Ahsan Y. Khan, MD

History: A tortured past

Ms. A, age 46, is referred to us by her primary care physician for a psychiatric evaluation. The patient endorses longstanding depression but has never seen a psychiatrist. She also reports that she was raped several years ago.

Ms. A meets DSM-IV-TR criteria for major depressive disorder, recurrent moderate; and posttraumatic stress disorder (PTSD). She complains of depressed mood, lack of energy, poor concentration and memory, anxiety, feelings of hopelessness and worthlessness, insomnia, and poor appetite. She has nightmares, flashbacks of her rape, and decreased interest in activities. She says she tries to avoid thoughts associated with her rape, feels detached from others, is easily startled, and at times is irritable.

Approximately 8 years ago—shortly after she started taking bupropion, 150 mg/d, to help her quit smoking—Ms. A suffered her first seizure-like episode. A neurologist diagnosed her with epilepsy based on EEG findings. He started her on carbamazepine, 200 mg bid, and titrated the dosage to 900 mg/d. After 2 years, however, her spells continued. Usually, she would black out for a few minutes and forget what she was doing. During some spells she would jerk her hands and feet, stare into space, repeat words over and over, and/or fumble with her hands.

After changing health insurance plans, Ms. A saw another neurologist who switched her to divalproex, 250 mg bid. She began having nausea, vomiting, and alopecia, so she stopped taking divalproex after 2 weeks. The neurologist switched her to topiramate, 25 mg bid, and titrated the dosage to 400 mg/d over 8 weeks with no side effects but minimal response. Reducing topiramate to 200 mg/d and adding phenytoin, 300 mg/d, produced little improvement.

Ms. A says these spells now come once or twice daily. She denies aura, loss of consciousness, tongue biting, or incontinence during seizures.

Medical history. Ms. A has undergone posterior fossa decompression for Arnold-Chiari type I malformation, right nephrectomy for renal cell carcinoma, a complete hysterectomy, an appendectomy, and bilateral breast implants. She has also had venous angiomas with head and neck pain.

Ms. A is frustrated over her lack of independence, her limited social life, and her inability to drive because of her seizure disorder. Once employed full-time for 12 years in a doctor’s office, she now gets by on disability benefits, which she finds degrading. She feels hopeless and helpless, as antiepileptics have not worked.

poll here

The authors’ observations

Ms. A complained of depression, sleep problems secondary to depression and PTSD, poor appetite, underlying anxiety, and decreased concentration, energy, and interest. We decided to address these symptoms with mirtazapine. Because she is thin (126 lb, body mass index 19.2 kg/m²), potential for weight gain with mirtazapine was not a concern.

We gauged Ms. A’s response to mirtazapine and her seizure history at our next visit, during which we customarily continue taking the patient’s history.

Treatment: Marriage by force?

Ms. A begins taking mirtazapine, 15 mg/d. At her next appointment the following week, she says she has stopped it because it has increased her appetite, which she fears will cause weight gain. She says her seizures, which usually occur at home, have continued with the same frequency.

Upon exploring her history further, we discover that Ms. A’s father was rarely around, and when he was he physically abused her. As a child she struggled with dyslexia, for which she received special education. She became pregnant while finishing high school and feels her mother forced her to marry her first husband.

Ms. A added that her three former husbands were physically and/or emotionally abusive toward her. About 10 years ago, she says, her third husband raped her.

We begin to suspect that Ms. A might not have epilepsy because of the seizures’ distinct nature, her vague symptoms, minimal or no response to antiepileptics, and comorbid mood and anxiety disorders. We refer her to another neurologist for video EEG (VEEG). She reluctantly agrees to the test, unwilling to believe that her seizures might have a psychiatric cause.

poll here

The authors’ observations

Recurrent seizures characteristic of epilepsy can significantly impair quality of life. Although the diagnosis often is straightforward, distinguishing epilepsy from psychogenic nonepileptic seizures (PNES) can be difficult.

PNES are sudden, episodic changes in behavior, perception, thinking, or feeling. These changes resemble epileptic events but are not prompted by abnormal brain electrical discharges as measured by EEG.¹

Formerly called pseudoseizures, PNES can have a physiologic or psychological cause (Table 1). They often are a somatic response to unbearable past events and/or current psychological tension or conflict. Most patients with PNES cite domestic abuse or family conflicts as key stressors.²

 

Few systematic studies have addressed how life events contribute to PNES. Associated life events—described mostly in case reports—fall into three general categories:

• childhood and adult trauma
  
• bereavement or loss
  
• acute or situational stressors.³
  

PNES diagnosis has become progressively refined over the last three decades. VEEG is used to diagnose PNES. Neuropsychological evaluation and VEEG are used together if PNES is believed to coexist with epilepsy or psychiatric disorders.^4,5

Table 1

Physiologic and psychological causes of nonepileptic seizures

Physiologic
Autonomic disorders
Cerebrovascular disease
Cardiac disorders
Vasovagal syncope
Ischemic heart disease
Valvular heart disease
Arrythmias
Drug toxicity
Endocrine disturbance
Metabolic disorders
Migraines
Paroxysmal movement disorder
Sleep disorder
Psychological
Anxiety disorders
Conversion disorder
Dissociative disorder
Factitious disorder
Malingering
Victim of physical, emotional, or sexual abuse
Posttraumatic stress disorder
Psychotic disorder
Somatoform disorder
Substance abuse/dependence

Continued treatment: Wasted years

Two weeks after our referral, Ms. A reports that the neurologist discontinued topiramate and phenytoin after VEEG showed no epileptic activity.

Ms. A now realizes she does not have epilepsy. She is angry that her first neurologist had misdiag-nosed her, effectively sentencing her to 8 years of needless dependency and disability.

We prescribe escitalopram, starting at 10 mg/d and titrating to 20 mg/d, to address Ms. A’s depressive/PTSD symptoms. We also refer her to a psychotherapist, who schedules twice-weekly supportive psychotherapy sessions. The therapist plans to teach her coping techniques and provide ego support and encouragement.

Ms. A’s psychotherapy progresses slowly at first, but by the fourth session she sets goals, which include getting off disability as soon as possible. With careful ego strengthening, she resumes driving and searches for a job. During one session, she tells her therapist she has long wanted to become a nurse, so she is encouraged to see a nursing school counselor for advice on selecting prerequisite nursing classes.

The authors’ observations

As with Ms. A, an erroneous epilepsy diagnosis can cause physical, psychosocial, and socioeconomic grief for the patient and can lead to needless restrictions, unemployment or underemployment, and dependence on disability benefits. After the misdiagnosis, Ms. A lost control of her future and considered her life a burden, leading to depression and anxiety. Her seizures caused most of her physical and psychological disturbances and diminished her overall function.

PNES are often mistaken for epileptic seizures, and 26% of seizure patients experience both.⁶ In a study of 50 patients, between 5% and 20% of patients evaluated for epilepsy and 10% to 40% of patients referred to comprehensive epilepsy centers were later found to have PNES.⁷

Like Ms. A, many patients with undiagnosed PNES receive antiepileptics to treat apparent epilepsy. These medications can cause troublesome side effects—from GI problems, to respiratory arrest in patients with pseudostatus, to potential teratogenicity.

In addition, comorbid epilepsy often goes undetected in patients with PNES. This could lead to inadequate treatment, increasing the patient’s morbidity and mortality risk.⁸

poll here

The authors’ observations

Patient history. Take a thorough history for patients with a history of seizures.

Too often, doctors assume a previous epilepsy diagnosis is correct, especially if rendered by a neurologist. In the United Kingdom, 20% to 31% of epilepsy diagnoses are incorrect because of incomplete history and misinterpreted EEG findings.⁸ When taking a patient’s seizure history, clinicians often do not get:

• a detailed history of seizures or seizurelike events, including onset, frequency, observations from family or friends, and seizure duration
  
• information on whether the patient remembers seizure details; has had prespell aura or loss of consciousness, or cries during the spells
  
• history of physical and/or sexual abuse.
  

Multiple daily seizures, repeated hospitalizations or emergency room visits, minimal response to antiepileptics, and no history of injury after seizures could suggest nonepileptic seizures. Seizures may be psychogenic if the patient was sexually abused, has a comorbid psychiatric disorder, or suffers attacks only when alone or only in public (Table 2).

Refer patients with features that may suggest PNES to a neurologist for VEEG to confirm or rule out epilepsy, because roughly one-quarter of seizure patients can have both.

Table 2

Patient features that suggest nonepileptic seizures

Comorbid psychiatric disorder(s)
Events occur only in presence of others or only when alone
Lack of concern or excessive emotional response to seizures
Minimal or no response to antiepileptics
Multiple daily seizures
No history of injury resulting from seizures
Normal neurologic history and examination
Repeated hospitalizations or emergency room visits
Unremarkable EEG and MRI findings
Victim of sexual abuse

Finding psychological causes. Psychological investigations become paramount after physiologic causes for nonepileptic seizures are ruled out.

The Minnesota Multiphasic Personality Inventory (MMPI) is often used to discriminate PNES from epilepsy. Wilkus et al⁹ reported significant differences in scores of MMPI hypochondriasis, hysteria, and schizophrenia scales among patients with PNES and epilepsy. Patients with PNES may have higher MMPI hypochondriasis, hysteria, schizophrenia, and psychopathic deviate scores than do patients with epilepsy.

 

Other authors, however, have found more variable MMPI results when using the test to distinguish PNES from epilepsy. Thus, the MMPI may provide supportive data for PNES diagnosis but is not a definitive tool.

Explaining the findings. Getting the patient to accept that the epilepsy is “in your head” is crucial to engaging him or her in treatment. The clinician needs to be honest with the patient while projecting a positive approach to the diagnosis. Tell the patient that not having epilepsy is “good news,” that antiepileptics are not needed, and that he or she can gain better control once stress or emotional issues are resolved.¹⁰

Follow-up: A learning experience

Within 4 months of her last seizure, Ms. A showed dramatic improvement. She began driving, working part-time and enrolled in nursing school. Her disability benefits program provided tuition assistance.

Ms. A has now been seizure-free for 1 year. Motivated and determined, she is taking up to 8 credit hours per semester and earning As and Bs but at times is anxious and fears failure. She needs much support and encouragement. Multiple therapy techniques—including direct teaching, admiring her progress, offering support, explaining, and ego strengthening—have produced good results. She is still taking escitalopram, 20 mg/d, and sees her therapist every 2 weeks.

Related resources

• Adetunji B, Mathews M, Williams A, Verma S. Psychogenic or epileptic seizures? How to clinch the diagnosis. Current Psychiatry 2004;3(11):25-35.
  
• Privitera MD. EEGs and epilepsy: When seizures mimic psychiatric illness. Current Psychiatry 2002;1(9):14-21.
  

Drug brand names

• Bupropion • Wellbutrin, Zyban
  
• Carbamazepine • Tegretol
  
• Divalproex sodium • Depakote
  
• Escitalopram • Lexapro
  
• Mirtazapine • Remeron
  
• Phenytoin • Dilantin
  
• Topiramate • Topamax
  

Disclosure

Dr. Khan is a speaker for Pfizer and Wyeth.

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

History: A tortured past

Ms. A, age 46, is referred to us by her primary care physician for a psychiatric evaluation. The patient endorses longstanding depression but has never seen a psychiatrist. She also reports that she was raped several years ago.

Ms. A meets DSM-IV-TR criteria for major depressive disorder, recurrent moderate; and posttraumatic stress disorder (PTSD). She complains of depressed mood, lack of energy, poor concentration and memory, anxiety, feelings of hopelessness and worthlessness, insomnia, and poor appetite. She has nightmares, flashbacks of her rape, and decreased interest in activities. She says she tries to avoid thoughts associated with her rape, feels detached from others, is easily startled, and at times is irritable.

Approximately 8 years ago—shortly after she started taking bupropion, 150 mg/d, to help her quit smoking—Ms. A suffered her first seizure-like episode. A neurologist diagnosed her with epilepsy based on EEG findings. He started her on carbamazepine, 200 mg bid, and titrated the dosage to 900 mg/d. After 2 years, however, her spells continued. Usually, she would black out for a few minutes and forget what she was doing. During some spells she would jerk her hands and feet, stare into space, repeat words over and over, and/or fumble with her hands.

After changing health insurance plans, Ms. A saw another neurologist who switched her to divalproex, 250 mg bid. She began having nausea, vomiting, and alopecia, so she stopped taking divalproex after 2 weeks. The neurologist switched her to topiramate, 25 mg bid, and titrated the dosage to 400 mg/d over 8 weeks with no side effects but minimal response. Reducing topiramate to 200 mg/d and adding phenytoin, 300 mg/d, produced little improvement.

Ms. A says these spells now come once or twice daily. She denies aura, loss of consciousness, tongue biting, or incontinence during seizures.

Medical history. Ms. A has undergone posterior fossa decompression for Arnold-Chiari type I malformation, right nephrectomy for renal cell carcinoma, a complete hysterectomy, an appendectomy, and bilateral breast implants. She has also had venous angiomas with head and neck pain.

Ms. A is frustrated over her lack of independence, her limited social life, and her inability to drive because of her seizure disorder. Once employed full-time for 12 years in a doctor’s office, she now gets by on disability benefits, which she finds degrading. She feels hopeless and helpless, as antiepileptics have not worked.

poll here

The authors’ observations

Ms. A complained of depression, sleep problems secondary to depression and PTSD, poor appetite, underlying anxiety, and decreased concentration, energy, and interest. We decided to address these symptoms with mirtazapine. Because she is thin (126 lb, body mass index 19.2 kg/m²), potential for weight gain with mirtazapine was not a concern.

We gauged Ms. A’s response to mirtazapine and her seizure history at our next visit, during which we customarily continue taking the patient’s history.

Treatment: Marriage by force?

Ms. A begins taking mirtazapine, 15 mg/d. At her next appointment the following week, she says she has stopped it because it has increased her appetite, which she fears will cause weight gain. She says her seizures, which usually occur at home, have continued with the same frequency.

Upon exploring her history further, we discover that Ms. A’s father was rarely around, and when he was he physically abused her. As a child she struggled with dyslexia, for which she received special education. She became pregnant while finishing high school and feels her mother forced her to marry her first husband.

Ms. A added that her three former husbands were physically and/or emotionally abusive toward her. About 10 years ago, she says, her third husband raped her.

We begin to suspect that Ms. A might not have epilepsy because of the seizures’ distinct nature, her vague symptoms, minimal or no response to antiepileptics, and comorbid mood and anxiety disorders. We refer her to another neurologist for video EEG (VEEG). She reluctantly agrees to the test, unwilling to believe that her seizures might have a psychiatric cause.

poll here

The authors’ observations

Recurrent seizures characteristic of epilepsy can significantly impair quality of life. Although the diagnosis often is straightforward, distinguishing epilepsy from psychogenic nonepileptic seizures (PNES) can be difficult.

PNES are sudden, episodic changes in behavior, perception, thinking, or feeling. These changes resemble epileptic events but are not prompted by abnormal brain electrical discharges as measured by EEG.¹

Formerly called pseudoseizures, PNES can have a physiologic or psychological cause (Table 1). They often are a somatic response to unbearable past events and/or current psychological tension or conflict. Most patients with PNES cite domestic abuse or family conflicts as key stressors.²

 

Few systematic studies have addressed how life events contribute to PNES. Associated life events—described mostly in case reports—fall into three general categories:

• childhood and adult trauma
  
• bereavement or loss
  
• acute or situational stressors.³
  

PNES diagnosis has become progressively refined over the last three decades. VEEG is used to diagnose PNES. Neuropsychological evaluation and VEEG are used together if PNES is believed to coexist with epilepsy or psychiatric disorders.^4,5

Table 1

Physiologic and psychological causes of nonepileptic seizures

Physiologic
Autonomic disorders
Cerebrovascular disease
Cardiac disorders
Vasovagal syncope
Ischemic heart disease
Valvular heart disease
Arrythmias
Drug toxicity
Endocrine disturbance
Metabolic disorders
Migraines
Paroxysmal movement disorder
Sleep disorder
Psychological
Anxiety disorders
Conversion disorder
Dissociative disorder
Factitious disorder
Malingering
Victim of physical, emotional, or sexual abuse
Posttraumatic stress disorder
Psychotic disorder
Somatoform disorder
Substance abuse/dependence

Continued treatment: Wasted years

Two weeks after our referral, Ms. A reports that the neurologist discontinued topiramate and phenytoin after VEEG showed no epileptic activity.

Ms. A now realizes she does not have epilepsy. She is angry that her first neurologist had misdiag-nosed her, effectively sentencing her to 8 years of needless dependency and disability.

We prescribe escitalopram, starting at 10 mg/d and titrating to 20 mg/d, to address Ms. A’s depressive/PTSD symptoms. We also refer her to a psychotherapist, who schedules twice-weekly supportive psychotherapy sessions. The therapist plans to teach her coping techniques and provide ego support and encouragement.

Ms. A’s psychotherapy progresses slowly at first, but by the fourth session she sets goals, which include getting off disability as soon as possible. With careful ego strengthening, she resumes driving and searches for a job. During one session, she tells her therapist she has long wanted to become a nurse, so she is encouraged to see a nursing school counselor for advice on selecting prerequisite nursing classes.

The authors’ observations

As with Ms. A, an erroneous epilepsy diagnosis can cause physical, psychosocial, and socioeconomic grief for the patient and can lead to needless restrictions, unemployment or underemployment, and dependence on disability benefits. After the misdiagnosis, Ms. A lost control of her future and considered her life a burden, leading to depression and anxiety. Her seizures caused most of her physical and psychological disturbances and diminished her overall function.

PNES are often mistaken for epileptic seizures, and 26% of seizure patients experience both.⁶ In a study of 50 patients, between 5% and 20% of patients evaluated for epilepsy and 10% to 40% of patients referred to comprehensive epilepsy centers were later found to have PNES.⁷

Like Ms. A, many patients with undiagnosed PNES receive antiepileptics to treat apparent epilepsy. These medications can cause troublesome side effects—from GI problems, to respiratory arrest in patients with pseudostatus, to potential teratogenicity.

In addition, comorbid epilepsy often goes undetected in patients with PNES. This could lead to inadequate treatment, increasing the patient’s morbidity and mortality risk.⁸

poll here

The authors’ observations

Patient history. Take a thorough history for patients with a history of seizures.

Too often, doctors assume a previous epilepsy diagnosis is correct, especially if rendered by a neurologist. In the United Kingdom, 20% to 31% of epilepsy diagnoses are incorrect because of incomplete history and misinterpreted EEG findings.⁸ When taking a patient’s seizure history, clinicians often do not get:

• a detailed history of seizures or seizurelike events, including onset, frequency, observations from family or friends, and seizure duration
  
• information on whether the patient remembers seizure details; has had prespell aura or loss of consciousness, or cries during the spells
  
• history of physical and/or sexual abuse.
  

Multiple daily seizures, repeated hospitalizations or emergency room visits, minimal response to antiepileptics, and no history of injury after seizures could suggest nonepileptic seizures. Seizures may be psychogenic if the patient was sexually abused, has a comorbid psychiatric disorder, or suffers attacks only when alone or only in public (Table 2).

Refer patients with features that may suggest PNES to a neurologist for VEEG to confirm or rule out epilepsy, because roughly one-quarter of seizure patients can have both.

Table 2

Patient features that suggest nonepileptic seizures

Comorbid psychiatric disorder(s)
Events occur only in presence of others or only when alone
Lack of concern or excessive emotional response to seizures
Minimal or no response to antiepileptics
Multiple daily seizures
No history of injury resulting from seizures
Normal neurologic history and examination
Repeated hospitalizations or emergency room visits
Unremarkable EEG and MRI findings
Victim of sexual abuse

Finding psychological causes. Psychological investigations become paramount after physiologic causes for nonepileptic seizures are ruled out.

The Minnesota Multiphasic Personality Inventory (MMPI) is often used to discriminate PNES from epilepsy. Wilkus et al⁹ reported significant differences in scores of MMPI hypochondriasis, hysteria, and schizophrenia scales among patients with PNES and epilepsy. Patients with PNES may have higher MMPI hypochondriasis, hysteria, schizophrenia, and psychopathic deviate scores than do patients with epilepsy.

 

Other authors, however, have found more variable MMPI results when using the test to distinguish PNES from epilepsy. Thus, the MMPI may provide supportive data for PNES diagnosis but is not a definitive tool.

Explaining the findings. Getting the patient to accept that the epilepsy is “in your head” is crucial to engaging him or her in treatment. The clinician needs to be honest with the patient while projecting a positive approach to the diagnosis. Tell the patient that not having epilepsy is “good news,” that antiepileptics are not needed, and that he or she can gain better control once stress or emotional issues are resolved.¹⁰

Follow-up: A learning experience

Within 4 months of her last seizure, Ms. A showed dramatic improvement. She began driving, working part-time and enrolled in nursing school. Her disability benefits program provided tuition assistance.

Ms. A has now been seizure-free for 1 year. Motivated and determined, she is taking up to 8 credit hours per semester and earning As and Bs but at times is anxious and fears failure. She needs much support and encouragement. Multiple therapy techniques—including direct teaching, admiring her progress, offering support, explaining, and ego strengthening—have produced good results. She is still taking escitalopram, 20 mg/d, and sees her therapist every 2 weeks.

Related resources

• Adetunji B, Mathews M, Williams A, Verma S. Psychogenic or epileptic seizures? How to clinch the diagnosis. Current Psychiatry 2004;3(11):25-35.
  
• Privitera MD. EEGs and epilepsy: When seizures mimic psychiatric illness. Current Psychiatry 2002;1(9):14-21.
  

Drug brand names

• Bupropion • Wellbutrin, Zyban
  
• Carbamazepine • Tegretol
  
• Divalproex sodium • Depakote
  
• Escitalopram • Lexapro
  
• Mirtazapine • Remeron
  
• Phenytoin • Dilantin
  
• Topiramate • Topamax
  

Disclosure

Dr. Khan is a speaker for Pfizer and Wyeth.

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

History: A tortured past

Ms. A, age 46, is referred to us by her primary care physician for a psychiatric evaluation. The patient endorses longstanding depression but has never seen a psychiatrist. She also reports that she was raped several years ago.

Ms. A meets DSM-IV-TR criteria for major depressive disorder, recurrent moderate; and posttraumatic stress disorder (PTSD). She complains of depressed mood, lack of energy, poor concentration and memory, anxiety, feelings of hopelessness and worthlessness, insomnia, and poor appetite. She has nightmares, flashbacks of her rape, and decreased interest in activities. She says she tries to avoid thoughts associated with her rape, feels detached from others, is easily startled, and at times is irritable.

Approximately 8 years ago—shortly after she started taking bupropion, 150 mg/d, to help her quit smoking—Ms. A suffered her first seizure-like episode. A neurologist diagnosed her with epilepsy based on EEG findings. He started her on carbamazepine, 200 mg bid, and titrated the dosage to 900 mg/d. After 2 years, however, her spells continued. Usually, she would black out for a few minutes and forget what she was doing. During some spells she would jerk her hands and feet, stare into space, repeat words over and over, and/or fumble with her hands.

After changing health insurance plans, Ms. A saw another neurologist who switched her to divalproex, 250 mg bid. She began having nausea, vomiting, and alopecia, so she stopped taking divalproex after 2 weeks. The neurologist switched her to topiramate, 25 mg bid, and titrated the dosage to 400 mg/d over 8 weeks with no side effects but minimal response. Reducing topiramate to 200 mg/d and adding phenytoin, 300 mg/d, produced little improvement.

Ms. A says these spells now come once or twice daily. She denies aura, loss of consciousness, tongue biting, or incontinence during seizures.

Medical history. Ms. A has undergone posterior fossa decompression for Arnold-Chiari type I malformation, right nephrectomy for renal cell carcinoma, a complete hysterectomy, an appendectomy, and bilateral breast implants. She has also had venous angiomas with head and neck pain.

Ms. A is frustrated over her lack of independence, her limited social life, and her inability to drive because of her seizure disorder. Once employed full-time for 12 years in a doctor’s office, she now gets by on disability benefits, which she finds degrading. She feels hopeless and helpless, as antiepileptics have not worked.

poll here

The authors’ observations

Ms. A complained of depression, sleep problems secondary to depression and PTSD, poor appetite, underlying anxiety, and decreased concentration, energy, and interest. We decided to address these symptoms with mirtazapine. Because she is thin (126 lb, body mass index 19.2 kg/m²), potential for weight gain with mirtazapine was not a concern.

We gauged Ms. A’s response to mirtazapine and her seizure history at our next visit, during which we customarily continue taking the patient’s history.

Treatment: Marriage by force?

Ms. A begins taking mirtazapine, 15 mg/d. At her next appointment the following week, she says she has stopped it because it has increased her appetite, which she fears will cause weight gain. She says her seizures, which usually occur at home, have continued with the same frequency.

Upon exploring her history further, we discover that Ms. A’s father was rarely around, and when he was he physically abused her. As a child she struggled with dyslexia, for which she received special education. She became pregnant while finishing high school and feels her mother forced her to marry her first husband.

Ms. A added that her three former husbands were physically and/or emotionally abusive toward her. About 10 years ago, she says, her third husband raped her.

We begin to suspect that Ms. A might not have epilepsy because of the seizures’ distinct nature, her vague symptoms, minimal or no response to antiepileptics, and comorbid mood and anxiety disorders. We refer her to another neurologist for video EEG (VEEG). She reluctantly agrees to the test, unwilling to believe that her seizures might have a psychiatric cause.

poll here

The authors’ observations

Recurrent seizures characteristic of epilepsy can significantly impair quality of life. Although the diagnosis often is straightforward, distinguishing epilepsy from psychogenic nonepileptic seizures (PNES) can be difficult.

PNES are sudden, episodic changes in behavior, perception, thinking, or feeling. These changes resemble epileptic events but are not prompted by abnormal brain electrical discharges as measured by EEG.¹

Formerly called pseudoseizures, PNES can have a physiologic or psychological cause (Table 1). They often are a somatic response to unbearable past events and/or current psychological tension or conflict. Most patients with PNES cite domestic abuse or family conflicts as key stressors.²

 

Few systematic studies have addressed how life events contribute to PNES. Associated life events—described mostly in case reports—fall into three general categories:

• childhood and adult trauma
  
• bereavement or loss
  
• acute or situational stressors.³
  

PNES diagnosis has become progressively refined over the last three decades. VEEG is used to diagnose PNES. Neuropsychological evaluation and VEEG are used together if PNES is believed to coexist with epilepsy or psychiatric disorders.^4,5

Table 1

Physiologic and psychological causes of nonepileptic seizures

Physiologic
Autonomic disorders
Cerebrovascular disease
Cardiac disorders
Vasovagal syncope
Ischemic heart disease
Valvular heart disease
Arrythmias
Drug toxicity
Endocrine disturbance
Metabolic disorders
Migraines
Paroxysmal movement disorder
Sleep disorder
Psychological
Anxiety disorders
Conversion disorder
Dissociative disorder
Factitious disorder
Malingering
Victim of physical, emotional, or sexual abuse
Posttraumatic stress disorder
Psychotic disorder
Somatoform disorder
Substance abuse/dependence

Continued treatment: Wasted years

Two weeks after our referral, Ms. A reports that the neurologist discontinued topiramate and phenytoin after VEEG showed no epileptic activity.

Ms. A now realizes she does not have epilepsy. She is angry that her first neurologist had misdiag-nosed her, effectively sentencing her to 8 years of needless dependency and disability.

We prescribe escitalopram, starting at 10 mg/d and titrating to 20 mg/d, to address Ms. A’s depressive/PTSD symptoms. We also refer her to a psychotherapist, who schedules twice-weekly supportive psychotherapy sessions. The therapist plans to teach her coping techniques and provide ego support and encouragement.

Ms. A’s psychotherapy progresses slowly at first, but by the fourth session she sets goals, which include getting off disability as soon as possible. With careful ego strengthening, she resumes driving and searches for a job. During one session, she tells her therapist she has long wanted to become a nurse, so she is encouraged to see a nursing school counselor for advice on selecting prerequisite nursing classes.

The authors’ observations

As with Ms. A, an erroneous epilepsy diagnosis can cause physical, psychosocial, and socioeconomic grief for the patient and can lead to needless restrictions, unemployment or underemployment, and dependence on disability benefits. After the misdiagnosis, Ms. A lost control of her future and considered her life a burden, leading to depression and anxiety. Her seizures caused most of her physical and psychological disturbances and diminished her overall function.

PNES are often mistaken for epileptic seizures, and 26% of seizure patients experience both.⁶ In a study of 50 patients, between 5% and 20% of patients evaluated for epilepsy and 10% to 40% of patients referred to comprehensive epilepsy centers were later found to have PNES.⁷

Like Ms. A, many patients with undiagnosed PNES receive antiepileptics to treat apparent epilepsy. These medications can cause troublesome side effects—from GI problems, to respiratory arrest in patients with pseudostatus, to potential teratogenicity.

In addition, comorbid epilepsy often goes undetected in patients with PNES. This could lead to inadequate treatment, increasing the patient’s morbidity and mortality risk.⁸

poll here

The authors’ observations

Patient history. Take a thorough history for patients with a history of seizures.

Too often, doctors assume a previous epilepsy diagnosis is correct, especially if rendered by a neurologist. In the United Kingdom, 20% to 31% of epilepsy diagnoses are incorrect because of incomplete history and misinterpreted EEG findings.⁸ When taking a patient’s seizure history, clinicians often do not get:

• a detailed history of seizures or seizurelike events, including onset, frequency, observations from family or friends, and seizure duration
  
• information on whether the patient remembers seizure details; has had prespell aura or loss of consciousness, or cries during the spells
  
• history of physical and/or sexual abuse.
  

Multiple daily seizures, repeated hospitalizations or emergency room visits, minimal response to antiepileptics, and no history of injury after seizures could suggest nonepileptic seizures. Seizures may be psychogenic if the patient was sexually abused, has a comorbid psychiatric disorder, or suffers attacks only when alone or only in public (Table 2).

Refer patients with features that may suggest PNES to a neurologist for VEEG to confirm or rule out epilepsy, because roughly one-quarter of seizure patients can have both.

Table 2

Patient features that suggest nonepileptic seizures

Comorbid psychiatric disorder(s)
Events occur only in presence of others or only when alone
Lack of concern or excessive emotional response to seizures
Minimal or no response to antiepileptics
Multiple daily seizures
No history of injury resulting from seizures
Normal neurologic history and examination
Repeated hospitalizations or emergency room visits
Unremarkable EEG and MRI findings
Victim of sexual abuse

Finding psychological causes. Psychological investigations become paramount after physiologic causes for nonepileptic seizures are ruled out.

The Minnesota Multiphasic Personality Inventory (MMPI) is often used to discriminate PNES from epilepsy. Wilkus et al⁹ reported significant differences in scores of MMPI hypochondriasis, hysteria, and schizophrenia scales among patients with PNES and epilepsy. Patients with PNES may have higher MMPI hypochondriasis, hysteria, schizophrenia, and psychopathic deviate scores than do patients with epilepsy.

 

Other authors, however, have found more variable MMPI results when using the test to distinguish PNES from epilepsy. Thus, the MMPI may provide supportive data for PNES diagnosis but is not a definitive tool.

Explaining the findings. Getting the patient to accept that the epilepsy is “in your head” is crucial to engaging him or her in treatment. The clinician needs to be honest with the patient while projecting a positive approach to the diagnosis. Tell the patient that not having epilepsy is “good news,” that antiepileptics are not needed, and that he or she can gain better control once stress or emotional issues are resolved.¹⁰

Follow-up: A learning experience

Within 4 months of her last seizure, Ms. A showed dramatic improvement. She began driving, working part-time and enrolled in nursing school. Her disability benefits program provided tuition assistance.

Ms. A has now been seizure-free for 1 year. Motivated and determined, she is taking up to 8 credit hours per semester and earning As and Bs but at times is anxious and fears failure. She needs much support and encouragement. Multiple therapy techniques—including direct teaching, admiring her progress, offering support, explaining, and ego strengthening—have produced good results. She is still taking escitalopram, 20 mg/d, and sees her therapist every 2 weeks.

Related resources

• Adetunji B, Mathews M, Williams A, Verma S. Psychogenic or epileptic seizures? How to clinch the diagnosis. Current Psychiatry 2004;3(11):25-35.
  
• Privitera MD. EEGs and epilepsy: When seizures mimic psychiatric illness. Current Psychiatry 2002;1(9):14-21.
  

Drug brand names

• Bupropion • Wellbutrin, Zyban
  
• Carbamazepine • Tegretol
  
• Divalproex sodium • Depakote
  
• Escitalopram • Lexapro
  
• Mirtazapine • Remeron
  
• Phenytoin • Dilantin
  
• Topiramate • Topamax
  

Disclosure

Dr. Khan is a speaker for Pfizer and Wyeth.

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

Presentation: ‘they’re stalking me’

Ms. P, age 30, fears she is being stalked and is too terrified to be home alone. Worried, her ex-boyfriend calls police, who bring her to the emergency room

At the ER, Ms. P reports that surveillance cameras have been planted inside her house, that men often stand on her roof and watch her go to her car, and that men constantly are stalking her. She also hears voices and reports frightening peripheral visions of “outsiders.” The ER doctor consults the psychiatry service and orders laboratory tests, but all results—including urine drug screen findings—are negative.

Ms. P says she has been sleeping 3 to 4 hours nightly. She acknowledges depressed mood and decreased appetite, leading to a 10-lb weight loss over 1 month. She says she has felt depressed off and on for several years but has received no treatment for her mood symptoms. We admit her to the psychiatric unit to treat her acute-onset psychosis.

Lately, Ms. P’s life has been difficult. A college sophomore, she is failing all her classes. She was recently fired from her job as a case manager because of inappropriate behavior, such as buying gifts for the children she was managing and taking them for hair-cuts without their parents’ permission. Several months ago, she broke up with her boyfriend of 6 years. In addition to these stressors, she recently moved into an apartment and for the first time was living on her own.

Medical history. Ms. P has no major medical problems. Her mother has battled alcohol and drug dependence and depression but to Ms. P’s knowledge has never experienced psychosis. Ms. P, who admits that she binge drinks once or twice monthly, meets DSM-IV-TR criteria for alcohol abuse disorder. She denies using illicit drugs but admits that she regularly takes “energy pills” purchased over the Internet because she cannot wake up without them.

Physical exam is normal, but Ms. P’s body mass index (BMI) is 18 kg/m², slightly below normal (height: 5 feet 8 inches; weight: 117.5 lb).

The authors’ observations

We diagnosed Ms. P as having recurrent and severe major depressive disorder with psychotic features because of her longstanding depressive symptoms. We considered substance-induced psychosis, but her urine drug screen is negative.

Treatment at this point should address both the paranoid delusions and depressive symptoms.

Treatment: starved for energy

We start haloperidol, 1 mg nightly, to treat Ms. P’s paranoid delusions, and mirtazapine, 15 mg nightly, to improve her sleep. We choose mirtazapine—which can increase appetite and lead to weight gain—because Ms. P is underweight. We also choose haloperidol because Ms. P is unemployed and cannot afford a second-generation antipsychotic.

Shortly afterward, we interview Ms. P’s ex-boyfriend. He tells us that she has been using diet pills regularly for 3 to 4 years, and that her chronic use has been escalating by the month. Lately, he says, she has been “popping the pills like candy.”

When we ask Ms. P about her diet pill use, she says she had mainly been using Xenadrine, an over-the-counter weight-loss supplement. Five months ago, she also started taking prescription phentermine, which she purchases over the Internet. She says that before her hospitalization, she was taking three phentermine tablets daily to boost her energy.

According to her ex-boyfriend, Ms. P began showing signs of psychosis 3 to 4 weeks after starting phentermine, and Ms. P notes that her initial paranoia and gustatory hallucinations have worsened. She now fears her bathroom is rigged with cameras. She showers with her swimsuit on.

We change Ms. P’s diagnosis to diet pill-induced psychosis. Because she had discarded the pill packaging before admission, we could not examine it for dosing information or ingredients.

The authors’ observations

Differentiating drug-induced psychosis from other psychoses often is difficult. Mood disorder with psychosis, schizophrenia, and substance-induced psychosis have similar characteristics (Table).

Ms. P has no personal or family history of psychosis that would suggest a thought disorder. She had good pre-morbid functioning (going to college, steady employment, long-term relationship with boyfriend) before her psychosis onset. She did, however, have a personal and family history of depression and was confronting many stressors (losing her job, failing grades at school, breaking up with her longtime boyfriend) that would suggest a primary mood disorder with psychosis.

We suspected an eating disorder and asked Ms. P more than once about her eating habits, but she insists she does not take the pills to lose weight. Also, her ex-boyfriend believes she is eating normally. Her low BMI and suspected obsession with weight loss could have signaled anorexia nervosa, but no other signs were present and her history does not support the diagnosis.

 

Table

Three causes of psychosis—and different characteristics of each presentation

Characteristic	Mood disorder with psychosis	Schizophrenia	Substance-induced psychosis
Acute onset	x	-	x
Delusions	x	x	x
Disorganized or catatonic behavior	x	x	x
Family history of psychosis	x	x	_
Good premorbid function	x	_	x
Hallucinations	x	x	x
Negative symptoms	x	x	x
Personal history of psychosis	x	x	_
Prodromal and residual symptoms	_	x	_

Relapse: cameras ‘off’ for 1 week

Five days after admission, we discharge Ms. P as her psychosis has improved significantly.

Later that day at the outpatient clinic, Ms. P requests a medication change, voicing fears about haloperidol’s long term side effects and mirtazapine-induced weight gain. Risperidone, 2 mg nightly, and citalopram, 20 mg/d, are started instead.

One week later, Ms. P’s parents again bring her to the ER after police find her sitting in her car, confused and paranoid. She complains that cameras have been set up in her car, and she responds to voices when alone.

On the way to the ER, Ms. P tries to jump from the moving car. She assaults her mother as she stops her from jumping.

Blood pressure is 155/92, heart rate is 82 beats per minute, respiratory rate is 18 breaths per minute, and temperature is 96°F.

On interview, Ms. P admits that she stopped risperidone and citalopram and restarted Xenadrine and phentermine. She also reports orthostasis from risperidone. We again admit her to the acute-care psychiatric unit and restart haloperidol, 1 mg/d, and citalopram, 20 mg/d.

The authors’ observations

Although we knew Ms. P was abusing diet pills, we could have easily ruled out drug-induced psychosis based on her three negative urine drug screens.

The clinical course of Ms. P’s psychosis, however, closely followed her diet pill use—emerging soon after starting phentermine and remitting soon after stopping it. Also:

• she was taking 2 to 3 times the recommended dosage of phentermine for several months. Phentermine is indicated for short-term (a few weeks) treatment of exogenous obesity (BMI ≥27 kg/m² in persons with hypertension, diabetes, or hyperlipidemia; BMI ≥30 kg/m² in persons without these risk factors)¹
  
• her BMI was below normal
  
• her psychosis remains in remission without use of an antipsychotic.
  

These factors, combined with the potentiating effects of these stimulating agents, apparently led to psychosis.

Stimulant medications such as amphetamines and stimulant drugs such as cocaine can produce psychotic symptoms including paranoid delusions, hallucinations, and bizarre behavior. Farrell and colleagues⁵ found that cannabis and psychostimulants increase the risk of psychosis.

Genetic load could have influenced Ms. P’s response to diet pills, but we have no information to support a genetic predisposition. Also, we saw no clear family history of a formal thought disorder.

The authors’ observations

Urine drug screens can pick up the main drug classes and often their derivatives, but this testing method is limited.²

Urine tests employ assays with semi-quantitative results. A urine sample may contain an abused substance but at levels below the cutoff. Also, because no correlation exists between cutoff levels and drug effect, a patient can have drug-induced symptoms but a negative urine drug screen. This makes detecting a suspected but unknown drug of abuse extremely difficult.

A routine urine screen can detect phentermine and other stimulants, but the phentermine level needed for a positive assay is 50 times that of pure amphetamine.² Ms. P’s last urine drug screen showed an amphetamine level just under the cutoff.

Use of cocaine—undetectable in urine 3 to 4 days after use—could be considered when drug-induced psychosis is suspected. Ms. P’s psychosis correlated with her phentermine relapse, however, and both she and her ex-boyfriend denied that she uses street drugs.

Obtain specific drug levels when you suspect medication abuse. Request gas chromatography or mass spectrometry to provide a quantitative result and confirm medication abuse.^2,3 These tests would have been appropriate for Ms. P once her ex-boyfriend revealed the diet pill abuse.

Detecting diet pill abuse

Use of weight-loss supplements and appetite suppressants is alarmingly common (Box). Many patients suffer adverse effects from diet pills but do not tell their doctors they are using them because they:

• fear the physician will scold them for circumventing his or her advice by obtaining medications online
  
• sense that obtaining diet pills over the Internet might be illegal
  
• do not realize the doctor needs to know about nonprescription drug use
  
• or fear the physician will tell them to stop taking the drug.
  

On the other hand, physicians often do not ask about diet pill use. They may perceive OTC appetite suppressants and weight-loss agents as harmless, or—as with Ms. P—may not suspect diet pill use because the patient is not overweight.

Rapid or unexplained weight loss, hypertension, tachycardia, tremors, psychomotor agitation, and hyperalertness could signal diet pill abuse. Emotional lability, such as euphoria during a high and fatigue and dysphoria during withdrawal, also could be indicative. Collateral information from family members or significant others can narrow the differential diagnosis.

 

Cognitive-behavioral therapy (CBT) can help Ms. P, who claimed she used diet pills to boost her energy. CBT would challenge her unrealistically high goals, teach and explain the consequences of drug use, and offer support to reinforce abstinence from diet pills. Educating patients about potential adverse drug effects also is essential.

Box

Conclusion: back to baseline

After 10 weeks, Ms. P’s condition returns to baseline. She starts a new job and abstains from diet pills. Her thought process and cognition improve significantly, and she reports no depressive symptoms at her most-recent visit. She maintains her weight at 139 lb. BMI is 21.1kg/m² (normal).

Haloperidol is slowly tapered across 2 weeks with no return of psychosis. Although Ms. P wants to stop haloperidol, we taper instead to guard against psychotic relapse. She continues to take citalopram, 20 mg/d, to prevent depressive symptom re-emergence and is receiving supportive psychotherapy to aid her relapse prevention.

Related resources

• Supplement Research Foundation. Supplement reviews. www.tsrf.com/supplements.htm
  
• Devan GS. Phentermine and Psychosis. Br J Psychiatry 1990;156:442-3.
  
• Cleare AJ. Phentermine, psychosis, and family history. J Clin Psychopharmacol 1996;16:470-1.
  
• Hoffman BF. Diet pill psychosis. CMAJ 1977;116:351-5.
  

Drug brand names

• Citalopram • Celexa
  
• Haloperidol • Haldol
  
• Mirtazapine • Remeron
  
• Phenteramine • Adipex
  
• Risperidone • Risperdal
  

Disclosure

Dr. Khan is a speaker for Pfizer and Wyeth Pharmaceuticals.

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

Presentation: ‘they’re stalking me’

Ms. P, age 30, fears she is being stalked and is too terrified to be home alone. Worried, her ex-boyfriend calls police, who bring her to the emergency room

At the ER, Ms. P reports that surveillance cameras have been planted inside her house, that men often stand on her roof and watch her go to her car, and that men constantly are stalking her. She also hears voices and reports frightening peripheral visions of “outsiders.” The ER doctor consults the psychiatry service and orders laboratory tests, but all results—including urine drug screen findings—are negative.

Ms. P says she has been sleeping 3 to 4 hours nightly. She acknowledges depressed mood and decreased appetite, leading to a 10-lb weight loss over 1 month. She says she has felt depressed off and on for several years but has received no treatment for her mood symptoms. We admit her to the psychiatric unit to treat her acute-onset psychosis.

Lately, Ms. P’s life has been difficult. A college sophomore, she is failing all her classes. She was recently fired from her job as a case manager because of inappropriate behavior, such as buying gifts for the children she was managing and taking them for hair-cuts without their parents’ permission. Several months ago, she broke up with her boyfriend of 6 years. In addition to these stressors, she recently moved into an apartment and for the first time was living on her own.

Medical history. Ms. P has no major medical problems. Her mother has battled alcohol and drug dependence and depression but to Ms. P’s knowledge has never experienced psychosis. Ms. P, who admits that she binge drinks once or twice monthly, meets DSM-IV-TR criteria for alcohol abuse disorder. She denies using illicit drugs but admits that she regularly takes “energy pills” purchased over the Internet because she cannot wake up without them.

Physical exam is normal, but Ms. P’s body mass index (BMI) is 18 kg/m², slightly below normal (height: 5 feet 8 inches; weight: 117.5 lb).

The authors’ observations

We diagnosed Ms. P as having recurrent and severe major depressive disorder with psychotic features because of her longstanding depressive symptoms. We considered substance-induced psychosis, but her urine drug screen is negative.

Treatment at this point should address both the paranoid delusions and depressive symptoms.

Treatment: starved for energy

We start haloperidol, 1 mg nightly, to treat Ms. P’s paranoid delusions, and mirtazapine, 15 mg nightly, to improve her sleep. We choose mirtazapine—which can increase appetite and lead to weight gain—because Ms. P is underweight. We also choose haloperidol because Ms. P is unemployed and cannot afford a second-generation antipsychotic.

Shortly afterward, we interview Ms. P’s ex-boyfriend. He tells us that she has been using diet pills regularly for 3 to 4 years, and that her chronic use has been escalating by the month. Lately, he says, she has been “popping the pills like candy.”

When we ask Ms. P about her diet pill use, she says she had mainly been using Xenadrine, an over-the-counter weight-loss supplement. Five months ago, she also started taking prescription phentermine, which she purchases over the Internet. She says that before her hospitalization, she was taking three phentermine tablets daily to boost her energy.

According to her ex-boyfriend, Ms. P began showing signs of psychosis 3 to 4 weeks after starting phentermine, and Ms. P notes that her initial paranoia and gustatory hallucinations have worsened. She now fears her bathroom is rigged with cameras. She showers with her swimsuit on.

We change Ms. P’s diagnosis to diet pill-induced psychosis. Because she had discarded the pill packaging before admission, we could not examine it for dosing information or ingredients.

The authors’ observations

Differentiating drug-induced psychosis from other psychoses often is difficult. Mood disorder with psychosis, schizophrenia, and substance-induced psychosis have similar characteristics (Table).

Ms. P has no personal or family history of psychosis that would suggest a thought disorder. She had good pre-morbid functioning (going to college, steady employment, long-term relationship with boyfriend) before her psychosis onset. She did, however, have a personal and family history of depression and was confronting many stressors (losing her job, failing grades at school, breaking up with her longtime boyfriend) that would suggest a primary mood disorder with psychosis.

We suspected an eating disorder and asked Ms. P more than once about her eating habits, but she insists she does not take the pills to lose weight. Also, her ex-boyfriend believes she is eating normally. Her low BMI and suspected obsession with weight loss could have signaled anorexia nervosa, but no other signs were present and her history does not support the diagnosis.

 

Table

Three causes of psychosis—and different characteristics of each presentation

Characteristic	Mood disorder with psychosis	Schizophrenia	Substance-induced psychosis
Acute onset	x	-	x
Delusions	x	x	x
Disorganized or catatonic behavior	x	x	x
Family history of psychosis	x	x	_
Good premorbid function	x	_	x
Hallucinations	x	x	x
Negative symptoms	x	x	x
Personal history of psychosis	x	x	_
Prodromal and residual symptoms	_	x	_

Relapse: cameras ‘off’ for 1 week

Five days after admission, we discharge Ms. P as her psychosis has improved significantly.

Later that day at the outpatient clinic, Ms. P requests a medication change, voicing fears about haloperidol’s long term side effects and mirtazapine-induced weight gain. Risperidone, 2 mg nightly, and citalopram, 20 mg/d, are started instead.

One week later, Ms. P’s parents again bring her to the ER after police find her sitting in her car, confused and paranoid. She complains that cameras have been set up in her car, and she responds to voices when alone.

On the way to the ER, Ms. P tries to jump from the moving car. She assaults her mother as she stops her from jumping.

Blood pressure is 155/92, heart rate is 82 beats per minute, respiratory rate is 18 breaths per minute, and temperature is 96°F.

On interview, Ms. P admits that she stopped risperidone and citalopram and restarted Xenadrine and phentermine. She also reports orthostasis from risperidone. We again admit her to the acute-care psychiatric unit and restart haloperidol, 1 mg/d, and citalopram, 20 mg/d.

The authors’ observations

Although we knew Ms. P was abusing diet pills, we could have easily ruled out drug-induced psychosis based on her three negative urine drug screens.

The clinical course of Ms. P’s psychosis, however, closely followed her diet pill use—emerging soon after starting phentermine and remitting soon after stopping it. Also:

• she was taking 2 to 3 times the recommended dosage of phentermine for several months. Phentermine is indicated for short-term (a few weeks) treatment of exogenous obesity (BMI ≥27 kg/m² in persons with hypertension, diabetes, or hyperlipidemia; BMI ≥30 kg/m² in persons without these risk factors)¹
  
• her BMI was below normal
  
• her psychosis remains in remission without use of an antipsychotic.
  

These factors, combined with the potentiating effects of these stimulating agents, apparently led to psychosis.

Stimulant medications such as amphetamines and stimulant drugs such as cocaine can produce psychotic symptoms including paranoid delusions, hallucinations, and bizarre behavior. Farrell and colleagues⁵ found that cannabis and psychostimulants increase the risk of psychosis.

Genetic load could have influenced Ms. P’s response to diet pills, but we have no information to support a genetic predisposition. Also, we saw no clear family history of a formal thought disorder.

The authors’ observations

Urine drug screens can pick up the main drug classes and often their derivatives, but this testing method is limited.²

Urine tests employ assays with semi-quantitative results. A urine sample may contain an abused substance but at levels below the cutoff. Also, because no correlation exists between cutoff levels and drug effect, a patient can have drug-induced symptoms but a negative urine drug screen. This makes detecting a suspected but unknown drug of abuse extremely difficult.

A routine urine screen can detect phentermine and other stimulants, but the phentermine level needed for a positive assay is 50 times that of pure amphetamine.² Ms. P’s last urine drug screen showed an amphetamine level just under the cutoff.

Use of cocaine—undetectable in urine 3 to 4 days after use—could be considered when drug-induced psychosis is suspected. Ms. P’s psychosis correlated with her phentermine relapse, however, and both she and her ex-boyfriend denied that she uses street drugs.

Obtain specific drug levels when you suspect medication abuse. Request gas chromatography or mass spectrometry to provide a quantitative result and confirm medication abuse.^2,3 These tests would have been appropriate for Ms. P once her ex-boyfriend revealed the diet pill abuse.

Detecting diet pill abuse

Use of weight-loss supplements and appetite suppressants is alarmingly common (Box). Many patients suffer adverse effects from diet pills but do not tell their doctors they are using them because they:

• fear the physician will scold them for circumventing his or her advice by obtaining medications online
  
• sense that obtaining diet pills over the Internet might be illegal
  
• do not realize the doctor needs to know about nonprescription drug use
  
• or fear the physician will tell them to stop taking the drug.
  

On the other hand, physicians often do not ask about diet pill use. They may perceive OTC appetite suppressants and weight-loss agents as harmless, or—as with Ms. P—may not suspect diet pill use because the patient is not overweight.

Rapid or unexplained weight loss, hypertension, tachycardia, tremors, psychomotor agitation, and hyperalertness could signal diet pill abuse. Emotional lability, such as euphoria during a high and fatigue and dysphoria during withdrawal, also could be indicative. Collateral information from family members or significant others can narrow the differential diagnosis.

 

Cognitive-behavioral therapy (CBT) can help Ms. P, who claimed she used diet pills to boost her energy. CBT would challenge her unrealistically high goals, teach and explain the consequences of drug use, and offer support to reinforce abstinence from diet pills. Educating patients about potential adverse drug effects also is essential.

Box

Conclusion: back to baseline

After 10 weeks, Ms. P’s condition returns to baseline. She starts a new job and abstains from diet pills. Her thought process and cognition improve significantly, and she reports no depressive symptoms at her most-recent visit. She maintains her weight at 139 lb. BMI is 21.1kg/m² (normal).

Haloperidol is slowly tapered across 2 weeks with no return of psychosis. Although Ms. P wants to stop haloperidol, we taper instead to guard against psychotic relapse. She continues to take citalopram, 20 mg/d, to prevent depressive symptom re-emergence and is receiving supportive psychotherapy to aid her relapse prevention.

Related resources

• Supplement Research Foundation. Supplement reviews. www.tsrf.com/supplements.htm
  
• Devan GS. Phentermine and Psychosis. Br J Psychiatry 1990;156:442-3.
  
• Cleare AJ. Phentermine, psychosis, and family history. J Clin Psychopharmacol 1996;16:470-1.
  
• Hoffman BF. Diet pill psychosis. CMAJ 1977;116:351-5.
  

Drug brand names

• Citalopram • Celexa
  
• Haloperidol • Haldol
  
• Mirtazapine • Remeron
  
• Phenteramine • Adipex
  
• Risperidone • Risperdal
  

Disclosure

Dr. Khan is a speaker for Pfizer and Wyeth Pharmaceuticals.

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

Presentation: ‘they’re stalking me’

Ms. P, age 30, fears she is being stalked and is too terrified to be home alone. Worried, her ex-boyfriend calls police, who bring her to the emergency room

At the ER, Ms. P reports that surveillance cameras have been planted inside her house, that men often stand on her roof and watch her go to her car, and that men constantly are stalking her. She also hears voices and reports frightening peripheral visions of “outsiders.” The ER doctor consults the psychiatry service and orders laboratory tests, but all results—including urine drug screen findings—are negative.

Ms. P says she has been sleeping 3 to 4 hours nightly. She acknowledges depressed mood and decreased appetite, leading to a 10-lb weight loss over 1 month. She says she has felt depressed off and on for several years but has received no treatment for her mood symptoms. We admit her to the psychiatric unit to treat her acute-onset psychosis.

Lately, Ms. P’s life has been difficult. A college sophomore, she is failing all her classes. She was recently fired from her job as a case manager because of inappropriate behavior, such as buying gifts for the children she was managing and taking them for hair-cuts without their parents’ permission. Several months ago, she broke up with her boyfriend of 6 years. In addition to these stressors, she recently moved into an apartment and for the first time was living on her own.

Medical history. Ms. P has no major medical problems. Her mother has battled alcohol and drug dependence and depression but to Ms. P’s knowledge has never experienced psychosis. Ms. P, who admits that she binge drinks once or twice monthly, meets DSM-IV-TR criteria for alcohol abuse disorder. She denies using illicit drugs but admits that she regularly takes “energy pills” purchased over the Internet because she cannot wake up without them.

Physical exam is normal, but Ms. P’s body mass index (BMI) is 18 kg/m², slightly below normal (height: 5 feet 8 inches; weight: 117.5 lb).

The authors’ observations

We diagnosed Ms. P as having recurrent and severe major depressive disorder with psychotic features because of her longstanding depressive symptoms. We considered substance-induced psychosis, but her urine drug screen is negative.

Treatment at this point should address both the paranoid delusions and depressive symptoms.

Treatment: starved for energy

We start haloperidol, 1 mg nightly, to treat Ms. P’s paranoid delusions, and mirtazapine, 15 mg nightly, to improve her sleep. We choose mirtazapine—which can increase appetite and lead to weight gain—because Ms. P is underweight. We also choose haloperidol because Ms. P is unemployed and cannot afford a second-generation antipsychotic.

Shortly afterward, we interview Ms. P’s ex-boyfriend. He tells us that she has been using diet pills regularly for 3 to 4 years, and that her chronic use has been escalating by the month. Lately, he says, she has been “popping the pills like candy.”

When we ask Ms. P about her diet pill use, she says she had mainly been using Xenadrine, an over-the-counter weight-loss supplement. Five months ago, she also started taking prescription phentermine, which she purchases over the Internet. She says that before her hospitalization, she was taking three phentermine tablets daily to boost her energy.

According to her ex-boyfriend, Ms. P began showing signs of psychosis 3 to 4 weeks after starting phentermine, and Ms. P notes that her initial paranoia and gustatory hallucinations have worsened. She now fears her bathroom is rigged with cameras. She showers with her swimsuit on.

We change Ms. P’s diagnosis to diet pill-induced psychosis. Because she had discarded the pill packaging before admission, we could not examine it for dosing information or ingredients.

The authors’ observations

Differentiating drug-induced psychosis from other psychoses often is difficult. Mood disorder with psychosis, schizophrenia, and substance-induced psychosis have similar characteristics (Table).

Ms. P has no personal or family history of psychosis that would suggest a thought disorder. She had good pre-morbid functioning (going to college, steady employment, long-term relationship with boyfriend) before her psychosis onset. She did, however, have a personal and family history of depression and was confronting many stressors (losing her job, failing grades at school, breaking up with her longtime boyfriend) that would suggest a primary mood disorder with psychosis.

We suspected an eating disorder and asked Ms. P more than once about her eating habits, but she insists she does not take the pills to lose weight. Also, her ex-boyfriend believes she is eating normally. Her low BMI and suspected obsession with weight loss could have signaled anorexia nervosa, but no other signs were present and her history does not support the diagnosis.

 

Table

Three causes of psychosis—and different characteristics of each presentation

Characteristic	Mood disorder with psychosis	Schizophrenia	Substance-induced psychosis
Acute onset	x	-	x
Delusions	x	x	x
Disorganized or catatonic behavior	x	x	x
Family history of psychosis	x	x	_
Good premorbid function	x	_	x
Hallucinations	x	x	x
Negative symptoms	x	x	x
Personal history of psychosis	x	x	_
Prodromal and residual symptoms	_	x	_

Relapse: cameras ‘off’ for 1 week

Five days after admission, we discharge Ms. P as her psychosis has improved significantly.

Later that day at the outpatient clinic, Ms. P requests a medication change, voicing fears about haloperidol’s long term side effects and mirtazapine-induced weight gain. Risperidone, 2 mg nightly, and citalopram, 20 mg/d, are started instead.

One week later, Ms. P’s parents again bring her to the ER after police find her sitting in her car, confused and paranoid. She complains that cameras have been set up in her car, and she responds to voices when alone.

On the way to the ER, Ms. P tries to jump from the moving car. She assaults her mother as she stops her from jumping.

Blood pressure is 155/92, heart rate is 82 beats per minute, respiratory rate is 18 breaths per minute, and temperature is 96°F.

On interview, Ms. P admits that she stopped risperidone and citalopram and restarted Xenadrine and phentermine. She also reports orthostasis from risperidone. We again admit her to the acute-care psychiatric unit and restart haloperidol, 1 mg/d, and citalopram, 20 mg/d.

The authors’ observations

Although we knew Ms. P was abusing diet pills, we could have easily ruled out drug-induced psychosis based on her three negative urine drug screens.

The clinical course of Ms. P’s psychosis, however, closely followed her diet pill use—emerging soon after starting phentermine and remitting soon after stopping it. Also:

• she was taking 2 to 3 times the recommended dosage of phentermine for several months. Phentermine is indicated for short-term (a few weeks) treatment of exogenous obesity (BMI ≥27 kg/m² in persons with hypertension, diabetes, or hyperlipidemia; BMI ≥30 kg/m² in persons without these risk factors)¹
  
• her BMI was below normal
  
• her psychosis remains in remission without use of an antipsychotic.
  

These factors, combined with the potentiating effects of these stimulating agents, apparently led to psychosis.

Stimulant medications such as amphetamines and stimulant drugs such as cocaine can produce psychotic symptoms including paranoid delusions, hallucinations, and bizarre behavior. Farrell and colleagues⁵ found that cannabis and psychostimulants increase the risk of psychosis.

Genetic load could have influenced Ms. P’s response to diet pills, but we have no information to support a genetic predisposition. Also, we saw no clear family history of a formal thought disorder.

The authors’ observations

Urine drug screens can pick up the main drug classes and often their derivatives, but this testing method is limited.²

Urine tests employ assays with semi-quantitative results. A urine sample may contain an abused substance but at levels below the cutoff. Also, because no correlation exists between cutoff levels and drug effect, a patient can have drug-induced symptoms but a negative urine drug screen. This makes detecting a suspected but unknown drug of abuse extremely difficult.

A routine urine screen can detect phentermine and other stimulants, but the phentermine level needed for a positive assay is 50 times that of pure amphetamine.² Ms. P’s last urine drug screen showed an amphetamine level just under the cutoff.

Use of cocaine—undetectable in urine 3 to 4 days after use—could be considered when drug-induced psychosis is suspected. Ms. P’s psychosis correlated with her phentermine relapse, however, and both she and her ex-boyfriend denied that she uses street drugs.

Obtain specific drug levels when you suspect medication abuse. Request gas chromatography or mass spectrometry to provide a quantitative result and confirm medication abuse.^2,3 These tests would have been appropriate for Ms. P once her ex-boyfriend revealed the diet pill abuse.

Detecting diet pill abuse

Use of weight-loss supplements and appetite suppressants is alarmingly common (Box). Many patients suffer adverse effects from diet pills but do not tell their doctors they are using them because they:

• fear the physician will scold them for circumventing his or her advice by obtaining medications online
  
• sense that obtaining diet pills over the Internet might be illegal
  
• do not realize the doctor needs to know about nonprescription drug use
  
• or fear the physician will tell them to stop taking the drug.
  

On the other hand, physicians often do not ask about diet pill use. They may perceive OTC appetite suppressants and weight-loss agents as harmless, or—as with Ms. P—may not suspect diet pill use because the patient is not overweight.

Rapid or unexplained weight loss, hypertension, tachycardia, tremors, psychomotor agitation, and hyperalertness could signal diet pill abuse. Emotional lability, such as euphoria during a high and fatigue and dysphoria during withdrawal, also could be indicative. Collateral information from family members or significant others can narrow the differential diagnosis.

 

Cognitive-behavioral therapy (CBT) can help Ms. P, who claimed she used diet pills to boost her energy. CBT would challenge her unrealistically high goals, teach and explain the consequences of drug use, and offer support to reinforce abstinence from diet pills. Educating patients about potential adverse drug effects also is essential.

Box

Conclusion: back to baseline

After 10 weeks, Ms. P’s condition returns to baseline. She starts a new job and abstains from diet pills. Her thought process and cognition improve significantly, and she reports no depressive symptoms at her most-recent visit. She maintains her weight at 139 lb. BMI is 21.1kg/m² (normal).

Haloperidol is slowly tapered across 2 weeks with no return of psychosis. Although Ms. P wants to stop haloperidol, we taper instead to guard against psychotic relapse. She continues to take citalopram, 20 mg/d, to prevent depressive symptom re-emergence and is receiving supportive psychotherapy to aid her relapse prevention.

Related resources

• Supplement Research Foundation. Supplement reviews. www.tsrf.com/supplements.htm
  
• Devan GS. Phentermine and Psychosis. Br J Psychiatry 1990;156:442-3.
  
• Cleare AJ. Phentermine, psychosis, and family history. J Clin Psychopharmacol 1996;16:470-1.
  
• Hoffman BF. Diet pill psychosis. CMAJ 1977;116:351-5.
  

Drug brand names

• Citalopram • Celexa
  
• Haloperidol • Haldol
  
• Mirtazapine • Remeron
  
• Phenteramine • Adipex
  
• Risperidone • Risperdal
  

Disclosure

Dr. Khan is a speaker for Pfizer and Wyeth Pharmaceuticals.

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

History: losing his ‘drive’

Mr. D, age 49, has been treated for major depressive disorder for approximately 1 year but reports only occasional minor symptom improvement. At presentation, he had been irritable and lethargic for about 2 weeks and had increased appetite, decreased concentration, and trouble falling asleep at night.

A once-gregarious family man, Mr. D had become apathetic and too tired to enjoy socializing. He denied suicidal thoughts or feelings of worthlessness and hopelessness but feared his fatigue was interfering with his job as a truck driver. He tired after driving only a few hours.

Mr. D had been diagnosed with sleep apnea when he was younger but had no other medical history. He said his erratic work schedule kept him from using his continuous positive airway pressure (CPAP) machine regularly. He was taking no medications and had not seen a primary care physician for more than 2 years because of lack of coverage. He denied past or current substance abuse.

The patient weighed 280 lbs at intake. His body mass index (BMI) was 37.5, indicating clinical obesity.

Because Mr. D lacked health insurance, we enrolled him 1 year ago in a free depression study at a psychiatric outpatient clinic. At intake, he said numerous life stresses—particularly the recent death of his brother in a motor vehicle accident—had left him feeling depressed.

We started Mr. D on citalopram, 20 mg/d, which was the study protocol. Two weeks later, he complained of dry mouth and sedation with minimal symptom improvement. We stopped citalopram and started sertraline, 25 mg/d.

Two weeks later, Mr. D again complained he had “no energy” and was “sleeping all day.” We titrated sertraline to 200 mg/d over 2 months, but his excessive tiredness, increased appetite, and decreased motivation persisted. Mr. D needed routine laboratory tests, so we referred him to a local clinic that charges on a sliding scale. He did not complete the tests, however, for fear of incurring medical expenses.

We tried to improve Mr. D’s mood symptoms by adding lithium—225 mg/d titrated to 675 mg/d over 7 weeks—but his depression and fatigue kept worsening. We tapered him off lithium and sertraline and switched to the monoamine oxidase inhibitor tranylcypromine, 30 mg/d, which was also part of the study protocol. We warned him not to eat pizza, fermented dry sausages, or other foods that could interact adversely with tranylcypromine. After 4 weeks, Mr. D stopped taking the agent, saying he could not follow the dietary restrictions while on the road.

We released Mr. D from the study because of nonresponse. Bupropion, started at 100 mg bid and titrated to 300 mg each morning and 150 mg nightly across 5 months, did not resolve his fatigue. He also started having agitation and “anger problems,” often getting into shouting matches over his CBradio with other truck drivers. We started quetiapine, 25 mg bid, hoping the low dose would calm his mood.

Until now, Mr. D has ignored our requests to undergo routine laboratory testing. We referred him to the local clinic four times over the past year but he has not complied, citing lack of health insurance and financial concerns.

The authors’ observations

Although Mr. D’s symptoms (constantly depressed mood, loss of interest in usual activities) clearly suggest treatment-resistant major depressive disorder, an underlying medical disorder cannot be ruled out, yet he refuses to get needed tests.

Medical comorbidities are more prevalent in patients with mental illness than in the general population.¹ As many as 43% of patients referred to some psychiatry clinics have medical disorders, and almost one-half the diagnoses were missed by the referring physician.²

Compared to patients without psychiatric diagnoses, those with mental illness have more difficulty gaining access to medical care and are less likely to receive and follow guidelines for preventive care. Mental illness symptoms often compromise one’s ability to seek health care or follow a doctor’s orders. For example, a psychotic person may be overly suspicious of doctors, whereas someone with anxiety may seek care inappropriately.^3,4 Also, some studies estimate that 1 in 5 persons with mental illness are uninsured.^1,5,6

Mr. D denies substance abuse, but primary care and behavioral health clinicians often miss substance use disorders.⁷ Accuracy of substance abuse self-reports varies widely; some studies report high accuracy, whereas almost 33% of patients in other studies do not disclose substance abuse.⁸

Testing: stimulating findings

At his next visit, Mr. D reports worsening thirst and increased urination and complains of increased appetite, easy bruising, excessive sleepiness, and apathy. He also reveals that for 2 months he has been taking 2 to 3 fat-burning stimulant capsules a day to stay awake while driving.

 

Alarmed by his elevated blood pressure (177/99 mm Hg) and worsening physical symptoms, Mr. D finally consents to baseline laboratory testing. Blood glucose is 306 mg/dL (normal 70 to 110 mg/dL), and glycosylated hemoglobin is 12% (normal

Mr. D, who now weighs 270 lbs, is diagnosed as having hypertension and type 2 diabetes mellitus. Clinic doctors start him on metformin, 500 mg bid titrated to 1,000 mg bid, and glyburide, 5 mg/d, to control his glucose, and lisinopril, 10 mg/d, to control his hypertension, reduce cardiovascular risk, and preserve renal function. Clinicians also order Mr. D to follow an 1,800-calorie, American Diabetes Association-approved diet. We stop quetiapine and bupropion.

Mr. D’s diabetes and hypertension diagnosis, combined with his habitus and history of easy bruising, suggest Cushing’s syndrome. Doctors rule out this disorder based on a 24-hour free cortisol reading of 59 mg/L and normal dexamethasone suppression. Lab findings suggest he is not taking stimulants away from work.

The authors’ observations

Ideally, Mr. D should have undergone laboratory testing after the initial intake visit, before psychotropics were started. Routine vital signs also should have been taken.

Symptoms of major depressive disorder and early type 2 diabetes are strikingly similar (Table 1). For example, early diabetes symptoms such as fatigue can mimic depression or other medical problems. In one study of 69 diabetic patients who were referred by their primary care doctors to a psychiatric clinic, 57 had not been diagnosed as having diabetes before referral.⁹

Aside from its medical complications, diabetes also doubles the risk of comorbid depression, which can alter diabetes’ course and outcome.¹⁰

Earlier laboratory testing could have uncovered Mr. D’s comorbid stimulant abuse, which also can mimic depression and complicate its treatment.¹¹ Signs of amphetamine withdrawal—such as dysphoric mood, fatigue, insomnia or hypersomnia, increased appetite, and psychomotor retardation—can be mistaken for depression (Table 1).

Patients with Cushing’s syndrome may present with nonspecific complaints of fatigue, decreased energy, apathy, depressed mood, and hypersomnia. A 24-hour free cortisol reading and dexamethasone suppression testing can differentiate Cushing’s syndrome from depression.

Costly, unnecessary care. Missing a medical cause of apparent psychiatric symptoms can lead to unnecessary treatment and needless expense. A complete metabolic profile and urine drug screen—approximately $60—could have saved the nearly $5,000 spent on treating Mr. D’s “resistant” depression ( Table 2).

Psychiatrists need to watch for potential medical problems and for cormorbidities associated with mental illness. Patients with frequent mental distress—defined as ≥ 14 mentally unhealthy days within 30 days—were found to be more likely to smoke, drink heavily, and be physically inactive and obese than were mentally healthy persons. Mentally distressed patients also were more likely to lack health care coverage and to engage in multiple adverse behaviors, increasing their risk for mental and physical illness.¹²

Ensuring proper medical care. Based on our experience with Mr. D, routine vital signs—including BMI, weight, blood pressure, and pulse rate—should be recorded at each visit. At intake, we recommend that psychiatrists:

• find out when the patient last saw a primary health provider other than in the emergency room, and whether the patient is receiving preventive medical care
  
• assess for unhealthy lifestyle habits (smoking, drug use, poor diet) or family history of serious medical illnesses.
  

Mr. D, for example, had not received preventative care for at least 2 to 3 years and had obesity, a family history of diabetes, a sedentary lifestyle, and an unhealthy diet.

Educate patients about the interplay between physical and mental illness to help them understand the importance of seeing a primary care doctor. Finally, be familiar with local indigent health clinics and their fee scales.

Table 1

Medical symptoms that mimic depression

Symptom	Amphetamine withdrawal	Cushing’s syndrome	Diabetes
Anxiety		×
Dysphoric mood	×
Fatigue	×	×	×
Hypersomnia	×
Increased appetite	×		×
Insomnia	×
Irritability		×	×
Muscle aches and cramps			×
Psychomotor retardation	×
Vivid, unpleasant dreams	×
Weakness		×
Weight gain or loss			×

Table 2

The cost of treating Mr. D’s ‘resistant depression’

Medication/dosage	Start date	Stop date	Approximate cost
Citalopram, 20 mg/d	10/3/03	10/24/03	$58.50
Sertraline, 25 to 200 mg/d	10/24/03	12/24/03	$283.00
Sertraline 150 mg/d, with lithium, 225 to 675 mg/d	12/24/03	2/6/04	$343.00
Tranylcypromine, 10 mg each morning, 20 mg at bedtime	2/27/04	4/20/04	$322.00
Bupropion (sustained release) up to 450 mg/d	5/7/04	8/30/04	$372.00
Bupropion (sustained release), 450 mg/d, plus quetiapine, 25 mg/d	8/30/04	11/8/04	$554.00
Total cost of psychotropics			$1,932.50
Total cost of office visits ($95 X 30 visits)			$2,850.00
TOTAL COST OF TREATMENT			$4,782.50
Source: Walgreens Co. retail prices in Wichita, KS

Follow-up: 30 lbs in 4 months

Mr. D has lost >30 lbs over 4 months, and his blood pressure and serum glucose are normal. BMI is now 32, in the lower range of clinical obesity. He feels more energetic and active, no longer reports excessive sedation and apathy, and has stopped taking stimulants. His depressive symptoms have remitted.

 

Related resources

• WrongDiagnosis.com. Information on differential diagnosis of medical and psychiatric problems. www.wrongdiagnosis.com.
  
• Mauksch LB, Tucker SM, Katon WJ, et al. Mental illness, functional impairment, and patient preferences for collaborative care in an uninsured, primary care population. J Fam Pract 2001;50:41-7.
  
• Glied S, Little SE. The uninsured and the benefits of medical progress. Health Aff (Millwood) 2003;22:210-9.
  

Drug brand names

• Bupropion • Wellbutrin
  
• Citalopram • Celexa
  
• Dexamethasone • Ciprodex, others
  
• Glucophage • Metformin
  
• Glyburide • DiaBeta, others
  
• Lisinopril • Prinivil, Zestril
  
• Lithium • Eskalith, others
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  
• Tranylcypromine •Parnate
  

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: losing his ‘drive’

Mr. D, age 49, has been treated for major depressive disorder for approximately 1 year but reports only occasional minor symptom improvement. At presentation, he had been irritable and lethargic for about 2 weeks and had increased appetite, decreased concentration, and trouble falling asleep at night.

A once-gregarious family man, Mr. D had become apathetic and too tired to enjoy socializing. He denied suicidal thoughts or feelings of worthlessness and hopelessness but feared his fatigue was interfering with his job as a truck driver. He tired after driving only a few hours.

Mr. D had been diagnosed with sleep apnea when he was younger but had no other medical history. He said his erratic work schedule kept him from using his continuous positive airway pressure (CPAP) machine regularly. He was taking no medications and had not seen a primary care physician for more than 2 years because of lack of coverage. He denied past or current substance abuse.

The patient weighed 280 lbs at intake. His body mass index (BMI) was 37.5, indicating clinical obesity.

Because Mr. D lacked health insurance, we enrolled him 1 year ago in a free depression study at a psychiatric outpatient clinic. At intake, he said numerous life stresses—particularly the recent death of his brother in a motor vehicle accident—had left him feeling depressed.

We started Mr. D on citalopram, 20 mg/d, which was the study protocol. Two weeks later, he complained of dry mouth and sedation with minimal symptom improvement. We stopped citalopram and started sertraline, 25 mg/d.

Two weeks later, Mr. D again complained he had “no energy” and was “sleeping all day.” We titrated sertraline to 200 mg/d over 2 months, but his excessive tiredness, increased appetite, and decreased motivation persisted. Mr. D needed routine laboratory tests, so we referred him to a local clinic that charges on a sliding scale. He did not complete the tests, however, for fear of incurring medical expenses.

We tried to improve Mr. D’s mood symptoms by adding lithium—225 mg/d titrated to 675 mg/d over 7 weeks—but his depression and fatigue kept worsening. We tapered him off lithium and sertraline and switched to the monoamine oxidase inhibitor tranylcypromine, 30 mg/d, which was also part of the study protocol. We warned him not to eat pizza, fermented dry sausages, or other foods that could interact adversely with tranylcypromine. After 4 weeks, Mr. D stopped taking the agent, saying he could not follow the dietary restrictions while on the road.

We released Mr. D from the study because of nonresponse. Bupropion, started at 100 mg bid and titrated to 300 mg each morning and 150 mg nightly across 5 months, did not resolve his fatigue. He also started having agitation and “anger problems,” often getting into shouting matches over his CBradio with other truck drivers. We started quetiapine, 25 mg bid, hoping the low dose would calm his mood.

Until now, Mr. D has ignored our requests to undergo routine laboratory testing. We referred him to the local clinic four times over the past year but he has not complied, citing lack of health insurance and financial concerns.

The authors’ observations

Although Mr. D’s symptoms (constantly depressed mood, loss of interest in usual activities) clearly suggest treatment-resistant major depressive disorder, an underlying medical disorder cannot be ruled out, yet he refuses to get needed tests.

Medical comorbidities are more prevalent in patients with mental illness than in the general population.¹ As many as 43% of patients referred to some psychiatry clinics have medical disorders, and almost one-half the diagnoses were missed by the referring physician.²

Compared to patients without psychiatric diagnoses, those with mental illness have more difficulty gaining access to medical care and are less likely to receive and follow guidelines for preventive care. Mental illness symptoms often compromise one’s ability to seek health care or follow a doctor’s orders. For example, a psychotic person may be overly suspicious of doctors, whereas someone with anxiety may seek care inappropriately.^3,4 Also, some studies estimate that 1 in 5 persons with mental illness are uninsured.^1,5,6

Mr. D denies substance abuse, but primary care and behavioral health clinicians often miss substance use disorders.⁷ Accuracy of substance abuse self-reports varies widely; some studies report high accuracy, whereas almost 33% of patients in other studies do not disclose substance abuse.⁸

Testing: stimulating findings

At his next visit, Mr. D reports worsening thirst and increased urination and complains of increased appetite, easy bruising, excessive sleepiness, and apathy. He also reveals that for 2 months he has been taking 2 to 3 fat-burning stimulant capsules a day to stay awake while driving.

 

Alarmed by his elevated blood pressure (177/99 mm Hg) and worsening physical symptoms, Mr. D finally consents to baseline laboratory testing. Blood glucose is 306 mg/dL (normal 70 to 110 mg/dL), and glycosylated hemoglobin is 12% (normal

Mr. D, who now weighs 270 lbs, is diagnosed as having hypertension and type 2 diabetes mellitus. Clinic doctors start him on metformin, 500 mg bid titrated to 1,000 mg bid, and glyburide, 5 mg/d, to control his glucose, and lisinopril, 10 mg/d, to control his hypertension, reduce cardiovascular risk, and preserve renal function. Clinicians also order Mr. D to follow an 1,800-calorie, American Diabetes Association-approved diet. We stop quetiapine and bupropion.

Mr. D’s diabetes and hypertension diagnosis, combined with his habitus and history of easy bruising, suggest Cushing’s syndrome. Doctors rule out this disorder based on a 24-hour free cortisol reading of 59 mg/L and normal dexamethasone suppression. Lab findings suggest he is not taking stimulants away from work.

The authors’ observations

Ideally, Mr. D should have undergone laboratory testing after the initial intake visit, before psychotropics were started. Routine vital signs also should have been taken.

Symptoms of major depressive disorder and early type 2 diabetes are strikingly similar (Table 1). For example, early diabetes symptoms such as fatigue can mimic depression or other medical problems. In one study of 69 diabetic patients who were referred by their primary care doctors to a psychiatric clinic, 57 had not been diagnosed as having diabetes before referral.⁹

Aside from its medical complications, diabetes also doubles the risk of comorbid depression, which can alter diabetes’ course and outcome.¹⁰

Earlier laboratory testing could have uncovered Mr. D’s comorbid stimulant abuse, which also can mimic depression and complicate its treatment.¹¹ Signs of amphetamine withdrawal—such as dysphoric mood, fatigue, insomnia or hypersomnia, increased appetite, and psychomotor retardation—can be mistaken for depression (Table 1).

Patients with Cushing’s syndrome may present with nonspecific complaints of fatigue, decreased energy, apathy, depressed mood, and hypersomnia. A 24-hour free cortisol reading and dexamethasone suppression testing can differentiate Cushing’s syndrome from depression.

Costly, unnecessary care. Missing a medical cause of apparent psychiatric symptoms can lead to unnecessary treatment and needless expense. A complete metabolic profile and urine drug screen—approximately $60—could have saved the nearly $5,000 spent on treating Mr. D’s “resistant” depression ( Table 2).

Psychiatrists need to watch for potential medical problems and for cormorbidities associated with mental illness. Patients with frequent mental distress—defined as ≥ 14 mentally unhealthy days within 30 days—were found to be more likely to smoke, drink heavily, and be physically inactive and obese than were mentally healthy persons. Mentally distressed patients also were more likely to lack health care coverage and to engage in multiple adverse behaviors, increasing their risk for mental and physical illness.¹²

Ensuring proper medical care. Based on our experience with Mr. D, routine vital signs—including BMI, weight, blood pressure, and pulse rate—should be recorded at each visit. At intake, we recommend that psychiatrists:

• find out when the patient last saw a primary health provider other than in the emergency room, and whether the patient is receiving preventive medical care
  
• assess for unhealthy lifestyle habits (smoking, drug use, poor diet) or family history of serious medical illnesses.
  

Mr. D, for example, had not received preventative care for at least 2 to 3 years and had obesity, a family history of diabetes, a sedentary lifestyle, and an unhealthy diet.

Educate patients about the interplay between physical and mental illness to help them understand the importance of seeing a primary care doctor. Finally, be familiar with local indigent health clinics and their fee scales.

Table 1

Medical symptoms that mimic depression

Symptom	Amphetamine withdrawal	Cushing’s syndrome	Diabetes
Anxiety		×
Dysphoric mood	×
Fatigue	×	×	×
Hypersomnia	×
Increased appetite	×		×
Insomnia	×
Irritability		×	×
Muscle aches and cramps			×
Psychomotor retardation	×
Vivid, unpleasant dreams	×
Weakness		×
Weight gain or loss			×

Table 2

The cost of treating Mr. D’s ‘resistant depression’

Medication/dosage	Start date	Stop date	Approximate cost
Citalopram, 20 mg/d	10/3/03	10/24/03	$58.50
Sertraline, 25 to 200 mg/d	10/24/03	12/24/03	$283.00
Sertraline 150 mg/d, with lithium, 225 to 675 mg/d	12/24/03	2/6/04	$343.00
Tranylcypromine, 10 mg each morning, 20 mg at bedtime	2/27/04	4/20/04	$322.00
Bupropion (sustained release) up to 450 mg/d	5/7/04	8/30/04	$372.00
Bupropion (sustained release), 450 mg/d, plus quetiapine, 25 mg/d	8/30/04	11/8/04	$554.00
Total cost of psychotropics			$1,932.50
Total cost of office visits ($95 X 30 visits)			$2,850.00
TOTAL COST OF TREATMENT			$4,782.50
Source: Walgreens Co. retail prices in Wichita, KS

Follow-up: 30 lbs in 4 months

Mr. D has lost >30 lbs over 4 months, and his blood pressure and serum glucose are normal. BMI is now 32, in the lower range of clinical obesity. He feels more energetic and active, no longer reports excessive sedation and apathy, and has stopped taking stimulants. His depressive symptoms have remitted.

 

Related resources

• WrongDiagnosis.com. Information on differential diagnosis of medical and psychiatric problems. www.wrongdiagnosis.com.
  
• Mauksch LB, Tucker SM, Katon WJ, et al. Mental illness, functional impairment, and patient preferences for collaborative care in an uninsured, primary care population. J Fam Pract 2001;50:41-7.
  
• Glied S, Little SE. The uninsured and the benefits of medical progress. Health Aff (Millwood) 2003;22:210-9.
  

Drug brand names

• Bupropion • Wellbutrin
  
• Citalopram • Celexa
  
• Dexamethasone • Ciprodex, others
  
• Glucophage • Metformin
  
• Glyburide • DiaBeta, others
  
• Lisinopril • Prinivil, Zestril
  
• Lithium • Eskalith, others
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  
• Tranylcypromine •Parnate
  

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: losing his ‘drive’

Mr. D, age 49, has been treated for major depressive disorder for approximately 1 year but reports only occasional minor symptom improvement. At presentation, he had been irritable and lethargic for about 2 weeks and had increased appetite, decreased concentration, and trouble falling asleep at night.

A once-gregarious family man, Mr. D had become apathetic and too tired to enjoy socializing. He denied suicidal thoughts or feelings of worthlessness and hopelessness but feared his fatigue was interfering with his job as a truck driver. He tired after driving only a few hours.

Mr. D had been diagnosed with sleep apnea when he was younger but had no other medical history. He said his erratic work schedule kept him from using his continuous positive airway pressure (CPAP) machine regularly. He was taking no medications and had not seen a primary care physician for more than 2 years because of lack of coverage. He denied past or current substance abuse.

The patient weighed 280 lbs at intake. His body mass index (BMI) was 37.5, indicating clinical obesity.

Because Mr. D lacked health insurance, we enrolled him 1 year ago in a free depression study at a psychiatric outpatient clinic. At intake, he said numerous life stresses—particularly the recent death of his brother in a motor vehicle accident—had left him feeling depressed.

We started Mr. D on citalopram, 20 mg/d, which was the study protocol. Two weeks later, he complained of dry mouth and sedation with minimal symptom improvement. We stopped citalopram and started sertraline, 25 mg/d.

Two weeks later, Mr. D again complained he had “no energy” and was “sleeping all day.” We titrated sertraline to 200 mg/d over 2 months, but his excessive tiredness, increased appetite, and decreased motivation persisted. Mr. D needed routine laboratory tests, so we referred him to a local clinic that charges on a sliding scale. He did not complete the tests, however, for fear of incurring medical expenses.

We tried to improve Mr. D’s mood symptoms by adding lithium—225 mg/d titrated to 675 mg/d over 7 weeks—but his depression and fatigue kept worsening. We tapered him off lithium and sertraline and switched to the monoamine oxidase inhibitor tranylcypromine, 30 mg/d, which was also part of the study protocol. We warned him not to eat pizza, fermented dry sausages, or other foods that could interact adversely with tranylcypromine. After 4 weeks, Mr. D stopped taking the agent, saying he could not follow the dietary restrictions while on the road.

We released Mr. D from the study because of nonresponse. Bupropion, started at 100 mg bid and titrated to 300 mg each morning and 150 mg nightly across 5 months, did not resolve his fatigue. He also started having agitation and “anger problems,” often getting into shouting matches over his CBradio with other truck drivers. We started quetiapine, 25 mg bid, hoping the low dose would calm his mood.

Until now, Mr. D has ignored our requests to undergo routine laboratory testing. We referred him to the local clinic four times over the past year but he has not complied, citing lack of health insurance and financial concerns.

The authors’ observations

Although Mr. D’s symptoms (constantly depressed mood, loss of interest in usual activities) clearly suggest treatment-resistant major depressive disorder, an underlying medical disorder cannot be ruled out, yet he refuses to get needed tests.

Medical comorbidities are more prevalent in patients with mental illness than in the general population.¹ As many as 43% of patients referred to some psychiatry clinics have medical disorders, and almost one-half the diagnoses were missed by the referring physician.²

Compared to patients without psychiatric diagnoses, those with mental illness have more difficulty gaining access to medical care and are less likely to receive and follow guidelines for preventive care. Mental illness symptoms often compromise one’s ability to seek health care or follow a doctor’s orders. For example, a psychotic person may be overly suspicious of doctors, whereas someone with anxiety may seek care inappropriately.^3,4 Also, some studies estimate that 1 in 5 persons with mental illness are uninsured.^1,5,6

Mr. D denies substance abuse, but primary care and behavioral health clinicians often miss substance use disorders.⁷ Accuracy of substance abuse self-reports varies widely; some studies report high accuracy, whereas almost 33% of patients in other studies do not disclose substance abuse.⁸

Testing: stimulating findings

At his next visit, Mr. D reports worsening thirst and increased urination and complains of increased appetite, easy bruising, excessive sleepiness, and apathy. He also reveals that for 2 months he has been taking 2 to 3 fat-burning stimulant capsules a day to stay awake while driving.

 

Alarmed by his elevated blood pressure (177/99 mm Hg) and worsening physical symptoms, Mr. D finally consents to baseline laboratory testing. Blood glucose is 306 mg/dL (normal 70 to 110 mg/dL), and glycosylated hemoglobin is 12% (normal

Mr. D, who now weighs 270 lbs, is diagnosed as having hypertension and type 2 diabetes mellitus. Clinic doctors start him on metformin, 500 mg bid titrated to 1,000 mg bid, and glyburide, 5 mg/d, to control his glucose, and lisinopril, 10 mg/d, to control his hypertension, reduce cardiovascular risk, and preserve renal function. Clinicians also order Mr. D to follow an 1,800-calorie, American Diabetes Association-approved diet. We stop quetiapine and bupropion.

Mr. D’s diabetes and hypertension diagnosis, combined with his habitus and history of easy bruising, suggest Cushing’s syndrome. Doctors rule out this disorder based on a 24-hour free cortisol reading of 59 mg/L and normal dexamethasone suppression. Lab findings suggest he is not taking stimulants away from work.

The authors’ observations

Ideally, Mr. D should have undergone laboratory testing after the initial intake visit, before psychotropics were started. Routine vital signs also should have been taken.

Symptoms of major depressive disorder and early type 2 diabetes are strikingly similar (Table 1). For example, early diabetes symptoms such as fatigue can mimic depression or other medical problems. In one study of 69 diabetic patients who were referred by their primary care doctors to a psychiatric clinic, 57 had not been diagnosed as having diabetes before referral.⁹

Aside from its medical complications, diabetes also doubles the risk of comorbid depression, which can alter diabetes’ course and outcome.¹⁰

Earlier laboratory testing could have uncovered Mr. D’s comorbid stimulant abuse, which also can mimic depression and complicate its treatment.¹¹ Signs of amphetamine withdrawal—such as dysphoric mood, fatigue, insomnia or hypersomnia, increased appetite, and psychomotor retardation—can be mistaken for depression (Table 1).

Patients with Cushing’s syndrome may present with nonspecific complaints of fatigue, decreased energy, apathy, depressed mood, and hypersomnia. A 24-hour free cortisol reading and dexamethasone suppression testing can differentiate Cushing’s syndrome from depression.

Costly, unnecessary care. Missing a medical cause of apparent psychiatric symptoms can lead to unnecessary treatment and needless expense. A complete metabolic profile and urine drug screen—approximately $60—could have saved the nearly $5,000 spent on treating Mr. D’s “resistant” depression ( Table 2).

Psychiatrists need to watch for potential medical problems and for cormorbidities associated with mental illness. Patients with frequent mental distress—defined as ≥ 14 mentally unhealthy days within 30 days—were found to be more likely to smoke, drink heavily, and be physically inactive and obese than were mentally healthy persons. Mentally distressed patients also were more likely to lack health care coverage and to engage in multiple adverse behaviors, increasing their risk for mental and physical illness.¹²

Ensuring proper medical care. Based on our experience with Mr. D, routine vital signs—including BMI, weight, blood pressure, and pulse rate—should be recorded at each visit. At intake, we recommend that psychiatrists:

• find out when the patient last saw a primary health provider other than in the emergency room, and whether the patient is receiving preventive medical care
  
• assess for unhealthy lifestyle habits (smoking, drug use, poor diet) or family history of serious medical illnesses.
  

Mr. D, for example, had not received preventative care for at least 2 to 3 years and had obesity, a family history of diabetes, a sedentary lifestyle, and an unhealthy diet.

Educate patients about the interplay between physical and mental illness to help them understand the importance of seeing a primary care doctor. Finally, be familiar with local indigent health clinics and their fee scales.

Table 1

Medical symptoms that mimic depression

Symptom	Amphetamine withdrawal	Cushing’s syndrome	Diabetes
Anxiety		×
Dysphoric mood	×
Fatigue	×	×	×
Hypersomnia	×
Increased appetite	×		×
Insomnia	×
Irritability		×	×
Muscle aches and cramps			×
Psychomotor retardation	×
Vivid, unpleasant dreams	×
Weakness		×
Weight gain or loss			×

Table 2

The cost of treating Mr. D’s ‘resistant depression’

Medication/dosage	Start date	Stop date	Approximate cost
Citalopram, 20 mg/d	10/3/03	10/24/03	$58.50
Sertraline, 25 to 200 mg/d	10/24/03	12/24/03	$283.00
Sertraline 150 mg/d, with lithium, 225 to 675 mg/d	12/24/03	2/6/04	$343.00
Tranylcypromine, 10 mg each morning, 20 mg at bedtime	2/27/04	4/20/04	$322.00
Bupropion (sustained release) up to 450 mg/d	5/7/04	8/30/04	$372.00
Bupropion (sustained release), 450 mg/d, plus quetiapine, 25 mg/d	8/30/04	11/8/04	$554.00
Total cost of psychotropics			$1,932.50
Total cost of office visits ($95 X 30 visits)			$2,850.00
TOTAL COST OF TREATMENT			$4,782.50
Source: Walgreens Co. retail prices in Wichita, KS

Follow-up: 30 lbs in 4 months

Mr. D has lost >30 lbs over 4 months, and his blood pressure and serum glucose are normal. BMI is now 32, in the lower range of clinical obesity. He feels more energetic and active, no longer reports excessive sedation and apathy, and has stopped taking stimulants. His depressive symptoms have remitted.

 

Related resources

• WrongDiagnosis.com. Information on differential diagnosis of medical and psychiatric problems. www.wrongdiagnosis.com.
  
• Mauksch LB, Tucker SM, Katon WJ, et al. Mental illness, functional impairment, and patient preferences for collaborative care in an uninsured, primary care population. J Fam Pract 2001;50:41-7.
  
• Glied S, Little SE. The uninsured and the benefits of medical progress. Health Aff (Millwood) 2003;22:210-9.
  

Drug brand names

• Bupropion • Wellbutrin
  
• Citalopram • Celexa
  
• Dexamethasone • Ciprodex, others
  
• Glucophage • Metformin
  
• Glyburide • DiaBeta, others
  
• Lisinopril • Prinivil, Zestril
  
• Lithium • Eskalith, others
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  
• Tranylcypromine •Parnate
  

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.

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: 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.

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.

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.