Case-Based Review

HISTORY: TIRED OF LIVING

Mr. F, age 43, presents to the emergency room with complications of type 2 diabetes mellitus: blurry vision, increased urination, fatigue, and polydipsia. Blood glucose is 676 mg/dL.

The patient flees during treatment—possibly to attempt suicide—but returns 36 hours later, noticeably disoriented. He is readmitted to the ER, where he tells staff he is considering suicide and plans to self-inject a lethal substance. The ER staff refers him to the psychiatry service.

Mr. F also complains of shortness of breath after minimal exertion, aching joints throughout his body, and intense pain in his right great toe. He has been sleeping 12 to 20 hours daily, yet has trouble sleeping at night. He persistently feels fatigued, hopeless, and helpless. He says his suicidal urges have become more intense over 2 months, but he fears he will lose his computer repair job if he is admitted. He also shows difficulties with short-term memory. We admit him for observation.

Mental status examination suggests that Mr. F is generally withdrawn. Eye contact is poor and he is quiet and evasive, possibly signaling paranoia. He spends most of his stay watching television. His thought process is linear, and he thinks constantly of suicide. During the Mini-Mental State Examination, he gives the incorrect date and county. He misses two other items on recall but gets them correct with prompts.

A mild intention tremor distorts his handwriting. He has trouble keeping his balance during the Romberg test, and his gait is mildly ataxic. Ophthalmology consult suggests that diabetic retinopathy and optic disc cupping secondary to glaucoma may be blurring his vision.

Mr. F is taking no medications but had previously used insulin twice a day, and his outpatient doctor insists he should go back on insulin. He smokes 1 pack of cigarettes per day, drinks alcohol moderately (one to two drinks/day), and does not abuse illicit drugs.

The authors’ observations

Mr. F’s depressed mood, hopelessness, concentration problems, psychomotor retardation, and suicidal thoughts suggest major depressive disorder. Depression or a delirium secondary to diabetes may account for his referential ideas.

FURTHER HISTORY: ONE SHOT AT SATISFACTION

Over the following week, Mr. F becomes more talkative as the psychiatry staff develops a therapeutic rapport. He tells his treatment team that he feels urges to self-inject liquids he finds in his hospital room, such as shower gel and beverages.

Mr. F tells us that approximately 2 years ago, he tried to kill himself by swallowing boric acid. After 6 weeks in intensive care, the poison’s physical effects resolved and he no longer appeared suicidal. The staff at that time prepared to discharge Mr. F when, while left alone in his room, he dislodged a wall-mounted sphygmomanometer, disassembled it, and broke open the mercury tube. He then injected about 3 mL of mercury into his intravenous port and swallowed another 3 mL.

A nurse who checked on Mr. F minutes after the incident did not notice the sphygmomanometer was missing. He showed the broken device to the nurse, saying, “Look what I did.” When the nurse asked why, he responded, “I was just sitting here alone and saw the thing on the wall. I thought to myself, I can do this.”

The hospital viewed the episode as another suicide attempt. Staff immediately began chelation therapy with dimercaprol, 10 mg/kg every 8 hours for 5 days, then 10 mg/kg every 12 hours for 2 weeks. Within 24 hours of ingesting mercury, Mr. F developed shortness of breath, tachycardia (104 BPM), a fever (101.8°F), and had GI complaints. Increased blood urea nitrogen, increased creatinine, and decreased urination suggested declining renal function. He developed a pruritic rash over his back and mild skin loss on his soles.

Mr. F’s mercury levels were 20.8 mg/dL (serum) and 216 mg/dL (urine) 36 hours after ingestation, and 24.8 mg/dL (serum) and 397 mg/dL (urine) after chelation. Serum mercury >5 mg/dL is usually symptomatic.

Approximately 72 hours after the incident, most pulmonary, renal, and dermal manifestations of mercury toxicity began to improve. Mr. F was discharged after 21 days. He was diagnosed with major depression and started on sertraline, 150 mg/d.

‘The best feeling.’ Two years later, Mr. F tells us he has attempted suicide at least six times. Diffuse metallic foreign bodies throughout his lung vasculature and a 9.6 mg/dL serum mercury reading confirm he has injected mercury. His painful toe is x-rayed to check for mercury deposits, but he ultimately is diagnosed with gout.

During our evaluation, Mr. F admits that “the calmest, best feeling I have ever had” was while injecting mercury, yet he fears the incident has caused permanent physical and mental damage. He describes his desire to self-inject liquids as “impulses” triggered by twice-daily subcutaneous insulin use. For this reason, he has stopped taking insulin against his doctor’s advice.

 

The authors’ observations

Mr. F’s mental status changes and serum mercury suggest mercury poisoning. He shows numerous heavy-metal poisoning symptoms (Box 1) as well as erethism, a malaise that can result from heavy-metal exposure.²

The patient insists that insulin shots bring on self-injection urges, but his impulsive and repetitive suicidal behavior, dysphoria, and transient paranoia suggest borderline personality disorder. His impulses may reflect a subtle, long-term personality change caused by mercury’s neurotoxic effects.¹ Or they could be akin to cutting behaviors shown by some patients with personality disorders, particularly borderline personality disorder.

We ruled out substance abuse disorder, as Mr. F’s mercury ingestion was not premeditated, he has no history of illicit drug use, and intravenous elemental mercury is not psychoactive.

Box 1

An ever-present threat. Mercury exists in many organic, inorganic, and elemental forms—all toxic.

Elemental mercury found in thermometers, lamps, and dental amalgams slowly ionizes in the blood stream before crossing the blood-brain barrier. Mercury and carbon form toxic “organic” compounds, including methylmercury (found in the environment), phenylmercury (used in some commercial products), and dimethylmercury (found in solid waste sites).

Because mercury’s half-life is 60 days, it dissipates slowly, can accumulate with chronic exposure, and stays in the blood stream long after high-dose exposure.³

Serum mercury >5 mg/dL can cause subtle, enduring neurotoxic effects, including tremor, dizziness, shortness of breath, blurry vision, decreased visual fields, depression, memory loss, and irritability.³ Serum mercury rarely exceeds 1.5 mg/dL without direct exposure.

Irritability, depressive symptoms, and renal manifestations emerge when urine mercury reaches 200 to 1,000 mg/dL. Renal, respiratory, and GI effects are seen at 1,000 to 2,000 mg/dL.

Means of exposure. Vapor inhalation is the most common means of elemental mercury exposure.³ Elemental mercury used in manufacturing vaporizes at room temperature.

Orally ingested elemental mercury is poorly absorbed from the GI tract, mostly passes unabsorbed, and is toxic only at high doses. Injected elemental mercury is poorly absorbed but can cause mechanical and immunologic effects. The psychiatric literature describes some 200 cases of mercury self-injection^4-8 but offers little information on cognitive effects or long-term follow-up.

Consider heavy-metal poisoning in the differential diagnosis of patients with depressive symptoms. Ask about risk factors for environmental mercury exposure, including use of folk medicines, some cosmetics, over-the-counter nasal sprays, ophthalmic solutions, skin-lightening creams, daily fish consumption (particularly tuna or swordfish), living in a house painted with latex paint, or continuous exposure at work (Box 2).

Also ask if the patient or a household member recently ingested mercury or handled a broken thermometer. Liquid mercury on clothing and in bodily fluids may cause secondary contamination, whereas mercury vapor cannot.

Order serum mercury testing if you suspect chronic exposure. Refer patients with serum mercury ≥ 1.5 mg/dL to their primary care physicians and to a poison control center for evaluation and possible chelation. Refer patients with acute mercury exposure symptoms to the ER.

Box 2

The authors’ observations

Antidepressants generally will not reduce depression, irritability, personality changes, or apathy secondary to mercury poisoning. We have found that a psychostimulant such as methylphenidate, starting at 10 mg bid and titrating to therapeutic effect, can help treat mercury-related apathy.

 

We did not give Mr. F a psychostimulant, however, fearing it would worsen his impulsive behavior and disordered sleep. Also, more effectively managing Mr. F’s diabetes should improve his depression.

DISCHARGE: CHELATION CHALLENGE

Mr. F’s suicidal thoughts continued intermittently. Chelation was tried again with succimer, 1,000 mg tid for 5 days and bid for 5 more days, but the agent caused severe nausea without significantly decreasing serum mercury. He declined outpatient chelation.

After 2 weeks, Mr. F denied suicidal thoughts and said he felt physically better. He was discharged on venlafaxine, 300 mg/d, for his depressive symptoms; and metformin, 1,000 mg/d, glipizide, 10 mg bid, and rosiglitazone, 4 mg/d, to control his blood glucose. We arranged for medication management at a community mental health center. Mr. F was also told to visit the hospital’s outpatient clinic for endocrine follow-up but has not returned for 18 months.

Related resources

• Agency for Toxic Substances and Disease Registry. Information about toxic substances in the environment and diseases they may cause. www.atsdr.cdc.gov.
  

Drug brand names

• Dimercaprol • BAL in Oil
  
• Glipizide • Glucotrol
  
• Metformin • Glucophage
  
• Methylphenidate • Ritalin, Concerta
  
• Rosiglitazone • Avandia
  
• Sertraline • Zoloft
  
• Succimer • Chemet
  
• Venlafaxine • Effexor
  

Disclosure

Dr. Matthews is an American Psychiatric Association Bristol-Myers Squibb Co. fellow in public and community psychiatry.

Dr. Hauser receives research/grant support from GlaxoSmithKline, Hoffman LaRoche, and AstraZeneca Pharmaceuticals. He is a speaker for Abbott Laboratories, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., GlaxoSmithKline, and Janssen Pharmaceuticals.

HISTORY: TIRED OF LIVING

Mr. F, age 43, presents to the emergency room with complications of type 2 diabetes mellitus: blurry vision, increased urination, fatigue, and polydipsia. Blood glucose is 676 mg/dL.

The patient flees during treatment—possibly to attempt suicide—but returns 36 hours later, noticeably disoriented. He is readmitted to the ER, where he tells staff he is considering suicide and plans to self-inject a lethal substance. The ER staff refers him to the psychiatry service.

Mr. F also complains of shortness of breath after minimal exertion, aching joints throughout his body, and intense pain in his right great toe. He has been sleeping 12 to 20 hours daily, yet has trouble sleeping at night. He persistently feels fatigued, hopeless, and helpless. He says his suicidal urges have become more intense over 2 months, but he fears he will lose his computer repair job if he is admitted. He also shows difficulties with short-term memory. We admit him for observation.

Mental status examination suggests that Mr. F is generally withdrawn. Eye contact is poor and he is quiet and evasive, possibly signaling paranoia. He spends most of his stay watching television. His thought process is linear, and he thinks constantly of suicide. During the Mini-Mental State Examination, he gives the incorrect date and county. He misses two other items on recall but gets them correct with prompts.

A mild intention tremor distorts his handwriting. He has trouble keeping his balance during the Romberg test, and his gait is mildly ataxic. Ophthalmology consult suggests that diabetic retinopathy and optic disc cupping secondary to glaucoma may be blurring his vision.

Mr. F is taking no medications but had previously used insulin twice a day, and his outpatient doctor insists he should go back on insulin. He smokes 1 pack of cigarettes per day, drinks alcohol moderately (one to two drinks/day), and does not abuse illicit drugs.

The authors’ observations

Mr. F’s depressed mood, hopelessness, concentration problems, psychomotor retardation, and suicidal thoughts suggest major depressive disorder. Depression or a delirium secondary to diabetes may account for his referential ideas.

FURTHER HISTORY: ONE SHOT AT SATISFACTION

Over the following week, Mr. F becomes more talkative as the psychiatry staff develops a therapeutic rapport. He tells his treatment team that he feels urges to self-inject liquids he finds in his hospital room, such as shower gel and beverages.

Mr. F tells us that approximately 2 years ago, he tried to kill himself by swallowing boric acid. After 6 weeks in intensive care, the poison’s physical effects resolved and he no longer appeared suicidal. The staff at that time prepared to discharge Mr. F when, while left alone in his room, he dislodged a wall-mounted sphygmomanometer, disassembled it, and broke open the mercury tube. He then injected about 3 mL of mercury into his intravenous port and swallowed another 3 mL.

A nurse who checked on Mr. F minutes after the incident did not notice the sphygmomanometer was missing. He showed the broken device to the nurse, saying, “Look what I did.” When the nurse asked why, he responded, “I was just sitting here alone and saw the thing on the wall. I thought to myself, I can do this.”

The hospital viewed the episode as another suicide attempt. Staff immediately began chelation therapy with dimercaprol, 10 mg/kg every 8 hours for 5 days, then 10 mg/kg every 12 hours for 2 weeks. Within 24 hours of ingesting mercury, Mr. F developed shortness of breath, tachycardia (104 BPM), a fever (101.8°F), and had GI complaints. Increased blood urea nitrogen, increased creatinine, and decreased urination suggested declining renal function. He developed a pruritic rash over his back and mild skin loss on his soles.

Mr. F’s mercury levels were 20.8 mg/dL (serum) and 216 mg/dL (urine) 36 hours after ingestation, and 24.8 mg/dL (serum) and 397 mg/dL (urine) after chelation. Serum mercury >5 mg/dL is usually symptomatic.

Approximately 72 hours after the incident, most pulmonary, renal, and dermal manifestations of mercury toxicity began to improve. Mr. F was discharged after 21 days. He was diagnosed with major depression and started on sertraline, 150 mg/d.

‘The best feeling.’ Two years later, Mr. F tells us he has attempted suicide at least six times. Diffuse metallic foreign bodies throughout his lung vasculature and a 9.6 mg/dL serum mercury reading confirm he has injected mercury. His painful toe is x-rayed to check for mercury deposits, but he ultimately is diagnosed with gout.

During our evaluation, Mr. F admits that “the calmest, best feeling I have ever had” was while injecting mercury, yet he fears the incident has caused permanent physical and mental damage. He describes his desire to self-inject liquids as “impulses” triggered by twice-daily subcutaneous insulin use. For this reason, he has stopped taking insulin against his doctor’s advice.

 

The authors’ observations

Mr. F’s mental status changes and serum mercury suggest mercury poisoning. He shows numerous heavy-metal poisoning symptoms (Box 1) as well as erethism, a malaise that can result from heavy-metal exposure.²

The patient insists that insulin shots bring on self-injection urges, but his impulsive and repetitive suicidal behavior, dysphoria, and transient paranoia suggest borderline personality disorder. His impulses may reflect a subtle, long-term personality change caused by mercury’s neurotoxic effects.¹ Or they could be akin to cutting behaviors shown by some patients with personality disorders, particularly borderline personality disorder.

We ruled out substance abuse disorder, as Mr. F’s mercury ingestion was not premeditated, he has no history of illicit drug use, and intravenous elemental mercury is not psychoactive.

Box 1

An ever-present threat. Mercury exists in many organic, inorganic, and elemental forms—all toxic.

Elemental mercury found in thermometers, lamps, and dental amalgams slowly ionizes in the blood stream before crossing the blood-brain barrier. Mercury and carbon form toxic “organic” compounds, including methylmercury (found in the environment), phenylmercury (used in some commercial products), and dimethylmercury (found in solid waste sites).

Because mercury’s half-life is 60 days, it dissipates slowly, can accumulate with chronic exposure, and stays in the blood stream long after high-dose exposure.³

Serum mercury >5 mg/dL can cause subtle, enduring neurotoxic effects, including tremor, dizziness, shortness of breath, blurry vision, decreased visual fields, depression, memory loss, and irritability.³ Serum mercury rarely exceeds 1.5 mg/dL without direct exposure.

Irritability, depressive symptoms, and renal manifestations emerge when urine mercury reaches 200 to 1,000 mg/dL. Renal, respiratory, and GI effects are seen at 1,000 to 2,000 mg/dL.

Means of exposure. Vapor inhalation is the most common means of elemental mercury exposure.³ Elemental mercury used in manufacturing vaporizes at room temperature.

Orally ingested elemental mercury is poorly absorbed from the GI tract, mostly passes unabsorbed, and is toxic only at high doses. Injected elemental mercury is poorly absorbed but can cause mechanical and immunologic effects. The psychiatric literature describes some 200 cases of mercury self-injection^4-8 but offers little information on cognitive effects or long-term follow-up.

Consider heavy-metal poisoning in the differential diagnosis of patients with depressive symptoms. Ask about risk factors for environmental mercury exposure, including use of folk medicines, some cosmetics, over-the-counter nasal sprays, ophthalmic solutions, skin-lightening creams, daily fish consumption (particularly tuna or swordfish), living in a house painted with latex paint, or continuous exposure at work (Box 2).

Also ask if the patient or a household member recently ingested mercury or handled a broken thermometer. Liquid mercury on clothing and in bodily fluids may cause secondary contamination, whereas mercury vapor cannot.

Order serum mercury testing if you suspect chronic exposure. Refer patients with serum mercury ≥ 1.5 mg/dL to their primary care physicians and to a poison control center for evaluation and possible chelation. Refer patients with acute mercury exposure symptoms to the ER.

Box 2

The authors’ observations

Antidepressants generally will not reduce depression, irritability, personality changes, or apathy secondary to mercury poisoning. We have found that a psychostimulant such as methylphenidate, starting at 10 mg bid and titrating to therapeutic effect, can help treat mercury-related apathy.

 

We did not give Mr. F a psychostimulant, however, fearing it would worsen his impulsive behavior and disordered sleep. Also, more effectively managing Mr. F’s diabetes should improve his depression.

DISCHARGE: CHELATION CHALLENGE

Mr. F’s suicidal thoughts continued intermittently. Chelation was tried again with succimer, 1,000 mg tid for 5 days and bid for 5 more days, but the agent caused severe nausea without significantly decreasing serum mercury. He declined outpatient chelation.

After 2 weeks, Mr. F denied suicidal thoughts and said he felt physically better. He was discharged on venlafaxine, 300 mg/d, for his depressive symptoms; and metformin, 1,000 mg/d, glipizide, 10 mg bid, and rosiglitazone, 4 mg/d, to control his blood glucose. We arranged for medication management at a community mental health center. Mr. F was also told to visit the hospital’s outpatient clinic for endocrine follow-up but has not returned for 18 months.

Related resources

• Agency for Toxic Substances and Disease Registry. Information about toxic substances in the environment and diseases they may cause. www.atsdr.cdc.gov.
  

Drug brand names

• Dimercaprol • BAL in Oil
  
• Glipizide • Glucotrol
  
• Metformin • Glucophage
  
• Methylphenidate • Ritalin, Concerta
  
• Rosiglitazone • Avandia
  
• Sertraline • Zoloft
  
• Succimer • Chemet
  
• Venlafaxine • Effexor
  

Disclosure

Dr. Matthews is an American Psychiatric Association Bristol-Myers Squibb Co. fellow in public and community psychiatry.

Dr. Hauser receives research/grant support from GlaxoSmithKline, Hoffman LaRoche, and AstraZeneca Pharmaceuticals. He is a speaker for Abbott Laboratories, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., GlaxoSmithKline, and Janssen Pharmaceuticals.

HISTORY: TIRED OF LIVING

Mr. F, age 43, presents to the emergency room with complications of type 2 diabetes mellitus: blurry vision, increased urination, fatigue, and polydipsia. Blood glucose is 676 mg/dL.

The patient flees during treatment—possibly to attempt suicide—but returns 36 hours later, noticeably disoriented. He is readmitted to the ER, where he tells staff he is considering suicide and plans to self-inject a lethal substance. The ER staff refers him to the psychiatry service.

Mr. F also complains of shortness of breath after minimal exertion, aching joints throughout his body, and intense pain in his right great toe. He has been sleeping 12 to 20 hours daily, yet has trouble sleeping at night. He persistently feels fatigued, hopeless, and helpless. He says his suicidal urges have become more intense over 2 months, but he fears he will lose his computer repair job if he is admitted. He also shows difficulties with short-term memory. We admit him for observation.

Mental status examination suggests that Mr. F is generally withdrawn. Eye contact is poor and he is quiet and evasive, possibly signaling paranoia. He spends most of his stay watching television. His thought process is linear, and he thinks constantly of suicide. During the Mini-Mental State Examination, he gives the incorrect date and county. He misses two other items on recall but gets them correct with prompts.

A mild intention tremor distorts his handwriting. He has trouble keeping his balance during the Romberg test, and his gait is mildly ataxic. Ophthalmology consult suggests that diabetic retinopathy and optic disc cupping secondary to glaucoma may be blurring his vision.

Mr. F is taking no medications but had previously used insulin twice a day, and his outpatient doctor insists he should go back on insulin. He smokes 1 pack of cigarettes per day, drinks alcohol moderately (one to two drinks/day), and does not abuse illicit drugs.

The authors’ observations

Mr. F’s depressed mood, hopelessness, concentration problems, psychomotor retardation, and suicidal thoughts suggest major depressive disorder. Depression or a delirium secondary to diabetes may account for his referential ideas.

FURTHER HISTORY: ONE SHOT AT SATISFACTION

Over the following week, Mr. F becomes more talkative as the psychiatry staff develops a therapeutic rapport. He tells his treatment team that he feels urges to self-inject liquids he finds in his hospital room, such as shower gel and beverages.

Mr. F tells us that approximately 2 years ago, he tried to kill himself by swallowing boric acid. After 6 weeks in intensive care, the poison’s physical effects resolved and he no longer appeared suicidal. The staff at that time prepared to discharge Mr. F when, while left alone in his room, he dislodged a wall-mounted sphygmomanometer, disassembled it, and broke open the mercury tube. He then injected about 3 mL of mercury into his intravenous port and swallowed another 3 mL.

A nurse who checked on Mr. F minutes after the incident did not notice the sphygmomanometer was missing. He showed the broken device to the nurse, saying, “Look what I did.” When the nurse asked why, he responded, “I was just sitting here alone and saw the thing on the wall. I thought to myself, I can do this.”

The hospital viewed the episode as another suicide attempt. Staff immediately began chelation therapy with dimercaprol, 10 mg/kg every 8 hours for 5 days, then 10 mg/kg every 12 hours for 2 weeks. Within 24 hours of ingesting mercury, Mr. F developed shortness of breath, tachycardia (104 BPM), a fever (101.8°F), and had GI complaints. Increased blood urea nitrogen, increased creatinine, and decreased urination suggested declining renal function. He developed a pruritic rash over his back and mild skin loss on his soles.

Mr. F’s mercury levels were 20.8 mg/dL (serum) and 216 mg/dL (urine) 36 hours after ingestation, and 24.8 mg/dL (serum) and 397 mg/dL (urine) after chelation. Serum mercury >5 mg/dL is usually symptomatic.

Approximately 72 hours after the incident, most pulmonary, renal, and dermal manifestations of mercury toxicity began to improve. Mr. F was discharged after 21 days. He was diagnosed with major depression and started on sertraline, 150 mg/d.

‘The best feeling.’ Two years later, Mr. F tells us he has attempted suicide at least six times. Diffuse metallic foreign bodies throughout his lung vasculature and a 9.6 mg/dL serum mercury reading confirm he has injected mercury. His painful toe is x-rayed to check for mercury deposits, but he ultimately is diagnosed with gout.

During our evaluation, Mr. F admits that “the calmest, best feeling I have ever had” was while injecting mercury, yet he fears the incident has caused permanent physical and mental damage. He describes his desire to self-inject liquids as “impulses” triggered by twice-daily subcutaneous insulin use. For this reason, he has stopped taking insulin against his doctor’s advice.

 

The authors’ observations

Mr. F’s mental status changes and serum mercury suggest mercury poisoning. He shows numerous heavy-metal poisoning symptoms (Box 1) as well as erethism, a malaise that can result from heavy-metal exposure.²

The patient insists that insulin shots bring on self-injection urges, but his impulsive and repetitive suicidal behavior, dysphoria, and transient paranoia suggest borderline personality disorder. His impulses may reflect a subtle, long-term personality change caused by mercury’s neurotoxic effects.¹ Or they could be akin to cutting behaviors shown by some patients with personality disorders, particularly borderline personality disorder.

We ruled out substance abuse disorder, as Mr. F’s mercury ingestion was not premeditated, he has no history of illicit drug use, and intravenous elemental mercury is not psychoactive.

Box 1

An ever-present threat. Mercury exists in many organic, inorganic, and elemental forms—all toxic.

Elemental mercury found in thermometers, lamps, and dental amalgams slowly ionizes in the blood stream before crossing the blood-brain barrier. Mercury and carbon form toxic “organic” compounds, including methylmercury (found in the environment), phenylmercury (used in some commercial products), and dimethylmercury (found in solid waste sites).

Because mercury’s half-life is 60 days, it dissipates slowly, can accumulate with chronic exposure, and stays in the blood stream long after high-dose exposure.³

Serum mercury >5 mg/dL can cause subtle, enduring neurotoxic effects, including tremor, dizziness, shortness of breath, blurry vision, decreased visual fields, depression, memory loss, and irritability.³ Serum mercury rarely exceeds 1.5 mg/dL without direct exposure.

Irritability, depressive symptoms, and renal manifestations emerge when urine mercury reaches 200 to 1,000 mg/dL. Renal, respiratory, and GI effects are seen at 1,000 to 2,000 mg/dL.

Means of exposure. Vapor inhalation is the most common means of elemental mercury exposure.³ Elemental mercury used in manufacturing vaporizes at room temperature.

Orally ingested elemental mercury is poorly absorbed from the GI tract, mostly passes unabsorbed, and is toxic only at high doses. Injected elemental mercury is poorly absorbed but can cause mechanical and immunologic effects. The psychiatric literature describes some 200 cases of mercury self-injection^4-8 but offers little information on cognitive effects or long-term follow-up.

Consider heavy-metal poisoning in the differential diagnosis of patients with depressive symptoms. Ask about risk factors for environmental mercury exposure, including use of folk medicines, some cosmetics, over-the-counter nasal sprays, ophthalmic solutions, skin-lightening creams, daily fish consumption (particularly tuna or swordfish), living in a house painted with latex paint, or continuous exposure at work (Box 2).

Also ask if the patient or a household member recently ingested mercury or handled a broken thermometer. Liquid mercury on clothing and in bodily fluids may cause secondary contamination, whereas mercury vapor cannot.

Order serum mercury testing if you suspect chronic exposure. Refer patients with serum mercury ≥ 1.5 mg/dL to their primary care physicians and to a poison control center for evaluation and possible chelation. Refer patients with acute mercury exposure symptoms to the ER.

Box 2

The authors’ observations

Antidepressants generally will not reduce depression, irritability, personality changes, or apathy secondary to mercury poisoning. We have found that a psychostimulant such as methylphenidate, starting at 10 mg bid and titrating to therapeutic effect, can help treat mercury-related apathy.

 

We did not give Mr. F a psychostimulant, however, fearing it would worsen his impulsive behavior and disordered sleep. Also, more effectively managing Mr. F’s diabetes should improve his depression.

DISCHARGE: CHELATION CHALLENGE

Mr. F’s suicidal thoughts continued intermittently. Chelation was tried again with succimer, 1,000 mg tid for 5 days and bid for 5 more days, but the agent caused severe nausea without significantly decreasing serum mercury. He declined outpatient chelation.

After 2 weeks, Mr. F denied suicidal thoughts and said he felt physically better. He was discharged on venlafaxine, 300 mg/d, for his depressive symptoms; and metformin, 1,000 mg/d, glipizide, 10 mg bid, and rosiglitazone, 4 mg/d, to control his blood glucose. We arranged for medication management at a community mental health center. Mr. F was also told to visit the hospital’s outpatient clinic for endocrine follow-up but has not returned for 18 months.

Related resources

• Agency for Toxic Substances and Disease Registry. Information about toxic substances in the environment and diseases they may cause. www.atsdr.cdc.gov.
  

Drug brand names

• Dimercaprol • BAL in Oil
  
• Glipizide • Glucotrol
  
• Metformin • Glucophage
  
• Methylphenidate • Ritalin, Concerta
  
• Rosiglitazone • Avandia
  
• Sertraline • Zoloft
  
• Succimer • Chemet
  
• Venlafaxine • Effexor
  

Disclosure

Dr. Matthews is an American Psychiatric Association Bristol-Myers Squibb Co. fellow in public and community psychiatry.

Dr. Hauser receives research/grant support from GlaxoSmithKline, Hoffman LaRoche, and AstraZeneca Pharmaceuticals. He is a speaker for Abbott Laboratories, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., GlaxoSmithKline, and Janssen Pharmaceuticals.

HISTORY: THREE DIAGNOSES BY AGE 15

Matthew, age 17, has been hospitalized twice for psychiatric treatment. At school, he has no friends, is extremely energetic and volatile, and has paranoid delusional thoughts. At night, he becomes depressed over his inability to “fit in.”

Brilliant and deeply spiritual, Matthew obsesses over sins he believes he committed, yet he is angry with God over his illness, its impact on his life, and his apparently dimmed prospects for the future.

His troubles started early. While in preschool, a teacher said he had “autistic tendencies.” He was shy and larger than most children (>90th percentile in height and weight). He acquired language slowly, beginning at 18 months, and slept poorly, waking several times nightly.

Throughout grade school, Matthew was both bright and eccentric. His Wechsler Intelligence Scale for Children-III scores, taken at age 9, were 133 (full scale), 143 (verbal), and 111 (performance). By the third grade, he struggled with the meaning of the universe and other existential issues. In sixth grade, he believed his mouth stank and frequently used mouthwash, even at school. He also had periods of excessive hand-washing.

In fifth grade, a pediatrician diagnosed Matthew as having attention-deficit/hyperactivity disorder after his teacher complained about his behavior in class (blurting out answers, correcting the teacher, restlessness, questioning authority). The doctor prescribed methylphenidate and dextroamphetamine, but the combination made Matthew feel both “drugged and wired.” He stopped taking the agents after 8 weeks.

At age 15, Matthew saw a psychiatrist. His parents said he was depressed and obsessively afraid of being abandoned. Every day, they said, he kissed both parents twice on each cheek.

The psychiatrist diagnosed Matthew with obsessive-compulsive disorder. A trial of paroxetine, 20 mg/d, caused mild irritability with no symptom improvement. After 2 months, Matthew was switched to fluoxetine, initially 10 mg/d and increased to 20 mg/d, but after 6 weeks he suffered an acute manic episode. He claimed he was one with the universe and reported auditory hallucinations, intense suicidal thoughts, and sleeplessness for days on end.

Matthew was hospitalized for 7 days. Haloperidol, dosage unknown, decreased his psychosis but did not return him to baseline. The psychiatrist stopped fluoxetine because Matthew’s parents feared the antidepressant was causing his suicidality. No other agent was tried at this time.

The authors’ observations

Soon after Matthew began taking fluoxetine for apparent OCD and depressive symptoms, profound psychotic symptoms surfaced. These included command hallucinations, delusions, disordered and disorganized thought, high suicidality, motoric hyperarousal, and marked anxiety.

Although positive schizophrenia symptoms were predominant, mood and affect instability were also pronounced. The admitting psychiatrist diagnosed Matthew with schizoaffective disorder but did not include in the record the basis for this diagnosis.

Matthew’s OCD symptoms did not appear to derive from a delusional system or impaired reality testing. These symptoms were often associated with guilt and were consistent with other excessive behaviors.

HOSPITALIZATION: NEW DIAGNOSIS

Out of the hospital, Matthew’s ability to function declined over several months and he began to look disheveled and dirty. He was acutely suicidal, excessively guilty, isolative, and slept 1 to 2 hours nightly.

Matthew was again hospitalized, this time for 2 months. The psychiatrist revised the diagnosis to schizoaffective disorder, bipolar type, based on Matthew’s psychotic episodes, emerging positive symptoms, social withdrawal, and family history. (A male maternal cousin has paranoid schizophrenia.)

Risperidone, initially 0.5 mg nightly and titrated to 0.5 mg each morning and 1.5 mg nightly, gradually improved Matthew’s psychotic symptoms. The psychiatrist added divalproex, 250 mg bid titrated to 250 mg each morning, 250 mg at noon and 500 mg nightly, to address Matthew’s affective lability. After another 2 months of partial hospitalization, he was discharged. Thought disorder symptoms persisted, but reality testing was intact.

Back in high school, Matthew has gotten into a screaming match with the principal and heated political arguments with his teachers. He shows bursts of energy, agitation, and euphoria and is at times overdramatic and grandiose. His rapid-fire creativity easily shifts to irritability and paranoid delusional thinking punctuated by rage.

Almost nightly, Matthew sinks into depression. He also compulsively washes his hands, binge eats, has difficulty reading social cues and making conversation, and believes he is a “misfit.” He views Internet pornography to relieve sexual obsessions, but this habit leads to guilt-ridden ruminations that trigger suicidal thoughts.

For Matthew, high school’s pattern of alternating regimentation and intellectual stimulation constantly provokes mania. He sometimes disguises these episodes by playing “class clown,” only to sink into despair at night over his dyscontrol. His desperation causes frequent anxiety attacks. Searching for answers, Matthew changes psychiatrists and turns to us for help.

 

The authors’ observations

Matthew’s positive symptoms, bipolar presentation, and the severity and duration of his psychotic episodes supported the schizoaffective disorder diagnosis,¹ yet his cardinal type I bipolar disorder features were striking. His severe thought disorder and perceptual distortions improved, but rapid cycles between euphoria, rage, and depression persisted, as did shifts from hypersomnia to insomnia.

Matthew’s lack of negative symptoms prompted me (Dr. Lundt) to rethink the diagnosis. Though isolated from peers, Matthew remained affable throughout treatment and was emotionally attached to his parents and treating psychiatrist. He rarely appeared flat or blunted and showed no hostility or other signs of resistance typical of a patient with schizophrenia. He cooperated with treatment and showed insight into his illness, even at the height of his acute psychosis. His language was never significantly disorganized but his depression and obsessive guilt were chronic, dominant, and treatment-resistant. I learn over time that Matthew finds certain events highly stressful, and these exacerbate his psychotic features.

Matthew’s diagnosis—and how to address it—came down to two issues:

• Treatment would be similar for schizoaffective disorder or type I bipolar disorder with severe psychotic features.
  
• Matthew viewed schizoaffective disorder as a life sentence of insanity. Changing the diagnosis to type I bipolar disorder would allow him and his family to see a more manageable and hopeful prognosis.
  

Matthew grapples with typical adolescence issues: identity, peer relationships, social pressure, body image, and insecurity. Because he lacks the coping skills to navigate to adulthood, his depression and mood instability are clinical priorities.

In managing Matthew’s care, I refer him to a psychologist (Dr. Brownsmith) whose psychotherapeutic approach will depart significantly from traditional medical-model psychotherapy. Because bipolar and psychotic symptoms have stalled Matthew’s development, the psychologist will combine cognitive-behavioral therapy (CBT) with psychoeducation that emphasizes skills acquisition and coping techniques (Table 1). The goal is to convince Matthew that he can learn to manage his life.²

Table 1

Why psychoeducation can help
patients with bipolar disorder

50% of patients have frequent recurrences despite treatment 40% do not adhere to treatment, often because of lack of insight Mood and coping improve among patients receiving family-focused psychotherapy and family psychoeducation CBT combined with psychoeducation leads to:
Source: Adapted from references 2, 5.

TREATMENT: TEAM MEETINGS

Matthew begins individual psychotherapy with periodic family therapy and continued medication. Risperidone, 0.5 mg each morning and 1.5 mg nightly, and divalproex, 500 mg bid, have minimized Matthew’s psychosis and stabilized his mood but caused a 45-lb weight gain across 6 months. Matthew alternately joined professional weight-loss programs and worked with a personal trainer to stabilize his weight.

Because day-to-day intervention is critical to keeping Matthew’s anger from derailing his progress, we meet regularly—sometimes weekly—with him, his parents, and his school social worker to plan treatment and provide psychoeducation (Table 2).³

Throughout his senior year, Matthew’s sexual obsessions cause severe guilt, and he begs to be “chemically castrated.” Clomipramine, started at 25 mg nightly and titrated to 300 mg nightly over 2 years, diminishes his obsessions. ECGs are performed and clomipramine plasma levels are checked quarterly to guard against cardiotoxicity. Risperidone is continued and divalproex is gradually increased to 1,000 mg bid, ultimately reaching valproic acid levels of 79 μg/mL.

Through our therapeutic alliance and the change in diagnosis, we help Matthew gradually overcome his initial anger, resistance, despair, and suicidality. Drawing from research data while offering emotional support, we engage Matthew in a team therapy approach.

Matthew acknowledges his grief and anger at having a severe mental illness and agrees to learn to regulate his moods and participate in CBT. Responding with humor to his rapid-fire, manic discussions and animation helps solidify the alliance. We stay highly involved with his parents, often responding to their after-hours phone calls.

After approximately 9 months of CBT, Matthew sees his disordered thoughts and perceived loss of control as symptoms to be overcome.⁴ He adapts some of his fantasy life to replace his obsessive fear and anger. He develops highly creative, embellished visual imagery of a “safe place” in which he feels nurtured and protected. This imagery, coupled with relaxation exercises, is audiotaped so that he can practice at home.⁵ Psychoeducation and problem-solving help him dress appropriately and improve his hygiene.

Matthew’s intelligence and social awareness underlie strongly held values and opinions that fuel his anger. Media coverage of politicians, political debates in school, extreme religious views, and judgmental statements about sexuality frequently provoke rage. (Matthew once battered a street preacher who was decrying homosexuality.) By acquiring anger management strategies, he learns to avoid potentially volatile situations.⁶

 

Frequent crisis intervention keeps Matthew stable, while family therapy helps him follow his psychologist’s plan to maintain medication adherence and manage his circadian rhythms, activities of daily living, and CBT. His parents prompt him to use therapeutic techniques, support him during crises, and make sure he has the structure and support to participate in treatment, school, and social activities.⁷

Thanks to this team effort, Matthew graduates high school and is accepted at a small coastal college 1,500 miles from home.

Table 2

Keys to successful psychotherapy
for bipolar disorder

Build a strong treatment team and therapeutic alliance Educate patient on skills, stress vulnerability Enhance treatment compliance with frequent appointments, psychoeducation, and family involvement Induce a routine, such as by having patient write out a schedule or buy a day planner Perform CBT to decrease automatic depressive thoughts Teach patient to recognize and control prodromal manic symptoms Suggest behavioral techniques to reduce environmental stress, promote social adaptation Promote cognitive restructuring to help patient cope with thought disorder Teach coping strategies to enhance behavioral control Monitor high-risk situations, behaviors, and symptoms Teach internal and external coping mechanisms to prevent relapse

CBT: Cognitive-behavioral therapy

The authors’ observations

We continue to work with Matthew’s parents to help him handle college life. His parents identify prospective mental health professionals near the college; we interview them and provide Matthew’s history and treatment information. We communicate during school holidays, home visits, and by phone as needed with Matthew, his new therapist and psychiatrist, and his parents.

CONTINUED TREATMENT: THE ‘AWAY TEAM’

Together, Matthew’s home- and college-based treatment teams ensure treatment continuity. During school breaks, Matthew’s “home team” continues medication management and psychotherapy. Thanks to such persistent monitoring, Matthew finishes college in 4 years.

Medications and careless eating habits, however, have taken a severe metabolic toll. To help Matthew confront the added pressures of college, risperidone was gradually increased to 1 mg bid, divalproex to 1,000 mg each morning and 1,500 mg nightly, and clomipramine to 350 mg/d. By graduation day, he weighs 330 lbs with a body mass index of 40 kg². His triglycerides have more than doubled (141 mg/dL before college, 307 mg/dL after), and he has developed hypothyroidism. Total cholesterol is 247 mg/dL. His family doctor prescribes thyroid supplementation and atorvastatin, titrated to 40 mg/d.

To stem Matthew’s weight gain, we taper him off divalproex and switch him to topiramate, 100 mg nightly, but topiramate alone does not control his mood. Subsequent trials of quetiapine, 200 mg nightly, olanzapine, 20 mg nightly, and ziprasidone, 80 mg bid, are ineffective.

The authors’ observations

Matthew’s problem is common. He responded well to risperidone and divalproex, but these agents contributed to significant weight gain. Topiramate augmentation and trials of other atypical antipsychotics were unsuccessful. The atypical antipsychotic aripiprazole or anticonvulsant lamotrigine might have stabilized Matthew’s mood and weight, but these drugs were not available while he was in college. Dietary interventions were tried but are difficult to enforce on a college student living away from home.

CONCLUSION: A LEARNING EXPERIENCE

We stop divalproex and restart topiramate, 200 mg nightly. Matthew continues to take risperidone, 2 mg each morning and 5 mg at night; clomipramine, 150 mg each morning; thyroid supplementation, 0.2 mg/d; and atorvastatin, 40 mg/d. He loses 10 lbs over 3 months; his weight eventually drops to 290 lbs and remains stable.

Matthew enters another university to pursue a master’s degree. He shifts to a new college-based mental health team and moves into an apartment.

There are setbacks. Missed therapy appointments cause treatment lapses, and a teaching assistantship leads to problems managing schoolwork. Working with Matthew’s treatment team and his parents, we intervene to resolve crises, re-establish treatment, and help him resolve issues of identity, confidence, coping, and routine. With this persistent follow-up, he earns his master’s degree.

Now age 26, Matthew is pursuing a doctorate. He is taking more responsibility for his appointments and medication and is undertaking bill-paying and travel arrangements. With ongoing psychotherapy and mediation, Matthew regulates his mood and is learning to recognize prodromal symptoms and anticipate stress.⁸ He is more comfortable in social settings and has some friends and study partners, although he continues to deeply ponder philosophical and spiritual issues.

Related resources

• Miklowitz D. The bipolar disorder survival guide. New York: Guilford Press, 2002.
  
• Averill PM, Reas DL, Shack A, et al. Is schizoaffective disorder a stable diagnostic category: A retrospective examination. Psychiatr Q 2004;75:215-27.
  
• Bipolar focus (information, chat room for families and patients). www.moodswing.org.
  

Drug brand names

• Atorvastatin • Lipitor
  
• Clomipramine • Anafranil
  
• Dextroamphetamine • Dexedrine
  
• Divalproex • Depakote
  
• Fluoxetine • Prozac
  
• Methylphenidate • Concerta, Ritalin
  
• Olanzapine • Zyprexa
  
• Paroxetine • Paxil
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Topiramate • Topamax
  
• Ziprasidone • Geodon
  

 

Disclosure

Dr. Brownsmith receives research support from Pfizer Inc.

Dr. Lundt receives research support from and is a speaker for Eli Lilly and Co., Pfizer Inc., and GlaxoSmithKline, and receives research support from Ortho-McNeil Pharmaceutical.

HISTORY: THREE DIAGNOSES BY AGE 15

Matthew, age 17, has been hospitalized twice for psychiatric treatment. At school, he has no friends, is extremely energetic and volatile, and has paranoid delusional thoughts. At night, he becomes depressed over his inability to “fit in.”

Brilliant and deeply spiritual, Matthew obsesses over sins he believes he committed, yet he is angry with God over his illness, its impact on his life, and his apparently dimmed prospects for the future.

His troubles started early. While in preschool, a teacher said he had “autistic tendencies.” He was shy and larger than most children (>90th percentile in height and weight). He acquired language slowly, beginning at 18 months, and slept poorly, waking several times nightly.

Throughout grade school, Matthew was both bright and eccentric. His Wechsler Intelligence Scale for Children-III scores, taken at age 9, were 133 (full scale), 143 (verbal), and 111 (performance). By the third grade, he struggled with the meaning of the universe and other existential issues. In sixth grade, he believed his mouth stank and frequently used mouthwash, even at school. He also had periods of excessive hand-washing.

In fifth grade, a pediatrician diagnosed Matthew as having attention-deficit/hyperactivity disorder after his teacher complained about his behavior in class (blurting out answers, correcting the teacher, restlessness, questioning authority). The doctor prescribed methylphenidate and dextroamphetamine, but the combination made Matthew feel both “drugged and wired.” He stopped taking the agents after 8 weeks.

At age 15, Matthew saw a psychiatrist. His parents said he was depressed and obsessively afraid of being abandoned. Every day, they said, he kissed both parents twice on each cheek.

The psychiatrist diagnosed Matthew with obsessive-compulsive disorder. A trial of paroxetine, 20 mg/d, caused mild irritability with no symptom improvement. After 2 months, Matthew was switched to fluoxetine, initially 10 mg/d and increased to 20 mg/d, but after 6 weeks he suffered an acute manic episode. He claimed he was one with the universe and reported auditory hallucinations, intense suicidal thoughts, and sleeplessness for days on end.

Matthew was hospitalized for 7 days. Haloperidol, dosage unknown, decreased his psychosis but did not return him to baseline. The psychiatrist stopped fluoxetine because Matthew’s parents feared the antidepressant was causing his suicidality. No other agent was tried at this time.

The authors’ observations

Soon after Matthew began taking fluoxetine for apparent OCD and depressive symptoms, profound psychotic symptoms surfaced. These included command hallucinations, delusions, disordered and disorganized thought, high suicidality, motoric hyperarousal, and marked anxiety.

Although positive schizophrenia symptoms were predominant, mood and affect instability were also pronounced. The admitting psychiatrist diagnosed Matthew with schizoaffective disorder but did not include in the record the basis for this diagnosis.

Matthew’s OCD symptoms did not appear to derive from a delusional system or impaired reality testing. These symptoms were often associated with guilt and were consistent with other excessive behaviors.

HOSPITALIZATION: NEW DIAGNOSIS

Out of the hospital, Matthew’s ability to function declined over several months and he began to look disheveled and dirty. He was acutely suicidal, excessively guilty, isolative, and slept 1 to 2 hours nightly.

Matthew was again hospitalized, this time for 2 months. The psychiatrist revised the diagnosis to schizoaffective disorder, bipolar type, based on Matthew’s psychotic episodes, emerging positive symptoms, social withdrawal, and family history. (A male maternal cousin has paranoid schizophrenia.)

Risperidone, initially 0.5 mg nightly and titrated to 0.5 mg each morning and 1.5 mg nightly, gradually improved Matthew’s psychotic symptoms. The psychiatrist added divalproex, 250 mg bid titrated to 250 mg each morning, 250 mg at noon and 500 mg nightly, to address Matthew’s affective lability. After another 2 months of partial hospitalization, he was discharged. Thought disorder symptoms persisted, but reality testing was intact.

Back in high school, Matthew has gotten into a screaming match with the principal and heated political arguments with his teachers. He shows bursts of energy, agitation, and euphoria and is at times overdramatic and grandiose. His rapid-fire creativity easily shifts to irritability and paranoid delusional thinking punctuated by rage.

Almost nightly, Matthew sinks into depression. He also compulsively washes his hands, binge eats, has difficulty reading social cues and making conversation, and believes he is a “misfit.” He views Internet pornography to relieve sexual obsessions, but this habit leads to guilt-ridden ruminations that trigger suicidal thoughts.

For Matthew, high school’s pattern of alternating regimentation and intellectual stimulation constantly provokes mania. He sometimes disguises these episodes by playing “class clown,” only to sink into despair at night over his dyscontrol. His desperation causes frequent anxiety attacks. Searching for answers, Matthew changes psychiatrists and turns to us for help.

 

The authors’ observations

Matthew’s positive symptoms, bipolar presentation, and the severity and duration of his psychotic episodes supported the schizoaffective disorder diagnosis,¹ yet his cardinal type I bipolar disorder features were striking. His severe thought disorder and perceptual distortions improved, but rapid cycles between euphoria, rage, and depression persisted, as did shifts from hypersomnia to insomnia.

Matthew’s lack of negative symptoms prompted me (Dr. Lundt) to rethink the diagnosis. Though isolated from peers, Matthew remained affable throughout treatment and was emotionally attached to his parents and treating psychiatrist. He rarely appeared flat or blunted and showed no hostility or other signs of resistance typical of a patient with schizophrenia. He cooperated with treatment and showed insight into his illness, even at the height of his acute psychosis. His language was never significantly disorganized but his depression and obsessive guilt were chronic, dominant, and treatment-resistant. I learn over time that Matthew finds certain events highly stressful, and these exacerbate his psychotic features.

Matthew’s diagnosis—and how to address it—came down to two issues:

• Treatment would be similar for schizoaffective disorder or type I bipolar disorder with severe psychotic features.
  
• Matthew viewed schizoaffective disorder as a life sentence of insanity. Changing the diagnosis to type I bipolar disorder would allow him and his family to see a more manageable and hopeful prognosis.
  

Matthew grapples with typical adolescence issues: identity, peer relationships, social pressure, body image, and insecurity. Because he lacks the coping skills to navigate to adulthood, his depression and mood instability are clinical priorities.

In managing Matthew’s care, I refer him to a psychologist (Dr. Brownsmith) whose psychotherapeutic approach will depart significantly from traditional medical-model psychotherapy. Because bipolar and psychotic symptoms have stalled Matthew’s development, the psychologist will combine cognitive-behavioral therapy (CBT) with psychoeducation that emphasizes skills acquisition and coping techniques (Table 1). The goal is to convince Matthew that he can learn to manage his life.²

Table 1

Why psychoeducation can help
patients with bipolar disorder

50% of patients have frequent recurrences despite treatment 40% do not adhere to treatment, often because of lack of insight Mood and coping improve among patients receiving family-focused psychotherapy and family psychoeducation CBT combined with psychoeducation leads to:
Source: Adapted from references 2, 5.

TREATMENT: TEAM MEETINGS

Matthew begins individual psychotherapy with periodic family therapy and continued medication. Risperidone, 0.5 mg each morning and 1.5 mg nightly, and divalproex, 500 mg bid, have minimized Matthew’s psychosis and stabilized his mood but caused a 45-lb weight gain across 6 months. Matthew alternately joined professional weight-loss programs and worked with a personal trainer to stabilize his weight.

Because day-to-day intervention is critical to keeping Matthew’s anger from derailing his progress, we meet regularly—sometimes weekly—with him, his parents, and his school social worker to plan treatment and provide psychoeducation (Table 2).³

Throughout his senior year, Matthew’s sexual obsessions cause severe guilt, and he begs to be “chemically castrated.” Clomipramine, started at 25 mg nightly and titrated to 300 mg nightly over 2 years, diminishes his obsessions. ECGs are performed and clomipramine plasma levels are checked quarterly to guard against cardiotoxicity. Risperidone is continued and divalproex is gradually increased to 1,000 mg bid, ultimately reaching valproic acid levels of 79 μg/mL.

Through our therapeutic alliance and the change in diagnosis, we help Matthew gradually overcome his initial anger, resistance, despair, and suicidality. Drawing from research data while offering emotional support, we engage Matthew in a team therapy approach.

Matthew acknowledges his grief and anger at having a severe mental illness and agrees to learn to regulate his moods and participate in CBT. Responding with humor to his rapid-fire, manic discussions and animation helps solidify the alliance. We stay highly involved with his parents, often responding to their after-hours phone calls.

After approximately 9 months of CBT, Matthew sees his disordered thoughts and perceived loss of control as symptoms to be overcome.⁴ He adapts some of his fantasy life to replace his obsessive fear and anger. He develops highly creative, embellished visual imagery of a “safe place” in which he feels nurtured and protected. This imagery, coupled with relaxation exercises, is audiotaped so that he can practice at home.⁵ Psychoeducation and problem-solving help him dress appropriately and improve his hygiene.

Matthew’s intelligence and social awareness underlie strongly held values and opinions that fuel his anger. Media coverage of politicians, political debates in school, extreme religious views, and judgmental statements about sexuality frequently provoke rage. (Matthew once battered a street preacher who was decrying homosexuality.) By acquiring anger management strategies, he learns to avoid potentially volatile situations.⁶

 

Frequent crisis intervention keeps Matthew stable, while family therapy helps him follow his psychologist’s plan to maintain medication adherence and manage his circadian rhythms, activities of daily living, and CBT. His parents prompt him to use therapeutic techniques, support him during crises, and make sure he has the structure and support to participate in treatment, school, and social activities.⁷

Thanks to this team effort, Matthew graduates high school and is accepted at a small coastal college 1,500 miles from home.

Table 2

Keys to successful psychotherapy
for bipolar disorder

Build a strong treatment team and therapeutic alliance Educate patient on skills, stress vulnerability Enhance treatment compliance with frequent appointments, psychoeducation, and family involvement Induce a routine, such as by having patient write out a schedule or buy a day planner Perform CBT to decrease automatic depressive thoughts Teach patient to recognize and control prodromal manic symptoms Suggest behavioral techniques to reduce environmental stress, promote social adaptation Promote cognitive restructuring to help patient cope with thought disorder Teach coping strategies to enhance behavioral control Monitor high-risk situations, behaviors, and symptoms Teach internal and external coping mechanisms to prevent relapse

CBT: Cognitive-behavioral therapy

The authors’ observations

We continue to work with Matthew’s parents to help him handle college life. His parents identify prospective mental health professionals near the college; we interview them and provide Matthew’s history and treatment information. We communicate during school holidays, home visits, and by phone as needed with Matthew, his new therapist and psychiatrist, and his parents.

CONTINUED TREATMENT: THE ‘AWAY TEAM’

Together, Matthew’s home- and college-based treatment teams ensure treatment continuity. During school breaks, Matthew’s “home team” continues medication management and psychotherapy. Thanks to such persistent monitoring, Matthew finishes college in 4 years.

Medications and careless eating habits, however, have taken a severe metabolic toll. To help Matthew confront the added pressures of college, risperidone was gradually increased to 1 mg bid, divalproex to 1,000 mg each morning and 1,500 mg nightly, and clomipramine to 350 mg/d. By graduation day, he weighs 330 lbs with a body mass index of 40 kg². His triglycerides have more than doubled (141 mg/dL before college, 307 mg/dL after), and he has developed hypothyroidism. Total cholesterol is 247 mg/dL. His family doctor prescribes thyroid supplementation and atorvastatin, titrated to 40 mg/d.

To stem Matthew’s weight gain, we taper him off divalproex and switch him to topiramate, 100 mg nightly, but topiramate alone does not control his mood. Subsequent trials of quetiapine, 200 mg nightly, olanzapine, 20 mg nightly, and ziprasidone, 80 mg bid, are ineffective.

The authors’ observations

Matthew’s problem is common. He responded well to risperidone and divalproex, but these agents contributed to significant weight gain. Topiramate augmentation and trials of other atypical antipsychotics were unsuccessful. The atypical antipsychotic aripiprazole or anticonvulsant lamotrigine might have stabilized Matthew’s mood and weight, but these drugs were not available while he was in college. Dietary interventions were tried but are difficult to enforce on a college student living away from home.

CONCLUSION: A LEARNING EXPERIENCE

We stop divalproex and restart topiramate, 200 mg nightly. Matthew continues to take risperidone, 2 mg each morning and 5 mg at night; clomipramine, 150 mg each morning; thyroid supplementation, 0.2 mg/d; and atorvastatin, 40 mg/d. He loses 10 lbs over 3 months; his weight eventually drops to 290 lbs and remains stable.

Matthew enters another university to pursue a master’s degree. He shifts to a new college-based mental health team and moves into an apartment.

There are setbacks. Missed therapy appointments cause treatment lapses, and a teaching assistantship leads to problems managing schoolwork. Working with Matthew’s treatment team and his parents, we intervene to resolve crises, re-establish treatment, and help him resolve issues of identity, confidence, coping, and routine. With this persistent follow-up, he earns his master’s degree.

Now age 26, Matthew is pursuing a doctorate. He is taking more responsibility for his appointments and medication and is undertaking bill-paying and travel arrangements. With ongoing psychotherapy and mediation, Matthew regulates his mood and is learning to recognize prodromal symptoms and anticipate stress.⁸ He is more comfortable in social settings and has some friends and study partners, although he continues to deeply ponder philosophical and spiritual issues.

Related resources

• Miklowitz D. The bipolar disorder survival guide. New York: Guilford Press, 2002.
  
• Averill PM, Reas DL, Shack A, et al. Is schizoaffective disorder a stable diagnostic category: A retrospective examination. Psychiatr Q 2004;75:215-27.
  
• Bipolar focus (information, chat room for families and patients). www.moodswing.org.
  

Drug brand names

• Atorvastatin • Lipitor
  
• Clomipramine • Anafranil
  
• Dextroamphetamine • Dexedrine
  
• Divalproex • Depakote
  
• Fluoxetine • Prozac
  
• Methylphenidate • Concerta, Ritalin
  
• Olanzapine • Zyprexa
  
• Paroxetine • Paxil
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Topiramate • Topamax
  
• Ziprasidone • Geodon
  

 

Disclosure

Dr. Brownsmith receives research support from Pfizer Inc.

Dr. Lundt receives research support from and is a speaker for Eli Lilly and Co., Pfizer Inc., and GlaxoSmithKline, and receives research support from Ortho-McNeil Pharmaceutical.

HISTORY: THREE DIAGNOSES BY AGE 15

Matthew, age 17, has been hospitalized twice for psychiatric treatment. At school, he has no friends, is extremely energetic and volatile, and has paranoid delusional thoughts. At night, he becomes depressed over his inability to “fit in.”

Brilliant and deeply spiritual, Matthew obsesses over sins he believes he committed, yet he is angry with God over his illness, its impact on his life, and his apparently dimmed prospects for the future.

His troubles started early. While in preschool, a teacher said he had “autistic tendencies.” He was shy and larger than most children (>90th percentile in height and weight). He acquired language slowly, beginning at 18 months, and slept poorly, waking several times nightly.

Throughout grade school, Matthew was both bright and eccentric. His Wechsler Intelligence Scale for Children-III scores, taken at age 9, were 133 (full scale), 143 (verbal), and 111 (performance). By the third grade, he struggled with the meaning of the universe and other existential issues. In sixth grade, he believed his mouth stank and frequently used mouthwash, even at school. He also had periods of excessive hand-washing.

In fifth grade, a pediatrician diagnosed Matthew as having attention-deficit/hyperactivity disorder after his teacher complained about his behavior in class (blurting out answers, correcting the teacher, restlessness, questioning authority). The doctor prescribed methylphenidate and dextroamphetamine, but the combination made Matthew feel both “drugged and wired.” He stopped taking the agents after 8 weeks.

At age 15, Matthew saw a psychiatrist. His parents said he was depressed and obsessively afraid of being abandoned. Every day, they said, he kissed both parents twice on each cheek.

The psychiatrist diagnosed Matthew with obsessive-compulsive disorder. A trial of paroxetine, 20 mg/d, caused mild irritability with no symptom improvement. After 2 months, Matthew was switched to fluoxetine, initially 10 mg/d and increased to 20 mg/d, but after 6 weeks he suffered an acute manic episode. He claimed he was one with the universe and reported auditory hallucinations, intense suicidal thoughts, and sleeplessness for days on end.

Matthew was hospitalized for 7 days. Haloperidol, dosage unknown, decreased his psychosis but did not return him to baseline. The psychiatrist stopped fluoxetine because Matthew’s parents feared the antidepressant was causing his suicidality. No other agent was tried at this time.

The authors’ observations

Soon after Matthew began taking fluoxetine for apparent OCD and depressive symptoms, profound psychotic symptoms surfaced. These included command hallucinations, delusions, disordered and disorganized thought, high suicidality, motoric hyperarousal, and marked anxiety.

Although positive schizophrenia symptoms were predominant, mood and affect instability were also pronounced. The admitting psychiatrist diagnosed Matthew with schizoaffective disorder but did not include in the record the basis for this diagnosis.

Matthew’s OCD symptoms did not appear to derive from a delusional system or impaired reality testing. These symptoms were often associated with guilt and were consistent with other excessive behaviors.

HOSPITALIZATION: NEW DIAGNOSIS

Out of the hospital, Matthew’s ability to function declined over several months and he began to look disheveled and dirty. He was acutely suicidal, excessively guilty, isolative, and slept 1 to 2 hours nightly.

Matthew was again hospitalized, this time for 2 months. The psychiatrist revised the diagnosis to schizoaffective disorder, bipolar type, based on Matthew’s psychotic episodes, emerging positive symptoms, social withdrawal, and family history. (A male maternal cousin has paranoid schizophrenia.)

Risperidone, initially 0.5 mg nightly and titrated to 0.5 mg each morning and 1.5 mg nightly, gradually improved Matthew’s psychotic symptoms. The psychiatrist added divalproex, 250 mg bid titrated to 250 mg each morning, 250 mg at noon and 500 mg nightly, to address Matthew’s affective lability. After another 2 months of partial hospitalization, he was discharged. Thought disorder symptoms persisted, but reality testing was intact.

Back in high school, Matthew has gotten into a screaming match with the principal and heated political arguments with his teachers. He shows bursts of energy, agitation, and euphoria and is at times overdramatic and grandiose. His rapid-fire creativity easily shifts to irritability and paranoid delusional thinking punctuated by rage.

Almost nightly, Matthew sinks into depression. He also compulsively washes his hands, binge eats, has difficulty reading social cues and making conversation, and believes he is a “misfit.” He views Internet pornography to relieve sexual obsessions, but this habit leads to guilt-ridden ruminations that trigger suicidal thoughts.

For Matthew, high school’s pattern of alternating regimentation and intellectual stimulation constantly provokes mania. He sometimes disguises these episodes by playing “class clown,” only to sink into despair at night over his dyscontrol. His desperation causes frequent anxiety attacks. Searching for answers, Matthew changes psychiatrists and turns to us for help.

 

The authors’ observations

Matthew’s positive symptoms, bipolar presentation, and the severity and duration of his psychotic episodes supported the schizoaffective disorder diagnosis,¹ yet his cardinal type I bipolar disorder features were striking. His severe thought disorder and perceptual distortions improved, but rapid cycles between euphoria, rage, and depression persisted, as did shifts from hypersomnia to insomnia.

Matthew’s lack of negative symptoms prompted me (Dr. Lundt) to rethink the diagnosis. Though isolated from peers, Matthew remained affable throughout treatment and was emotionally attached to his parents and treating psychiatrist. He rarely appeared flat or blunted and showed no hostility or other signs of resistance typical of a patient with schizophrenia. He cooperated with treatment and showed insight into his illness, even at the height of his acute psychosis. His language was never significantly disorganized but his depression and obsessive guilt were chronic, dominant, and treatment-resistant. I learn over time that Matthew finds certain events highly stressful, and these exacerbate his psychotic features.

Matthew’s diagnosis—and how to address it—came down to two issues:

• Treatment would be similar for schizoaffective disorder or type I bipolar disorder with severe psychotic features.
  
• Matthew viewed schizoaffective disorder as a life sentence of insanity. Changing the diagnosis to type I bipolar disorder would allow him and his family to see a more manageable and hopeful prognosis.
  

Matthew grapples with typical adolescence issues: identity, peer relationships, social pressure, body image, and insecurity. Because he lacks the coping skills to navigate to adulthood, his depression and mood instability are clinical priorities.

In managing Matthew’s care, I refer him to a psychologist (Dr. Brownsmith) whose psychotherapeutic approach will depart significantly from traditional medical-model psychotherapy. Because bipolar and psychotic symptoms have stalled Matthew’s development, the psychologist will combine cognitive-behavioral therapy (CBT) with psychoeducation that emphasizes skills acquisition and coping techniques (Table 1). The goal is to convince Matthew that he can learn to manage his life.²

Table 1

Why psychoeducation can help
patients with bipolar disorder

50% of patients have frequent recurrences despite treatment 40% do not adhere to treatment, often because of lack of insight Mood and coping improve among patients receiving family-focused psychotherapy and family psychoeducation CBT combined with psychoeducation leads to:
Source: Adapted from references 2, 5.

TREATMENT: TEAM MEETINGS

Matthew begins individual psychotherapy with periodic family therapy and continued medication. Risperidone, 0.5 mg each morning and 1.5 mg nightly, and divalproex, 500 mg bid, have minimized Matthew’s psychosis and stabilized his mood but caused a 45-lb weight gain across 6 months. Matthew alternately joined professional weight-loss programs and worked with a personal trainer to stabilize his weight.

Because day-to-day intervention is critical to keeping Matthew’s anger from derailing his progress, we meet regularly—sometimes weekly—with him, his parents, and his school social worker to plan treatment and provide psychoeducation (Table 2).³

Throughout his senior year, Matthew’s sexual obsessions cause severe guilt, and he begs to be “chemically castrated.” Clomipramine, started at 25 mg nightly and titrated to 300 mg nightly over 2 years, diminishes his obsessions. ECGs are performed and clomipramine plasma levels are checked quarterly to guard against cardiotoxicity. Risperidone is continued and divalproex is gradually increased to 1,000 mg bid, ultimately reaching valproic acid levels of 79 μg/mL.

Through our therapeutic alliance and the change in diagnosis, we help Matthew gradually overcome his initial anger, resistance, despair, and suicidality. Drawing from research data while offering emotional support, we engage Matthew in a team therapy approach.

Matthew acknowledges his grief and anger at having a severe mental illness and agrees to learn to regulate his moods and participate in CBT. Responding with humor to his rapid-fire, manic discussions and animation helps solidify the alliance. We stay highly involved with his parents, often responding to their after-hours phone calls.

After approximately 9 months of CBT, Matthew sees his disordered thoughts and perceived loss of control as symptoms to be overcome.⁴ He adapts some of his fantasy life to replace his obsessive fear and anger. He develops highly creative, embellished visual imagery of a “safe place” in which he feels nurtured and protected. This imagery, coupled with relaxation exercises, is audiotaped so that he can practice at home.⁵ Psychoeducation and problem-solving help him dress appropriately and improve his hygiene.

Matthew’s intelligence and social awareness underlie strongly held values and opinions that fuel his anger. Media coverage of politicians, political debates in school, extreme religious views, and judgmental statements about sexuality frequently provoke rage. (Matthew once battered a street preacher who was decrying homosexuality.) By acquiring anger management strategies, he learns to avoid potentially volatile situations.⁶

 

Frequent crisis intervention keeps Matthew stable, while family therapy helps him follow his psychologist’s plan to maintain medication adherence and manage his circadian rhythms, activities of daily living, and CBT. His parents prompt him to use therapeutic techniques, support him during crises, and make sure he has the structure and support to participate in treatment, school, and social activities.⁷

Thanks to this team effort, Matthew graduates high school and is accepted at a small coastal college 1,500 miles from home.

Table 2

Keys to successful psychotherapy
for bipolar disorder

Build a strong treatment team and therapeutic alliance Educate patient on skills, stress vulnerability Enhance treatment compliance with frequent appointments, psychoeducation, and family involvement Induce a routine, such as by having patient write out a schedule or buy a day planner Perform CBT to decrease automatic depressive thoughts Teach patient to recognize and control prodromal manic symptoms Suggest behavioral techniques to reduce environmental stress, promote social adaptation Promote cognitive restructuring to help patient cope with thought disorder Teach coping strategies to enhance behavioral control Monitor high-risk situations, behaviors, and symptoms Teach internal and external coping mechanisms to prevent relapse

CBT: Cognitive-behavioral therapy

The authors’ observations

We continue to work with Matthew’s parents to help him handle college life. His parents identify prospective mental health professionals near the college; we interview them and provide Matthew’s history and treatment information. We communicate during school holidays, home visits, and by phone as needed with Matthew, his new therapist and psychiatrist, and his parents.

CONTINUED TREATMENT: THE ‘AWAY TEAM’

Together, Matthew’s home- and college-based treatment teams ensure treatment continuity. During school breaks, Matthew’s “home team” continues medication management and psychotherapy. Thanks to such persistent monitoring, Matthew finishes college in 4 years.

Medications and careless eating habits, however, have taken a severe metabolic toll. To help Matthew confront the added pressures of college, risperidone was gradually increased to 1 mg bid, divalproex to 1,000 mg each morning and 1,500 mg nightly, and clomipramine to 350 mg/d. By graduation day, he weighs 330 lbs with a body mass index of 40 kg². His triglycerides have more than doubled (141 mg/dL before college, 307 mg/dL after), and he has developed hypothyroidism. Total cholesterol is 247 mg/dL. His family doctor prescribes thyroid supplementation and atorvastatin, titrated to 40 mg/d.

To stem Matthew’s weight gain, we taper him off divalproex and switch him to topiramate, 100 mg nightly, but topiramate alone does not control his mood. Subsequent trials of quetiapine, 200 mg nightly, olanzapine, 20 mg nightly, and ziprasidone, 80 mg bid, are ineffective.

The authors’ observations

Matthew’s problem is common. He responded well to risperidone and divalproex, but these agents contributed to significant weight gain. Topiramate augmentation and trials of other atypical antipsychotics were unsuccessful. The atypical antipsychotic aripiprazole or anticonvulsant lamotrigine might have stabilized Matthew’s mood and weight, but these drugs were not available while he was in college. Dietary interventions were tried but are difficult to enforce on a college student living away from home.

CONCLUSION: A LEARNING EXPERIENCE

We stop divalproex and restart topiramate, 200 mg nightly. Matthew continues to take risperidone, 2 mg each morning and 5 mg at night; clomipramine, 150 mg each morning; thyroid supplementation, 0.2 mg/d; and atorvastatin, 40 mg/d. He loses 10 lbs over 3 months; his weight eventually drops to 290 lbs and remains stable.

Matthew enters another university to pursue a master’s degree. He shifts to a new college-based mental health team and moves into an apartment.

There are setbacks. Missed therapy appointments cause treatment lapses, and a teaching assistantship leads to problems managing schoolwork. Working with Matthew’s treatment team and his parents, we intervene to resolve crises, re-establish treatment, and help him resolve issues of identity, confidence, coping, and routine. With this persistent follow-up, he earns his master’s degree.

Now age 26, Matthew is pursuing a doctorate. He is taking more responsibility for his appointments and medication and is undertaking bill-paying and travel arrangements. With ongoing psychotherapy and mediation, Matthew regulates his mood and is learning to recognize prodromal symptoms and anticipate stress.⁸ He is more comfortable in social settings and has some friends and study partners, although he continues to deeply ponder philosophical and spiritual issues.

Related resources

• Miklowitz D. The bipolar disorder survival guide. New York: Guilford Press, 2002.
  
• Averill PM, Reas DL, Shack A, et al. Is schizoaffective disorder a stable diagnostic category: A retrospective examination. Psychiatr Q 2004;75:215-27.
  
• Bipolar focus (information, chat room for families and patients). www.moodswing.org.
  

Drug brand names

• Atorvastatin • Lipitor
  
• Clomipramine • Anafranil
  
• Dextroamphetamine • Dexedrine
  
• Divalproex • Depakote
  
• Fluoxetine • Prozac
  
• Methylphenidate • Concerta, Ritalin
  
• Olanzapine • Zyprexa
  
• Paroxetine • Paxil
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Topiramate • Topamax
  
• Ziprasidone • Geodon
  

 

Disclosure

Dr. Brownsmith receives research support from Pfizer Inc.

Dr. Lundt receives research support from and is a speaker for Eli Lilly and Co., Pfizer Inc., and GlaxoSmithKline, and receives research support from Ortho-McNeil Pharmaceutical.

HISTORY: ‘THEY’RE TRYING TO KILL ME’

For the past 7 months Ms. G, age 47, has had worsening paranoid thoughts and sleep disturbances. She sleeps 4 hours or less a night, and her appetite and energy are diminished.

Her mother reports that Ms. G, who lives in an extended-care facility, believes the staff has injected embalming fluid into her body and is plotting to kill her. She says her daughter also has “fits” during which she hears a deafening noise that sounds like a vacuum cleaner, followed by a feeling of being pushed to the ground. Ms. G tells us that someone or something invisible is trying to control her.

Ms. G was diagnosed 2 years ago as having Parkinson’s disease and has chronically high liver transaminase enzymes. She also has moderate mental retardation secondary to cerebral palsy. She fears she will be harmed if she stays at the extendedcare facility, but we find no evidence that she has been abused or mistreated there.

Three months before presenting to us, Ms. G was hospitalized for 3 days to treat symptoms that suggested neuroleptic malignant syndrome (NMS) but were apparently caused by her inadvertently stopping her antiparkinson agents.

One month later, Ms. G was hospitalized again, this time for acute psychosis. Quetiapine, which she had been taking for antiparkinson medication-induced psychosis, was increased from 100 mg nightly to 75 mg bid, with reportedly good effect.

Shortly afterward, however, Ms. G’s paranoia worsened. At the facility, she has called 911 several times to report imagined threats from staff members. After referral from her primary care physician, we evaluate Ms. G and admit her to the adult inpatient psychiatric unit.

At intake, Ms. G is anxious and uncomfortable with notable muscle spasticity and twitching of her arms and legs. Mostly wheelchair-bound, she has longstanding physical abnormalities (shuffling gait; dystonia; drooling; slowed, dysarthric speech) secondary to comorbid Parkinson’s and cerebral palsy. She is agitated at first but grows calmer and cooperative.

Mental status examination shows a disorganized, tangential thought process and evidence of paranoid delusions and auditory hallucinations, but she denies visual hallucinations. She has poor insight into her illness but is oriented to time, place, and person. She can recall two of three objects after 3 minutes of distraction. Attention and concentration are intact.

Ms. G denies depressed mood, anhedonia, mania, or suicidal or homicidal thoughts. Her mother says no stressors other than the imagined threats to her life have affected her daughter.

The patient ’s temperature at admission is 98.0°F, her pulse is 108 beats per minute, and her blood pressure is 150/88 mm Hg. Laboratory workup shows a white blood cell count of 10,100/mm³ (normal range: 4,000 to 10,000/mm³), sodium level of 132 mEq/L (normal range: 135 to 145 mEq/L), and aspartate (AST) and alanine (ALT) transaminase levels of 611 U/L and 79 U/L, respectively (normal range for each: 0 to 35 U/L).

Aside from quetiapine, Ms. G also has been taking carbidopa/levodopa, seven 25/100-mg tablets daily, and pramipexole, 3 mg/d, for parkinsonism; citalopram, 20 mg/d, for depression; trazodone, 300 mg nightly, and lorazepam, 0.5 mg nightly, for insomnia; lopressor, 25 mg every 12 hours, for hypertension; and tolterodine, 1 mg bid, for urinary incontinence.

The authors’ observations

Parkinsonism typically responds to dopaminergic treatment. Excess dopamine agonism is believed to contribute to medication-induced psychosis, a common and often disabling complication of Parkinson’s disease^1,2 that often necessitates nursing home placement and may increase mortality.^2,3

Paranoia occurs in approximately 8% of patients treated for drug-induced Parkinson’s psychosis, and hallucinations (typically visual) may occur in as many as 30%.² Quetiapine, 50 to 225 mg/d, is considered a good first-line treatment for psychosis in Parkinson’s, although the agent has been tested for this use only in open-label trials.^2,3

Mental retardation and pre-existing parkinsonism, however, may increase Ms. G’s risk for NMS, a rare but potentially fatal reaction to antipsychotics believed to be caused by a sudden D₂ dopamine receptor blockade.^4,5 Signs include autonomic instability, extrapyramidal symptoms, hyperpyrexia, and altered mental status.

Of 68 patients with NMS studied by Ananth et al,⁴ 13.2% were mentally retarded, and uncontrolled studies⁶ have proposed mental retardation as a potential risk factor (Table 1). A 2003 case control study⁶ found a higher incidence of NMS among mentally retarded patients than among nonretarded persons, but the difference was not statistically significant. There are no known links between specific causes of mental retardation and NMS.

Even so, Ms. G’s psychosis is compromising her already diminished quality of life. We will increase her quetiapine dosage slightly and watch for early signs of NMS, including fever, confusion, and increased muscle rigidity.

 

Table 1

Factors that increase risk of neuroleptic malignant syndrome*

Abrupt antipsychotic cessation
Ambient heat
Catatonia
Dehydration
Exhaustion
Genetic predisposition
Greater dosage increases
Higher neuroleptic doses, especially with typical and atypical IM agents
Low serum iron
Malnutrition
Mental retardation
Pre-existing EPS or parkinsonism
Previous NMS episode
Psychomotor agitation
* Infection or concurrent organic brain disease are predisposing factors, but their association with NMS is less clear.
EPS: extrapyramidal symptoms
Source: References: 4-7, 14-15.

TREATMENT: MEDICATION CHANGE

Upon admission, quetiapine is increased to 75 mg in the morning and 125 mg at bedtime—still well below the dosage at which quetiapine increases the risk of NMS (Table 2). Trazodone is decreased to 100 mg/d because of quetiapine’s sedating properties. Citalopram and tolterodine are stopped for fear that either agent would aggravate her psychosis. We continue all other drugs as previously prescribed. Her paranoia begins to subside.

Three days later, Ms. G’s is increasingly confused and agitated, and her temperature rises to 101.3°F. Physical exam shows increased muscle rigidity. She is given lorazepam, 1 mg, and transferred to the emergency room for evaluation.

In the ER, Ms. G’s temperature rises to 102.3°F. Other vital signs include:

• heart rate, 112 to 120 beats per minute
  
• respiratory rate, 18 to 20 breaths per minute
  
• oxygen saturation, 98% in room air
  
• blood pressure, 131/61 mm Hg while seated and 92/58 mm Hg while standing.
  

We suspect NMS based on her dry mucous membranes, tachycardic but otherwise normal heart, and hand and foot rigidity. Creatine kinase (CK) measured after ER admission is 11,500 U/L, well above the typically elevated levels for a patient with Parkinson’s.⁸ Also, Ms. G is alert to her name only.

CNS or systemic infection and myocardial infarction are considered less likely because of her reactive pupils, lack of nuchal rigidity, troponin 3. Additionally, CSF shows normal glucose and protein levels, ALT and AST are 217 and 261 U/L, respectively, and chest x-ray shows no acute cardiopulmonary abnormality.

Ms. G is admitted to the medical intensive care unit and given IV fluids. All psychotropic and antiparkinson medications are stopped for 12 hours. Ms. G is then transferred to the general medical service for continued observation and IV hydration.

Six hours later, lorazepam, 0.5 mg every 8 hours, is resumed to control Ms. G’s anxiety. Carbidopa/levodopa is resumed at the previous dosage; all other medications remain on hold.

Renal damage is not apparent, but repeat chest x-ray taken 2 days after admission to the ER shows right middle lobe pneumonia, which resolved with antibiotics.

Six days after entering the medical unit, Ms. G is no longer agitated or paranoid. She is discharged that day and continued on lorazepam, 1 mg every 8 hours as needed to control her anxiety and prevent paranoia, and carbidopa/levidopa 8-¹/₂ 25/100-mg tablets daily for her parkinsonism. Trazodone, 100 mg nightly, is continued for 3 days to help her sleep, as is amoxicillin/clavulanate, 500 mg every 8 hours, in case an underlying infection exists. Quetiapine, citalopram, and tolterodine are discontinued; all other medications are resumed as previously prescribed.

Table 2

Antipsychotic-related NMS risk increases at these dosages

Agent	Dosage (mg/d)
Aripiprazole	>30
Chlorpromazine	>400
Clozapine	318+/-299
Olanzapine	9.7+/-2.3
Quetiapine	412.5+/-317
Risperidone	4.3+/-3.1
Ziprasidone	>20
Source: References 4, 6, and 15.

The authors’ observations

Ms. G’s NMS symptoms surfaced 3 days after her quetiapine dosage was increased, suggesting that the antipsychotic may have caused this episode.

We ruled out antiparkinson agent withdrawal malignant syndrome—usually caused by abrupt cessation of Parkinson’s medications. Ms. G’s carbidopa/levodopa had not been adjusted before the symptoms emerged, and she did not worsen after the agent was stopped temporarily. Her brief pneumonia episode, however, could have caused symptoms that mimicked this withdrawal syndrome.

Antiparkinson agent withdrawal malignant syndrome symptoms resemble those of NMS.^9,10 Worsening parkinsonism, dehydration, and infection increase the risk.¹⁰ Some research suggests that leukocytosis or elevated inflammation-related cytokines may accelerate withdrawal syndrome.¹⁰

The authors’ observations

Ms. G’s case illustrates the difficulty of treating psychosis in a patient at risk for NMS.

Of the 68 patients in the Ananth et al study with atypical antipsychotic-induced NMS, 11 were rechallenged after an NMS episode with the same agent and 8 were switched to another atypical. NMS recurred in 4 of these 19 patients.⁴

Ms. G was stable on lorazepam at discharge, but we would consider rechallenging with quetiapine or another antipsychotic if necessary. NMS recurs in 30% to 50%¹¹ of patients after antipsychotic rechallenge, but waiting 2 weeks to resume antipsychotic therapy appears to reduce this risk.¹² Benzodiazepines and electroconvulsive therapy are acceptable—though unproven—second-line therapies if antipsychotic rechallenge is deemed too risky,^11,13 such as in some patients with a previous severe NMS episode; evidence of stroke, Parkinson’s or other neurodegenerative disease; or multiple acute medical problems.

 

CONTINUED TREATMENT: A RELAPSE

Three months later, Ms. G is readmitted to the neurology service for 3 weeks after being diagnosed with elevated CK, possibly caused by NMS or rhabdomyolysis secondary to persistent dyskinesia. We believe an inadvertent decrease in her carbidopa/levodopa caused the episode, as she had taken no neuroleptics between hospitalizations.

Ms. G is discharged on quetiapine, 25 mg nightly, along with her other medications. Her current psychiatric and neurologic status is unknown.

The authors’ observations

Detecting NMS symptoms early is critical to preventing mortality. Although NMS risk with atypical and typical antipsychotics is similar,⁴ fewer deaths from NMS have been reported after use of atypicals (3 deaths among 68 cases) than typical neuroleptics (30% mortality rate in the 1960s and 70s, and 10% mortality from 1980-87).¹⁴ Earlier recognition and treatment may be decreasing NMS-related mortality.⁴

Consider NMS in the differential diagnosis when the patient’s mental status changes.

Related resources

• Emedicine: Neuroleptic malignant syndrome. www.emedicine.com/med/topic2614.htm.
  
• Bhanushali MJ, Tuite PJ. The evaluation and management of patients with neuroleptic malignant syndrome. Neurol Clin 2004;22:389-411.
  
• Susman VL. Clinical management of neuroleptic malignant syndrome. Psychiatr Q 2001;72:325-36.
  

Drug brand names

• Amoxicillin/clavulanate • Augmentin
  
• Aripiprazole • Abilify
  
• Carbidopa/levodopa • Sinemet
  
• Chlorpromazine • Thorazine
  
• Citalopram • Celexa
  
• Clozapine • Clozaril
  
• Lopressor • Toprol
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Pramipexole • Mirapex
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Tolterodine • Detrol
  
• Trazodone • Desyrel
  
• Ziprasidone • Geodon
  

Disclosure

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

Acknowledgments

The authors wish to thank Robert B. Milstein, MD, PhD, and Benjamin Zigun, MD, JD, for their help in preparing this article for publication.

This project is supported by funds from the Division of State, Community, and Public Health, Bureau of Health Professions (BHPr), Health Resources and Services Administration (HSRA), Department of Health and Human Services (DHHS) under grant number 1 K01 HP 00071-02 and Geriatric Academic Career Award ($58,009). The content and conclusion are those of Dr. Tampi and are not the official position or policy of, nor should be any endorsements be inferred by, the Bureau of Health Professions, HRSA, DHHS or the United States Government.

HISTORY: ‘THEY’RE TRYING TO KILL ME’

For the past 7 months Ms. G, age 47, has had worsening paranoid thoughts and sleep disturbances. She sleeps 4 hours or less a night, and her appetite and energy are diminished.

Her mother reports that Ms. G, who lives in an extended-care facility, believes the staff has injected embalming fluid into her body and is plotting to kill her. She says her daughter also has “fits” during which she hears a deafening noise that sounds like a vacuum cleaner, followed by a feeling of being pushed to the ground. Ms. G tells us that someone or something invisible is trying to control her.

Ms. G was diagnosed 2 years ago as having Parkinson’s disease and has chronically high liver transaminase enzymes. She also has moderate mental retardation secondary to cerebral palsy. She fears she will be harmed if she stays at the extendedcare facility, but we find no evidence that she has been abused or mistreated there.

Three months before presenting to us, Ms. G was hospitalized for 3 days to treat symptoms that suggested neuroleptic malignant syndrome (NMS) but were apparently caused by her inadvertently stopping her antiparkinson agents.

One month later, Ms. G was hospitalized again, this time for acute psychosis. Quetiapine, which she had been taking for antiparkinson medication-induced psychosis, was increased from 100 mg nightly to 75 mg bid, with reportedly good effect.

Shortly afterward, however, Ms. G’s paranoia worsened. At the facility, she has called 911 several times to report imagined threats from staff members. After referral from her primary care physician, we evaluate Ms. G and admit her to the adult inpatient psychiatric unit.

At intake, Ms. G is anxious and uncomfortable with notable muscle spasticity and twitching of her arms and legs. Mostly wheelchair-bound, she has longstanding physical abnormalities (shuffling gait; dystonia; drooling; slowed, dysarthric speech) secondary to comorbid Parkinson’s and cerebral palsy. She is agitated at first but grows calmer and cooperative.

Mental status examination shows a disorganized, tangential thought process and evidence of paranoid delusions and auditory hallucinations, but she denies visual hallucinations. She has poor insight into her illness but is oriented to time, place, and person. She can recall two of three objects after 3 minutes of distraction. Attention and concentration are intact.

Ms. G denies depressed mood, anhedonia, mania, or suicidal or homicidal thoughts. Her mother says no stressors other than the imagined threats to her life have affected her daughter.

The patient ’s temperature at admission is 98.0°F, her pulse is 108 beats per minute, and her blood pressure is 150/88 mm Hg. Laboratory workup shows a white blood cell count of 10,100/mm³ (normal range: 4,000 to 10,000/mm³), sodium level of 132 mEq/L (normal range: 135 to 145 mEq/L), and aspartate (AST) and alanine (ALT) transaminase levels of 611 U/L and 79 U/L, respectively (normal range for each: 0 to 35 U/L).

Aside from quetiapine, Ms. G also has been taking carbidopa/levodopa, seven 25/100-mg tablets daily, and pramipexole, 3 mg/d, for parkinsonism; citalopram, 20 mg/d, for depression; trazodone, 300 mg nightly, and lorazepam, 0.5 mg nightly, for insomnia; lopressor, 25 mg every 12 hours, for hypertension; and tolterodine, 1 mg bid, for urinary incontinence.

The authors’ observations

Parkinsonism typically responds to dopaminergic treatment. Excess dopamine agonism is believed to contribute to medication-induced psychosis, a common and often disabling complication of Parkinson’s disease^1,2 that often necessitates nursing home placement and may increase mortality.^2,3

Paranoia occurs in approximately 8% of patients treated for drug-induced Parkinson’s psychosis, and hallucinations (typically visual) may occur in as many as 30%.² Quetiapine, 50 to 225 mg/d, is considered a good first-line treatment for psychosis in Parkinson’s, although the agent has been tested for this use only in open-label trials.^2,3

Mental retardation and pre-existing parkinsonism, however, may increase Ms. G’s risk for NMS, a rare but potentially fatal reaction to antipsychotics believed to be caused by a sudden D₂ dopamine receptor blockade.^4,5 Signs include autonomic instability, extrapyramidal symptoms, hyperpyrexia, and altered mental status.

Of 68 patients with NMS studied by Ananth et al,⁴ 13.2% were mentally retarded, and uncontrolled studies⁶ have proposed mental retardation as a potential risk factor (Table 1). A 2003 case control study⁶ found a higher incidence of NMS among mentally retarded patients than among nonretarded persons, but the difference was not statistically significant. There are no known links between specific causes of mental retardation and NMS.

Even so, Ms. G’s psychosis is compromising her already diminished quality of life. We will increase her quetiapine dosage slightly and watch for early signs of NMS, including fever, confusion, and increased muscle rigidity.

 

Table 1

Factors that increase risk of neuroleptic malignant syndrome*

Abrupt antipsychotic cessation
Ambient heat
Catatonia
Dehydration
Exhaustion
Genetic predisposition
Greater dosage increases
Higher neuroleptic doses, especially with typical and atypical IM agents
Low serum iron
Malnutrition
Mental retardation
Pre-existing EPS or parkinsonism
Previous NMS episode
Psychomotor agitation
* Infection or concurrent organic brain disease are predisposing factors, but their association with NMS is less clear.
EPS: extrapyramidal symptoms
Source: References: 4-7, 14-15.

TREATMENT: MEDICATION CHANGE

Upon admission, quetiapine is increased to 75 mg in the morning and 125 mg at bedtime—still well below the dosage at which quetiapine increases the risk of NMS (Table 2). Trazodone is decreased to 100 mg/d because of quetiapine’s sedating properties. Citalopram and tolterodine are stopped for fear that either agent would aggravate her psychosis. We continue all other drugs as previously prescribed. Her paranoia begins to subside.

Three days later, Ms. G’s is increasingly confused and agitated, and her temperature rises to 101.3°F. Physical exam shows increased muscle rigidity. She is given lorazepam, 1 mg, and transferred to the emergency room for evaluation.

In the ER, Ms. G’s temperature rises to 102.3°F. Other vital signs include:

• heart rate, 112 to 120 beats per minute
  
• respiratory rate, 18 to 20 breaths per minute
  
• oxygen saturation, 98% in room air
  
• blood pressure, 131/61 mm Hg while seated and 92/58 mm Hg while standing.
  

We suspect NMS based on her dry mucous membranes, tachycardic but otherwise normal heart, and hand and foot rigidity. Creatine kinase (CK) measured after ER admission is 11,500 U/L, well above the typically elevated levels for a patient with Parkinson’s.⁸ Also, Ms. G is alert to her name only.

CNS or systemic infection and myocardial infarction are considered less likely because of her reactive pupils, lack of nuchal rigidity, troponin 3. Additionally, CSF shows normal glucose and protein levels, ALT and AST are 217 and 261 U/L, respectively, and chest x-ray shows no acute cardiopulmonary abnormality.

Ms. G is admitted to the medical intensive care unit and given IV fluids. All psychotropic and antiparkinson medications are stopped for 12 hours. Ms. G is then transferred to the general medical service for continued observation and IV hydration.

Six hours later, lorazepam, 0.5 mg every 8 hours, is resumed to control Ms. G’s anxiety. Carbidopa/levodopa is resumed at the previous dosage; all other medications remain on hold.

Renal damage is not apparent, but repeat chest x-ray taken 2 days after admission to the ER shows right middle lobe pneumonia, which resolved with antibiotics.

Six days after entering the medical unit, Ms. G is no longer agitated or paranoid. She is discharged that day and continued on lorazepam, 1 mg every 8 hours as needed to control her anxiety and prevent paranoia, and carbidopa/levidopa 8-¹/₂ 25/100-mg tablets daily for her parkinsonism. Trazodone, 100 mg nightly, is continued for 3 days to help her sleep, as is amoxicillin/clavulanate, 500 mg every 8 hours, in case an underlying infection exists. Quetiapine, citalopram, and tolterodine are discontinued; all other medications are resumed as previously prescribed.

Table 2

Antipsychotic-related NMS risk increases at these dosages

Agent	Dosage (mg/d)
Aripiprazole	>30
Chlorpromazine	>400
Clozapine	318+/-299
Olanzapine	9.7+/-2.3
Quetiapine	412.5+/-317
Risperidone	4.3+/-3.1
Ziprasidone	>20
Source: References 4, 6, and 15.

The authors’ observations

Ms. G’s NMS symptoms surfaced 3 days after her quetiapine dosage was increased, suggesting that the antipsychotic may have caused this episode.

We ruled out antiparkinson agent withdrawal malignant syndrome—usually caused by abrupt cessation of Parkinson’s medications. Ms. G’s carbidopa/levodopa had not been adjusted before the symptoms emerged, and she did not worsen after the agent was stopped temporarily. Her brief pneumonia episode, however, could have caused symptoms that mimicked this withdrawal syndrome.

Antiparkinson agent withdrawal malignant syndrome symptoms resemble those of NMS.^9,10 Worsening parkinsonism, dehydration, and infection increase the risk.¹⁰ Some research suggests that leukocytosis or elevated inflammation-related cytokines may accelerate withdrawal syndrome.¹⁰

The authors’ observations

Ms. G’s case illustrates the difficulty of treating psychosis in a patient at risk for NMS.

Of the 68 patients in the Ananth et al study with atypical antipsychotic-induced NMS, 11 were rechallenged after an NMS episode with the same agent and 8 were switched to another atypical. NMS recurred in 4 of these 19 patients.⁴

Ms. G was stable on lorazepam at discharge, but we would consider rechallenging with quetiapine or another antipsychotic if necessary. NMS recurs in 30% to 50%¹¹ of patients after antipsychotic rechallenge, but waiting 2 weeks to resume antipsychotic therapy appears to reduce this risk.¹² Benzodiazepines and electroconvulsive therapy are acceptable—though unproven—second-line therapies if antipsychotic rechallenge is deemed too risky,^11,13 such as in some patients with a previous severe NMS episode; evidence of stroke, Parkinson’s or other neurodegenerative disease; or multiple acute medical problems.

 

CONTINUED TREATMENT: A RELAPSE

Three months later, Ms. G is readmitted to the neurology service for 3 weeks after being diagnosed with elevated CK, possibly caused by NMS or rhabdomyolysis secondary to persistent dyskinesia. We believe an inadvertent decrease in her carbidopa/levodopa caused the episode, as she had taken no neuroleptics between hospitalizations.

Ms. G is discharged on quetiapine, 25 mg nightly, along with her other medications. Her current psychiatric and neurologic status is unknown.

The authors’ observations

Detecting NMS symptoms early is critical to preventing mortality. Although NMS risk with atypical and typical antipsychotics is similar,⁴ fewer deaths from NMS have been reported after use of atypicals (3 deaths among 68 cases) than typical neuroleptics (30% mortality rate in the 1960s and 70s, and 10% mortality from 1980-87).¹⁴ Earlier recognition and treatment may be decreasing NMS-related mortality.⁴

Consider NMS in the differential diagnosis when the patient’s mental status changes.

Related resources

• Emedicine: Neuroleptic malignant syndrome. www.emedicine.com/med/topic2614.htm.
  
• Bhanushali MJ, Tuite PJ. The evaluation and management of patients with neuroleptic malignant syndrome. Neurol Clin 2004;22:389-411.
  
• Susman VL. Clinical management of neuroleptic malignant syndrome. Psychiatr Q 2001;72:325-36.
  

Drug brand names

• Amoxicillin/clavulanate • Augmentin
  
• Aripiprazole • Abilify
  
• Carbidopa/levodopa • Sinemet
  
• Chlorpromazine • Thorazine
  
• Citalopram • Celexa
  
• Clozapine • Clozaril
  
• Lopressor • Toprol
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Pramipexole • Mirapex
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Tolterodine • Detrol
  
• Trazodone • Desyrel
  
• Ziprasidone • Geodon
  

Disclosure

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

Acknowledgments

The authors wish to thank Robert B. Milstein, MD, PhD, and Benjamin Zigun, MD, JD, for their help in preparing this article for publication.

This project is supported by funds from the Division of State, Community, and Public Health, Bureau of Health Professions (BHPr), Health Resources and Services Administration (HSRA), Department of Health and Human Services (DHHS) under grant number 1 K01 HP 00071-02 and Geriatric Academic Career Award ($58,009). The content and conclusion are those of Dr. Tampi and are not the official position or policy of, nor should be any endorsements be inferred by, the Bureau of Health Professions, HRSA, DHHS or the United States Government.

HISTORY: ‘THEY’RE TRYING TO KILL ME’

For the past 7 months Ms. G, age 47, has had worsening paranoid thoughts and sleep disturbances. She sleeps 4 hours or less a night, and her appetite and energy are diminished.

Her mother reports that Ms. G, who lives in an extended-care facility, believes the staff has injected embalming fluid into her body and is plotting to kill her. She says her daughter also has “fits” during which she hears a deafening noise that sounds like a vacuum cleaner, followed by a feeling of being pushed to the ground. Ms. G tells us that someone or something invisible is trying to control her.

Ms. G was diagnosed 2 years ago as having Parkinson’s disease and has chronically high liver transaminase enzymes. She also has moderate mental retardation secondary to cerebral palsy. She fears she will be harmed if she stays at the extendedcare facility, but we find no evidence that she has been abused or mistreated there.

Three months before presenting to us, Ms. G was hospitalized for 3 days to treat symptoms that suggested neuroleptic malignant syndrome (NMS) but were apparently caused by her inadvertently stopping her antiparkinson agents.

One month later, Ms. G was hospitalized again, this time for acute psychosis. Quetiapine, which she had been taking for antiparkinson medication-induced psychosis, was increased from 100 mg nightly to 75 mg bid, with reportedly good effect.

Shortly afterward, however, Ms. G’s paranoia worsened. At the facility, she has called 911 several times to report imagined threats from staff members. After referral from her primary care physician, we evaluate Ms. G and admit her to the adult inpatient psychiatric unit.

At intake, Ms. G is anxious and uncomfortable with notable muscle spasticity and twitching of her arms and legs. Mostly wheelchair-bound, she has longstanding physical abnormalities (shuffling gait; dystonia; drooling; slowed, dysarthric speech) secondary to comorbid Parkinson’s and cerebral palsy. She is agitated at first but grows calmer and cooperative.

Mental status examination shows a disorganized, tangential thought process and evidence of paranoid delusions and auditory hallucinations, but she denies visual hallucinations. She has poor insight into her illness but is oriented to time, place, and person. She can recall two of three objects after 3 minutes of distraction. Attention and concentration are intact.

Ms. G denies depressed mood, anhedonia, mania, or suicidal or homicidal thoughts. Her mother says no stressors other than the imagined threats to her life have affected her daughter.

The patient ’s temperature at admission is 98.0°F, her pulse is 108 beats per minute, and her blood pressure is 150/88 mm Hg. Laboratory workup shows a white blood cell count of 10,100/mm³ (normal range: 4,000 to 10,000/mm³), sodium level of 132 mEq/L (normal range: 135 to 145 mEq/L), and aspartate (AST) and alanine (ALT) transaminase levels of 611 U/L and 79 U/L, respectively (normal range for each: 0 to 35 U/L).

Aside from quetiapine, Ms. G also has been taking carbidopa/levodopa, seven 25/100-mg tablets daily, and pramipexole, 3 mg/d, for parkinsonism; citalopram, 20 mg/d, for depression; trazodone, 300 mg nightly, and lorazepam, 0.5 mg nightly, for insomnia; lopressor, 25 mg every 12 hours, for hypertension; and tolterodine, 1 mg bid, for urinary incontinence.

The authors’ observations

Parkinsonism typically responds to dopaminergic treatment. Excess dopamine agonism is believed to contribute to medication-induced psychosis, a common and often disabling complication of Parkinson’s disease^1,2 that often necessitates nursing home placement and may increase mortality.^2,3

Paranoia occurs in approximately 8% of patients treated for drug-induced Parkinson’s psychosis, and hallucinations (typically visual) may occur in as many as 30%.² Quetiapine, 50 to 225 mg/d, is considered a good first-line treatment for psychosis in Parkinson’s, although the agent has been tested for this use only in open-label trials.^2,3

Mental retardation and pre-existing parkinsonism, however, may increase Ms. G’s risk for NMS, a rare but potentially fatal reaction to antipsychotics believed to be caused by a sudden D₂ dopamine receptor blockade.^4,5 Signs include autonomic instability, extrapyramidal symptoms, hyperpyrexia, and altered mental status.

Of 68 patients with NMS studied by Ananth et al,⁴ 13.2% were mentally retarded, and uncontrolled studies⁶ have proposed mental retardation as a potential risk factor (Table 1). A 2003 case control study⁶ found a higher incidence of NMS among mentally retarded patients than among nonretarded persons, but the difference was not statistically significant. There are no known links between specific causes of mental retardation and NMS.

Even so, Ms. G’s psychosis is compromising her already diminished quality of life. We will increase her quetiapine dosage slightly and watch for early signs of NMS, including fever, confusion, and increased muscle rigidity.

 

Table 1

Factors that increase risk of neuroleptic malignant syndrome*

Abrupt antipsychotic cessation
Ambient heat
Catatonia
Dehydration
Exhaustion
Genetic predisposition
Greater dosage increases
Higher neuroleptic doses, especially with typical and atypical IM agents
Low serum iron
Malnutrition
Mental retardation
Pre-existing EPS or parkinsonism
Previous NMS episode
Psychomotor agitation
* Infection or concurrent organic brain disease are predisposing factors, but their association with NMS is less clear.
EPS: extrapyramidal symptoms
Source: References: 4-7, 14-15.

TREATMENT: MEDICATION CHANGE

Upon admission, quetiapine is increased to 75 mg in the morning and 125 mg at bedtime—still well below the dosage at which quetiapine increases the risk of NMS (Table 2). Trazodone is decreased to 100 mg/d because of quetiapine’s sedating properties. Citalopram and tolterodine are stopped for fear that either agent would aggravate her psychosis. We continue all other drugs as previously prescribed. Her paranoia begins to subside.

Three days later, Ms. G’s is increasingly confused and agitated, and her temperature rises to 101.3°F. Physical exam shows increased muscle rigidity. She is given lorazepam, 1 mg, and transferred to the emergency room for evaluation.

In the ER, Ms. G’s temperature rises to 102.3°F. Other vital signs include:

• heart rate, 112 to 120 beats per minute
  
• respiratory rate, 18 to 20 breaths per minute
  
• oxygen saturation, 98% in room air
  
• blood pressure, 131/61 mm Hg while seated and 92/58 mm Hg while standing.
  

We suspect NMS based on her dry mucous membranes, tachycardic but otherwise normal heart, and hand and foot rigidity. Creatine kinase (CK) measured after ER admission is 11,500 U/L, well above the typically elevated levels for a patient with Parkinson’s.⁸ Also, Ms. G is alert to her name only.

CNS or systemic infection and myocardial infarction are considered less likely because of her reactive pupils, lack of nuchal rigidity, troponin 3. Additionally, CSF shows normal glucose and protein levels, ALT and AST are 217 and 261 U/L, respectively, and chest x-ray shows no acute cardiopulmonary abnormality.

Ms. G is admitted to the medical intensive care unit and given IV fluids. All psychotropic and antiparkinson medications are stopped for 12 hours. Ms. G is then transferred to the general medical service for continued observation and IV hydration.

Six hours later, lorazepam, 0.5 mg every 8 hours, is resumed to control Ms. G’s anxiety. Carbidopa/levodopa is resumed at the previous dosage; all other medications remain on hold.

Renal damage is not apparent, but repeat chest x-ray taken 2 days after admission to the ER shows right middle lobe pneumonia, which resolved with antibiotics.

Six days after entering the medical unit, Ms. G is no longer agitated or paranoid. She is discharged that day and continued on lorazepam, 1 mg every 8 hours as needed to control her anxiety and prevent paranoia, and carbidopa/levidopa 8-¹/₂ 25/100-mg tablets daily for her parkinsonism. Trazodone, 100 mg nightly, is continued for 3 days to help her sleep, as is amoxicillin/clavulanate, 500 mg every 8 hours, in case an underlying infection exists. Quetiapine, citalopram, and tolterodine are discontinued; all other medications are resumed as previously prescribed.

Table 2

Antipsychotic-related NMS risk increases at these dosages

Agent	Dosage (mg/d)
Aripiprazole	>30
Chlorpromazine	>400
Clozapine	318+/-299
Olanzapine	9.7+/-2.3
Quetiapine	412.5+/-317
Risperidone	4.3+/-3.1
Ziprasidone	>20
Source: References 4, 6, and 15.

The authors’ observations

Ms. G’s NMS symptoms surfaced 3 days after her quetiapine dosage was increased, suggesting that the antipsychotic may have caused this episode.

We ruled out antiparkinson agent withdrawal malignant syndrome—usually caused by abrupt cessation of Parkinson’s medications. Ms. G’s carbidopa/levodopa had not been adjusted before the symptoms emerged, and she did not worsen after the agent was stopped temporarily. Her brief pneumonia episode, however, could have caused symptoms that mimicked this withdrawal syndrome.

Antiparkinson agent withdrawal malignant syndrome symptoms resemble those of NMS.^9,10 Worsening parkinsonism, dehydration, and infection increase the risk.¹⁰ Some research suggests that leukocytosis or elevated inflammation-related cytokines may accelerate withdrawal syndrome.¹⁰

The authors’ observations

Ms. G’s case illustrates the difficulty of treating psychosis in a patient at risk for NMS.

Of the 68 patients in the Ananth et al study with atypical antipsychotic-induced NMS, 11 were rechallenged after an NMS episode with the same agent and 8 were switched to another atypical. NMS recurred in 4 of these 19 patients.⁴

Ms. G was stable on lorazepam at discharge, but we would consider rechallenging with quetiapine or another antipsychotic if necessary. NMS recurs in 30% to 50%¹¹ of patients after antipsychotic rechallenge, but waiting 2 weeks to resume antipsychotic therapy appears to reduce this risk.¹² Benzodiazepines and electroconvulsive therapy are acceptable—though unproven—second-line therapies if antipsychotic rechallenge is deemed too risky,^11,13 such as in some patients with a previous severe NMS episode; evidence of stroke, Parkinson’s or other neurodegenerative disease; or multiple acute medical problems.

 

CONTINUED TREATMENT: A RELAPSE

Three months later, Ms. G is readmitted to the neurology service for 3 weeks after being diagnosed with elevated CK, possibly caused by NMS or rhabdomyolysis secondary to persistent dyskinesia. We believe an inadvertent decrease in her carbidopa/levodopa caused the episode, as she had taken no neuroleptics between hospitalizations.

Ms. G is discharged on quetiapine, 25 mg nightly, along with her other medications. Her current psychiatric and neurologic status is unknown.

The authors’ observations

Detecting NMS symptoms early is critical to preventing mortality. Although NMS risk with atypical and typical antipsychotics is similar,⁴ fewer deaths from NMS have been reported after use of atypicals (3 deaths among 68 cases) than typical neuroleptics (30% mortality rate in the 1960s and 70s, and 10% mortality from 1980-87).¹⁴ Earlier recognition and treatment may be decreasing NMS-related mortality.⁴

Consider NMS in the differential diagnosis when the patient’s mental status changes.

Related resources

• Emedicine: Neuroleptic malignant syndrome. www.emedicine.com/med/topic2614.htm.
  
• Bhanushali MJ, Tuite PJ. The evaluation and management of patients with neuroleptic malignant syndrome. Neurol Clin 2004;22:389-411.
  
• Susman VL. Clinical management of neuroleptic malignant syndrome. Psychiatr Q 2001;72:325-36.
  

Drug brand names

• Amoxicillin/clavulanate • Augmentin
  
• Aripiprazole • Abilify
  
• Carbidopa/levodopa • Sinemet
  
• Chlorpromazine • Thorazine
  
• Citalopram • Celexa
  
• Clozapine • Clozaril
  
• Lopressor • Toprol
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Pramipexole • Mirapex
  
• Quetiapine • Seroquel
  
• Risperidone • Risperdal
  
• Tolterodine • Detrol
  
• Trazodone • Desyrel
  
• Ziprasidone • Geodon
  

Disclosure

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

Acknowledgments

The authors wish to thank Robert B. Milstein, MD, PhD, and Benjamin Zigun, MD, JD, for their help in preparing this article for publication.

This project is supported by funds from the Division of State, Community, and Public Health, Bureau of Health Professions (BHPr), Health Resources and Services Administration (HSRA), Department of Health and Human Services (DHHS) under grant number 1 K01 HP 00071-02 and Geriatric Academic Career Award ($58,009). The content and conclusion are those of Dr. Tampi and are not the official position or policy of, nor should be any endorsements be inferred by, the Bureau of Health Professions, HRSA, DHHS or the United States Government.

HISTORY: LIFE AT HOME

For nearly 10 years Mr. P, age 50, has had episodes of shortness of breath, increasing perspiration, and faintness that occur 2 to 3 times a month, usually when he’s out of the house. Fearing his legs will give out in public, he never goes out except to shop with his wife.

Once a welder for an aircraft company, he has been unable to work for 6 years. He worries incessantly about his medical expenses, and smokes 1 pack of cigarettes per day to help control the anxiety.

Baseline laboratory tests reveal a low-density lipoprotein cholesterol level of 199 mg/dL, exceeding the optimal range by 100 mg/dL. Total cholesterol is 288 mg/dL and triglycerides are 244 mg/dL. Thyroid stimulating hormone, liver function, renal function, serum electrolytes, and serum glucose are normal. Mr. P meets DSM-IV-TR criteria for panic disorder with agoraphobia and is started on citalopram, 20 mg/d.

At follow-up 2 weeks later, Mr. P complains that the citalopram is causing ‘aches and pains’ in his back and legs, so we switch to controlled-release paroxetine, 12.5 mg/d, which we found in clinical practice to be more tolerable than immediate-release paroxetine. After 2 weeks, he says he cannot tolerate the paroxetine because of ‘body aches.’

At Mr. P’s insistence, we switch to alprazolam, 0.5 mg tid, although his desire to start taking alprazolam makes us suspect that he might be trying to obtain this benzodiazepine for illicit use.

Neuropsychological tests—including a diagnostic interview, Minnesota Multiphasic Personality Inventory, and Millon Clinical Multiaxial Inventory—are ordered after Mr. P’s third visit. He seems guarded when answering questions about himself during these interviews. He acknowledges having severe physical symptoms but appears unwilling to accept a psychiatric diagnosis for them.

The authors’ observations

Panic disorder is usually chronic and can cause considerable morbidity. DSM-IV-TR criteria for panic disorder include recurrent or unexpected panic attacks and persistent fear of additional attacks and their implications and consequences.¹ Panic disorder can also lead to social problems including unemployment, financial dependence, and substance abuse or dependence.²

Mr. P’s anxiety, shortness of breath, faintness, and profuse sweating during episodes match DSM-IV-TR criteria for panic attacks (Table 1). His ruminative and obsessive attitude toward his physical problems does not suggest somatoform disorder because he also thinks obsessively about other issues, such as his medical expenses.

We will watch for signs of prescription drug abuse, including premature requests for refills, use of multiple pharmacies, or complaints of lost prescription or medication.³

FURTHER HISTORY: FAINT MEMORY

Mr. P first sought medical help in 1996 after fainting at home while standing up. A few weeks later he experienced sudden dizziness, faintness, and perspiration while shopping with his wife. During that episode, he said, he barely made it out of the store before passing out in his truck. His wife described him as ‘pale and gray’ and rushed him to the emergency room. The ER physician suspected that Mr. P suffered a ‘convulsive episode’ and ordered testing. Results of awake and sleep EEG and head MRI were normal. Laboratory work revealed a positive antinuclear antibody (ANA) and rheumatoid factor (RF), suggesting pulmonary vasculitis.

Table 1

DSM-IV-TR criteria for panic attack

A discrete period of intense fear or discomfort, in which four (or more) of the following symptoms developed abruptly and reached a peak within 10 minutes: palpitations sweating trembling or shaking shortness of breath or smothering feeling of choking chest pain or discomfort nausea or abdominal distress feeling dizzy, unsteady, lightheaded, or faint derealization or depersonalization fear of losing control or going crazy fear of dying paresthesias chills or hot flushes

Source: Adapted and reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders (4th ed, text revision). Copyright 2000. American Psychiatric Association.

Mr. P, who was still working at the aircraft company, continued to seek medical opinions. He was diagnosed alternately as having chronic fatigue syndrome, fibromyalgia, and sleep apnea. He said a pulmonologist told him he had lung fibrosis but that the disorder would resolve without treatment. At one point, he was prescribed a continuous positive airway pressure device (CPAP) to manage what was thought to be sleep apnea.

Two years and 17 doctors later, Mr. P’s physical symptoms persisted. He stopped working and began collecting disability insurance benefits. Frustrated over the lack of a definitive diagnosis, he then went 6 years without seeing a doctor.

TREATMENT: INTENSE ‘PANIC’

Mr. P has been coming to our clinic for 8 months. He takes 0.5 mg of alprazolam twice daily—less frequently than prescribed—and has never prematurely requested a refill, so prescription abuse is ruled out. He joins a fibromyalgia support group but laments that his symptoms differ from those of other group members. During follow-up visits, he continues to focus on his somatic symptoms.

 

During a routine visit, Mr. P tells us that he recently suffered an intense ‘panic’ episode—consisting of shortness of breath, dizziness, diaphoresis, chest pain, palpitations, and near syncope—less than 15 minutes after he started clearing brush in his backyard. We notice marked clubbing on Mr. P’s fingers, a physical sign seen in congenital heart disease, infective endocarditis, pulmonary fibrosis, and numerous other diseases.⁴

The clubbing prompts us to ask about his occupational history in detail, as work-related exposure to chemicals or fumes may result in pulmonary fibrosis. We then learn that for approximately 20 years before joining the aircraft company, Mr. P welded without wearing protective equipment—all that time inhaling noxious fumes while working.

We refer Mr. P to an internist, who finds clubbing of the fingers, decreased breath sounds, and increased pulmonic second heart sound (P2) on auscultation. The internist then orders:

• ECG, which reveals right axis deviation, incomplete right bundle branch block, and right ventricular hypertrophy (RVH)
  
• Pulmonary function tests, which show decreased diffusing capacity. Subsequent heart catheterization reveals RVH and concentric left ventricular hypertrophy.
  

Mr. P is told to quit smoking and to use his CPAP nightly to minimize progression of his right ventricular dysfunction. He had been using his CPAP sporadically because he found it uncomfortable.

The authors’ observations

Panic attacks often mimic symptoms of cardiac or pulmonary disease. By the same token, symptoms of an underlying cardiac or pulmonary disease can be mistaken for panic disorder, particularly in patients whose past episodes appear to meet DSM-IV-TR panic attack criteria (Table 2).⁵

Table 2

Panic attack symptoms that may suggest a cardiopulmonary disease

Panic attack symptom	Possible cardiopulmonary disorder
Palpitations, chest discomfort, feeling faint	Cardiac arrhythmia
Breathlessness, fatigue, weakness	Heart failure
Weakness, nausea, diaphoresis, feelings of hot/cold associated with diaphoresis, paresthesias, lightheadedness, fear of dying	Cardiac or neurologic syncope
Intense, escalating chest pain/discomfort; may be accompanied by nausea, diaphoresis, dizziness, feelings of hot/cold associated with diaphoresis	Acute myocardial infarction
Shortness of breath, fatigue, weakness, feeling of choking	Pulmonary congestion*
* Because the lung parenchyma and visceral pleura lack pain fibers, pulmonary abnormalities related to these structures can be advanced before symptoms are noticed.
Source: reference 5

Patients with panic disorder seek medical help more frequently than do patients with other anxiety disorders.⁶ About one-third of patients with panic disorder seek psychiatric treatment, and almost as many seek medical help,⁶ possibly because of the complicated array of symptoms simultaneously involving cardiac and pulmonary systems.

To avoid unnecessary referrals, psychiatrists need to quickly and accurately discern:

• when a medical problem is causing the patient’s symptoms
  
• how far to carry the medical evaluation, particularly for patients with palpitations, chest pain, or shortness of breath.
  

No reliable screening tool exists for differentiating panic from cardiopulmonary symptoms. A screening inventory developed by Barsky et al⁷ for patients complaining of palpitations focuses on somatization and hypochondriacal attitudes, which are common among psychiatric patients. This tool, however, does not take into account presence of cardiac risk factors.

Also, a psychiatric patient whose mental disorder or comorbid axis II pathology compromises speech or cognitive function may have trouble communicating potentially serious medical problems to other clinicians. Mr. P’s guarded demeanor and obsession toward his physical problems may have kept him from accurately describing his symptoms in a clinical setting. Alternately, he might have misinterpreted his pulmonologist’s explanation of pulmonary fibrosis, thus believing the disorder was not serious.

Finally, patients with panic disorder are more aware of their heartbeats and physiologic responses than are persons without panic disorder,⁸ thus further complicating diagnosis.

UNCOVERING A MEDICAL CAUSE

Suspect an underlying heart or lung problem when panic symptoms affect breathing or resemble a heart attack.

Check for predisposing risk factors for cardiac disease. Ask the patient detailed questions about past and current medical problems, including:

• smoking
  
• hyperlipidemia
  
• diabetes
  
• heart problems
  
• pulmonary disease
  
• family history of any medical problems
  
• work-related exposure to any metal that may increase risk of cardiopulmonary disease.
  

Refer the patient for medical evaluation if any of the above risk factors are discovered.

Review medical treatment history. Mentally ill persons are more likely than those without a mental illness to receive inadequate general medical and preventative care.⁹ Patient, provider, and health care system issues—such as lack of insurance or the patient’s inability to recognize or describe symptoms—may impede medical care delivery to the mentally ill.⁹

Review overall history. A deeper look into Mr. P’s work and diagnostic history uncovered numerous possible causes of right heart failure, including:

• pulmonary fibrosis secondary to inhalational injury
  
• possible pulmonary vasculitis as indicated by his positive ANA and RF.
  

As time progressed, either of these underlying lung pathologies amid sleep apnea and smoking could have increased Mr. P’s cardiopulmonary risk.

 

FOLLOW-UP: A PANIC-FREE FUTURE

Over the next 4 weeks, Mr. P has stopped taking alprazolam and begins to understand that his episodes were secondary to cardiopulmonary dysfunction. No longer afraid of developing a panic attack, he is going out more often.

Mr. P recently told us that he started a part-time job, decreased his smoking to a half pack/day, and has a plan to quit smoking completely. He adds that he is using his CPAP machine regularly and has remained free of panic-like episodes. He limits physical exertion to avoid cardiopulmonary symptoms.

Related resources

• Raj A, Sheehan DV. Medical evaluation of panic attacks. J Clin Psychiatry 1987;48:309-13.
  
• Jones DR, Macias C, Barreira PJ, et al. Prevalence, severity, and co-occurrence of chronic physical health problems of persons with serious mental illness. Psychiatr Serv 2004;55:1250-7.
  

Drug brand names

• Alprazolam • Xanax
  
• Citalopram • Celexa
  
• Paroxetine • Paxil
  

Disclosure

Dr. Khan is a speaker for Wyeth Pharmaceuticals.

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

HISTORY: LIFE AT HOME

For nearly 10 years Mr. P, age 50, has had episodes of shortness of breath, increasing perspiration, and faintness that occur 2 to 3 times a month, usually when he’s out of the house. Fearing his legs will give out in public, he never goes out except to shop with his wife.

Once a welder for an aircraft company, he has been unable to work for 6 years. He worries incessantly about his medical expenses, and smokes 1 pack of cigarettes per day to help control the anxiety.

Baseline laboratory tests reveal a low-density lipoprotein cholesterol level of 199 mg/dL, exceeding the optimal range by 100 mg/dL. Total cholesterol is 288 mg/dL and triglycerides are 244 mg/dL. Thyroid stimulating hormone, liver function, renal function, serum electrolytes, and serum glucose are normal. Mr. P meets DSM-IV-TR criteria for panic disorder with agoraphobia and is started on citalopram, 20 mg/d.

At follow-up 2 weeks later, Mr. P complains that the citalopram is causing ‘aches and pains’ in his back and legs, so we switch to controlled-release paroxetine, 12.5 mg/d, which we found in clinical practice to be more tolerable than immediate-release paroxetine. After 2 weeks, he says he cannot tolerate the paroxetine because of ‘body aches.’

At Mr. P’s insistence, we switch to alprazolam, 0.5 mg tid, although his desire to start taking alprazolam makes us suspect that he might be trying to obtain this benzodiazepine for illicit use.

Neuropsychological tests—including a diagnostic interview, Minnesota Multiphasic Personality Inventory, and Millon Clinical Multiaxial Inventory—are ordered after Mr. P’s third visit. He seems guarded when answering questions about himself during these interviews. He acknowledges having severe physical symptoms but appears unwilling to accept a psychiatric diagnosis for them.

The authors’ observations

Panic disorder is usually chronic and can cause considerable morbidity. DSM-IV-TR criteria for panic disorder include recurrent or unexpected panic attacks and persistent fear of additional attacks and their implications and consequences.¹ Panic disorder can also lead to social problems including unemployment, financial dependence, and substance abuse or dependence.²

Mr. P’s anxiety, shortness of breath, faintness, and profuse sweating during episodes match DSM-IV-TR criteria for panic attacks (Table 1). His ruminative and obsessive attitude toward his physical problems does not suggest somatoform disorder because he also thinks obsessively about other issues, such as his medical expenses.

We will watch for signs of prescription drug abuse, including premature requests for refills, use of multiple pharmacies, or complaints of lost prescription or medication.³

FURTHER HISTORY: FAINT MEMORY

Mr. P first sought medical help in 1996 after fainting at home while standing up. A few weeks later he experienced sudden dizziness, faintness, and perspiration while shopping with his wife. During that episode, he said, he barely made it out of the store before passing out in his truck. His wife described him as ‘pale and gray’ and rushed him to the emergency room. The ER physician suspected that Mr. P suffered a ‘convulsive episode’ and ordered testing. Results of awake and sleep EEG and head MRI were normal. Laboratory work revealed a positive antinuclear antibody (ANA) and rheumatoid factor (RF), suggesting pulmonary vasculitis.

Table 1

DSM-IV-TR criteria for panic attack

A discrete period of intense fear or discomfort, in which four (or more) of the following symptoms developed abruptly and reached a peak within 10 minutes: palpitations sweating trembling or shaking shortness of breath or smothering feeling of choking chest pain or discomfort nausea or abdominal distress feeling dizzy, unsteady, lightheaded, or faint derealization or depersonalization fear of losing control or going crazy fear of dying paresthesias chills or hot flushes

Source: Adapted and reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders (4th ed, text revision). Copyright 2000. American Psychiatric Association.

Mr. P, who was still working at the aircraft company, continued to seek medical opinions. He was diagnosed alternately as having chronic fatigue syndrome, fibromyalgia, and sleep apnea. He said a pulmonologist told him he had lung fibrosis but that the disorder would resolve without treatment. At one point, he was prescribed a continuous positive airway pressure device (CPAP) to manage what was thought to be sleep apnea.

Two years and 17 doctors later, Mr. P’s physical symptoms persisted. He stopped working and began collecting disability insurance benefits. Frustrated over the lack of a definitive diagnosis, he then went 6 years without seeing a doctor.

TREATMENT: INTENSE ‘PANIC’

Mr. P has been coming to our clinic for 8 months. He takes 0.5 mg of alprazolam twice daily—less frequently than prescribed—and has never prematurely requested a refill, so prescription abuse is ruled out. He joins a fibromyalgia support group but laments that his symptoms differ from those of other group members. During follow-up visits, he continues to focus on his somatic symptoms.

 

During a routine visit, Mr. P tells us that he recently suffered an intense ‘panic’ episode—consisting of shortness of breath, dizziness, diaphoresis, chest pain, palpitations, and near syncope—less than 15 minutes after he started clearing brush in his backyard. We notice marked clubbing on Mr. P’s fingers, a physical sign seen in congenital heart disease, infective endocarditis, pulmonary fibrosis, and numerous other diseases.⁴

The clubbing prompts us to ask about his occupational history in detail, as work-related exposure to chemicals or fumes may result in pulmonary fibrosis. We then learn that for approximately 20 years before joining the aircraft company, Mr. P welded without wearing protective equipment—all that time inhaling noxious fumes while working.

We refer Mr. P to an internist, who finds clubbing of the fingers, decreased breath sounds, and increased pulmonic second heart sound (P2) on auscultation. The internist then orders:

• ECG, which reveals right axis deviation, incomplete right bundle branch block, and right ventricular hypertrophy (RVH)
  
• Pulmonary function tests, which show decreased diffusing capacity. Subsequent heart catheterization reveals RVH and concentric left ventricular hypertrophy.
  

Mr. P is told to quit smoking and to use his CPAP nightly to minimize progression of his right ventricular dysfunction. He had been using his CPAP sporadically because he found it uncomfortable.

The authors’ observations

Panic attacks often mimic symptoms of cardiac or pulmonary disease. By the same token, symptoms of an underlying cardiac or pulmonary disease can be mistaken for panic disorder, particularly in patients whose past episodes appear to meet DSM-IV-TR panic attack criteria (Table 2).⁵

Table 2

Panic attack symptoms that may suggest a cardiopulmonary disease

Panic attack symptom	Possible cardiopulmonary disorder
Palpitations, chest discomfort, feeling faint	Cardiac arrhythmia
Breathlessness, fatigue, weakness	Heart failure
Weakness, nausea, diaphoresis, feelings of hot/cold associated with diaphoresis, paresthesias, lightheadedness, fear of dying	Cardiac or neurologic syncope
Intense, escalating chest pain/discomfort; may be accompanied by nausea, diaphoresis, dizziness, feelings of hot/cold associated with diaphoresis	Acute myocardial infarction
Shortness of breath, fatigue, weakness, feeling of choking	Pulmonary congestion*
* Because the lung parenchyma and visceral pleura lack pain fibers, pulmonary abnormalities related to these structures can be advanced before symptoms are noticed.
Source: reference 5

Patients with panic disorder seek medical help more frequently than do patients with other anxiety disorders.⁶ About one-third of patients with panic disorder seek psychiatric treatment, and almost as many seek medical help,⁶ possibly because of the complicated array of symptoms simultaneously involving cardiac and pulmonary systems.

To avoid unnecessary referrals, psychiatrists need to quickly and accurately discern:

• when a medical problem is causing the patient’s symptoms
  
• how far to carry the medical evaluation, particularly for patients with palpitations, chest pain, or shortness of breath.
  

No reliable screening tool exists for differentiating panic from cardiopulmonary symptoms. A screening inventory developed by Barsky et al⁷ for patients complaining of palpitations focuses on somatization and hypochondriacal attitudes, which are common among psychiatric patients. This tool, however, does not take into account presence of cardiac risk factors.

Also, a psychiatric patient whose mental disorder or comorbid axis II pathology compromises speech or cognitive function may have trouble communicating potentially serious medical problems to other clinicians. Mr. P’s guarded demeanor and obsession toward his physical problems may have kept him from accurately describing his symptoms in a clinical setting. Alternately, he might have misinterpreted his pulmonologist’s explanation of pulmonary fibrosis, thus believing the disorder was not serious.

Finally, patients with panic disorder are more aware of their heartbeats and physiologic responses than are persons without panic disorder,⁸ thus further complicating diagnosis.

UNCOVERING A MEDICAL CAUSE

Suspect an underlying heart or lung problem when panic symptoms affect breathing or resemble a heart attack.

Check for predisposing risk factors for cardiac disease. Ask the patient detailed questions about past and current medical problems, including:

• smoking
  
• hyperlipidemia
  
• diabetes
  
• heart problems
  
• pulmonary disease
  
• family history of any medical problems
  
• work-related exposure to any metal that may increase risk of cardiopulmonary disease.
  

Refer the patient for medical evaluation if any of the above risk factors are discovered.

Review medical treatment history. Mentally ill persons are more likely than those without a mental illness to receive inadequate general medical and preventative care.⁹ Patient, provider, and health care system issues—such as lack of insurance or the patient’s inability to recognize or describe symptoms—may impede medical care delivery to the mentally ill.⁹

Review overall history. A deeper look into Mr. P’s work and diagnostic history uncovered numerous possible causes of right heart failure, including:

• pulmonary fibrosis secondary to inhalational injury
  
• possible pulmonary vasculitis as indicated by his positive ANA and RF.
  

As time progressed, either of these underlying lung pathologies amid sleep apnea and smoking could have increased Mr. P’s cardiopulmonary risk.

 

FOLLOW-UP: A PANIC-FREE FUTURE

Over the next 4 weeks, Mr. P has stopped taking alprazolam and begins to understand that his episodes were secondary to cardiopulmonary dysfunction. No longer afraid of developing a panic attack, he is going out more often.

Mr. P recently told us that he started a part-time job, decreased his smoking to a half pack/day, and has a plan to quit smoking completely. He adds that he is using his CPAP machine regularly and has remained free of panic-like episodes. He limits physical exertion to avoid cardiopulmonary symptoms.

Related resources

• Raj A, Sheehan DV. Medical evaluation of panic attacks. J Clin Psychiatry 1987;48:309-13.
  
• Jones DR, Macias C, Barreira PJ, et al. Prevalence, severity, and co-occurrence of chronic physical health problems of persons with serious mental illness. Psychiatr Serv 2004;55:1250-7.
  

Drug brand names

• Alprazolam • Xanax
  
• Citalopram • Celexa
  
• Paroxetine • Paxil
  

Disclosure

Dr. Khan is a speaker for Wyeth Pharmaceuticals.

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

HISTORY: LIFE AT HOME

For nearly 10 years Mr. P, age 50, has had episodes of shortness of breath, increasing perspiration, and faintness that occur 2 to 3 times a month, usually when he’s out of the house. Fearing his legs will give out in public, he never goes out except to shop with his wife.

Once a welder for an aircraft company, he has been unable to work for 6 years. He worries incessantly about his medical expenses, and smokes 1 pack of cigarettes per day to help control the anxiety.

Baseline laboratory tests reveal a low-density lipoprotein cholesterol level of 199 mg/dL, exceeding the optimal range by 100 mg/dL. Total cholesterol is 288 mg/dL and triglycerides are 244 mg/dL. Thyroid stimulating hormone, liver function, renal function, serum electrolytes, and serum glucose are normal. Mr. P meets DSM-IV-TR criteria for panic disorder with agoraphobia and is started on citalopram, 20 mg/d.

At follow-up 2 weeks later, Mr. P complains that the citalopram is causing ‘aches and pains’ in his back and legs, so we switch to controlled-release paroxetine, 12.5 mg/d, which we found in clinical practice to be more tolerable than immediate-release paroxetine. After 2 weeks, he says he cannot tolerate the paroxetine because of ‘body aches.’

At Mr. P’s insistence, we switch to alprazolam, 0.5 mg tid, although his desire to start taking alprazolam makes us suspect that he might be trying to obtain this benzodiazepine for illicit use.

Neuropsychological tests—including a diagnostic interview, Minnesota Multiphasic Personality Inventory, and Millon Clinical Multiaxial Inventory—are ordered after Mr. P’s third visit. He seems guarded when answering questions about himself during these interviews. He acknowledges having severe physical symptoms but appears unwilling to accept a psychiatric diagnosis for them.

The authors’ observations

Panic disorder is usually chronic and can cause considerable morbidity. DSM-IV-TR criteria for panic disorder include recurrent or unexpected panic attacks and persistent fear of additional attacks and their implications and consequences.¹ Panic disorder can also lead to social problems including unemployment, financial dependence, and substance abuse or dependence.²

Mr. P’s anxiety, shortness of breath, faintness, and profuse sweating during episodes match DSM-IV-TR criteria for panic attacks (Table 1). His ruminative and obsessive attitude toward his physical problems does not suggest somatoform disorder because he also thinks obsessively about other issues, such as his medical expenses.

We will watch for signs of prescription drug abuse, including premature requests for refills, use of multiple pharmacies, or complaints of lost prescription or medication.³

FURTHER HISTORY: FAINT MEMORY

Mr. P first sought medical help in 1996 after fainting at home while standing up. A few weeks later he experienced sudden dizziness, faintness, and perspiration while shopping with his wife. During that episode, he said, he barely made it out of the store before passing out in his truck. His wife described him as ‘pale and gray’ and rushed him to the emergency room. The ER physician suspected that Mr. P suffered a ‘convulsive episode’ and ordered testing. Results of awake and sleep EEG and head MRI were normal. Laboratory work revealed a positive antinuclear antibody (ANA) and rheumatoid factor (RF), suggesting pulmonary vasculitis.

Table 1

DSM-IV-TR criteria for panic attack

A discrete period of intense fear or discomfort, in which four (or more) of the following symptoms developed abruptly and reached a peak within 10 minutes: palpitations sweating trembling or shaking shortness of breath or smothering feeling of choking chest pain or discomfort nausea or abdominal distress feeling dizzy, unsteady, lightheaded, or faint derealization or depersonalization fear of losing control or going crazy fear of dying paresthesias chills or hot flushes

Source: Adapted and reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders (4th ed, text revision). Copyright 2000. American Psychiatric Association.

Mr. P, who was still working at the aircraft company, continued to seek medical opinions. He was diagnosed alternately as having chronic fatigue syndrome, fibromyalgia, and sleep apnea. He said a pulmonologist told him he had lung fibrosis but that the disorder would resolve without treatment. At one point, he was prescribed a continuous positive airway pressure device (CPAP) to manage what was thought to be sleep apnea.

Two years and 17 doctors later, Mr. P’s physical symptoms persisted. He stopped working and began collecting disability insurance benefits. Frustrated over the lack of a definitive diagnosis, he then went 6 years without seeing a doctor.

TREATMENT: INTENSE ‘PANIC’

Mr. P has been coming to our clinic for 8 months. He takes 0.5 mg of alprazolam twice daily—less frequently than prescribed—and has never prematurely requested a refill, so prescription abuse is ruled out. He joins a fibromyalgia support group but laments that his symptoms differ from those of other group members. During follow-up visits, he continues to focus on his somatic symptoms.

 

During a routine visit, Mr. P tells us that he recently suffered an intense ‘panic’ episode—consisting of shortness of breath, dizziness, diaphoresis, chest pain, palpitations, and near syncope—less than 15 minutes after he started clearing brush in his backyard. We notice marked clubbing on Mr. P’s fingers, a physical sign seen in congenital heart disease, infective endocarditis, pulmonary fibrosis, and numerous other diseases.⁴

The clubbing prompts us to ask about his occupational history in detail, as work-related exposure to chemicals or fumes may result in pulmonary fibrosis. We then learn that for approximately 20 years before joining the aircraft company, Mr. P welded without wearing protective equipment—all that time inhaling noxious fumes while working.

We refer Mr. P to an internist, who finds clubbing of the fingers, decreased breath sounds, and increased pulmonic second heart sound (P2) on auscultation. The internist then orders:

• ECG, which reveals right axis deviation, incomplete right bundle branch block, and right ventricular hypertrophy (RVH)
  
• Pulmonary function tests, which show decreased diffusing capacity. Subsequent heart catheterization reveals RVH and concentric left ventricular hypertrophy.
  

Mr. P is told to quit smoking and to use his CPAP nightly to minimize progression of his right ventricular dysfunction. He had been using his CPAP sporadically because he found it uncomfortable.

The authors’ observations

Panic attacks often mimic symptoms of cardiac or pulmonary disease. By the same token, symptoms of an underlying cardiac or pulmonary disease can be mistaken for panic disorder, particularly in patients whose past episodes appear to meet DSM-IV-TR panic attack criteria (Table 2).⁵

Table 2

Panic attack symptoms that may suggest a cardiopulmonary disease

Panic attack symptom	Possible cardiopulmonary disorder
Palpitations, chest discomfort, feeling faint	Cardiac arrhythmia
Breathlessness, fatigue, weakness	Heart failure
Weakness, nausea, diaphoresis, feelings of hot/cold associated with diaphoresis, paresthesias, lightheadedness, fear of dying	Cardiac or neurologic syncope
Intense, escalating chest pain/discomfort; may be accompanied by nausea, diaphoresis, dizziness, feelings of hot/cold associated with diaphoresis	Acute myocardial infarction
Shortness of breath, fatigue, weakness, feeling of choking	Pulmonary congestion*
* Because the lung parenchyma and visceral pleura lack pain fibers, pulmonary abnormalities related to these structures can be advanced before symptoms are noticed.
Source: reference 5

Patients with panic disorder seek medical help more frequently than do patients with other anxiety disorders.⁶ About one-third of patients with panic disorder seek psychiatric treatment, and almost as many seek medical help,⁶ possibly because of the complicated array of symptoms simultaneously involving cardiac and pulmonary systems.

To avoid unnecessary referrals, psychiatrists need to quickly and accurately discern:

• when a medical problem is causing the patient’s symptoms
  
• how far to carry the medical evaluation, particularly for patients with palpitations, chest pain, or shortness of breath.
  

No reliable screening tool exists for differentiating panic from cardiopulmonary symptoms. A screening inventory developed by Barsky et al⁷ for patients complaining of palpitations focuses on somatization and hypochondriacal attitudes, which are common among psychiatric patients. This tool, however, does not take into account presence of cardiac risk factors.

Also, a psychiatric patient whose mental disorder or comorbid axis II pathology compromises speech or cognitive function may have trouble communicating potentially serious medical problems to other clinicians. Mr. P’s guarded demeanor and obsession toward his physical problems may have kept him from accurately describing his symptoms in a clinical setting. Alternately, he might have misinterpreted his pulmonologist’s explanation of pulmonary fibrosis, thus believing the disorder was not serious.

Finally, patients with panic disorder are more aware of their heartbeats and physiologic responses than are persons without panic disorder,⁸ thus further complicating diagnosis.

UNCOVERING A MEDICAL CAUSE

Suspect an underlying heart or lung problem when panic symptoms affect breathing or resemble a heart attack.

Check for predisposing risk factors for cardiac disease. Ask the patient detailed questions about past and current medical problems, including:

• smoking
  
• hyperlipidemia
  
• diabetes
  
• heart problems
  
• pulmonary disease
  
• family history of any medical problems
  
• work-related exposure to any metal that may increase risk of cardiopulmonary disease.
  

Refer the patient for medical evaluation if any of the above risk factors are discovered.

Review medical treatment history. Mentally ill persons are more likely than those without a mental illness to receive inadequate general medical and preventative care.⁹ Patient, provider, and health care system issues—such as lack of insurance or the patient’s inability to recognize or describe symptoms—may impede medical care delivery to the mentally ill.⁹

Review overall history. A deeper look into Mr. P’s work and diagnostic history uncovered numerous possible causes of right heart failure, including:

• pulmonary fibrosis secondary to inhalational injury
  
• possible pulmonary vasculitis as indicated by his positive ANA and RF.
  

As time progressed, either of these underlying lung pathologies amid sleep apnea and smoking could have increased Mr. P’s cardiopulmonary risk.

 

FOLLOW-UP: A PANIC-FREE FUTURE

Over the next 4 weeks, Mr. P has stopped taking alprazolam and begins to understand that his episodes were secondary to cardiopulmonary dysfunction. No longer afraid of developing a panic attack, he is going out more often.

Mr. P recently told us that he started a part-time job, decreased his smoking to a half pack/day, and has a plan to quit smoking completely. He adds that he is using his CPAP machine regularly and has remained free of panic-like episodes. He limits physical exertion to avoid cardiopulmonary symptoms.

Related resources

• Raj A, Sheehan DV. Medical evaluation of panic attacks. J Clin Psychiatry 1987;48:309-13.
  
• Jones DR, Macias C, Barreira PJ, et al. Prevalence, severity, and co-occurrence of chronic physical health problems of persons with serious mental illness. Psychiatr Serv 2004;55:1250-7.
  

Drug brand names

• Alprazolam • Xanax
  
• Citalopram • Celexa
  
• Paroxetine • Paxil
  

Disclosure

Dr. Khan is a speaker for Wyeth Pharmaceuticals.

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

Presentation: Strange change

Mr. A, age 66, has lived an active life but now just sits around most of the day. Once an early riser, he is sleeping until 11 AM or noon daily. His wife frequently must motivate him to get out of bed.

Mr. A’s wife describes him as good-natured and extroverted, but she says lately he has also become increasingly withdrawn and quiet. People often think he is angry with them.

His dining habits also have changed. He used to wait until everyone had been served before beginning his meal, but he now starts eating immediately. He often overeats and has gained 15 pounds over 1 year.

Mr. A has always driven manual-transmission vehicles but has trouble remembering how to shift gears on his new car. While visiting his daughter, he could not operate the bathroom faucets properly and scalded himself. His daughter also noticed he does not wash his hands before eating or after toileting.

Findings. Mr. A presents to our clinic at his wife’s and daughter’s insistence but says his memory is fine and he can perform all activities of daily living (ADL). He denies depressive, anxiety, or psychotic symptoms but has hypertension and probable benign prostatic hypertrophy. He is taking ramipril, 5 mg/d for hypertension, donepezil, 10 mg/d for cognitive deficits, and aspirin, 325 mg/d to prevent a heart attack. Physical exam shows no gross neurologic abnormalities. Organ systems are normal.

Mr. A’s Folstein Mini-Mental State Exam (MMSE) score (22/30) indicates cognitive impairment. During his mental status exam, he is pleasant, cooperative, and makes good eye contact. He answers appropriately, but his speech lacks spontaneity. He smiles throughout the interview, even while discussing serious questions regarding his health. He is fully oriented but lacks insight into his deficits.

Brain MRI, ordered after he had presented to another hospital with similar complaints, is normal. PET scan shows frontal lobe hypometabolism, right greater than left, and mild underperfusion of the right basal ganglia and right temporal lobe.

Table 1

Frontotemporal dementia subtypes and their clinical features

Type	Clinical features
Corticobasal degeneration	Onset around age 60
	Symptoms may be unilateral at first and progress slowly
	Poor coordination, akinesia, rigidity, disequilibrium, limb dystonia
	Cognitive and visual-spatial impairments, apraxia, hesitant/halting speech, myoclonus, dysphagia
	Eventual inability to walk
Frontotemporal dementia with motor neuron disease	Behavioral changes, emotional lability
	Decreased spontaneous speech
	Bulbar weakness with dysarthria and dysphagia, weakness, muscle wasting, fasciculations in hands and feet
Frontotemporal dementia with parkinsonism linked to chromosome 17	Behavioral disturbance, cognitive impairment, parkinsonism
	Neurologic symptoms usually arise in patients’ 30s to 50s
Progressive fluent aphasia (semantic dementia)	Trouble remembering words
	Loss of semantic memory, although episodic memory is good
	Symmetric anterolateral temporal atrophy; hippocampal formation relatively intact
	Atrophy usually more pronounced on the left side4
Progressive nonfluent aphasia	Behavioral changes rare
	Global cognition declines over time
	Speech dysfluency, difficulty finding words, phonologic errors in conversation; comprehension is preserved

The authors’ observations

Mr. A’s clinical course suggests frontotemporal dementia (FTD), a spectrum of non-Alzheimer’s dementias characterized by focal atrophy of the brain’s frontal and anterior temporal regions (Table 1). These dementias loosely share clinicopathologic features, including:

• decline in social interpersonal conduct
  
• emotional blunting
  
• loss of insight
  
• disinhibition.¹
  

The histologic profile is characterized by gliosis, neuronal loss, and superficial spongiform degeneration in the frontal and/or temporal cortices. Ballooned neurons (Pick cells) occur with variable frequency in all FTD subtypes.²

FTD is the second most-common cause of dementia after AD in the years preceding old age but remains underdiagnosed. Onset is most common between ages 45 to 65 but can occur before age 30 and in the elderly.

FTD’s clinical presentation usually reflects distribution of pathologic changes rather than a precise histologic subtype. Major clinical presentations include a frontal or behavioral variant (frontal variant FTD associated with corticobasal degeneration or motor neuron disease), a progressive fluent aphasia (temporal lobe variant FTD), and a progressive nonfluent aphasia. Mr. A’s lack of initiative, emotional reactivity, and loss of social graces with normal speech pattern suggest frontal variant FTD.

Behavioral changes associated with FTD include:

• Decline in social conduct, including tactlessness and breaches of etiquette, associated with predominantly right-hemisphere pathology.³
  
• Apathy, which correlates with severity of medial frontal-anterior cingulate involvement.
  
• Dietary changes—typically overeating (hyperorality) with a preference for sweets.⁴
  

Patients also exhibit emotional blunting, echolalia, and attenuated speech output; mutism eventually develops.

Cognitive changes in FTD—attentional deficits, poor abstraction, difficulty shifting mental set, and perseverative tendencies—point to frontal lobe involvement.³

Neurologic signs usually are absent early in the disease, although patients may display primitive reflexes. As FTD progresses, patients may develop parkinsonian signs of akinesia and rigidity, which can be marked. Some develop neurologic signs consistent with motor neuron disease.³

 

Differential diagnosis. FTD is most often mistaken for AD. In one study, FTD was found at autopsy in 18 of 21 patients who had been diagnosed with AD.⁵ Cerebrovascular dementia, Huntington’s disease, Lewy body dementia, and Creutzfeldt-Jakob disease are other differential diagnoses.

Suspect FTD if behavioral symptoms become more prominent than cognitive decline. In one study,⁶ patients with FTD exhibited:

• early loss of social awareness
  
• early loss of personal awareness
  
• progressive loss of speech
  
• stereotyped and perseverative behaviors
  
• and/or hyperorality.
  

Using these criteria, sensitivity for detecting FTD was 63.3% to 73.3%; specificity was 96.7% to 100%.⁶

The authors’ observations

Clinical evaluation for FTD should include a neuropsychiatric assessment, neuropsychological testing, and neuroimaging.

Neuropsychiatric assessment. Unlike AD, cholinergic acetyltransferase and acetylcholinesterase activity is well-preserved in FTD. Serotonergic disturbances are more common in FTD than in AD and are linked to impulsivity, irritability, and changes in affect and eating behavior.

On neuropsychological testing, memory is relatively intact. Orientation and recall of recent personal events is good, but anterograde memory test performance is variable. Patients with FTD often do poorly on recall-based tasks. Spontaneous conversation is often reduced, but patients perform well on semantic-based tasks and visuospatial tests when organizational aspects are minimized.

The MMSE is unreliable for detecting and monitoring patients with FTD. For example, some who require nursing home care have normal MMSE scores.⁴ Frontal executive tasks—such as the Wisconsin Card Sorting Test, Stroop Test, and verbal fluency examinations—can uncover dorsolateral dysfunction. Quantifiable decision-making and risk-taking exercises can reveal orbitobasal dysfunction.⁴

Neuroimaging. MRI shows left temporal lobe atrophy in patients with primary progressive aphasia; both frontal lobes are atrophic in frontal variant FTD. By contrast, the mesial temporal lobes are atrophic in AD.⁷ Frontal and anterior temporal lobe atrophy become more apparent in the latter stages of frontal variant FTD.⁴

Single-photon emission computed tomography (SPECT) using technetium and hexylmethylpropylene amineoxine can detect ventromedial frontal hypoperfusion before atrophy is evident. Order SPECT when the diagnosis is uncertain or the presentation or disease course is unusual.

Treatment: Taking aim at apathy

Donepezil, 10 mg/d, was continued to address Mr. A’s cognitive decline. Bupropion, 100 mg/d, was added to deal with his apathy and low energy. We saw him every 4 months.

Table 2

Medications shown beneficial for treating FTD

Drug	Targeted symptoms	Possible side effects
Donepezil	Cognition functions including memory	Nausea, anorexia, diarrhea, weight loss, sedation, confusion
Dopamine agonist (bromocriptine)	Behavioral disturbances*	Confusion, agitation, hallucinations
SSRIs (sertraline, fluoxetine)	Behavioral disturbances	Nausea, anorexia, diarrhea, weight loss, sexual dysfunction
Stimulants (methylphenidate)	Behavioral disturbances, somnolence	Insomnia, increased irritability, poor appetite, weight loss
Trazodone	Behavioral disturbances	Sedation, orthostasis, priapism
* Apathy, carbohydrate craving, disinhibition, irritability
SSRI: Selective serotonin reuptake inhibitor

Eight months later, Mr. A’s memory has worsened and he has lost several vital skills, such as operating the shower. His wife and daughter confiscated his car keys after he had driven on the wrong side of the road.

On follow-up, Mr. A’s gait is slower, and he has “shakiness” and mild finger clumsiness. Physical exam shows no problems and he is fully oriented, but his MMSE score (17/30) indicates further cognitive loss and he still lacks insight into his condition. Neuropsychological tests reveal:

• marked delays in processing and acting on information
  
• diminished working memory
  
• trouble understanding spatial functions
  
• decreased speech
  
• moderate to severe executive function impairments
  
• severe impairments in fine-motor dexterity, receptive and expressive language, and verbal and visual memory.
  

We also noticed several perseverative behaviors.

Bupropion alleviated Mr. A’s apathy at first, but an increase to 200 mg/d led to tremors and disrupted sleep. Bupropion was decreased to 150 mg/d; we would add a selective serotonin reuptake inhibitor (SSRI) if apathy persisted. We advised his wife and daughter to take him to adult day care and to make sure he does not drive. Follow-up interval is reduced to 2 months.

Eight weeks later, Mr. A is confused and anxious and his affect is remarkably flat, but he behaves appropriately in day care. We stopped bupropion because it did not resolve his apathy.

The authors’ observations

Treat apathy, avolition, anhedonia, social withdrawal, irritability, and/or inappropriate behaviors if these symptoms compromise quality of life for the patient and caregiver. Also try to preserve cognitive function.

Few large-scale clinical trials have addressed FTD pharmacotherapy (Table 2). In an open-label trial, 11 patients with FTD took sertraline, 50 to 125 mg/d, paroxetine, 20 mg/d, or fluoxetine, 20 mg/d. After 3 months, no one’s symptoms worsened and nine patients (82%) had reduced disinhibition, depressive symptoms, carbohydrate craving, and/or compulsions.⁵

In another open-label, uncontrolled trial, behavioral symptoms improved in eight patients with FTD who took paroxetine, up to 20 mg/d for 14 months. Baseline global performance, cognition, and planning scores remained stable, but attention and abstract reasoning were decreased. Side effects were tolerable.⁸

 

In a 12-week crossover study, 26 patients with FTD received placebo or trazodone, 150 or 300 mg/d depending on dose tolerability. Irritability, agitation, depressive symptoms, and/or eating disorders improved significantly in 10 patients, and behavioral disturbances decreased >25% in 16 patients. Trazodone also was well tolerated.⁹

Dopamine use in FTD can contribute to behavioral dysregulation. D₂ blockers occasionally are used to manage behavioral disturbances, but selective dopamine agonists might be more beneficial. Recent studies suggest that bromocriptine, a D₁ and D₂ dopaminergic agonist, may improve select frontal features and perseveration in dementia.¹⁰

In one case report, quantitative EEG correlated with SPECT showed that methylphenidate, dose unknown, helped improve behavior and normalize profoundly imbalanced bifrontotemporal slowing.¹¹

Recommendation. Try sertraline, 50 to 125 mg/d, or fluoxetine, 20 mg/d, to address behavioral symptoms. Paroxetine is another option, but use it cautiously as its anticholinergic properties could cause confusion in older patients. If the patient does not respond to the SSRI after 6 to 8 weeks, try trazodone, 150 to 300 mg/d.

Conclusion: The 15-month mark

We started citalopram, 20 mg/d, to treat Mr. A’s apathy and anxiety; and memantine, 5 mg/d titrated to 10 mg bid, to try to slow his cognitive and functional decline. Donepezil, 10 mg/d, was continued.

We encouraged Mr. A’s wife and daughter to take him to adult day care as often as possible. Mr. A also was placed on a waiting list for a skilled nursing facility.

Mr. A continued to worsen. Fifteen months after initial presentation, he is incontinent of urine and feces and needs help performing most basic ADLs. He continues to overeat and has gained 6.3 pounds over 4 months. His MMSE score (12/30) indicates severe cognitive impairment.

The authors’ observations

Many patients with FTD eventually need long-term placement, a change in environment marked by unfamiliar faces and disrupted routines. Patients often react by becoming disorganized, irritable, and agitated.

No standard method exists to structure this transition for FTD patients. In rare cases, patients have been transferred to secure units for medication management until stabilized.¹²

Help calm the patient’s fears by describing the typical nursing home and the range of services it offers. Arrange a meeting with the patient, primary care physician, and the nursing home’s intake coordinator to review available services. Make sure the patient and caregiver receive brochures and other literature about the facility.

Related resources

• Association for Frontotemporal Dementias. www.ftd-picks.org.
  
• National Institute of Neurological Disorders and Stroke. Pick’s Disease Information Page. Available at: www.ninds.nih.gov/disorders/picks/picks.htm. Accessed Jan. 11, 2005.
  
• Family Caregiver Alliance. Frontotemporal Dementia. Available at: www.caregiver.org/caregiver/jsp/content_node.jsp?nodeid=573&expandnodeid=384. Accessed Jan. 11, 2005.
  

Drug brand names

• Bromocriptine • Parlodel
  
• Bupropion • Wellbutrin
  
• Citalopram • Celexa
  
• Donepezil • Aricept
  
• Fluoxetine • Prozac
  
• Memantine • Namenda
  
• Methylphenidate • Concerta, Ritalin
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  
• 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

This project is supported by the Division of State, Community, and Public Health, Bureau of Health Professions (BHPr), Health Resources and Services Administration (HSRA), Department of Health and Human Services (DHHS) under grant 1 K01 HP 00071-01 and Geriatric Academic Career Award. 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 BPHr, HRSA, DHHS or the U.S. Government.”

Presentation: Strange change

Mr. A, age 66, has lived an active life but now just sits around most of the day. Once an early riser, he is sleeping until 11 AM or noon daily. His wife frequently must motivate him to get out of bed.

Mr. A’s wife describes him as good-natured and extroverted, but she says lately he has also become increasingly withdrawn and quiet. People often think he is angry with them.

His dining habits also have changed. He used to wait until everyone had been served before beginning his meal, but he now starts eating immediately. He often overeats and has gained 15 pounds over 1 year.

Mr. A has always driven manual-transmission vehicles but has trouble remembering how to shift gears on his new car. While visiting his daughter, he could not operate the bathroom faucets properly and scalded himself. His daughter also noticed he does not wash his hands before eating or after toileting.

Findings. Mr. A presents to our clinic at his wife’s and daughter’s insistence but says his memory is fine and he can perform all activities of daily living (ADL). He denies depressive, anxiety, or psychotic symptoms but has hypertension and probable benign prostatic hypertrophy. He is taking ramipril, 5 mg/d for hypertension, donepezil, 10 mg/d for cognitive deficits, and aspirin, 325 mg/d to prevent a heart attack. Physical exam shows no gross neurologic abnormalities. Organ systems are normal.

Mr. A’s Folstein Mini-Mental State Exam (MMSE) score (22/30) indicates cognitive impairment. During his mental status exam, he is pleasant, cooperative, and makes good eye contact. He answers appropriately, but his speech lacks spontaneity. He smiles throughout the interview, even while discussing serious questions regarding his health. He is fully oriented but lacks insight into his deficits.

Brain MRI, ordered after he had presented to another hospital with similar complaints, is normal. PET scan shows frontal lobe hypometabolism, right greater than left, and mild underperfusion of the right basal ganglia and right temporal lobe.

Table 1

Frontotemporal dementia subtypes and their clinical features

Type	Clinical features
Corticobasal degeneration	Onset around age 60
	Symptoms may be unilateral at first and progress slowly
	Poor coordination, akinesia, rigidity, disequilibrium, limb dystonia
	Cognitive and visual-spatial impairments, apraxia, hesitant/halting speech, myoclonus, dysphagia
	Eventual inability to walk
Frontotemporal dementia with motor neuron disease	Behavioral changes, emotional lability
	Decreased spontaneous speech
	Bulbar weakness with dysarthria and dysphagia, weakness, muscle wasting, fasciculations in hands and feet
Frontotemporal dementia with parkinsonism linked to chromosome 17	Behavioral disturbance, cognitive impairment, parkinsonism
	Neurologic symptoms usually arise in patients’ 30s to 50s
Progressive fluent aphasia (semantic dementia)	Trouble remembering words
	Loss of semantic memory, although episodic memory is good
	Symmetric anterolateral temporal atrophy; hippocampal formation relatively intact
	Atrophy usually more pronounced on the left side4
Progressive nonfluent aphasia	Behavioral changes rare
	Global cognition declines over time
	Speech dysfluency, difficulty finding words, phonologic errors in conversation; comprehension is preserved

The authors’ observations

Mr. A’s clinical course suggests frontotemporal dementia (FTD), a spectrum of non-Alzheimer’s dementias characterized by focal atrophy of the brain’s frontal and anterior temporal regions (Table 1). These dementias loosely share clinicopathologic features, including:

• decline in social interpersonal conduct
  
• emotional blunting
  
• loss of insight
  
• disinhibition.¹
  

The histologic profile is characterized by gliosis, neuronal loss, and superficial spongiform degeneration in the frontal and/or temporal cortices. Ballooned neurons (Pick cells) occur with variable frequency in all FTD subtypes.²

FTD is the second most-common cause of dementia after AD in the years preceding old age but remains underdiagnosed. Onset is most common between ages 45 to 65 but can occur before age 30 and in the elderly.

FTD’s clinical presentation usually reflects distribution of pathologic changes rather than a precise histologic subtype. Major clinical presentations include a frontal or behavioral variant (frontal variant FTD associated with corticobasal degeneration or motor neuron disease), a progressive fluent aphasia (temporal lobe variant FTD), and a progressive nonfluent aphasia. Mr. A’s lack of initiative, emotional reactivity, and loss of social graces with normal speech pattern suggest frontal variant FTD.

Behavioral changes associated with FTD include:

• Decline in social conduct, including tactlessness and breaches of etiquette, associated with predominantly right-hemisphere pathology.³
  
• Apathy, which correlates with severity of medial frontal-anterior cingulate involvement.
  
• Dietary changes—typically overeating (hyperorality) with a preference for sweets.⁴
  

Patients also exhibit emotional blunting, echolalia, and attenuated speech output; mutism eventually develops.

Cognitive changes in FTD—attentional deficits, poor abstraction, difficulty shifting mental set, and perseverative tendencies—point to frontal lobe involvement.³

Neurologic signs usually are absent early in the disease, although patients may display primitive reflexes. As FTD progresses, patients may develop parkinsonian signs of akinesia and rigidity, which can be marked. Some develop neurologic signs consistent with motor neuron disease.³

 

Differential diagnosis. FTD is most often mistaken for AD. In one study, FTD was found at autopsy in 18 of 21 patients who had been diagnosed with AD.⁵ Cerebrovascular dementia, Huntington’s disease, Lewy body dementia, and Creutzfeldt-Jakob disease are other differential diagnoses.

Suspect FTD if behavioral symptoms become more prominent than cognitive decline. In one study,⁶ patients with FTD exhibited:

• early loss of social awareness
  
• early loss of personal awareness
  
• progressive loss of speech
  
• stereotyped and perseverative behaviors
  
• and/or hyperorality.
  

Using these criteria, sensitivity for detecting FTD was 63.3% to 73.3%; specificity was 96.7% to 100%.⁶

The authors’ observations

Clinical evaluation for FTD should include a neuropsychiatric assessment, neuropsychological testing, and neuroimaging.

Neuropsychiatric assessment. Unlike AD, cholinergic acetyltransferase and acetylcholinesterase activity is well-preserved in FTD. Serotonergic disturbances are more common in FTD than in AD and are linked to impulsivity, irritability, and changes in affect and eating behavior.

On neuropsychological testing, memory is relatively intact. Orientation and recall of recent personal events is good, but anterograde memory test performance is variable. Patients with FTD often do poorly on recall-based tasks. Spontaneous conversation is often reduced, but patients perform well on semantic-based tasks and visuospatial tests when organizational aspects are minimized.

The MMSE is unreliable for detecting and monitoring patients with FTD. For example, some who require nursing home care have normal MMSE scores.⁴ Frontal executive tasks—such as the Wisconsin Card Sorting Test, Stroop Test, and verbal fluency examinations—can uncover dorsolateral dysfunction. Quantifiable decision-making and risk-taking exercises can reveal orbitobasal dysfunction.⁴

Neuroimaging. MRI shows left temporal lobe atrophy in patients with primary progressive aphasia; both frontal lobes are atrophic in frontal variant FTD. By contrast, the mesial temporal lobes are atrophic in AD.⁷ Frontal and anterior temporal lobe atrophy become more apparent in the latter stages of frontal variant FTD.⁴

Single-photon emission computed tomography (SPECT) using technetium and hexylmethylpropylene amineoxine can detect ventromedial frontal hypoperfusion before atrophy is evident. Order SPECT when the diagnosis is uncertain or the presentation or disease course is unusual.

Treatment: Taking aim at apathy

Donepezil, 10 mg/d, was continued to address Mr. A’s cognitive decline. Bupropion, 100 mg/d, was added to deal with his apathy and low energy. We saw him every 4 months.

Table 2

Medications shown beneficial for treating FTD

Drug	Targeted symptoms	Possible side effects
Donepezil	Cognition functions including memory	Nausea, anorexia, diarrhea, weight loss, sedation, confusion
Dopamine agonist (bromocriptine)	Behavioral disturbances*	Confusion, agitation, hallucinations
SSRIs (sertraline, fluoxetine)	Behavioral disturbances	Nausea, anorexia, diarrhea, weight loss, sexual dysfunction
Stimulants (methylphenidate)	Behavioral disturbances, somnolence	Insomnia, increased irritability, poor appetite, weight loss
Trazodone	Behavioral disturbances	Sedation, orthostasis, priapism
* Apathy, carbohydrate craving, disinhibition, irritability
SSRI: Selective serotonin reuptake inhibitor

Eight months later, Mr. A’s memory has worsened and he has lost several vital skills, such as operating the shower. His wife and daughter confiscated his car keys after he had driven on the wrong side of the road.

On follow-up, Mr. A’s gait is slower, and he has “shakiness” and mild finger clumsiness. Physical exam shows no problems and he is fully oriented, but his MMSE score (17/30) indicates further cognitive loss and he still lacks insight into his condition. Neuropsychological tests reveal:

• marked delays in processing and acting on information
  
• diminished working memory
  
• trouble understanding spatial functions
  
• decreased speech
  
• moderate to severe executive function impairments
  
• severe impairments in fine-motor dexterity, receptive and expressive language, and verbal and visual memory.
  

We also noticed several perseverative behaviors.

Bupropion alleviated Mr. A’s apathy at first, but an increase to 200 mg/d led to tremors and disrupted sleep. Bupropion was decreased to 150 mg/d; we would add a selective serotonin reuptake inhibitor (SSRI) if apathy persisted. We advised his wife and daughter to take him to adult day care and to make sure he does not drive. Follow-up interval is reduced to 2 months.

Eight weeks later, Mr. A is confused and anxious and his affect is remarkably flat, but he behaves appropriately in day care. We stopped bupropion because it did not resolve his apathy.

The authors’ observations

Treat apathy, avolition, anhedonia, social withdrawal, irritability, and/or inappropriate behaviors if these symptoms compromise quality of life for the patient and caregiver. Also try to preserve cognitive function.

Few large-scale clinical trials have addressed FTD pharmacotherapy (Table 2). In an open-label trial, 11 patients with FTD took sertraline, 50 to 125 mg/d, paroxetine, 20 mg/d, or fluoxetine, 20 mg/d. After 3 months, no one’s symptoms worsened and nine patients (82%) had reduced disinhibition, depressive symptoms, carbohydrate craving, and/or compulsions.⁵

In another open-label, uncontrolled trial, behavioral symptoms improved in eight patients with FTD who took paroxetine, up to 20 mg/d for 14 months. Baseline global performance, cognition, and planning scores remained stable, but attention and abstract reasoning were decreased. Side effects were tolerable.⁸

 

In a 12-week crossover study, 26 patients with FTD received placebo or trazodone, 150 or 300 mg/d depending on dose tolerability. Irritability, agitation, depressive symptoms, and/or eating disorders improved significantly in 10 patients, and behavioral disturbances decreased >25% in 16 patients. Trazodone also was well tolerated.⁹

Dopamine use in FTD can contribute to behavioral dysregulation. D₂ blockers occasionally are used to manage behavioral disturbances, but selective dopamine agonists might be more beneficial. Recent studies suggest that bromocriptine, a D₁ and D₂ dopaminergic agonist, may improve select frontal features and perseveration in dementia.¹⁰

In one case report, quantitative EEG correlated with SPECT showed that methylphenidate, dose unknown, helped improve behavior and normalize profoundly imbalanced bifrontotemporal slowing.¹¹

Recommendation. Try sertraline, 50 to 125 mg/d, or fluoxetine, 20 mg/d, to address behavioral symptoms. Paroxetine is another option, but use it cautiously as its anticholinergic properties could cause confusion in older patients. If the patient does not respond to the SSRI after 6 to 8 weeks, try trazodone, 150 to 300 mg/d.

Conclusion: The 15-month mark

We started citalopram, 20 mg/d, to treat Mr. A’s apathy and anxiety; and memantine, 5 mg/d titrated to 10 mg bid, to try to slow his cognitive and functional decline. Donepezil, 10 mg/d, was continued.

We encouraged Mr. A’s wife and daughter to take him to adult day care as often as possible. Mr. A also was placed on a waiting list for a skilled nursing facility.

Mr. A continued to worsen. Fifteen months after initial presentation, he is incontinent of urine and feces and needs help performing most basic ADLs. He continues to overeat and has gained 6.3 pounds over 4 months. His MMSE score (12/30) indicates severe cognitive impairment.

The authors’ observations

Many patients with FTD eventually need long-term placement, a change in environment marked by unfamiliar faces and disrupted routines. Patients often react by becoming disorganized, irritable, and agitated.

No standard method exists to structure this transition for FTD patients. In rare cases, patients have been transferred to secure units for medication management until stabilized.¹²

Help calm the patient’s fears by describing the typical nursing home and the range of services it offers. Arrange a meeting with the patient, primary care physician, and the nursing home’s intake coordinator to review available services. Make sure the patient and caregiver receive brochures and other literature about the facility.

Related resources

• Association for Frontotemporal Dementias. www.ftd-picks.org.
  
• National Institute of Neurological Disorders and Stroke. Pick’s Disease Information Page. Available at: www.ninds.nih.gov/disorders/picks/picks.htm. Accessed Jan. 11, 2005.
  
• Family Caregiver Alliance. Frontotemporal Dementia. Available at: www.caregiver.org/caregiver/jsp/content_node.jsp?nodeid=573&expandnodeid=384. Accessed Jan. 11, 2005.
  

Drug brand names

• Bromocriptine • Parlodel
  
• Bupropion • Wellbutrin
  
• Citalopram • Celexa
  
• Donepezil • Aricept
  
• Fluoxetine • Prozac
  
• Memantine • Namenda
  
• Methylphenidate • Concerta, Ritalin
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  
• 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

This project is supported by the Division of State, Community, and Public Health, Bureau of Health Professions (BHPr), Health Resources and Services Administration (HSRA), Department of Health and Human Services (DHHS) under grant 1 K01 HP 00071-01 and Geriatric Academic Career Award. 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 BPHr, HRSA, DHHS or the U.S. Government.”

Presentation: Strange change

Mr. A, age 66, has lived an active life but now just sits around most of the day. Once an early riser, he is sleeping until 11 AM or noon daily. His wife frequently must motivate him to get out of bed.

Mr. A’s wife describes him as good-natured and extroverted, but she says lately he has also become increasingly withdrawn and quiet. People often think he is angry with them.

His dining habits also have changed. He used to wait until everyone had been served before beginning his meal, but he now starts eating immediately. He often overeats and has gained 15 pounds over 1 year.

Mr. A has always driven manual-transmission vehicles but has trouble remembering how to shift gears on his new car. While visiting his daughter, he could not operate the bathroom faucets properly and scalded himself. His daughter also noticed he does not wash his hands before eating or after toileting.

Findings. Mr. A presents to our clinic at his wife’s and daughter’s insistence but says his memory is fine and he can perform all activities of daily living (ADL). He denies depressive, anxiety, or psychotic symptoms but has hypertension and probable benign prostatic hypertrophy. He is taking ramipril, 5 mg/d for hypertension, donepezil, 10 mg/d for cognitive deficits, and aspirin, 325 mg/d to prevent a heart attack. Physical exam shows no gross neurologic abnormalities. Organ systems are normal.

Mr. A’s Folstein Mini-Mental State Exam (MMSE) score (22/30) indicates cognitive impairment. During his mental status exam, he is pleasant, cooperative, and makes good eye contact. He answers appropriately, but his speech lacks spontaneity. He smiles throughout the interview, even while discussing serious questions regarding his health. He is fully oriented but lacks insight into his deficits.

Brain MRI, ordered after he had presented to another hospital with similar complaints, is normal. PET scan shows frontal lobe hypometabolism, right greater than left, and mild underperfusion of the right basal ganglia and right temporal lobe.

Table 1

Frontotemporal dementia subtypes and their clinical features

Type	Clinical features
Corticobasal degeneration	Onset around age 60
	Symptoms may be unilateral at first and progress slowly
	Poor coordination, akinesia, rigidity, disequilibrium, limb dystonia
	Cognitive and visual-spatial impairments, apraxia, hesitant/halting speech, myoclonus, dysphagia
	Eventual inability to walk
Frontotemporal dementia with motor neuron disease	Behavioral changes, emotional lability
	Decreased spontaneous speech
	Bulbar weakness with dysarthria and dysphagia, weakness, muscle wasting, fasciculations in hands and feet
Frontotemporal dementia with parkinsonism linked to chromosome 17	Behavioral disturbance, cognitive impairment, parkinsonism
	Neurologic symptoms usually arise in patients’ 30s to 50s
Progressive fluent aphasia (semantic dementia)	Trouble remembering words
	Loss of semantic memory, although episodic memory is good
	Symmetric anterolateral temporal atrophy; hippocampal formation relatively intact
	Atrophy usually more pronounced on the left side4
Progressive nonfluent aphasia	Behavioral changes rare
	Global cognition declines over time
	Speech dysfluency, difficulty finding words, phonologic errors in conversation; comprehension is preserved

The authors’ observations

Mr. A’s clinical course suggests frontotemporal dementia (FTD), a spectrum of non-Alzheimer’s dementias characterized by focal atrophy of the brain’s frontal and anterior temporal regions (Table 1). These dementias loosely share clinicopathologic features, including:

• decline in social interpersonal conduct
  
• emotional blunting
  
• loss of insight
  
• disinhibition.¹
  

The histologic profile is characterized by gliosis, neuronal loss, and superficial spongiform degeneration in the frontal and/or temporal cortices. Ballooned neurons (Pick cells) occur with variable frequency in all FTD subtypes.²

FTD is the second most-common cause of dementia after AD in the years preceding old age but remains underdiagnosed. Onset is most common between ages 45 to 65 but can occur before age 30 and in the elderly.

FTD’s clinical presentation usually reflects distribution of pathologic changes rather than a precise histologic subtype. Major clinical presentations include a frontal or behavioral variant (frontal variant FTD associated with corticobasal degeneration or motor neuron disease), a progressive fluent aphasia (temporal lobe variant FTD), and a progressive nonfluent aphasia. Mr. A’s lack of initiative, emotional reactivity, and loss of social graces with normal speech pattern suggest frontal variant FTD.

Behavioral changes associated with FTD include:

• Decline in social conduct, including tactlessness and breaches of etiquette, associated with predominantly right-hemisphere pathology.³
  
• Apathy, which correlates with severity of medial frontal-anterior cingulate involvement.
  
• Dietary changes—typically overeating (hyperorality) with a preference for sweets.⁴
  

Patients also exhibit emotional blunting, echolalia, and attenuated speech output; mutism eventually develops.

Cognitive changes in FTD—attentional deficits, poor abstraction, difficulty shifting mental set, and perseverative tendencies—point to frontal lobe involvement.³

Neurologic signs usually are absent early in the disease, although patients may display primitive reflexes. As FTD progresses, patients may develop parkinsonian signs of akinesia and rigidity, which can be marked. Some develop neurologic signs consistent with motor neuron disease.³

 

Differential diagnosis. FTD is most often mistaken for AD. In one study, FTD was found at autopsy in 18 of 21 patients who had been diagnosed with AD.⁵ Cerebrovascular dementia, Huntington’s disease, Lewy body dementia, and Creutzfeldt-Jakob disease are other differential diagnoses.

Suspect FTD if behavioral symptoms become more prominent than cognitive decline. In one study,⁶ patients with FTD exhibited:

• early loss of social awareness
  
• early loss of personal awareness
  
• progressive loss of speech
  
• stereotyped and perseverative behaviors
  
• and/or hyperorality.
  

Using these criteria, sensitivity for detecting FTD was 63.3% to 73.3%; specificity was 96.7% to 100%.⁶

The authors’ observations

Clinical evaluation for FTD should include a neuropsychiatric assessment, neuropsychological testing, and neuroimaging.

Neuropsychiatric assessment. Unlike AD, cholinergic acetyltransferase and acetylcholinesterase activity is well-preserved in FTD. Serotonergic disturbances are more common in FTD than in AD and are linked to impulsivity, irritability, and changes in affect and eating behavior.

On neuropsychological testing, memory is relatively intact. Orientation and recall of recent personal events is good, but anterograde memory test performance is variable. Patients with FTD often do poorly on recall-based tasks. Spontaneous conversation is often reduced, but patients perform well on semantic-based tasks and visuospatial tests when organizational aspects are minimized.

The MMSE is unreliable for detecting and monitoring patients with FTD. For example, some who require nursing home care have normal MMSE scores.⁴ Frontal executive tasks—such as the Wisconsin Card Sorting Test, Stroop Test, and verbal fluency examinations—can uncover dorsolateral dysfunction. Quantifiable decision-making and risk-taking exercises can reveal orbitobasal dysfunction.⁴

Neuroimaging. MRI shows left temporal lobe atrophy in patients with primary progressive aphasia; both frontal lobes are atrophic in frontal variant FTD. By contrast, the mesial temporal lobes are atrophic in AD.⁷ Frontal and anterior temporal lobe atrophy become more apparent in the latter stages of frontal variant FTD.⁴

Single-photon emission computed tomography (SPECT) using technetium and hexylmethylpropylene amineoxine can detect ventromedial frontal hypoperfusion before atrophy is evident. Order SPECT when the diagnosis is uncertain or the presentation or disease course is unusual.

Treatment: Taking aim at apathy

Donepezil, 10 mg/d, was continued to address Mr. A’s cognitive decline. Bupropion, 100 mg/d, was added to deal with his apathy and low energy. We saw him every 4 months.

Table 2

Medications shown beneficial for treating FTD

Drug	Targeted symptoms	Possible side effects
Donepezil	Cognition functions including memory	Nausea, anorexia, diarrhea, weight loss, sedation, confusion
Dopamine agonist (bromocriptine)	Behavioral disturbances*	Confusion, agitation, hallucinations
SSRIs (sertraline, fluoxetine)	Behavioral disturbances	Nausea, anorexia, diarrhea, weight loss, sexual dysfunction
Stimulants (methylphenidate)	Behavioral disturbances, somnolence	Insomnia, increased irritability, poor appetite, weight loss
Trazodone	Behavioral disturbances	Sedation, orthostasis, priapism
* Apathy, carbohydrate craving, disinhibition, irritability
SSRI: Selective serotonin reuptake inhibitor

Eight months later, Mr. A’s memory has worsened and he has lost several vital skills, such as operating the shower. His wife and daughter confiscated his car keys after he had driven on the wrong side of the road.

On follow-up, Mr. A’s gait is slower, and he has “shakiness” and mild finger clumsiness. Physical exam shows no problems and he is fully oriented, but his MMSE score (17/30) indicates further cognitive loss and he still lacks insight into his condition. Neuropsychological tests reveal:

• marked delays in processing and acting on information
  
• diminished working memory
  
• trouble understanding spatial functions
  
• decreased speech
  
• moderate to severe executive function impairments
  
• severe impairments in fine-motor dexterity, receptive and expressive language, and verbal and visual memory.
  

We also noticed several perseverative behaviors.

Bupropion alleviated Mr. A’s apathy at first, but an increase to 200 mg/d led to tremors and disrupted sleep. Bupropion was decreased to 150 mg/d; we would add a selective serotonin reuptake inhibitor (SSRI) if apathy persisted. We advised his wife and daughter to take him to adult day care and to make sure he does not drive. Follow-up interval is reduced to 2 months.

Eight weeks later, Mr. A is confused and anxious and his affect is remarkably flat, but he behaves appropriately in day care. We stopped bupropion because it did not resolve his apathy.

The authors’ observations

Treat apathy, avolition, anhedonia, social withdrawal, irritability, and/or inappropriate behaviors if these symptoms compromise quality of life for the patient and caregiver. Also try to preserve cognitive function.

Few large-scale clinical trials have addressed FTD pharmacotherapy (Table 2). In an open-label trial, 11 patients with FTD took sertraline, 50 to 125 mg/d, paroxetine, 20 mg/d, or fluoxetine, 20 mg/d. After 3 months, no one’s symptoms worsened and nine patients (82%) had reduced disinhibition, depressive symptoms, carbohydrate craving, and/or compulsions.⁵

In another open-label, uncontrolled trial, behavioral symptoms improved in eight patients with FTD who took paroxetine, up to 20 mg/d for 14 months. Baseline global performance, cognition, and planning scores remained stable, but attention and abstract reasoning were decreased. Side effects were tolerable.⁸

 

In a 12-week crossover study, 26 patients with FTD received placebo or trazodone, 150 or 300 mg/d depending on dose tolerability. Irritability, agitation, depressive symptoms, and/or eating disorders improved significantly in 10 patients, and behavioral disturbances decreased >25% in 16 patients. Trazodone also was well tolerated.⁹

Dopamine use in FTD can contribute to behavioral dysregulation. D₂ blockers occasionally are used to manage behavioral disturbances, but selective dopamine agonists might be more beneficial. Recent studies suggest that bromocriptine, a D₁ and D₂ dopaminergic agonist, may improve select frontal features and perseveration in dementia.¹⁰

In one case report, quantitative EEG correlated with SPECT showed that methylphenidate, dose unknown, helped improve behavior and normalize profoundly imbalanced bifrontotemporal slowing.¹¹

Recommendation. Try sertraline, 50 to 125 mg/d, or fluoxetine, 20 mg/d, to address behavioral symptoms. Paroxetine is another option, but use it cautiously as its anticholinergic properties could cause confusion in older patients. If the patient does not respond to the SSRI after 6 to 8 weeks, try trazodone, 150 to 300 mg/d.

Conclusion: The 15-month mark

We started citalopram, 20 mg/d, to treat Mr. A’s apathy and anxiety; and memantine, 5 mg/d titrated to 10 mg bid, to try to slow his cognitive and functional decline. Donepezil, 10 mg/d, was continued.

We encouraged Mr. A’s wife and daughter to take him to adult day care as often as possible. Mr. A also was placed on a waiting list for a skilled nursing facility.

Mr. A continued to worsen. Fifteen months after initial presentation, he is incontinent of urine and feces and needs help performing most basic ADLs. He continues to overeat and has gained 6.3 pounds over 4 months. His MMSE score (12/30) indicates severe cognitive impairment.

The authors’ observations

Many patients with FTD eventually need long-term placement, a change in environment marked by unfamiliar faces and disrupted routines. Patients often react by becoming disorganized, irritable, and agitated.

No standard method exists to structure this transition for FTD patients. In rare cases, patients have been transferred to secure units for medication management until stabilized.¹²

Help calm the patient’s fears by describing the typical nursing home and the range of services it offers. Arrange a meeting with the patient, primary care physician, and the nursing home’s intake coordinator to review available services. Make sure the patient and caregiver receive brochures and other literature about the facility.

Related resources

• Association for Frontotemporal Dementias. www.ftd-picks.org.
  
• National Institute of Neurological Disorders and Stroke. Pick’s Disease Information Page. Available at: www.ninds.nih.gov/disorders/picks/picks.htm. Accessed Jan. 11, 2005.
  
• Family Caregiver Alliance. Frontotemporal Dementia. Available at: www.caregiver.org/caregiver/jsp/content_node.jsp?nodeid=573&expandnodeid=384. Accessed Jan. 11, 2005.
  

Drug brand names

• Bromocriptine • Parlodel
  
• Bupropion • Wellbutrin
  
• Citalopram • Celexa
  
• Donepezil • Aricept
  
• Fluoxetine • Prozac
  
• Memantine • Namenda
  
• Methylphenidate • Concerta, Ritalin
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  
• 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

This project is supported by the Division of State, Community, and Public Health, Bureau of Health Professions (BHPr), Health Resources and Services Administration (HSRA), Department of Health and Human Services (DHHS) under grant 1 K01 HP 00071-01 and Geriatric Academic Career Award. 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 BPHr, HRSA, DHHS or the U.S. Government.”

History: A mite disturbing

Mrs. K, age 60, a social worker, saw mites on her arm 3 months ago while going through a client’s old belongings. Since then, she reports, she and her house have become infested with mites.

Despite using copious amounts of lotions, baths, sprays, and prescription creams, she sees increasingly visible “creatures” all over her body and in her stool. Three doctors found no physical evidence of infestation, however, and she became indignant after one told her the problem is “in her head.”

A veterinarian treated Mrs. K’s cat for mites. Days later, Mrs. K suspected that the cat had become reinfested at home and returned it to the veterinarian. He assured her the cat was fine, but she was afraid to bring it home. The cat has remained at the veterinarian’s office—to the doctor’s displeasure—for weeks.

Two weeks after Mrs. K first spotted the mites, her husband, age 82, started believing he is infested. Mr. K, who is retired, has battled depression and drinks about a half-gallon of liquor daily.

After 2 months, Mrs. K quit her job for fear she would infest her co-workers, then locked herself and her husband in their house and allowed no visitors. Day and night for nearly 3 weeks, Mrs. K repeatedly vacuumed the house, shampooed the carpets, and sprayed the walls and furniture with a homemade insecticide. She taped the windows closed to keep bugs out and covered all furniture and surface areas with plastic. A toxic stench of insecticide and shampoo permeated every room.

A neighbor told Mrs. K’s son that his parents were locked inside their house. He came over and knocked on their door, but was refused entry. He eventually got Mrs. K out by threatening to call the police, then brought her to the emergency room.

At presentation, Mrs. K’s right leg has scratches and scabs caused by frequent scratching at mites she saw there. Her hands are reddened and dry, suggesting chemical dermatitis caused by cleaning and repeated insecticide use. Ritual cleaning and spraying has kept her from eating or sleeping; she has lost 12 lbs over 3 weeks and looks pale and tired.

A recovered alcoholic, Mrs. K has been sober for 12 years. She has no other psychiatric, medical, or dermatologic history, and has few social contacts beyond her family and workplace acquaintances.

Blood chemistry, CBC, and urine drug test results are normal. Head MRI reveal no neurologic abnormalities. Her Mini-Mental State Examination (MMSE) score (29/30) indicates no cognitive impairment.

Mrs. K is hospitalized to separate her from her allegedly bug-infested household and husband. At intake, she is panicked over leaving her husband alone and distressed that no one except she and her husband can see the bugs infesting their house and covering her skin. She asks doctors to test a small piece of toilet paper, which she says contains a sample of the bugs. She also fears that she infested her son by letting him into her house.

poll here

The authors’ observations

Mrs. K’s presentation and clinical course suggest delusional parasitosis, a fixed false belief of a parasitic infestation that can cause significant social and occupational dysfunction and medical problems. One patient calls this disorder “bugaphobia.”

The disorder may start as a self-perceived invisible infestation and evolve into visual hallucinations of bugs. Patients usually believe their skin is infested; some believe their internal organs, gums, or skin and internal organs are infested.^1,2

Table 1

Medical conditions that may precede delusional parasitosis

Anemia (severe)
Cancer
CNS infections
Head injury
Hepatitis
Hypertension
Hypovitaminosis of vitamin B12, folate, or thiamine
Multiple sclerosis
Pulmonary disease
Renal disease
Rheumatologic disease
Sight or hearing loss
Source: Reference 6

Skin lesions can result, including physical trauma from picking at sites the patient believes is infested. Some patients have sustained ocular trauma from picking at their eyes, which they believed contained insects.² At least one patient, depressed after failing to kill the parasites, killed himself.¹ As with Mrs. K, profuse use of insecticides or topical sprays can cause chemical dermatitis. Many patients isolate themselves to avoid infesting others.³

Some patients misinterpret scabs, abrasions, or skin irritation secondary to pesticide use as signs of infestation. Delusional parasitosis can also develop after a real, one-time infestation, as may have happened with Mrs. K.

Convinced they are infested, patients consult multiple providers—including dermatologists, gastroenterologists, and ophthalmologists—in search of the “right” treatment. They undergo numerous tests or procedures and repeatedly apply prescription creams and lotions, leading to chemical dermatitis. Patients often try to prove they are infested by bringing skin, dirt, or toilet tissue samples to doctors—this is called the “matchbox sign” because patients generally bring these samples in small boxes.⁴ They also may repeatedly ask veterinarians to disinfest their pets.

 

Box

Patients, however, do not believe the disorder is psychiatric⁵ and resist seeing a psychiatrist. Often a primary care physician or dermatologist calls on a psychiatrist as a consultant,⁶ as happened here.

Delusional parasitosis is most often found in socially isolated women age >40 of average or higher intelligence. Persons in some cultures may be more susceptible than others to some types of parasitic delusions. For example, several persons in India who considered ear cleanliness crucial to attaining cultural and spiritual purity reported having ear infestation.⁷

Delusional parasitosis also is associated with:

• medical conditions (Table 1)⁶
  
• use of cocaine, amphetamines,⁸ corticosteroids,^3,9 or phenelzine¹⁰
  
• occipital-temporal cerebral infarction¹¹
  
• cognitive impairment related to dementia, depression, mental retardation, or schizophrenia/schizophreniform disorder.
  

Cognitive impairment secondary to a medical problem may foster the delusion, or the patient may misinterpret a physical symptom as evidence of internal infestation. For example, a patient with chronic stomach pain may think he has bugs in his gut.⁵

Mrs. K’s delusional parasitosis may be a primary psychiatric disorder (Box). She is medically healthy and does not use drugs or alcohol. Her MMSE score is essentially normal, and she exhibited no psychotic symptoms or loss of function before her first mite sighting.

Diagnosis. Delusional parasitosis is diagnosed as delusional disorder, somatic type, if symptoms persist >1 month. Thorough laboratory and neurologic evaluation is recommended to rule out medical causes (Table 2). Eliminate schizophrenia and schizophreniform disorder with a detailed patient history and cognitive testing.

Also check for a comorbid psychiatric disorder that may be perpetuating the delusion. Delusional parasitosis often co-occurs with axis I disorders including major depressive disorder, substance abuse, dementia, and mental retardation.

poll here

The authors’ observations

Mr. K’s “bugaphobia” most likely was a form of shared secondary delusion called folie-a-deux. Between 11% and 25% of persons with primary delusional parasitosis induce secondary delusional parasitosis in another person, usually a spouse or longtime friend.² About 50% of folie-a-deux disorders involve a married couple. Often both partners are socially isolated.⁴

poll here

Treatment: Between two worlds

Mrs. K was given risperidone, 2 mg/d, for delusions and anxiety, and escitalopram, 10 mg/d, preventatively for a suspected underlying depression.

As her symptoms began to clear across 2 to 3 days, Mrs. K realized most times that she was not infested, but on occasion still feared that she was. She continued to worry about her husband being alone in a mite-infested house. We reassured her that her husband would be OK and told her to let us know if the mites resurfaced on her skin.

The authors’ observations

Building rapport. When treating delusional parasitosis, be accepting and non-confrontational. These patients tend to switch doctors until they find someone who understands their problem. Developing rapport can promote treatment adherence and prevent or minimize relapse.

Table 2

5 steps to confirm ‘bugaphobia’

Rule out infestation with skin scrapings/biopsy Get a thorough alcohol and drug use history to rule out substance abuse/dependence (particularly stimulant use) Perform a complete physical examination Order a CBC, urinalysis, liver function tests, thyroid function test, vitamin B 12 , folate, iron studies, blood urea nitrogen, serum electrolytes, and glucose to screen for associated medicalconditions Order head CT or MRI to rule out infarction or mass

Source: Adapted from Driscoll MS, Rothe MJ, Grant-Kels JM, Hale MS. Delusions of parasitosis: a dermatologic, psychiatric, and pharmacologic approach. J Am Acad Dermatol 1993;29:1023-33.

Start by getting the patient to leave the environment that feeds the delusion. Tell the patient, for example, “The hospital may have experts on your disorder who can help you.” Hospitalize the patient if he or she cannot function independently or will not leave the offending environment. Wait 1 to 2 days before starting medication to see if symptoms remit spontaneously, which they frequently do.

 

⁴

Also communicate with other specialists to gauge medication history, confirm test findings, and rule out medical causes.

Pharmacotherapy. If symptoms do not resolve after 1 or 2 days of observation, look for a comorbid medical or mental disorder. Prescribe an atypical antipsychotic such as risperidone, 2 to 4 mg/d, or olanzapine, 2.5 mg/d, both of which have been effective against delusional parasitosis.^14,16 Keep dosages low to reduce risk of sedation, extrapyramidal symptoms (EPS), and tardive dyskinesia.

Suggesting a psychotropic to patients who are convinced their problem is not psychiatric can be difficult. Try saying:

• Some people are more sensitive than others to sensations on their skin or in their body. This medication will help you tolerate the sensations.”
  
• or, “This drug will help reduce the anxiety your problem is causing.”
  

If symptoms persist another 3 days, try a different atypical or a conventional neuroleptic. Watch for EPS or other neuroleptic-related side effects in patients age >65.

Pimozide has shown efficacy against delusional parasitosis in placebo-controlled trials,^17,18 but it can alter cardiac conduction, especially at higherthan-recommended dosages. Start pimozide at 1 mg/d and increase by 1 mg/week until clinical response is achieved. Most patients respond to dosages used to treat psychotic disorders (4 to 10 mg/d).¹⁹ Order a baseline and periodic ECG to monitor for QTc prolongation, and do an abnormal involuntary movement scale examination every 3 to 6 months to test for EPS.

Other treatments that have shown benefit in case reports include naloxone, 10 mg/d;²⁰ haloperidol, 10 mg/d; trifluoperazine, 15 mg/d; chlorpromazine, 150 to 300 mg/d; and electroconvulsive therapy.⁷

We have found that prognosis usually is poor after first- and second-line treatments have failed. Continue to search for a missed disorder, and add an antidepressant if an underlying depression is found or suspected.

Psychotherapy. Perform supportive and harm reduction psychotherapy immediately after diagnosis. Supportive, rapport-building approaches can get the patient to comfortably discuss the issues that led to the delusion and help him/her confront a relapse. Harm reduction can discourage patients from requesting unnecessary invasive tests, using medications and toxic insecticides, or other potentially harmful behaviors.

Cognitive-behavioral therapy may help some patients with refractory delusional parasitosis, if they have enough insight to continue treatment.

Follow-up: A bug-free future

Mrs. K was released from the hospital after 4 days, and her delusional symptoms were gone after another 3 days. We followed her for 6 months.

Upon discharge, Mrs. K and her cat moved in with her daughter’s family. Within a few weeks she was able to visit her workplace and explain what had happened. She stopped taking risperidone after 2 weeks because of excessive sedation. No depressive symptoms were present after 3 months; escitalopram was stopped.

Mrs. K’s husband continued to drink and confine himself to the house. Upon visiting him, she was horrified to find the furniture still covered with plastic and the windows taped shut. Mrs. K threatened to divorce him if he did not seek help. He eventually was treated and has been sober—and bug-free—for 15 months.

Related resources

• Bohart Museum of Entomology, University of California, Davis: Delusional parasitosis. http://delusion.ucdavis.edu.
  

Drug brand names

• Chlorpromazine • Thorazine
  
• Escitalopram • Lexapro
  
• Haloperidol • Haldol
  
• naloxone • Narcan
  
• Olanzapine • Zyprexa
  
• Pimozide • Orap
  
• Phenelzine • Nardil
  
• Risperidone • Risperdal
  
• Trifluoperazine • Stelazine
  

Disclosure

Dr. Matthews is an American Psychiatric Association Bristol-Myers Squibb Co. fellow in public and community psychiatry.

Dr. Hauser receives research/grant support from and is a speaker for AstraZeneca Pharmaceuticals, Eli Lilly and Co., GlaxoSmithKline, and Hoffman LaRoche. He is also receives research/grant support from Schering-Plough Corp. and is a speaker for Abbott Laboratories and Janssen Pharmaceutica.

History: A mite disturbing

Mrs. K, age 60, a social worker, saw mites on her arm 3 months ago while going through a client’s old belongings. Since then, she reports, she and her house have become infested with mites.

Despite using copious amounts of lotions, baths, sprays, and prescription creams, she sees increasingly visible “creatures” all over her body and in her stool. Three doctors found no physical evidence of infestation, however, and she became indignant after one told her the problem is “in her head.”

A veterinarian treated Mrs. K’s cat for mites. Days later, Mrs. K suspected that the cat had become reinfested at home and returned it to the veterinarian. He assured her the cat was fine, but she was afraid to bring it home. The cat has remained at the veterinarian’s office—to the doctor’s displeasure—for weeks.

Two weeks after Mrs. K first spotted the mites, her husband, age 82, started believing he is infested. Mr. K, who is retired, has battled depression and drinks about a half-gallon of liquor daily.

After 2 months, Mrs. K quit her job for fear she would infest her co-workers, then locked herself and her husband in their house and allowed no visitors. Day and night for nearly 3 weeks, Mrs. K repeatedly vacuumed the house, shampooed the carpets, and sprayed the walls and furniture with a homemade insecticide. She taped the windows closed to keep bugs out and covered all furniture and surface areas with plastic. A toxic stench of insecticide and shampoo permeated every room.

A neighbor told Mrs. K’s son that his parents were locked inside their house. He came over and knocked on their door, but was refused entry. He eventually got Mrs. K out by threatening to call the police, then brought her to the emergency room.

At presentation, Mrs. K’s right leg has scratches and scabs caused by frequent scratching at mites she saw there. Her hands are reddened and dry, suggesting chemical dermatitis caused by cleaning and repeated insecticide use. Ritual cleaning and spraying has kept her from eating or sleeping; she has lost 12 lbs over 3 weeks and looks pale and tired.

A recovered alcoholic, Mrs. K has been sober for 12 years. She has no other psychiatric, medical, or dermatologic history, and has few social contacts beyond her family and workplace acquaintances.

Blood chemistry, CBC, and urine drug test results are normal. Head MRI reveal no neurologic abnormalities. Her Mini-Mental State Examination (MMSE) score (29/30) indicates no cognitive impairment.

Mrs. K is hospitalized to separate her from her allegedly bug-infested household and husband. At intake, she is panicked over leaving her husband alone and distressed that no one except she and her husband can see the bugs infesting their house and covering her skin. She asks doctors to test a small piece of toilet paper, which she says contains a sample of the bugs. She also fears that she infested her son by letting him into her house.

poll here

The authors’ observations

Mrs. K’s presentation and clinical course suggest delusional parasitosis, a fixed false belief of a parasitic infestation that can cause significant social and occupational dysfunction and medical problems. One patient calls this disorder “bugaphobia.”

The disorder may start as a self-perceived invisible infestation and evolve into visual hallucinations of bugs. Patients usually believe their skin is infested; some believe their internal organs, gums, or skin and internal organs are infested.^1,2

Table 1

Medical conditions that may precede delusional parasitosis

Anemia (severe)
Cancer
CNS infections
Head injury
Hepatitis
Hypertension
Hypovitaminosis of vitamin B12, folate, or thiamine
Multiple sclerosis
Pulmonary disease
Renal disease
Rheumatologic disease
Sight or hearing loss
Source: Reference 6

Skin lesions can result, including physical trauma from picking at sites the patient believes is infested. Some patients have sustained ocular trauma from picking at their eyes, which they believed contained insects.² At least one patient, depressed after failing to kill the parasites, killed himself.¹ As with Mrs. K, profuse use of insecticides or topical sprays can cause chemical dermatitis. Many patients isolate themselves to avoid infesting others.³

Some patients misinterpret scabs, abrasions, or skin irritation secondary to pesticide use as signs of infestation. Delusional parasitosis can also develop after a real, one-time infestation, as may have happened with Mrs. K.

Convinced they are infested, patients consult multiple providers—including dermatologists, gastroenterologists, and ophthalmologists—in search of the “right” treatment. They undergo numerous tests or procedures and repeatedly apply prescription creams and lotions, leading to chemical dermatitis. Patients often try to prove they are infested by bringing skin, dirt, or toilet tissue samples to doctors—this is called the “matchbox sign” because patients generally bring these samples in small boxes.⁴ They also may repeatedly ask veterinarians to disinfest their pets.

 

Box

Patients, however, do not believe the disorder is psychiatric⁵ and resist seeing a psychiatrist. Often a primary care physician or dermatologist calls on a psychiatrist as a consultant,⁶ as happened here.

Delusional parasitosis is most often found in socially isolated women age >40 of average or higher intelligence. Persons in some cultures may be more susceptible than others to some types of parasitic delusions. For example, several persons in India who considered ear cleanliness crucial to attaining cultural and spiritual purity reported having ear infestation.⁷

Delusional parasitosis also is associated with:

• medical conditions (Table 1)⁶
  
• use of cocaine, amphetamines,⁸ corticosteroids,^3,9 or phenelzine¹⁰
  
• occipital-temporal cerebral infarction¹¹
  
• cognitive impairment related to dementia, depression, mental retardation, or schizophrenia/schizophreniform disorder.
  

Cognitive impairment secondary to a medical problem may foster the delusion, or the patient may misinterpret a physical symptom as evidence of internal infestation. For example, a patient with chronic stomach pain may think he has bugs in his gut.⁵

Mrs. K’s delusional parasitosis may be a primary psychiatric disorder (Box). She is medically healthy and does not use drugs or alcohol. Her MMSE score is essentially normal, and she exhibited no psychotic symptoms or loss of function before her first mite sighting.

Diagnosis. Delusional parasitosis is diagnosed as delusional disorder, somatic type, if symptoms persist >1 month. Thorough laboratory and neurologic evaluation is recommended to rule out medical causes (Table 2). Eliminate schizophrenia and schizophreniform disorder with a detailed patient history and cognitive testing.

Also check for a comorbid psychiatric disorder that may be perpetuating the delusion. Delusional parasitosis often co-occurs with axis I disorders including major depressive disorder, substance abuse, dementia, and mental retardation.

poll here

The authors’ observations

Mr. K’s “bugaphobia” most likely was a form of shared secondary delusion called folie-a-deux. Between 11% and 25% of persons with primary delusional parasitosis induce secondary delusional parasitosis in another person, usually a spouse or longtime friend.² About 50% of folie-a-deux disorders involve a married couple. Often both partners are socially isolated.⁴

poll here

Treatment: Between two worlds

Mrs. K was given risperidone, 2 mg/d, for delusions and anxiety, and escitalopram, 10 mg/d, preventatively for a suspected underlying depression.

As her symptoms began to clear across 2 to 3 days, Mrs. K realized most times that she was not infested, but on occasion still feared that she was. She continued to worry about her husband being alone in a mite-infested house. We reassured her that her husband would be OK and told her to let us know if the mites resurfaced on her skin.

The authors’ observations

Building rapport. When treating delusional parasitosis, be accepting and non-confrontational. These patients tend to switch doctors until they find someone who understands their problem. Developing rapport can promote treatment adherence and prevent or minimize relapse.

Table 2

5 steps to confirm ‘bugaphobia’

Rule out infestation with skin scrapings/biopsy Get a thorough alcohol and drug use history to rule out substance abuse/dependence (particularly stimulant use) Perform a complete physical examination Order a CBC, urinalysis, liver function tests, thyroid function test, vitamin B 12 , folate, iron studies, blood urea nitrogen, serum electrolytes, and glucose to screen for associated medicalconditions Order head CT or MRI to rule out infarction or mass

Source: Adapted from Driscoll MS, Rothe MJ, Grant-Kels JM, Hale MS. Delusions of parasitosis: a dermatologic, psychiatric, and pharmacologic approach. J Am Acad Dermatol 1993;29:1023-33.

Start by getting the patient to leave the environment that feeds the delusion. Tell the patient, for example, “The hospital may have experts on your disorder who can help you.” Hospitalize the patient if he or she cannot function independently or will not leave the offending environment. Wait 1 to 2 days before starting medication to see if symptoms remit spontaneously, which they frequently do.

 

⁴

Also communicate with other specialists to gauge medication history, confirm test findings, and rule out medical causes.

Pharmacotherapy. If symptoms do not resolve after 1 or 2 days of observation, look for a comorbid medical or mental disorder. Prescribe an atypical antipsychotic such as risperidone, 2 to 4 mg/d, or olanzapine, 2.5 mg/d, both of which have been effective against delusional parasitosis.^14,16 Keep dosages low to reduce risk of sedation, extrapyramidal symptoms (EPS), and tardive dyskinesia.

Suggesting a psychotropic to patients who are convinced their problem is not psychiatric can be difficult. Try saying:

• Some people are more sensitive than others to sensations on their skin or in their body. This medication will help you tolerate the sensations.”
  
• or, “This drug will help reduce the anxiety your problem is causing.”
  

If symptoms persist another 3 days, try a different atypical or a conventional neuroleptic. Watch for EPS or other neuroleptic-related side effects in patients age >65.

Pimozide has shown efficacy against delusional parasitosis in placebo-controlled trials,^17,18 but it can alter cardiac conduction, especially at higherthan-recommended dosages. Start pimozide at 1 mg/d and increase by 1 mg/week until clinical response is achieved. Most patients respond to dosages used to treat psychotic disorders (4 to 10 mg/d).¹⁹ Order a baseline and periodic ECG to monitor for QTc prolongation, and do an abnormal involuntary movement scale examination every 3 to 6 months to test for EPS.

Other treatments that have shown benefit in case reports include naloxone, 10 mg/d;²⁰ haloperidol, 10 mg/d; trifluoperazine, 15 mg/d; chlorpromazine, 150 to 300 mg/d; and electroconvulsive therapy.⁷

We have found that prognosis usually is poor after first- and second-line treatments have failed. Continue to search for a missed disorder, and add an antidepressant if an underlying depression is found or suspected.

Psychotherapy. Perform supportive and harm reduction psychotherapy immediately after diagnosis. Supportive, rapport-building approaches can get the patient to comfortably discuss the issues that led to the delusion and help him/her confront a relapse. Harm reduction can discourage patients from requesting unnecessary invasive tests, using medications and toxic insecticides, or other potentially harmful behaviors.

Cognitive-behavioral therapy may help some patients with refractory delusional parasitosis, if they have enough insight to continue treatment.

Follow-up: A bug-free future

Mrs. K was released from the hospital after 4 days, and her delusional symptoms were gone after another 3 days. We followed her for 6 months.

Upon discharge, Mrs. K and her cat moved in with her daughter’s family. Within a few weeks she was able to visit her workplace and explain what had happened. She stopped taking risperidone after 2 weeks because of excessive sedation. No depressive symptoms were present after 3 months; escitalopram was stopped.

Mrs. K’s husband continued to drink and confine himself to the house. Upon visiting him, she was horrified to find the furniture still covered with plastic and the windows taped shut. Mrs. K threatened to divorce him if he did not seek help. He eventually was treated and has been sober—and bug-free—for 15 months.

Related resources

• Bohart Museum of Entomology, University of California, Davis: Delusional parasitosis. http://delusion.ucdavis.edu.
  

Drug brand names

• Chlorpromazine • Thorazine
  
• Escitalopram • Lexapro
  
• Haloperidol • Haldol
  
• naloxone • Narcan
  
• Olanzapine • Zyprexa
  
• Pimozide • Orap
  
• Phenelzine • Nardil
  
• Risperidone • Risperdal
  
• Trifluoperazine • Stelazine
  

Disclosure

Dr. Matthews is an American Psychiatric Association Bristol-Myers Squibb Co. fellow in public and community psychiatry.

Dr. Hauser receives research/grant support from and is a speaker for AstraZeneca Pharmaceuticals, Eli Lilly and Co., GlaxoSmithKline, and Hoffman LaRoche. He is also receives research/grant support from Schering-Plough Corp. and is a speaker for Abbott Laboratories and Janssen Pharmaceutica.

History: A mite disturbing

Mrs. K, age 60, a social worker, saw mites on her arm 3 months ago while going through a client’s old belongings. Since then, she reports, she and her house have become infested with mites.

Despite using copious amounts of lotions, baths, sprays, and prescription creams, she sees increasingly visible “creatures” all over her body and in her stool. Three doctors found no physical evidence of infestation, however, and she became indignant after one told her the problem is “in her head.”

A veterinarian treated Mrs. K’s cat for mites. Days later, Mrs. K suspected that the cat had become reinfested at home and returned it to the veterinarian. He assured her the cat was fine, but she was afraid to bring it home. The cat has remained at the veterinarian’s office—to the doctor’s displeasure—for weeks.

Two weeks after Mrs. K first spotted the mites, her husband, age 82, started believing he is infested. Mr. K, who is retired, has battled depression and drinks about a half-gallon of liquor daily.

After 2 months, Mrs. K quit her job for fear she would infest her co-workers, then locked herself and her husband in their house and allowed no visitors. Day and night for nearly 3 weeks, Mrs. K repeatedly vacuumed the house, shampooed the carpets, and sprayed the walls and furniture with a homemade insecticide. She taped the windows closed to keep bugs out and covered all furniture and surface areas with plastic. A toxic stench of insecticide and shampoo permeated every room.

A neighbor told Mrs. K’s son that his parents were locked inside their house. He came over and knocked on their door, but was refused entry. He eventually got Mrs. K out by threatening to call the police, then brought her to the emergency room.

At presentation, Mrs. K’s right leg has scratches and scabs caused by frequent scratching at mites she saw there. Her hands are reddened and dry, suggesting chemical dermatitis caused by cleaning and repeated insecticide use. Ritual cleaning and spraying has kept her from eating or sleeping; she has lost 12 lbs over 3 weeks and looks pale and tired.

A recovered alcoholic, Mrs. K has been sober for 12 years. She has no other psychiatric, medical, or dermatologic history, and has few social contacts beyond her family and workplace acquaintances.

Blood chemistry, CBC, and urine drug test results are normal. Head MRI reveal no neurologic abnormalities. Her Mini-Mental State Examination (MMSE) score (29/30) indicates no cognitive impairment.

Mrs. K is hospitalized to separate her from her allegedly bug-infested household and husband. At intake, she is panicked over leaving her husband alone and distressed that no one except she and her husband can see the bugs infesting their house and covering her skin. She asks doctors to test a small piece of toilet paper, which she says contains a sample of the bugs. She also fears that she infested her son by letting him into her house.

poll here

The authors’ observations

Mrs. K’s presentation and clinical course suggest delusional parasitosis, a fixed false belief of a parasitic infestation that can cause significant social and occupational dysfunction and medical problems. One patient calls this disorder “bugaphobia.”

The disorder may start as a self-perceived invisible infestation and evolve into visual hallucinations of bugs. Patients usually believe their skin is infested; some believe their internal organs, gums, or skin and internal organs are infested.^1,2

Table 1

Medical conditions that may precede delusional parasitosis

Anemia (severe)
Cancer
CNS infections
Head injury
Hepatitis
Hypertension
Hypovitaminosis of vitamin B12, folate, or thiamine
Multiple sclerosis
Pulmonary disease
Renal disease
Rheumatologic disease
Sight or hearing loss
Source: Reference 6

Skin lesions can result, including physical trauma from picking at sites the patient believes is infested. Some patients have sustained ocular trauma from picking at their eyes, which they believed contained insects.² At least one patient, depressed after failing to kill the parasites, killed himself.¹ As with Mrs. K, profuse use of insecticides or topical sprays can cause chemical dermatitis. Many patients isolate themselves to avoid infesting others.³

Some patients misinterpret scabs, abrasions, or skin irritation secondary to pesticide use as signs of infestation. Delusional parasitosis can also develop after a real, one-time infestation, as may have happened with Mrs. K.

Convinced they are infested, patients consult multiple providers—including dermatologists, gastroenterologists, and ophthalmologists—in search of the “right” treatment. They undergo numerous tests or procedures and repeatedly apply prescription creams and lotions, leading to chemical dermatitis. Patients often try to prove they are infested by bringing skin, dirt, or toilet tissue samples to doctors—this is called the “matchbox sign” because patients generally bring these samples in small boxes.⁴ They also may repeatedly ask veterinarians to disinfest their pets.

 

Box

Patients, however, do not believe the disorder is psychiatric⁵ and resist seeing a psychiatrist. Often a primary care physician or dermatologist calls on a psychiatrist as a consultant,⁶ as happened here.

Delusional parasitosis is most often found in socially isolated women age >40 of average or higher intelligence. Persons in some cultures may be more susceptible than others to some types of parasitic delusions. For example, several persons in India who considered ear cleanliness crucial to attaining cultural and spiritual purity reported having ear infestation.⁷

Delusional parasitosis also is associated with:

• medical conditions (Table 1)⁶
  
• use of cocaine, amphetamines,⁸ corticosteroids,^3,9 or phenelzine¹⁰
  
• occipital-temporal cerebral infarction¹¹
  
• cognitive impairment related to dementia, depression, mental retardation, or schizophrenia/schizophreniform disorder.
  

Cognitive impairment secondary to a medical problem may foster the delusion, or the patient may misinterpret a physical symptom as evidence of internal infestation. For example, a patient with chronic stomach pain may think he has bugs in his gut.⁵

Mrs. K’s delusional parasitosis may be a primary psychiatric disorder (Box). She is medically healthy and does not use drugs or alcohol. Her MMSE score is essentially normal, and she exhibited no psychotic symptoms or loss of function before her first mite sighting.

Diagnosis. Delusional parasitosis is diagnosed as delusional disorder, somatic type, if symptoms persist >1 month. Thorough laboratory and neurologic evaluation is recommended to rule out medical causes (Table 2). Eliminate schizophrenia and schizophreniform disorder with a detailed patient history and cognitive testing.

Also check for a comorbid psychiatric disorder that may be perpetuating the delusion. Delusional parasitosis often co-occurs with axis I disorders including major depressive disorder, substance abuse, dementia, and mental retardation.

poll here

The authors’ observations

Mr. K’s “bugaphobia” most likely was a form of shared secondary delusion called folie-a-deux. Between 11% and 25% of persons with primary delusional parasitosis induce secondary delusional parasitosis in another person, usually a spouse or longtime friend.² About 50% of folie-a-deux disorders involve a married couple. Often both partners are socially isolated.⁴

poll here

Treatment: Between two worlds

Mrs. K was given risperidone, 2 mg/d, for delusions and anxiety, and escitalopram, 10 mg/d, preventatively for a suspected underlying depression.

As her symptoms began to clear across 2 to 3 days, Mrs. K realized most times that she was not infested, but on occasion still feared that she was. She continued to worry about her husband being alone in a mite-infested house. We reassured her that her husband would be OK and told her to let us know if the mites resurfaced on her skin.

The authors’ observations

Building rapport. When treating delusional parasitosis, be accepting and non-confrontational. These patients tend to switch doctors until they find someone who understands their problem. Developing rapport can promote treatment adherence and prevent or minimize relapse.

Table 2

5 steps to confirm ‘bugaphobia’

Rule out infestation with skin scrapings/biopsy Get a thorough alcohol and drug use history to rule out substance abuse/dependence (particularly stimulant use) Perform a complete physical examination Order a CBC, urinalysis, liver function tests, thyroid function test, vitamin B 12 , folate, iron studies, blood urea nitrogen, serum electrolytes, and glucose to screen for associated medicalconditions Order head CT or MRI to rule out infarction or mass

Source: Adapted from Driscoll MS, Rothe MJ, Grant-Kels JM, Hale MS. Delusions of parasitosis: a dermatologic, psychiatric, and pharmacologic approach. J Am Acad Dermatol 1993;29:1023-33.

Start by getting the patient to leave the environment that feeds the delusion. Tell the patient, for example, “The hospital may have experts on your disorder who can help you.” Hospitalize the patient if he or she cannot function independently or will not leave the offending environment. Wait 1 to 2 days before starting medication to see if symptoms remit spontaneously, which they frequently do.

 

⁴

Also communicate with other specialists to gauge medication history, confirm test findings, and rule out medical causes.

Pharmacotherapy. If symptoms do not resolve after 1 or 2 days of observation, look for a comorbid medical or mental disorder. Prescribe an atypical antipsychotic such as risperidone, 2 to 4 mg/d, or olanzapine, 2.5 mg/d, both of which have been effective against delusional parasitosis.^14,16 Keep dosages low to reduce risk of sedation, extrapyramidal symptoms (EPS), and tardive dyskinesia.

Suggesting a psychotropic to patients who are convinced their problem is not psychiatric can be difficult. Try saying:

• Some people are more sensitive than others to sensations on their skin or in their body. This medication will help you tolerate the sensations.”
  
• or, “This drug will help reduce the anxiety your problem is causing.”
  

If symptoms persist another 3 days, try a different atypical or a conventional neuroleptic. Watch for EPS or other neuroleptic-related side effects in patients age >65.

Pimozide has shown efficacy against delusional parasitosis in placebo-controlled trials,^17,18 but it can alter cardiac conduction, especially at higherthan-recommended dosages. Start pimozide at 1 mg/d and increase by 1 mg/week until clinical response is achieved. Most patients respond to dosages used to treat psychotic disorders (4 to 10 mg/d).¹⁹ Order a baseline and periodic ECG to monitor for QTc prolongation, and do an abnormal involuntary movement scale examination every 3 to 6 months to test for EPS.

Other treatments that have shown benefit in case reports include naloxone, 10 mg/d;²⁰ haloperidol, 10 mg/d; trifluoperazine, 15 mg/d; chlorpromazine, 150 to 300 mg/d; and electroconvulsive therapy.⁷

We have found that prognosis usually is poor after first- and second-line treatments have failed. Continue to search for a missed disorder, and add an antidepressant if an underlying depression is found or suspected.

Psychotherapy. Perform supportive and harm reduction psychotherapy immediately after diagnosis. Supportive, rapport-building approaches can get the patient to comfortably discuss the issues that led to the delusion and help him/her confront a relapse. Harm reduction can discourage patients from requesting unnecessary invasive tests, using medications and toxic insecticides, or other potentially harmful behaviors.

Cognitive-behavioral therapy may help some patients with refractory delusional parasitosis, if they have enough insight to continue treatment.

Follow-up: A bug-free future

Mrs. K was released from the hospital after 4 days, and her delusional symptoms were gone after another 3 days. We followed her for 6 months.

Upon discharge, Mrs. K and her cat moved in with her daughter’s family. Within a few weeks she was able to visit her workplace and explain what had happened. She stopped taking risperidone after 2 weeks because of excessive sedation. No depressive symptoms were present after 3 months; escitalopram was stopped.

Mrs. K’s husband continued to drink and confine himself to the house. Upon visiting him, she was horrified to find the furniture still covered with plastic and the windows taped shut. Mrs. K threatened to divorce him if he did not seek help. He eventually was treated and has been sober—and bug-free—for 15 months.

Related resources

• Bohart Museum of Entomology, University of California, Davis: Delusional parasitosis. http://delusion.ucdavis.edu.
  

Drug brand names

• Chlorpromazine • Thorazine
  
• Escitalopram • Lexapro
  
• Haloperidol • Haldol
  
• naloxone • Narcan
  
• Olanzapine • Zyprexa
  
• Pimozide • Orap
  
• Phenelzine • Nardil
  
• Risperidone • Risperdal
  
• Trifluoperazine • Stelazine
  

Disclosure

Dr. Matthews is an American Psychiatric Association Bristol-Myers Squibb Co. fellow in public and community psychiatry.

Dr. Hauser receives research/grant support from and is a speaker for AstraZeneca Pharmaceuticals, Eli Lilly and Co., GlaxoSmithKline, and Hoffman LaRoche. He is also receives research/grant support from Schering-Plough Corp. and is a speaker for Abbott Laboratories and Janssen Pharmaceutica.

HISTORY: WINTER WOES

Mrs. A, age 64, lives alone in an old farmhouse. For approximately 8 months, she had complained of depressed mood, decreased interest, difficulty sleeping, low energy, decreased concentration, and feelings of hopelessness. She met DSM-IV-TR criteria for major depressive disorder with underlying anxiety.

Mrs. A also reported having sinus headaches throughout the fall and winter. Blood chemistry, CBC with differential, thyroid profile including T₄& TSH, urine drug screen, urine analysis, and ECG results were normal.

In April, Mrs. A was enrolled in an outpatient study of depression relapse prevention treatment. After taking the active study drug for 2 months, she reported continued low mood, low energy, difficulty concentrating, poor sleep and worsening headaches. Because her depression did not improve sufficiently, she was dropped from the study.

In July, Mrs. A saw a psychiatrist and was started on sertraline, 50 mg/d. By November, the dosage had been increased to 150 mg/d. At this time, she reported unsteadiness, dizziness, frequent falls, and intolerable headaches in addition to her depressive symptoms. She was referred to a neurologist to rule out a neurologic disorder.

Table 1

Symptoms that suggest major depression and/or chronic CO poisoning

Symptom	Major depression	Chronic low-level CO poisoning
Depressed mood	+	+
Diminished interest	+	-
Weight loss	+	-
Decreased appetite	+	-
Difficulty sleeping	+	+
Diminished concentration	+	+
Suicidal thoughts	+	-
Fatigue, weakness	+	+
Headaches	+	+
Palpitations	+	+
Shortness of breath	+	+
Nausea	+	+
Abdominal pain	+	+
Vomiting	+	+
Diarrhea	+	+
Confusion	-	+
Diminished cognitive function	+	+
Sexual dysfunction	+	-
+ = suggests disorder
- = does not suggest disorder
CO = Carbon monoxide
Source: Diagnostic and Statistical Manual of Mental Disorders (4th ed, rev).
Copyright 2000. American Psychiatric Association; and Tierney LM, McPhee SJ, Papadakis MA (eds). Current Medical Diagnosis and Treatment. New York: McGraw Hill, 2003.

The authors’ observations

Chronic fatigue syndrome is characterized by severe unexplained fatigue that persists for >6 months. The new-onset fatigue is not abated with rest. Other symptoms include impaired memory or concentration, sore throat, tender lymph nodes, muscle pain, headaches, pain in several joints, and disturbed sleep.¹

Mrs. A, however, never complained of sore throat or joint or muscle pain, and her laboratory findings were normal.

Seasonal affective disorder (SAD) is characterized by a temporal relationship between onset of depressive symptoms and a particular time of year (eg, symptoms emerge each winter) for at least 2 years. Full remission also occurs at a characteristic time (eg, each summer).²

Mrs. A’s headaches, frequent falls, dizziness, and difficulties with balance do not suggest SAD. Also, these symptoms have not persisted long enough for an SAD diagnosis.

Thyroid disorder. Hypothyroidism symptoms—particularly low mood, decreased energy, fatigue, psychomotor retardation, and lack of motivation—can mimic depression. Mrs. A’s T₄ and TSH readings were normal, however.

Metabolic dysfunction. Symptoms secondary to decreased serum concentrations of sodium, potassium, magnesium, or calcium can mimic depression, but blood tests showed Mrs. A has normal electrolyte levels.

Brain tumor. Patients with a brain tumor can present with mood symptoms, psychosis, headaches, mania, cognitive impairments, seizure problems, and other symptoms depending on the tumor’s size and location.

FURTHER TREATMENT: SUDDEN RELIEF

By late November Mrs. A’s fatigue, once present only mornings, plagued her throughout the day. We considered changing antidepressants because of her complaints and sertraline’s lack of efficacy.

The following month, however, Mrs. A told us that her fatigue and headaches were gone. Mood, sleep, and concentration were also improved. Her Hamilton Rating Scale for Depression score had improved from 21 when she entered the study—indicating moderate severity—to 6, indicating remission. Her neurologic referral was cancelled.

Mrs. A then mentioned that her home’s water heater had been malfunctioning for several months. She said she could not afford to get it repaired during the summer but finally hired plumbers to fix it in late November.

After working all day in Mrs. A’s basement, two workers suffered acute headaches and nausea. The symptoms prompted the workers to search the basement for a carbon monoxide leak; they found a small leak in the water heater, which they replaced.

The next morning, Mrs. A said, her headache disappeared. Her other symptoms were gone within 4 days.

The authors’ observations

The sudden disappearance of Mrs. A’s symptoms after her water heater was replaced and emergence of severe physical symptoms in the two plumbers suggest carbon monoxide (CO) poisoning, a common and potentially lethal medical problem.

Low-level CO poisoning usually results from repeated exposure to incomplete combustion in a defective heating appliance, such as a water heater (Box 1).^3,4 Symptoms usually surface in the winter, when heating appliance use peaks and windows are left closed, allowing indoor CO to accumulate in high concentrations.⁷

Box 1

 

Whereas severe, acute CO poisoning typically is detected immediately after exposure, symptoms of chronic low-level CO exposure are easily mistaken for a primary depressive (Table 1) or other neuropsychiatric disorder—or overlooked altogether. Some cases persist for months before CO exposure is diagnosed. Clinicians often give unnecessary—sometimes costly—medical treatment while ignoring the underlying poisoning.

Mechanism of action. CO binds with hemoglobin (with an affinity >200 times that of oxygen) to form carboxyhemoglobin (COHb), which causes cellular anoxia by blocking transport of oxygen to the tissues, including the brain.^4,6,8

CO poisoning symptoms vary depending on COHb concentration (Table 2). COHb >5% in a symptomatic nonsmoker may indicate chronic low-level CO poisoning and require further evaluation.⁹ Levels >10% are common in heavy smokers (2 to 4 packs/day). It should be noted that Mrs. A does not smoke.

Presentation. Patients with chronic low-level CO poisoning often present with vague, nonspecific symptoms, such as weakness and fatigue, abdominal pain, nausea, vomiting, diarrhea, decreased concentration, diminished cognitive abilities, persistent headaches, and trouble sleeping.^4,8,10,11 Patients age >65 especially may present with multiple cognitive and somatic complaints that suggest Parkinson’s disease, chronic fatigue syndrome, dementia, or—in Mrs. A’s case—depression.^5,10,12

Table 2

Signs, symptoms of CO poisoning that emerge at different carboxyhemoglobin levels

Carboxyhemoglobin level (% HgB)	Signs, symptoms
5-10 %	Exacerbates angina in some patients with heart disease
10-20 %	Mild headache, breathlessness on exertion
20-30 %	Throbbing headache, irritability, mental status changes, fatigue
30-40 %	Severe headache, weakness, nausea, dizziness, visual problems, confusion
40-50%	Increased confusion, hallucinations, severe ataxia, rapid breathing
50-60 %	Syncope or coma with convulsions, tachycardia with weak pulse
60-70 %	Deep coma, incontinence
70-80%	Profound coma, depressed respiration, absent reflexes
>80 %	Rapid death from respiratory arrest
Source: Adapted from Gilman AG, Rall TW, Nies AS, Taylor P (eds). Goodman and Gilman’s the pharmacological basis of therapeutics (8th ed). New York: Pergamon Press, 1990.

Health effects of CO exposure range from subtle cardiovascular and neurobehavioral sequelae at low concentrations to loss of consciousness and death after acute exposure to higher concentrations.^3,5

Hypoxia of the brain and other organs resulting from low-level CO poisoning can cause a range of physiologic effects, including mental status changes.^10,11 Low-level CO exposure is particularly dangerous to pregnant women and to patients with a pre-existing ischemic illness.

Pregnancy. Chronic low-level CO exposure during pregnancy can harm the fetus, leading to low birth weight, short neonatal length, prematurity, perinatal death, and increased risk of developmental dysfunction.¹³

Ischemic illnesses. Because COHb cannot transport oxygen, the tissues that demand the most oxygen—such as the brain, heart, and skeletal muscles—are most affected. Because cardiac muscles extract approximately 75% of available oxygen from blood, patients with cardiac and pulmonary ischemic illnesses face a high risk for tissue injury with CO poisoning. At COHb levels >10%, patients with pre-existing cardiac disease experience increased severity and duration of angina; concentrations >15% place them at risk of myocardial infarction.⁶

Length of recovery from chronic CO exposure varies widely depending on severity of exposure and the patient’s general health.^3,5 CO has a 4- to 6-hour half-life and is excreted via the lungs fairly rapidly, so recovery can be swift once CO exposure is stopped. Emergency room referral depends upon severity of symptoms and CO exposure duration and nature (accidental or intentional).

The authors’ observations

CO poisoning can lead to long-term mental status changes. In a 3-year follow-up of patients repeatedly exposed to low CO levels:

• 43% developed neurologic sequelae including memory impairment
• 33% experienced personality changes including irritability, verbal aggression, violence and impulsivity, moodiness, distractibility, and sexual promiscuity
• 11% suffered gross neuropsychological effects, including psychosis, disorientation, and blindness.⁴

Primary care physicians and psychiatrists should monitor patients who have recovered from CO poisoning for symptoms of these disorders.

DETECTING CHRONIC CO EXPOSURE

Mrs. A’s case illustrates the seriousness and diagnostic complexity of chronic low-level CO exposure in older patients, especially during the fall and winter with increased home heating appliance use.⁷ CO exposure was not considered as a cause of Mrs. A’s symptoms until heating contractors found the water heater leak.

Watch for patients whose neuropsychiatric symptoms do not respond to treatment. Ask them about possible environmental, seasonal, or diurnal variations in symptoms. Also ask if the patient’s home heating system or water heater is ≥10 years old or has been malfunctioning (Box 2).

Checking COHb blood levels is the simplest way to confirm CO poisoning.^6,14

Box 2

 

FOLLOW-UP: ANXIOUS MOMENTS

Mrs. A’s depressive symptoms, headaches, dizziness, and balance problems have not returned. Her underlying anxiety symptoms worsened, however, when the psychiatrist tried to taper sertraline. She was diagnosed with generalized anxiety disorder and continued on sertraline, 100 mg/d.

The psychiatrist sees her every 4 to 6 weeks, and she routinely sees her primary care physician. No long-term effects of CO poisoning have been found.

Related resources

• U.S. Centers for Disease Control and Prevention. Enter “carbon monoxide poisoning” in search field. http://www.cdc.gov.
• Kao LW, Nanagas KA. Carbon monoxide poisoning. Emerg Med Clin North America 2004;22:985-1018.

Drug brand names

• Sertraline • Zoloft

Disclosure

Drs. Khan and D’Empaire report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Preskorn has been a speaker for, consultant to, or principal investigator for several antidepressant manufacturers, including Pfizer Inc.