that she was sleeping nearly 8 hours per night. Her BDI score was 12, indicating normal mood. She was functioning much more effectively at work and could once again routinely perform her daily activities.

Ms. F continued her medication regimen for 8 months, after which she was lost to follow-up. At her most recent visit, her depression remained in remission. Her pain persisted, though at a lower intensity.

Related resources

• Fishbain DA, Cutler R, Rosomoff HL, Rosomoff RS. Chronic pain-associated depression: antecedent or consequence of chronic pain? A review. Clin J Pain 1997;13:116-37.

Drug brand names

• Amitriptyline • Elavil
• Duloxetine • Cymbalta
• Meclizine • Antivert
• Modafinil • Provigil
• Paroxetine • Paxil
• Prochlorperazine • Compazine
• Venlafaxine • Effexor
• Zolpidem • Ambien

Disclosure

Dr. Fishbain is a consultant to Eli Lilly and Co. and a speaker for Purdue Pharmaceuticals.

History: Initial symptoms

Ms. F, age 39, presented with depression, severe anxiety, and disturbed sleep. She denied psychiatric or medical history, but reported that her depressive symptoms hampered her performance at work and led to work-related stress.

Ms. F’s Beck Depression Inventory (BDI) score at baseline was 21, indicating moderate depression. The psychiatrist diagnosed her as having generalized anxiety disorder and adjustment disorder with depressed mood.

The patient was started on paroxetine, 10 mg/d. Five weeks later, her anxiety had decreased significantly and her BDI score had dropped to 10, indicating normal mood. Both the patient and clinician decided at this point that Ms. F had reached remission. The patient demanded that paroxetine be stopped, saying that she “does not like medication.” The psychiatrist reluctantly agreed.

Eight weeks later, during a follow-up examination, Ms. F complained of severely depressed mood with frequent crying spells. She complained of fatigue, nausea, headaches, decreased appetite, and dizziness. Her work performance, which had improved during the paroxetine trial, was again compromised. Her BDI score was 32, indicating severe depression.

Was the psychiatrist justified in stopping paroxetine therapy after 5 weeks?

Dr. Fishbain’s observations

Premature paroxetine discontinuation cannot be ruled out as a cause for Ms. F’s relapse. Sood et al¹ found that duration of antidepressant therapy beyond treatment guidelines correlated with longer times to relapse.

By contrast, Ms. F’s initial therapy duration fell short of the 6 to 8 weeks recommended by the American Psychiatric Association.²

Patients commonly cite adverse events as a reason for wanting to stop antidepressant therapy.³ Ms. F reported no adverse effects, however; she said only that she did “not like medication.” Despite her insistence to the contrary, antidepressant therapy probably should not have been stopped.

Further history: A painful discovery

After questioning, Ms. F told the psychiatrist that she had been involved in a motor vehicle accident 2 weeks before the follow-up visit and had since been suffering lower back and neck pain.

After more questioning, Mr. F revealed that the pain was disrupting her sleep. She was getting about 4 hours of fragmented sleep per night, resulting in lack of energy during the day. The pain made it hard for her to sit, further impairing her work performance.

Ms. F was restarted on paroxetine, 10 mg/d titrated across 6 weeks to 60 mg/d for her depression, and zolpidem, 10 mg at bedtime, to help her sleep. After 6 weeks, her BDI score improved to 20, and she was less labile. Her depressive symptoms persisted, however, as did her pain, fatigue, headaches, nausea, dizziness, and sleep disturbances.

What role did Ms. F’s pain play in her relapse? How can clinicians detect somatic symptoms and gauge their effect on mood?

Dr. Fishbain’s observations

Pain most likely caused Ms. F’s depression relapse. McBeth et al⁴ have demonstrated that pain can contribute to depression’s development. In another study,⁵ 43.4% of subjects who met criteria for major depression reported painful symptoms. The presence of a chronic painful condition was also found to contribute to major depression.⁵

Nakao et al⁶ screened 2,215 outpatients who were referred with mind/body complaints. Patients who were diagnosed with major depression had significantly higher rates of fatigue (86% vs. 65%), insomnia (79% vs. 58%), nausea/vomiting (51% vs. 40%), and low-back pain (36% vs. 24%) than those who were not. Within the major depression group, somatic symptoms were more abundant in patients with severe depressive episodes than in those with mild depressive episodes (5.8 vs. 3.7, P < 0.05).

Depression prevalence appears to increase when somatic symptoms are considered in the diagnosis. Posse and Hallstrom⁷ used a two-stage design to screen for depression. In the first stage, depression prevalence was 1.8%. In the second stage, 62 patients with high somatic complaint scores were re-evaluated. Of this group, 41 were diagnosed with a major depressive disorder or dysthymia.

Patients with continued pain after depression treatment are at high risk for depression recurrence.⁸ Diffuseness of pain and extent to which it interferes with daily activities strongly predict depression.⁹

Diagnostic challenges. Patients with depression often present to their primary care physicians with somatic rather than behavioral symptoms, making it hard for the family doctor to diagnose depression.¹⁰ By contrast, when presenting to a psychiatrist, depressed patients tend to discuss their emotional symptoms but not their physical complaints.¹¹ This is because patients often:

• attribute physical symptoms to an unrelated medical illness
• consider aches and pains a normal part of aging
• or are not aware that psychiatrists can treat physical symptoms.¹¹

Psychiatrists in the past have emphasized emotional symptoms while barely addressing physical symptoms. This trend is changing, however, as the link between physical pain and depression has become clearer.

 

Be sure to include chronic pain or other somatic symptoms in the systems review. Screening tools such as the Visual Analogue Scale can measure pain intensity, while the Cornell Medical Index can uncover somatic symptoms. No all-inclusive tool exists to help detect depression-related somatic symptoms. however.

Should the psychiatrist continue to address Ms. F’s depressive symptoms, or should the focus shift to her somatic symptoms?

Dr. Fishbain’s observations

Patients who do not respond to depression treatment (ie, achieve >50% symptom reduction), or who respond without achieving remission, usually have residual physical symptoms—often fatigue, sleep disturbance, decreased appetite, anxiety, sexual dysfunction, and/or pain.^12-14 Severe pain and other somatic symptoms are likely prolonging Ms. F’s depression, despite increased paroxetine dosages.

Paykel et al⁸ have associated residual depression symptoms with early relapse of depression. In their study, 94% of depressed patients with lingering depressive symptoms had mild to moderate physical symptoms. By contrast, degree of physical symptom improvement has been shown to correlate with likelihood of depression remission.¹⁵

Although emotional symptoms improve with antidepressants,¹⁶ some evidence¹⁷ indicates that physical symptoms associated with depression may be less responsive.

Also, because many psychiatrists have been taught to track emotional symptoms and only some physical symptoms, somatic symptoms of depression often are not targeted for treatment.¹⁷ Lack of rating scales to track somatic symptoms compounds this problem.¹⁷

Psychiatrists need to target both the physical and emotional symptoms of depression. When pain prolongs depression, it should be the primary target of antidepressant drug therapy (Algorithm).

To date, several meta-analyses^18-20 have demonstrated that antidepressants have a separate analgesic effect on all forms of chronic pain. Evidence^21,22 also indicates that the dualaction antidepressants—such as amitriptyline, bupropion, venlafaxine, and (awaiting FDA approval) duloxetine—have a more-consistent analgesic effect than do the serotonin reuptake inhibitors.

The analgesic effects of bupropion, duloxetine, and venlafaxine have not been compared with those of tricyclics or other older antidepressants. If one of the newer dualaction antidepressants does not reduce somatic conditions or produce an adequate response, consider switching to a tricyclic.

Treatment: No pain, some gain

Another psychiatrist who specializes in pain medicine targeted some of Ms. F’s somatic symptoms with antidepressants. Paroxetine and zolpidem were discontinued and the patient was started on:

• venlafaxine, 37.5 mg bid, titrated to 225 mg/d across 2 weeks. Because of its activating properties, venlafaxine was chosen to address Ms. F’s pain and daytime fatigue.
• amitriptyline, 50 mg at bedtime nightly, to promote sleep
• prochlorperazine, 10 mg as needed, and meclizine, 25 mg as needed, to treat her nausea and dizziness, respectively.

Algorithm Suggested drug treatment of depression with somatic symptoms

Ms. F also was advised to take an abortive migraine compound (Midrin, 2 tablets at headache onset and 1 additional tablet every half-hour as needed, maximum 5 tablets per day). Mr. F’s primary care physician also referred her to a physical therapist to treat her neck and low-back pain; workup revealed no surgically treatable problem.

Four weeks later, Ms. F reported that her somatic symptoms significantly improved and that she was sleeping nearly 8 hours per night. Her BDI score was 12, indicating normal mood. She was functioning much more effectively at work and could once again routinely perform her daily activities.

Ms. F continued her medication regimen for 8 months, after which she was lost to follow-up. At her most recent visit, her depression remained in remission. Her pain persisted, though at a lower intensity.

Related resources

• Fishbain DA, Cutler R, Rosomoff HL, Rosomoff RS. Chronic pain-associated depression: antecedent or consequence of chronic pain? A review. Clin J Pain 1997;13:116-37.

Drug brand names

• Amitriptyline • Elavil
• Duloxetine • Cymbalta
• Meclizine • Antivert
• Modafinil • Provigil
• Paroxetine • Paxil
• Prochlorperazine • Compazine
• Venlafaxine • Effexor
• Zolpidem • Ambien

Disclosure

Dr. Fishbain is a consultant to Eli Lilly and Co. and a speaker for Purdue Pharmaceuticals.

History: Initial symptoms

Ms. F, age 39, presented with depression, severe anxiety, and disturbed sleep. She denied psychiatric or medical history, but reported that her depressive symptoms hampered her performance at work and led to work-related stress.

Ms. F’s Beck Depression Inventory (BDI) score at baseline was 21, indicating moderate depression. The psychiatrist diagnosed her as having generalized anxiety disorder and adjustment disorder with depressed mood.

The patient was started on paroxetine, 10 mg/d. Five weeks later, her anxiety had decreased significantly and her BDI score had dropped to 10, indicating normal mood. Both the patient and clinician decided at this point that Ms. F had reached remission. The patient demanded that paroxetine be stopped, saying that she “does not like medication.” The psychiatrist reluctantly agreed.

Eight weeks later, during a follow-up examination, Ms. F complained of severely depressed mood with frequent crying spells. She complained of fatigue, nausea, headaches, decreased appetite, and dizziness. Her work performance, which had improved during the paroxetine trial, was again compromised. Her BDI score was 32, indicating severe depression.

Was the psychiatrist justified in stopping paroxetine therapy after 5 weeks?

Dr. Fishbain’s observations

Premature paroxetine discontinuation cannot be ruled out as a cause for Ms. F’s relapse. Sood et al¹ found that duration of antidepressant therapy beyond treatment guidelines correlated with longer times to relapse.

By contrast, Ms. F’s initial therapy duration fell short of the 6 to 8 weeks recommended by the American Psychiatric Association.²

Patients commonly cite adverse events as a reason for wanting to stop antidepressant therapy.³ Ms. F reported no adverse effects, however; she said only that she did “not like medication.” Despite her insistence to the contrary, antidepressant therapy probably should not have been stopped.

Further history: A painful discovery

After questioning, Ms. F told the psychiatrist that she had been involved in a motor vehicle accident 2 weeks before the follow-up visit and had since been suffering lower back and neck pain.

After more questioning, Mr. F revealed that the pain was disrupting her sleep. She was getting about 4 hours of fragmented sleep per night, resulting in lack of energy during the day. The pain made it hard for her to sit, further impairing her work performance.

Ms. F was restarted on paroxetine, 10 mg/d titrated across 6 weeks to 60 mg/d for her depression, and zolpidem, 10 mg at bedtime, to help her sleep. After 6 weeks, her BDI score improved to 20, and she was less labile. Her depressive symptoms persisted, however, as did her pain, fatigue, headaches, nausea, dizziness, and sleep disturbances.

What role did Ms. F’s pain play in her relapse? How can clinicians detect somatic symptoms and gauge their effect on mood?

Dr. Fishbain’s observations

Pain most likely caused Ms. F’s depression relapse. McBeth et al⁴ have demonstrated that pain can contribute to depression’s development. In another study,⁵ 43.4% of subjects who met criteria for major depression reported painful symptoms. The presence of a chronic painful condition was also found to contribute to major depression.⁵

Nakao et al⁶ screened 2,215 outpatients who were referred with mind/body complaints. Patients who were diagnosed with major depression had significantly higher rates of fatigue (86% vs. 65%), insomnia (79% vs. 58%), nausea/vomiting (51% vs. 40%), and low-back pain (36% vs. 24%) than those who were not. Within the major depression group, somatic symptoms were more abundant in patients with severe depressive episodes than in those with mild depressive episodes (5.8 vs. 3.7, P < 0.05).

Depression prevalence appears to increase when somatic symptoms are considered in the diagnosis. Posse and Hallstrom⁷ used a two-stage design to screen for depression. In the first stage, depression prevalence was 1.8%. In the second stage, 62 patients with high somatic complaint scores were re-evaluated. Of this group, 41 were diagnosed with a major depressive disorder or dysthymia.

Patients with continued pain after depression treatment are at high risk for depression recurrence.⁸ Diffuseness of pain and extent to which it interferes with daily activities strongly predict depression.⁹

Diagnostic challenges. Patients with depression often present to their primary care physicians with somatic rather than behavioral symptoms, making it hard for the family doctor to diagnose depression.¹⁰ By contrast, when presenting to a psychiatrist, depressed patients tend to discuss their emotional symptoms but not their physical complaints.¹¹ This is because patients often:

• attribute physical symptoms to an unrelated medical illness
• consider aches and pains a normal part of aging
• or are not aware that psychiatrists can treat physical symptoms.¹¹

Psychiatrists in the past have emphasized emotional symptoms while barely addressing physical symptoms. This trend is changing, however, as the link between physical pain and depression has become clearer.

 

Be sure to include chronic pain or other somatic symptoms in the systems review. Screening tools such as the Visual Analogue Scale can measure pain intensity, while the Cornell Medical Index can uncover somatic symptoms. No all-inclusive tool exists to help detect depression-related somatic symptoms. however.

Should the psychiatrist continue to address Ms. F’s depressive symptoms, or should the focus shift to her somatic symptoms?

Dr. Fishbain’s observations

Patients who do not respond to depression treatment (ie, achieve >50% symptom reduction), or who respond without achieving remission, usually have residual physical symptoms—often fatigue, sleep disturbance, decreased appetite, anxiety, sexual dysfunction, and/or pain.^12-14 Severe pain and other somatic symptoms are likely prolonging Ms. F’s depression, despite increased paroxetine dosages.

Paykel et al⁸ have associated residual depression symptoms with early relapse of depression. In their study, 94% of depressed patients with lingering depressive symptoms had mild to moderate physical symptoms. By contrast, degree of physical symptom improvement has been shown to correlate with likelihood of depression remission.¹⁵

Although emotional symptoms improve with antidepressants,¹⁶ some evidence¹⁷ indicates that physical symptoms associated with depression may be less responsive.

Also, because many psychiatrists have been taught to track emotional symptoms and only some physical symptoms, somatic symptoms of depression often are not targeted for treatment.¹⁷ Lack of rating scales to track somatic symptoms compounds this problem.¹⁷

Psychiatrists need to target both the physical and emotional symptoms of depression. When pain prolongs depression, it should be the primary target of antidepressant drug therapy (Algorithm).

To date, several meta-analyses^18-20 have demonstrated that antidepressants have a separate analgesic effect on all forms of chronic pain. Evidence^21,22 also indicates that the dualaction antidepressants—such as amitriptyline, bupropion, venlafaxine, and (awaiting FDA approval) duloxetine—have a more-consistent analgesic effect than do the serotonin reuptake inhibitors.

The analgesic effects of bupropion, duloxetine, and venlafaxine have not been compared with those of tricyclics or other older antidepressants. If one of the newer dualaction antidepressants does not reduce somatic conditions or produce an adequate response, consider switching to a tricyclic.

Treatment: No pain, some gain

Another psychiatrist who specializes in pain medicine targeted some of Ms. F’s somatic symptoms with antidepressants. Paroxetine and zolpidem were discontinued and the patient was started on:

• venlafaxine, 37.5 mg bid, titrated to 225 mg/d across 2 weeks. Because of its activating properties, venlafaxine was chosen to address Ms. F’s pain and daytime fatigue.
• amitriptyline, 50 mg at bedtime nightly, to promote sleep
• prochlorperazine, 10 mg as needed, and meclizine, 25 mg as needed, to treat her nausea and dizziness, respectively.

Algorithm Suggested drug treatment of depression with somatic symptoms

Ms. F also was advised to take an abortive migraine compound (Midrin, 2 tablets at headache onset and 1 additional tablet every half-hour as needed, maximum 5 tablets per day). Mr. F’s primary care physician also referred her to a physical therapist to treat her neck and low-back pain; workup revealed no surgically treatable problem.

Four weeks later, Ms. F reported that her somatic symptoms significantly improved and that she was sleeping nearly 8 hours per night. Her BDI score was 12, indicating normal mood. She was functioning much more effectively at work and could once again routinely perform her daily activities.

Ms. F continued her medication regimen for 8 months, after which she was lost to follow-up. At her most recent visit, her depression remained in remission. Her pain persisted, though at a lower intensity.

Related resources

• Fishbain DA, Cutler R, Rosomoff HL, Rosomoff RS. Chronic pain-associated depression: antecedent or consequence of chronic pain? A review. Clin J Pain 1997;13:116-37.

Drug brand names

• Amitriptyline • Elavil
• Duloxetine • Cymbalta
• Meclizine • Antivert
• Modafinil • Provigil
• Paroxetine • Paxil
• Prochlorperazine • Compazine
• Venlafaxine • Effexor
• Zolpidem • Ambien

Disclosure

Dr. Fishbain is a consultant to Eli Lilly and Co. and a speaker for Purdue Pharmaceuticals.

Emergency presentation: A rough commute

Mr. R, age 25, presented to the emergency room confused and severely agitated. That morning, his parents found him in his Philadelphia apartment covering his mouth and nose with a T-shirt to guard against imminent chemical warfare.

The day before, Mr. R had developed auditory and visual hallucinations and paranoid and persecutory delusions. That day, on his way to work, he said he had seen “terrorists releasing toxic chemicals into the air” and heard “whispers of terrorists plotting an attack on the East Coast.”

Mr. R showed no suicidal or homicidal ideations. He denied significant medical or surgical history but reported that he had recently been diagnosed with depression after a “bad Ecstasy experience.” For 6 months he had been taking paroxetine, 20 mg once daily, and bupropion, 150 mg once daily, for his depression.

At age 18, Mr. R was diagnosed with attention-deficit/hyperactivity disorder (ADHD) after years of struggling through school with impaired concentration. At that time, he began taking methylphenidate, 10 mg each morning, and completed 3 years of college in North Carolina. He then dropped out of college and attempted suicide twice.

After the second suicide attempt, a psychiatrist diagnosed Mr. R as having major depression. The psychiatrist discontinued methylphenidate and started bupropion, dosage unknown. After 1 year, he stopped taking the antidepressant, thinking he no longer needed it.

Last year, Mr. R moved back to Philadelphia to be closer to his parents. Shortly afterward, he began obtaining methylphenidate illegally and later starting using cocaine, marijuana, amphetamines, and 3,4-methylenedioxymethamphetamine (“Ecstasy”).

At presentation, Mr. R’s mood was dysphoric with bizarre affect. Eye contact was poor with easy distractibility. Speech was pressured, with full range. His thought process was grossly disorganized with tangential thinking and flight of ideas. His short- and long-term memory were intact; insight and judgment were limited. A Mini-Mental State Examination could not be completed because of his disorganization and distractibility.

Does Mr. R. have schizophrenia or schizoaffective disorder? Or are his symptoms related to ADHD or substance abuse?

The authors’ observations

Mr. R’s paranoid delusions and hallucinations may suggest schizophrenia. With his history of suicide attempts, a depressive or schizoaffective disorder may also be considered.

However, Mr. R is close with his family and has several friends. His parents say he has not been withdrawn or paranoid, and there is no known family history of mood disorder, substance abuse, or other psychiatric illness. Mr. R also has been working steadily and had worked the night before presenting to us, so schizophrenia and schizoaffective disorder are ruled out. ADHD and abuse of multiple substances could explain his behavior because overdose of stimulants and illicit drugs may produce a psychotic event.

Further history: The power of addiction

After more questioning, Mr. R said that he had recently started using gamma butyrolactone (GBL) in a failed attempt to build muscle. For 4 months he had been taking 3.5 oz of GBL daily—0.25 oz every 2 to 3 hours and 0.75 oz at night to help him sleep.

Within 6 hours of his most recent GBL dose (reportedly 1 oz), Mr. R developed intractable nausea, vomiting, and flatus, followed quickly by anxiety, palpitations, and generalized hand/body tremors that disturbed his sleep. Hallucinations and delusions started the next day.

At presentation, Mr. R’s blood pressure was 188/92 mm Hg, his heart rate was 110 bpm, and his respiratory rate was 22 breaths per minute. Pupils were 5 mm and reactive with intact extraocular movement. A urine drug screen indicated amphetamine use.

Mr. R was tentatively diagnosed as having GBL withdrawal syndrome and was admitted for observation and treatment. The psychiatry service followed him for change in mental status and drug dependence.

Can a withdrawal syndrome reasonably account for Mr. R’s symptoms?

The authors’ observations

GBL is a precursor of gamma-hydroxybutyrate (GHB), a highly addictive agent that is used illicitly, typically at parties and nightclubs (Box). GBL is among the clinical analogues of GHB that have become popular street drugs.

GHB withdrawal syndrome has only recently been described in the literature and is virtually indistinguishable from withdrawal after cessation of GBL and other precursors. To date, 71 deaths have been attributed to GHB withdrawal.²

A constellation of symptoms exhibited by Mr. R point to GHB withdrawal, which should be included in the differential diagnosis of any sedative/hypnotic withdrawal (Table 1).

How GHB works. GHB easily crosses the blood-brain barrier. Like other sedative/hypnotics, its depressant effects on the brain in low doses (2 to 4 grams) produce a euphoric feeling as inhibitions are depressed. Profound coma or death result from higher doses (>4 grams).³ Heart rate may also be slowed and CNS effects may result in myoclonus, producing seizure-like movements. Combining GHB with other drugs can increase the other agents’ depressant effects, leading to confusion, amnesia, vomiting, irregular breathing, or death.²

 

Box

A tiny increase in GHB dose can dramatically increase the symptoms and risk of overdose.⁴ GHB’s effects are also variable: A 1-teaspoon dose can produce the desired “high” one time and an overdose the next.

GHB and ethanol share a common mechanism of action.⁵ At pharmacologic doses, GHB appears to act in part through effects on the structurally related GABA neurotransmitter or its receptors.

Not surprisingly, a withdrawal syndrome characterized by delirium and autonomic instability ensues after GHB use is abruptly stopped. By functioning as indirect GABA agonists and ultimately evoking inhibitory neurotransmission, benzodiazepines and most barbiturates may alleviate GHB withdrawal symptoms.⁴ Thiamine is added to prevent Wernicke-Korsakoff syndrome, as is seen in alcohol withdrawal.⁵

GHB withdrawal. Symptoms are divided into three phases:

• Phase 1 (acute, first 24 hours). Presenting symptoms include anxiety, restlessness, insomnia, tremor, diaphoresis, tachycardia, and hypertension. Nausea and vomiting are variable but can be unrelenting.

While symptoms vary in severity, most prominent are agitation, restlessness, and insomnia. Some patients do not sleep for days after their last dose, and diffuse body tremors prevent them from sitting or lying still. Tachycardia and hypertension are hard to evaluate at this phase because patients present at different stages of withdrawal. Initial blood pressure readings as high as 240/130 mm Hg and heart rates of 120 bpm have been reported, however.

• Phase 2 (days 2 through 6). Worsening autonomic symptoms, progressive GI symptoms, and overall worsening of the withdrawal mark this tumultuous period. Patients usually present at this point—in acute distress and no longer able to self-treat.

Confusion, delirium, and florid psychosis characterize this phase. Mr. R’s paranoid delusions and hallucinations are the most common form of psychosis seen in GHB withdrawal.⁵ In some cases, the psychosis impairs social, occupational, and other functioning.

Table 1

Comparison of sedative-hypnotic withdrawal syndromes

Substance	Onset	Duration of severe symptoms	Autonomic instability*	Neurologic/psychiatric symptoms	Mortality	Major mechanism inducing withdrawal state‡
GHB	<6 hours	5 to 12 days	Mild	Severe	<1%	Loss of GHB, GABAA, and GABAB-mediated inhibition
Benzodiazepines	1 to 3 days	5 to 9 days	Moderate	Moderate	1%	Loss of GABAA-mediated inhibition
Baclofen	12 to 96 hours	8 days	Moderate	Severe	None reported	Loss of GABAB-mediated inhibition
Ethanol	<6 hours	10 to 14 days	Severe	Moderate to severe	5% to 15%	Loss of GABAA-mediated inhibition; disinhibition of NMDA receptors
NMDA: N-methyl D-aspartate.
GHB: Gamma-hydroxybutyrate
*Marked by tachycardia, fever, hypertension, and/or diaphoresis.
‡All withdrawal states involve multifactorial processes.
Source: Reference 5

Underlying or concurrent causes of delirium must be ruled out. Patients at this stage often require physical restraint or immediate sedation to prevent injury and dangerous complications, including hyperthermia and rhabdomyolysis. Benzodiazepines are often used in high doses¹ for sedation. IV hydration and antiemetics are also treatment mainstays. Atypical antipsychotics are added ASAP to control the paranoia.

• Phase 3 (days 7 through 13). Symptoms usually resolve at this stage. The delirium most often clears first, followed by restored autonomic stability and GI rest. While decreased sleep and periods of psychosis persist, agitation is less severe. The patient is discharged on average after 11 days.

Intense outpatient follow-up should include individual psychotherapy, substance abuse counseling, and drug therapy. Highly addictive medications should be avoided because of the patient’s substance abuse history.

Did Mr. R accurately report the amount of GBL he had taken? How should GBL and GHB blood levels be measured, given the agents’ rapid absorption rates?

The authors’ observations

As with most drugs of abuse, high doses over time contribute to severe GHB withdrawal syndrome. GHB doses taken before withdrawal are up to 10 times greater than those taken in typical recreational use.⁵

However, quantifying GHB levels with standard urine drug screens is nearly impossible because:

 

• the agent is absorbed within 20 to 60 minutes
• only 2% to 5% of the agent is eliminated in the urine.

GHB—which comes in powder, tablet, and liquid form and is usually dissolved in water before use—often is mixed with other drugs or alcohol. Varying preparations and use with multiple substances can produce inconsistent GHB levels and decrease sensitivity and specificity in routine drug screening. GHB abusers also report the amount ingested in “capfuls,” ounces, and teaspoons, making accurate quantification harder still.²

Though infrequently used because of feasibility and cost, gas chromatography and infrared spectroscopy of a urine specimen are the only known methods for determining GHB levels. Chronic GHB use, negative polypharmacy history, and negative urine and blood analysis for alcohol, benzodiazepines, sedative-hypnotics, or other substances usually confirm GHB withdrawal diagnosis.¹

Treatment: ‘Bad’ medicine

In the ER, Mr. R was given two 1-mg doses of lorazepam IV 1 hour apart. After 1 hour, his vital signs improved slightly (heart rate: 100/min; blood pressure: 165/99 mm Hg). Thiamine and folate were also started. Mr. R’s severe agitation and paranoia persisted, so three more 2-mg doses of lorazepam IV were given at 4-hour intervals.

Within 2 days, Mr. R was transferred to the voluntary inpatient psychiatric unit. His nausea, vomiting, and autonomic instability resolved, but his delirium and psychosis persisted. Quetiapine, 100 mg bid, was started to address his psychosis, and bupropion, 150 mg once daily, was restarted to manage his previously diagnosed depression. Three days after starting bupropion, Mr. R’s mood improved based on patient reports and Clinical Global Impression scores (6 at baseline, 2 at discharge), but his persecutory delusions persisted, causing mild anxiety.

The next day, Mr. R’s auditory and visual hallucinations had ceased, his preoccupation with terrorists began to subside, and his concentration, sleep, and appetite were improving. By day 6 of hospitalization, he still complained of mild tremors and anxiety, but his persecutory delusions resolved.

After 9 days, Mr. R was discharged. Autonomic stability was achieved and his delirium had mostly resolved. Outpatient drug rehabilitation and psychiatric services were arranged.

As of this writing, Mr. R had not sought outpatient treatment. His current medical status is unknown.

Related resources

• Miglani J, Kim K, Chahil R. Gamma-hydroxybutyrate withdrawal delirium: a case report. Gen Hosp Psychiatry. 2000;22:213-6.
• Columbo G, Agabio R, Lobina C, et al. Cross tolerance to ethanol and gamma-hydroxybutyric acid. Eur J Pharmacol. 1995;273:235-8.
• Project GHB. www.projectghb.org

Drug brand names

• Bupropion • Wellbutrin
• Lorazepam • Ativan
• Methylphenidate • Ritalin, Concerta
• Paroxetine • Paxil
• Quetiapine • Seroquel

Disclosure

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

Emergency presentation: A rough commute

Mr. R, age 25, presented to the emergency room confused and severely agitated. That morning, his parents found him in his Philadelphia apartment covering his mouth and nose with a T-shirt to guard against imminent chemical warfare.

The day before, Mr. R had developed auditory and visual hallucinations and paranoid and persecutory delusions. That day, on his way to work, he said he had seen “terrorists releasing toxic chemicals into the air” and heard “whispers of terrorists plotting an attack on the East Coast.”

Mr. R showed no suicidal or homicidal ideations. He denied significant medical or surgical history but reported that he had recently been diagnosed with depression after a “bad Ecstasy experience.” For 6 months he had been taking paroxetine, 20 mg once daily, and bupropion, 150 mg once daily, for his depression.

At age 18, Mr. R was diagnosed with attention-deficit/hyperactivity disorder (ADHD) after years of struggling through school with impaired concentration. At that time, he began taking methylphenidate, 10 mg each morning, and completed 3 years of college in North Carolina. He then dropped out of college and attempted suicide twice.

After the second suicide attempt, a psychiatrist diagnosed Mr. R as having major depression. The psychiatrist discontinued methylphenidate and started bupropion, dosage unknown. After 1 year, he stopped taking the antidepressant, thinking he no longer needed it.

Last year, Mr. R moved back to Philadelphia to be closer to his parents. Shortly afterward, he began obtaining methylphenidate illegally and later starting using cocaine, marijuana, amphetamines, and 3,4-methylenedioxymethamphetamine (“Ecstasy”).

At presentation, Mr. R’s mood was dysphoric with bizarre affect. Eye contact was poor with easy distractibility. Speech was pressured, with full range. His thought process was grossly disorganized with tangential thinking and flight of ideas. His short- and long-term memory were intact; insight and judgment were limited. A Mini-Mental State Examination could not be completed because of his disorganization and distractibility.

Does Mr. R. have schizophrenia or schizoaffective disorder? Or are his symptoms related to ADHD or substance abuse?

The authors’ observations

Mr. R’s paranoid delusions and hallucinations may suggest schizophrenia. With his history of suicide attempts, a depressive or schizoaffective disorder may also be considered.

However, Mr. R is close with his family and has several friends. His parents say he has not been withdrawn or paranoid, and there is no known family history of mood disorder, substance abuse, or other psychiatric illness. Mr. R also has been working steadily and had worked the night before presenting to us, so schizophrenia and schizoaffective disorder are ruled out. ADHD and abuse of multiple substances could explain his behavior because overdose of stimulants and illicit drugs may produce a psychotic event.

Further history: The power of addiction

After more questioning, Mr. R said that he had recently started using gamma butyrolactone (GBL) in a failed attempt to build muscle. For 4 months he had been taking 3.5 oz of GBL daily—0.25 oz every 2 to 3 hours and 0.75 oz at night to help him sleep.

Within 6 hours of his most recent GBL dose (reportedly 1 oz), Mr. R developed intractable nausea, vomiting, and flatus, followed quickly by anxiety, palpitations, and generalized hand/body tremors that disturbed his sleep. Hallucinations and delusions started the next day.

At presentation, Mr. R’s blood pressure was 188/92 mm Hg, his heart rate was 110 bpm, and his respiratory rate was 22 breaths per minute. Pupils were 5 mm and reactive with intact extraocular movement. A urine drug screen indicated amphetamine use.

Mr. R was tentatively diagnosed as having GBL withdrawal syndrome and was admitted for observation and treatment. The psychiatry service followed him for change in mental status and drug dependence.

Can a withdrawal syndrome reasonably account for Mr. R’s symptoms?

The authors’ observations

GBL is a precursor of gamma-hydroxybutyrate (GHB), a highly addictive agent that is used illicitly, typically at parties and nightclubs (Box). GBL is among the clinical analogues of GHB that have become popular street drugs.

GHB withdrawal syndrome has only recently been described in the literature and is virtually indistinguishable from withdrawal after cessation of GBL and other precursors. To date, 71 deaths have been attributed to GHB withdrawal.²

A constellation of symptoms exhibited by Mr. R point to GHB withdrawal, which should be included in the differential diagnosis of any sedative/hypnotic withdrawal (Table 1).

How GHB works. GHB easily crosses the blood-brain barrier. Like other sedative/hypnotics, its depressant effects on the brain in low doses (2 to 4 grams) produce a euphoric feeling as inhibitions are depressed. Profound coma or death result from higher doses (>4 grams).³ Heart rate may also be slowed and CNS effects may result in myoclonus, producing seizure-like movements. Combining GHB with other drugs can increase the other agents’ depressant effects, leading to confusion, amnesia, vomiting, irregular breathing, or death.²

 

Box

A tiny increase in GHB dose can dramatically increase the symptoms and risk of overdose.⁴ GHB’s effects are also variable: A 1-teaspoon dose can produce the desired “high” one time and an overdose the next.

GHB and ethanol share a common mechanism of action.⁵ At pharmacologic doses, GHB appears to act in part through effects on the structurally related GABA neurotransmitter or its receptors.

Not surprisingly, a withdrawal syndrome characterized by delirium and autonomic instability ensues after GHB use is abruptly stopped. By functioning as indirect GABA agonists and ultimately evoking inhibitory neurotransmission, benzodiazepines and most barbiturates may alleviate GHB withdrawal symptoms.⁴ Thiamine is added to prevent Wernicke-Korsakoff syndrome, as is seen in alcohol withdrawal.⁵

GHB withdrawal. Symptoms are divided into three phases:

• Phase 1 (acute, first 24 hours). Presenting symptoms include anxiety, restlessness, insomnia, tremor, diaphoresis, tachycardia, and hypertension. Nausea and vomiting are variable but can be unrelenting.

While symptoms vary in severity, most prominent are agitation, restlessness, and insomnia. Some patients do not sleep for days after their last dose, and diffuse body tremors prevent them from sitting or lying still. Tachycardia and hypertension are hard to evaluate at this phase because patients present at different stages of withdrawal. Initial blood pressure readings as high as 240/130 mm Hg and heart rates of 120 bpm have been reported, however.

• Phase 2 (days 2 through 6). Worsening autonomic symptoms, progressive GI symptoms, and overall worsening of the withdrawal mark this tumultuous period. Patients usually present at this point—in acute distress and no longer able to self-treat.

Confusion, delirium, and florid psychosis characterize this phase. Mr. R’s paranoid delusions and hallucinations are the most common form of psychosis seen in GHB withdrawal.⁵ In some cases, the psychosis impairs social, occupational, and other functioning.

Table 1

Comparison of sedative-hypnotic withdrawal syndromes

Substance	Onset	Duration of severe symptoms	Autonomic instability*	Neurologic/psychiatric symptoms	Mortality	Major mechanism inducing withdrawal state‡
GHB	<6 hours	5 to 12 days	Mild	Severe	<1%	Loss of GHB, GABAA, and GABAB-mediated inhibition
Benzodiazepines	1 to 3 days	5 to 9 days	Moderate	Moderate	1%	Loss of GABAA-mediated inhibition
Baclofen	12 to 96 hours	8 days	Moderate	Severe	None reported	Loss of GABAB-mediated inhibition
Ethanol	<6 hours	10 to 14 days	Severe	Moderate to severe	5% to 15%	Loss of GABAA-mediated inhibition; disinhibition of NMDA receptors
NMDA: N-methyl D-aspartate.
GHB: Gamma-hydroxybutyrate
*Marked by tachycardia, fever, hypertension, and/or diaphoresis.
‡All withdrawal states involve multifactorial processes.
Source: Reference 5

Underlying or concurrent causes of delirium must be ruled out. Patients at this stage often require physical restraint or immediate sedation to prevent injury and dangerous complications, including hyperthermia and rhabdomyolysis. Benzodiazepines are often used in high doses¹ for sedation. IV hydration and antiemetics are also treatment mainstays. Atypical antipsychotics are added ASAP to control the paranoia.

• Phase 3 (days 7 through 13). Symptoms usually resolve at this stage. The delirium most often clears first, followed by restored autonomic stability and GI rest. While decreased sleep and periods of psychosis persist, agitation is less severe. The patient is discharged on average after 11 days.

Intense outpatient follow-up should include individual psychotherapy, substance abuse counseling, and drug therapy. Highly addictive medications should be avoided because of the patient’s substance abuse history.

Did Mr. R accurately report the amount of GBL he had taken? How should GBL and GHB blood levels be measured, given the agents’ rapid absorption rates?

The authors’ observations

As with most drugs of abuse, high doses over time contribute to severe GHB withdrawal syndrome. GHB doses taken before withdrawal are up to 10 times greater than those taken in typical recreational use.⁵

However, quantifying GHB levels with standard urine drug screens is nearly impossible because:

 

• the agent is absorbed within 20 to 60 minutes
• only 2% to 5% of the agent is eliminated in the urine.

GHB—which comes in powder, tablet, and liquid form and is usually dissolved in water before use—often is mixed with other drugs or alcohol. Varying preparations and use with multiple substances can produce inconsistent GHB levels and decrease sensitivity and specificity in routine drug screening. GHB abusers also report the amount ingested in “capfuls,” ounces, and teaspoons, making accurate quantification harder still.²

Though infrequently used because of feasibility and cost, gas chromatography and infrared spectroscopy of a urine specimen are the only known methods for determining GHB levels. Chronic GHB use, negative polypharmacy history, and negative urine and blood analysis for alcohol, benzodiazepines, sedative-hypnotics, or other substances usually confirm GHB withdrawal diagnosis.¹

Treatment: ‘Bad’ medicine

In the ER, Mr. R was given two 1-mg doses of lorazepam IV 1 hour apart. After 1 hour, his vital signs improved slightly (heart rate: 100/min; blood pressure: 165/99 mm Hg). Thiamine and folate were also started. Mr. R’s severe agitation and paranoia persisted, so three more 2-mg doses of lorazepam IV were given at 4-hour intervals.

Within 2 days, Mr. R was transferred to the voluntary inpatient psychiatric unit. His nausea, vomiting, and autonomic instability resolved, but his delirium and psychosis persisted. Quetiapine, 100 mg bid, was started to address his psychosis, and bupropion, 150 mg once daily, was restarted to manage his previously diagnosed depression. Three days after starting bupropion, Mr. R’s mood improved based on patient reports and Clinical Global Impression scores (6 at baseline, 2 at discharge), but his persecutory delusions persisted, causing mild anxiety.

The next day, Mr. R’s auditory and visual hallucinations had ceased, his preoccupation with terrorists began to subside, and his concentration, sleep, and appetite were improving. By day 6 of hospitalization, he still complained of mild tremors and anxiety, but his persecutory delusions resolved.

After 9 days, Mr. R was discharged. Autonomic stability was achieved and his delirium had mostly resolved. Outpatient drug rehabilitation and psychiatric services were arranged.

As of this writing, Mr. R had not sought outpatient treatment. His current medical status is unknown.

Related resources

• Miglani J, Kim K, Chahil R. Gamma-hydroxybutyrate withdrawal delirium: a case report. Gen Hosp Psychiatry. 2000;22:213-6.
• Columbo G, Agabio R, Lobina C, et al. Cross tolerance to ethanol and gamma-hydroxybutyric acid. Eur J Pharmacol. 1995;273:235-8.
• Project GHB. www.projectghb.org

Drug brand names

• Bupropion • Wellbutrin
• Lorazepam • Ativan
• Methylphenidate • Ritalin, Concerta
• Paroxetine • Paxil
• Quetiapine • Seroquel

Disclosure

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

Emergency presentation: A rough commute

Mr. R, age 25, presented to the emergency room confused and severely agitated. That morning, his parents found him in his Philadelphia apartment covering his mouth and nose with a T-shirt to guard against imminent chemical warfare.

The day before, Mr. R had developed auditory and visual hallucinations and paranoid and persecutory delusions. That day, on his way to work, he said he had seen “terrorists releasing toxic chemicals into the air” and heard “whispers of terrorists plotting an attack on the East Coast.”

Mr. R showed no suicidal or homicidal ideations. He denied significant medical or surgical history but reported that he had recently been diagnosed with depression after a “bad Ecstasy experience.” For 6 months he had been taking paroxetine, 20 mg once daily, and bupropion, 150 mg once daily, for his depression.

At age 18, Mr. R was diagnosed with attention-deficit/hyperactivity disorder (ADHD) after years of struggling through school with impaired concentration. At that time, he began taking methylphenidate, 10 mg each morning, and completed 3 years of college in North Carolina. He then dropped out of college and attempted suicide twice.

After the second suicide attempt, a psychiatrist diagnosed Mr. R as having major depression. The psychiatrist discontinued methylphenidate and started bupropion, dosage unknown. After 1 year, he stopped taking the antidepressant, thinking he no longer needed it.

Last year, Mr. R moved back to Philadelphia to be closer to his parents. Shortly afterward, he began obtaining methylphenidate illegally and later starting using cocaine, marijuana, amphetamines, and 3,4-methylenedioxymethamphetamine (“Ecstasy”).

At presentation, Mr. R’s mood was dysphoric with bizarre affect. Eye contact was poor with easy distractibility. Speech was pressured, with full range. His thought process was grossly disorganized with tangential thinking and flight of ideas. His short- and long-term memory were intact; insight and judgment were limited. A Mini-Mental State Examination could not be completed because of his disorganization and distractibility.

Does Mr. R. have schizophrenia or schizoaffective disorder? Or are his symptoms related to ADHD or substance abuse?

The authors’ observations

Mr. R’s paranoid delusions and hallucinations may suggest schizophrenia. With his history of suicide attempts, a depressive or schizoaffective disorder may also be considered.

However, Mr. R is close with his family and has several friends. His parents say he has not been withdrawn or paranoid, and there is no known family history of mood disorder, substance abuse, or other psychiatric illness. Mr. R also has been working steadily and had worked the night before presenting to us, so schizophrenia and schizoaffective disorder are ruled out. ADHD and abuse of multiple substances could explain his behavior because overdose of stimulants and illicit drugs may produce a psychotic event.

Further history: The power of addiction

After more questioning, Mr. R said that he had recently started using gamma butyrolactone (GBL) in a failed attempt to build muscle. For 4 months he had been taking 3.5 oz of GBL daily—0.25 oz every 2 to 3 hours and 0.75 oz at night to help him sleep.

Within 6 hours of his most recent GBL dose (reportedly 1 oz), Mr. R developed intractable nausea, vomiting, and flatus, followed quickly by anxiety, palpitations, and generalized hand/body tremors that disturbed his sleep. Hallucinations and delusions started the next day.

At presentation, Mr. R’s blood pressure was 188/92 mm Hg, his heart rate was 110 bpm, and his respiratory rate was 22 breaths per minute. Pupils were 5 mm and reactive with intact extraocular movement. A urine drug screen indicated amphetamine use.

Mr. R was tentatively diagnosed as having GBL withdrawal syndrome and was admitted for observation and treatment. The psychiatry service followed him for change in mental status and drug dependence.

Can a withdrawal syndrome reasonably account for Mr. R’s symptoms?

The authors’ observations

GBL is a precursor of gamma-hydroxybutyrate (GHB), a highly addictive agent that is used illicitly, typically at parties and nightclubs (Box). GBL is among the clinical analogues of GHB that have become popular street drugs.

GHB withdrawal syndrome has only recently been described in the literature and is virtually indistinguishable from withdrawal after cessation of GBL and other precursors. To date, 71 deaths have been attributed to GHB withdrawal.²

A constellation of symptoms exhibited by Mr. R point to GHB withdrawal, which should be included in the differential diagnosis of any sedative/hypnotic withdrawal (Table 1).

How GHB works. GHB easily crosses the blood-brain barrier. Like other sedative/hypnotics, its depressant effects on the brain in low doses (2 to 4 grams) produce a euphoric feeling as inhibitions are depressed. Profound coma or death result from higher doses (>4 grams).³ Heart rate may also be slowed and CNS effects may result in myoclonus, producing seizure-like movements. Combining GHB with other drugs can increase the other agents’ depressant effects, leading to confusion, amnesia, vomiting, irregular breathing, or death.²

 

Box

A tiny increase in GHB dose can dramatically increase the symptoms and risk of overdose.⁴ GHB’s effects are also variable: A 1-teaspoon dose can produce the desired “high” one time and an overdose the next.

GHB and ethanol share a common mechanism of action.⁵ At pharmacologic doses, GHB appears to act in part through effects on the structurally related GABA neurotransmitter or its receptors.

Not surprisingly, a withdrawal syndrome characterized by delirium and autonomic instability ensues after GHB use is abruptly stopped. By functioning as indirect GABA agonists and ultimately evoking inhibitory neurotransmission, benzodiazepines and most barbiturates may alleviate GHB withdrawal symptoms.⁴ Thiamine is added to prevent Wernicke-Korsakoff syndrome, as is seen in alcohol withdrawal.⁵

GHB withdrawal. Symptoms are divided into three phases:

• Phase 1 (acute, first 24 hours). Presenting symptoms include anxiety, restlessness, insomnia, tremor, diaphoresis, tachycardia, and hypertension. Nausea and vomiting are variable but can be unrelenting.

While symptoms vary in severity, most prominent are agitation, restlessness, and insomnia. Some patients do not sleep for days after their last dose, and diffuse body tremors prevent them from sitting or lying still. Tachycardia and hypertension are hard to evaluate at this phase because patients present at different stages of withdrawal. Initial blood pressure readings as high as 240/130 mm Hg and heart rates of 120 bpm have been reported, however.

• Phase 2 (days 2 through 6). Worsening autonomic symptoms, progressive GI symptoms, and overall worsening of the withdrawal mark this tumultuous period. Patients usually present at this point—in acute distress and no longer able to self-treat.

Confusion, delirium, and florid psychosis characterize this phase. Mr. R’s paranoid delusions and hallucinations are the most common form of psychosis seen in GHB withdrawal.⁵ In some cases, the psychosis impairs social, occupational, and other functioning.

Table 1

Comparison of sedative-hypnotic withdrawal syndromes

Substance	Onset	Duration of severe symptoms	Autonomic instability*	Neurologic/psychiatric symptoms	Mortality	Major mechanism inducing withdrawal state‡
GHB	<6 hours	5 to 12 days	Mild	Severe	<1%	Loss of GHB, GABAA, and GABAB-mediated inhibition
Benzodiazepines	1 to 3 days	5 to 9 days	Moderate	Moderate	1%	Loss of GABAA-mediated inhibition
Baclofen	12 to 96 hours	8 days	Moderate	Severe	None reported	Loss of GABAB-mediated inhibition
Ethanol	<6 hours	10 to 14 days	Severe	Moderate to severe	5% to 15%	Loss of GABAA-mediated inhibition; disinhibition of NMDA receptors
NMDA: N-methyl D-aspartate.
GHB: Gamma-hydroxybutyrate
*Marked by tachycardia, fever, hypertension, and/or diaphoresis.
‡All withdrawal states involve multifactorial processes.
Source: Reference 5

Underlying or concurrent causes of delirium must be ruled out. Patients at this stage often require physical restraint or immediate sedation to prevent injury and dangerous complications, including hyperthermia and rhabdomyolysis. Benzodiazepines are often used in high doses¹ for sedation. IV hydration and antiemetics are also treatment mainstays. Atypical antipsychotics are added ASAP to control the paranoia.

• Phase 3 (days 7 through 13). Symptoms usually resolve at this stage. The delirium most often clears first, followed by restored autonomic stability and GI rest. While decreased sleep and periods of psychosis persist, agitation is less severe. The patient is discharged on average after 11 days.

Intense outpatient follow-up should include individual psychotherapy, substance abuse counseling, and drug therapy. Highly addictive medications should be avoided because of the patient’s substance abuse history.

Did Mr. R accurately report the amount of GBL he had taken? How should GBL and GHB blood levels be measured, given the agents’ rapid absorption rates?

The authors’ observations

As with most drugs of abuse, high doses over time contribute to severe GHB withdrawal syndrome. GHB doses taken before withdrawal are up to 10 times greater than those taken in typical recreational use.⁵

However, quantifying GHB levels with standard urine drug screens is nearly impossible because:

 

• the agent is absorbed within 20 to 60 minutes
• only 2% to 5% of the agent is eliminated in the urine.

GHB—which comes in powder, tablet, and liquid form and is usually dissolved in water before use—often is mixed with other drugs or alcohol. Varying preparations and use with multiple substances can produce inconsistent GHB levels and decrease sensitivity and specificity in routine drug screening. GHB abusers also report the amount ingested in “capfuls,” ounces, and teaspoons, making accurate quantification harder still.²

Though infrequently used because of feasibility and cost, gas chromatography and infrared spectroscopy of a urine specimen are the only known methods for determining GHB levels. Chronic GHB use, negative polypharmacy history, and negative urine and blood analysis for alcohol, benzodiazepines, sedative-hypnotics, or other substances usually confirm GHB withdrawal diagnosis.¹

Treatment: ‘Bad’ medicine

In the ER, Mr. R was given two 1-mg doses of lorazepam IV 1 hour apart. After 1 hour, his vital signs improved slightly (heart rate: 100/min; blood pressure: 165/99 mm Hg). Thiamine and folate were also started. Mr. R’s severe agitation and paranoia persisted, so three more 2-mg doses of lorazepam IV were given at 4-hour intervals.

Within 2 days, Mr. R was transferred to the voluntary inpatient psychiatric unit. His nausea, vomiting, and autonomic instability resolved, but his delirium and psychosis persisted. Quetiapine, 100 mg bid, was started to address his psychosis, and bupropion, 150 mg once daily, was restarted to manage his previously diagnosed depression. Three days after starting bupropion, Mr. R’s mood improved based on patient reports and Clinical Global Impression scores (6 at baseline, 2 at discharge), but his persecutory delusions persisted, causing mild anxiety.

The next day, Mr. R’s auditory and visual hallucinations had ceased, his preoccupation with terrorists began to subside, and his concentration, sleep, and appetite were improving. By day 6 of hospitalization, he still complained of mild tremors and anxiety, but his persecutory delusions resolved.

After 9 days, Mr. R was discharged. Autonomic stability was achieved and his delirium had mostly resolved. Outpatient drug rehabilitation and psychiatric services were arranged.

As of this writing, Mr. R had not sought outpatient treatment. His current medical status is unknown.

Related resources

• Miglani J, Kim K, Chahil R. Gamma-hydroxybutyrate withdrawal delirium: a case report. Gen Hosp Psychiatry. 2000;22:213-6.
• Columbo G, Agabio R, Lobina C, et al. Cross tolerance to ethanol and gamma-hydroxybutyric acid. Eur J Pharmacol. 1995;273:235-8.
• Project GHB. www.projectghb.org

Drug brand names

• Bupropion • Wellbutrin
• Lorazepam • Ativan
• Methylphenidate • Ritalin, Concerta
• Paroxetine • Paxil
• Quetiapine • Seroquel

Disclosure

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