Cases That Test Your Skills

CASE: Scared and confused

Mr. C, age 28, presents to the emergency department (ED) in police custody with agitation and altered mental status. Earlier that evening, Mr. C’s girlfriend noticed he was talking to himself while watching television. A few hours later, Mr. C thought someone was breaking into his house. Mr. C ran out of the house screaming for help, broke his neighbor’s window, and eventually called the police. When the police arrived Mr. C was wearing only his underwear, shaking, and bleeding from his hands. He said he was afraid and refused to respond to police instructions. Police officers used an electronic stun gun to facilitate transport to the hospital.

Mr. C admits to smoking 3 to 4 marijuana joints daily for the past 16 years. His last drug use was 2 hours before his symptoms began. Mr. C suggests that someone may have adulterated his marijuana joint but he has no factual basis for this accusation. He denies using alcohol and other illicit drugs and has no personal or family psychiatric history. He denies recent fever, loss of consciousness, chest pain, weakness, myalgia, or headache. Medically stable, his only complaint is mild hand pain.

Mr. C is alert, awake, and oriented to his name, and he responds properly to questions. He is tachycardic (101 bpm), his blood pressure is 149/57 mm Hg with normal S1 and S2 sounds, and he has no meningismus or nystagmus. Glasgow Coma Scale score is 15. He has increased deep tendon reflexes on the right upper and lower limb with good hand-grip and multiple abrasions and lacerations on his hands.

The authors’ observations

New-onset psychosis can have a wide differential diagnosis, particularly when reliable history is not available. Mr. C’s allegation that someone tampered with his marijuana raises 2 possibilities: embalming fluid (form-aldehyde) toxicity or PCP intoxication.

Embalming fluid toxicity can cause:

• agitation and sudden unpredictable behavior
• confusion or toxic delirium
• coma or seizure
• cerebral and pulmonary edema or death in severe cases.

The terms “wet,” “sherm,” “fly,” “amp,” or “illy” are used to describe a marijuana cigarette that has been dipped into embalming fluid, dried, and then smoked.¹ The effect is similar to that of PCP and causes extreme hallucinations. Reported highs last 30 minutes to 1 hour.²

Symptomatology of PCP intoxication may be indistinguishable from functional psychosis (Table 1).³ Visual, auditory, and tactile misperceptions are common and highly changeable disorientation often is accompanied by alternating periods of lethargy and fearful agitation. These patients typically show catatonic posturing and/or stereotyped movement. Somatic sensations appear to be disassociated; patients may misperceive pain, distance, and time. Patients taking PCP rarely admit to true hallucinations; however their thinking usually is grossly disoriented.⁴ Symptoms of delirium may last from 30 minutes to 6 hours in 80% of cases; 12% of patients may remain symptomatic for 12 hours. Violent behavior and agitation usually lasts only a few hours.⁵

Long-term marijuana abuse can lead to psychosis⁶ but acute onset is not typical, and recent prospective trials raised doubts that cannabis would be a sole factor.⁷ Instead, cannabis may be 1 of several factors that contribute to psychosis, particularly in patients who are predisposed.

Table 1

Phencyclidine (PCP) intoxication: What to look for

Possible neurologic causes

Complex partial seizures—also known as psychomotor epilepsy—are caused by a surge of electrical activity in the brain. Seizures often involve 1 of the brain’s temporal lobes but can affect any brain region. Symptoms include:

• impaired social interaction
• inability to control one’s movements
• alogia
• amnesia.

Episodes typically start with a blank stare followed by automatisms. The actions and movements often are unorganized or confused. Motor symptoms typically last for 1 to 2 minutes and confusion persists for another 1 to 2 minutes.⁸ In rare cases, a patient may become agitated or engage in behaviors such as undressing. Complex partial seizures may cause a person to run in apparent fear, cry out, or repeat a phrase.⁹ Electroencephalogram, CT, MRI, or positron-emission tomography scan could reveal any intracranial focus of complex partial seizures.

We suspect PCP or embalming fluid intoxication and initiate supportive therapy.

EVALUATION: Still confused

Initial baseline labs include a urine drug screen (UDS), chest radiography, ECG, and head CT. Mr. C’s UDS is positive for cannabis. A specific PCP assay is negative. White blood cell count (WBC) is 22,000/μL with high neutrophil count (88%), creatine kinase (CK) is 458 U/L, and urinalyis reveals protein 75 mg/dL and ketone 50 mg/dL. Head CT is negative for any acute process (click here for detailed description of Mr. C�s hospital course while in the ED).

During psychiatric evaluation 7 hours after presentation, Mr. C’s speech is loose and somewhat pressured, but intelligible. He cannot follow commands. Mr. C is delusional and appears to be hallucinating. He can repeat 3 words immediately but not after 3 minutes. We start Mr. C on divalproex, 1,500 mg/d, haloperidol, 6 mg/d, and IV lorazepam, 2 mg as needed for agitation. Although mildly disoriented, he gradually becomes less agitated.

The authors’ observations

At this point further evaluation is needed. Mr. C’s elevated WBC count could explain his fluctuating symptoms. He cannot provide further history and his family denies any past psychiatric episodes. Thyroid-stimulating hormone, B12, and folate levels are within normal limits. A negative LP rules out meningitic infection. We give Mr. C a diagnosis of psychosis NOS (Table 2).¹⁰

Table 2

DSM-IV-TR criteria for psychotic disorder, not otherwise specified

TREATMENT: Medication choices

After 8 hours in the ED, Mr. C is transferred to the medical unit, where he becomes agitated and complains of auditory and visual hallucinations. He receives divalproex, 750 mg, haloperidol, 3 mg, and IM diphenhydramine, 50 mg, to calm him. He remains agitated but not violent until bedtime. At midnight he is agitated and violent and receives another dose of haloperidol and IM diphenhydramine with IV lorazepam, 2 mg. These medications calm him and he is able to sleep until morning.

Morning labs reveal CK is 674 U/L and WBC decreased to 13,200/μL. Mr. C denies any distress but after the fourth dose of haloperidol, he develops dystonia of his arms so we discontinue this medication. We start aripiprazole, 10 mg/d gradually increased to 30 mg/d, and Mr. C receives 1 injection of diphenhydramine. He responds well to the treatment.

The next few hours are uneventful but then Mr. C becomes verbally abusive to his relatives and sitter; physical restraints are ordered and he receives IM ziprasidone, 20 mg, and IV lorazepam, 2 mg. He remains awake and babbling. His perception continues to wax and wane and his words are jumbled. He remains calm until the next morning (click here for detailed description of Mr. C�s hospital course while on the medical unit).

After 4 days on the medical unit Mr. C is transferred to the psychiatry unit, where he is angry, belligerent, and hostile, but not placed in restraints. His symptoms resolve in 2 days without any further episodes of violent behavior.

OUTCOME: Solving the puzzle

When Mr. C becomes cooperative, he gives a detailed history. He repeats his suspicion of smoking adulterated marijuana, but during detailed questioning, he admits to using alprazolam, which he purchased illegally, to sleep for the past 6 to 7 months. He started with 1 or 2 “footballs” (1 to 2 mg) and gradually increased to 3 or 4 “bars” (6 to 8 mg) each day. Mr. C could no longer afford the drug and last took alprazolam 6 days before his symptoms began. He says that after stopping alprazolam he felt anxious and could not sleep. His girlfriend adds that he was irritable and “he had not been acting himself” several days before admission. She says he complained of hearing the voice of God, particularly when he was not taking alprazolam.

Mr. C’s hand wounds heal and his vitals are normal during his 1-week stay on the psychiatric unit. His interactions with staff and peers improve. Aripiprazole is tapered and discontinued; divalproex is reduced to 1,000 mg/d. Mr. C is discharged 11 days after presentation and prescribed divalproex, 1,000 mg/d, with instructions to taper the drug over several days to prevent withdrawal seizures before stopping it in 1 week.

Mr. C does not return for his follow-up appointment; however, in a telephone follow-up 6 months later, he denies experiencing withdrawal symptoms after discharge. Mr. C is now undergoing drug rehabilitation.

The authors’ observations

Benzodiazepine withdrawal symptoms occur 7 to 10 days after abrupt cessation (Table 3).¹⁰ Symptoms are similar to those of alcohol withdrawal and include tachycardia, hypertension, clouding of consciousness, and auditory and visual hallucinations.¹¹ Serious reactions to benzodiazepine withdrawal include seizures and death.¹²

Because of the high prevalence of poly-substance misuse, obtain a detailed substance use history in patients undergoing benzodiazepine withdrawal to determine the likelihood of polysubstance withdrawal.¹³ A cross-tolerant sedative such as clonazepam could prevent withdrawal symptoms as the dose is gradually decreased. Long-acting benzodiazepines such as clonazepam or diazepam are recommended.¹⁴

In Mr. C’s case, minor withdrawal symptoms, such as disturbed sleep and irritability, began 3 to 4 days after discontinuing benzodiazepines¹⁵ and preceded development of psychosis. Withdrawal symptoms usually resolve after 2 weeks.¹⁶ Mr. C responded only partially to IV lorazepam because he did not receive the total replacement dose. Had we known he was experiencing benzodiazepine withdrawal, Mr. C could have been managed with detoxi"cation of the primary drug, alprazolam, with diazepam substitution and tapering over 3 weeks.¹⁷

Table 3

Criteria for sedative, hypnotic, or anxiolytic withdrawal

Related Resource

• Vikander B, Koechling UM, Borg S, et al. Benzodiazepine tapering: a prospective study. Nord J Psychiatry. 2010; 64(4):273-282.

Drug Brand Names

• Alprazolam • Xanax
• Aripiprazole • Abilify
• Chlordiazepoxide • Librium
• Diazepam • Valium
• Diphenhydramine • Diphenhydramine injection
• Divalproex • Depakote
• Haloperidol • Haldol
• Lorazepam • Ativan
• Ziprasidone • Geodon

Acknowledgements

The authors wish to thank Reena Kumar, MD, and Sonja Gennuso, fourth-year medical student at Louisiana State University Health Sciences Center, Shreveport, for their help in preparing this manuscript.

Disclosure

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

Table 1

Mr. C’s hospital course in the emergency department

Table 2

Mr. C’s hospital course on the medical unit

CASE: Scared and confused

Mr. C, age 28, presents to the emergency department (ED) in police custody with agitation and altered mental status. Earlier that evening, Mr. C’s girlfriend noticed he was talking to himself while watching television. A few hours later, Mr. C thought someone was breaking into his house. Mr. C ran out of the house screaming for help, broke his neighbor’s window, and eventually called the police. When the police arrived Mr. C was wearing only his underwear, shaking, and bleeding from his hands. He said he was afraid and refused to respond to police instructions. Police officers used an electronic stun gun to facilitate transport to the hospital.

Mr. C admits to smoking 3 to 4 marijuana joints daily for the past 16 years. His last drug use was 2 hours before his symptoms began. Mr. C suggests that someone may have adulterated his marijuana joint but he has no factual basis for this accusation. He denies using alcohol and other illicit drugs and has no personal or family psychiatric history. He denies recent fever, loss of consciousness, chest pain, weakness, myalgia, or headache. Medically stable, his only complaint is mild hand pain.

Mr. C is alert, awake, and oriented to his name, and he responds properly to questions. He is tachycardic (101 bpm), his blood pressure is 149/57 mm Hg with normal S1 and S2 sounds, and he has no meningismus or nystagmus. Glasgow Coma Scale score is 15. He has increased deep tendon reflexes on the right upper and lower limb with good hand-grip and multiple abrasions and lacerations on his hands.

The authors’ observations

New-onset psychosis can have a wide differential diagnosis, particularly when reliable history is not available. Mr. C’s allegation that someone tampered with his marijuana raises 2 possibilities: embalming fluid (form-aldehyde) toxicity or PCP intoxication.

Embalming fluid toxicity can cause:

• agitation and sudden unpredictable behavior
• confusion or toxic delirium
• coma or seizure
• cerebral and pulmonary edema or death in severe cases.

The terms “wet,” “sherm,” “fly,” “amp,” or “illy” are used to describe a marijuana cigarette that has been dipped into embalming fluid, dried, and then smoked.¹ The effect is similar to that of PCP and causes extreme hallucinations. Reported highs last 30 minutes to 1 hour.²

Symptomatology of PCP intoxication may be indistinguishable from functional psychosis (Table 1).³ Visual, auditory, and tactile misperceptions are common and highly changeable disorientation often is accompanied by alternating periods of lethargy and fearful agitation. These patients typically show catatonic posturing and/or stereotyped movement. Somatic sensations appear to be disassociated; patients may misperceive pain, distance, and time. Patients taking PCP rarely admit to true hallucinations; however their thinking usually is grossly disoriented.⁴ Symptoms of delirium may last from 30 minutes to 6 hours in 80% of cases; 12% of patients may remain symptomatic for 12 hours. Violent behavior and agitation usually lasts only a few hours.⁵

Long-term marijuana abuse can lead to psychosis⁶ but acute onset is not typical, and recent prospective trials raised doubts that cannabis would be a sole factor.⁷ Instead, cannabis may be 1 of several factors that contribute to psychosis, particularly in patients who are predisposed.

Table 1

Phencyclidine (PCP) intoxication: What to look for

Possible neurologic causes

Complex partial seizures—also known as psychomotor epilepsy—are caused by a surge of electrical activity in the brain. Seizures often involve 1 of the brain’s temporal lobes but can affect any brain region. Symptoms include:

• impaired social interaction
• inability to control one’s movements
• alogia
• amnesia.

Episodes typically start with a blank stare followed by automatisms. The actions and movements often are unorganized or confused. Motor symptoms typically last for 1 to 2 minutes and confusion persists for another 1 to 2 minutes.⁸ In rare cases, a patient may become agitated or engage in behaviors such as undressing. Complex partial seizures may cause a person to run in apparent fear, cry out, or repeat a phrase.⁹ Electroencephalogram, CT, MRI, or positron-emission tomography scan could reveal any intracranial focus of complex partial seizures.

We suspect PCP or embalming fluid intoxication and initiate supportive therapy.

EVALUATION: Still confused

Initial baseline labs include a urine drug screen (UDS), chest radiography, ECG, and head CT. Mr. C’s UDS is positive for cannabis. A specific PCP assay is negative. White blood cell count (WBC) is 22,000/μL with high neutrophil count (88%), creatine kinase (CK) is 458 U/L, and urinalyis reveals protein 75 mg/dL and ketone 50 mg/dL. Head CT is negative for any acute process (click here for detailed description of Mr. C�s hospital course while in the ED).

During psychiatric evaluation 7 hours after presentation, Mr. C’s speech is loose and somewhat pressured, but intelligible. He cannot follow commands. Mr. C is delusional and appears to be hallucinating. He can repeat 3 words immediately but not after 3 minutes. We start Mr. C on divalproex, 1,500 mg/d, haloperidol, 6 mg/d, and IV lorazepam, 2 mg as needed for agitation. Although mildly disoriented, he gradually becomes less agitated.

The authors’ observations

At this point further evaluation is needed. Mr. C’s elevated WBC count could explain his fluctuating symptoms. He cannot provide further history and his family denies any past psychiatric episodes. Thyroid-stimulating hormone, B12, and folate levels are within normal limits. A negative LP rules out meningitic infection. We give Mr. C a diagnosis of psychosis NOS (Table 2).¹⁰

Table 2

DSM-IV-TR criteria for psychotic disorder, not otherwise specified

TREATMENT: Medication choices

After 8 hours in the ED, Mr. C is transferred to the medical unit, where he becomes agitated and complains of auditory and visual hallucinations. He receives divalproex, 750 mg, haloperidol, 3 mg, and IM diphenhydramine, 50 mg, to calm him. He remains agitated but not violent until bedtime. At midnight he is agitated and violent and receives another dose of haloperidol and IM diphenhydramine with IV lorazepam, 2 mg. These medications calm him and he is able to sleep until morning.

Morning labs reveal CK is 674 U/L and WBC decreased to 13,200/μL. Mr. C denies any distress but after the fourth dose of haloperidol, he develops dystonia of his arms so we discontinue this medication. We start aripiprazole, 10 mg/d gradually increased to 30 mg/d, and Mr. C receives 1 injection of diphenhydramine. He responds well to the treatment.

The next few hours are uneventful but then Mr. C becomes verbally abusive to his relatives and sitter; physical restraints are ordered and he receives IM ziprasidone, 20 mg, and IV lorazepam, 2 mg. He remains awake and babbling. His perception continues to wax and wane and his words are jumbled. He remains calm until the next morning (click here for detailed description of Mr. C�s hospital course while on the medical unit).

After 4 days on the medical unit Mr. C is transferred to the psychiatry unit, where he is angry, belligerent, and hostile, but not placed in restraints. His symptoms resolve in 2 days without any further episodes of violent behavior.

OUTCOME: Solving the puzzle

When Mr. C becomes cooperative, he gives a detailed history. He repeats his suspicion of smoking adulterated marijuana, but during detailed questioning, he admits to using alprazolam, which he purchased illegally, to sleep for the past 6 to 7 months. He started with 1 or 2 “footballs” (1 to 2 mg) and gradually increased to 3 or 4 “bars” (6 to 8 mg) each day. Mr. C could no longer afford the drug and last took alprazolam 6 days before his symptoms began. He says that after stopping alprazolam he felt anxious and could not sleep. His girlfriend adds that he was irritable and “he had not been acting himself” several days before admission. She says he complained of hearing the voice of God, particularly when he was not taking alprazolam.

Mr. C’s hand wounds heal and his vitals are normal during his 1-week stay on the psychiatric unit. His interactions with staff and peers improve. Aripiprazole is tapered and discontinued; divalproex is reduced to 1,000 mg/d. Mr. C is discharged 11 days after presentation and prescribed divalproex, 1,000 mg/d, with instructions to taper the drug over several days to prevent withdrawal seizures before stopping it in 1 week.

Mr. C does not return for his follow-up appointment; however, in a telephone follow-up 6 months later, he denies experiencing withdrawal symptoms after discharge. Mr. C is now undergoing drug rehabilitation.

The authors’ observations

Benzodiazepine withdrawal symptoms occur 7 to 10 days after abrupt cessation (Table 3).¹⁰ Symptoms are similar to those of alcohol withdrawal and include tachycardia, hypertension, clouding of consciousness, and auditory and visual hallucinations.¹¹ Serious reactions to benzodiazepine withdrawal include seizures and death.¹²

Because of the high prevalence of poly-substance misuse, obtain a detailed substance use history in patients undergoing benzodiazepine withdrawal to determine the likelihood of polysubstance withdrawal.¹³ A cross-tolerant sedative such as clonazepam could prevent withdrawal symptoms as the dose is gradually decreased. Long-acting benzodiazepines such as clonazepam or diazepam are recommended.¹⁴

In Mr. C’s case, minor withdrawal symptoms, such as disturbed sleep and irritability, began 3 to 4 days after discontinuing benzodiazepines¹⁵ and preceded development of psychosis. Withdrawal symptoms usually resolve after 2 weeks.¹⁶ Mr. C responded only partially to IV lorazepam because he did not receive the total replacement dose. Had we known he was experiencing benzodiazepine withdrawal, Mr. C could have been managed with detoxi"cation of the primary drug, alprazolam, with diazepam substitution and tapering over 3 weeks.¹⁷

Table 3

Criteria for sedative, hypnotic, or anxiolytic withdrawal

Related Resource

• Vikander B, Koechling UM, Borg S, et al. Benzodiazepine tapering: a prospective study. Nord J Psychiatry. 2010; 64(4):273-282.

Drug Brand Names

• Alprazolam • Xanax
• Aripiprazole • Abilify
• Chlordiazepoxide • Librium
• Diazepam • Valium
• Diphenhydramine • Diphenhydramine injection
• Divalproex • Depakote
• Haloperidol • Haldol
• Lorazepam • Ativan
• Ziprasidone • Geodon

Acknowledgements

The authors wish to thank Reena Kumar, MD, and Sonja Gennuso, fourth-year medical student at Louisiana State University Health Sciences Center, Shreveport, for their help in preparing this manuscript.

Disclosure

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

Table 1

Mr. C’s hospital course in the emergency department

Table 2

Mr. C’s hospital course on the medical unit

CASE: Scared and confused

Mr. C, age 28, presents to the emergency department (ED) in police custody with agitation and altered mental status. Earlier that evening, Mr. C’s girlfriend noticed he was talking to himself while watching television. A few hours later, Mr. C thought someone was breaking into his house. Mr. C ran out of the house screaming for help, broke his neighbor’s window, and eventually called the police. When the police arrived Mr. C was wearing only his underwear, shaking, and bleeding from his hands. He said he was afraid and refused to respond to police instructions. Police officers used an electronic stun gun to facilitate transport to the hospital.

Mr. C admits to smoking 3 to 4 marijuana joints daily for the past 16 years. His last drug use was 2 hours before his symptoms began. Mr. C suggests that someone may have adulterated his marijuana joint but he has no factual basis for this accusation. He denies using alcohol and other illicit drugs and has no personal or family psychiatric history. He denies recent fever, loss of consciousness, chest pain, weakness, myalgia, or headache. Medically stable, his only complaint is mild hand pain.

Mr. C is alert, awake, and oriented to his name, and he responds properly to questions. He is tachycardic (101 bpm), his blood pressure is 149/57 mm Hg with normal S1 and S2 sounds, and he has no meningismus or nystagmus. Glasgow Coma Scale score is 15. He has increased deep tendon reflexes on the right upper and lower limb with good hand-grip and multiple abrasions and lacerations on his hands.

The authors’ observations

New-onset psychosis can have a wide differential diagnosis, particularly when reliable history is not available. Mr. C’s allegation that someone tampered with his marijuana raises 2 possibilities: embalming fluid (form-aldehyde) toxicity or PCP intoxication.

Embalming fluid toxicity can cause:

• agitation and sudden unpredictable behavior
• confusion or toxic delirium
• coma or seizure
• cerebral and pulmonary edema or death in severe cases.

The terms “wet,” “sherm,” “fly,” “amp,” or “illy” are used to describe a marijuana cigarette that has been dipped into embalming fluid, dried, and then smoked.¹ The effect is similar to that of PCP and causes extreme hallucinations. Reported highs last 30 minutes to 1 hour.²

Symptomatology of PCP intoxication may be indistinguishable from functional psychosis (Table 1).³ Visual, auditory, and tactile misperceptions are common and highly changeable disorientation often is accompanied by alternating periods of lethargy and fearful agitation. These patients typically show catatonic posturing and/or stereotyped movement. Somatic sensations appear to be disassociated; patients may misperceive pain, distance, and time. Patients taking PCP rarely admit to true hallucinations; however their thinking usually is grossly disoriented.⁴ Symptoms of delirium may last from 30 minutes to 6 hours in 80% of cases; 12% of patients may remain symptomatic for 12 hours. Violent behavior and agitation usually lasts only a few hours.⁵

Long-term marijuana abuse can lead to psychosis⁶ but acute onset is not typical, and recent prospective trials raised doubts that cannabis would be a sole factor.⁷ Instead, cannabis may be 1 of several factors that contribute to psychosis, particularly in patients who are predisposed.

Table 1

Phencyclidine (PCP) intoxication: What to look for

Possible neurologic causes

Complex partial seizures—also known as psychomotor epilepsy—are caused by a surge of electrical activity in the brain. Seizures often involve 1 of the brain’s temporal lobes but can affect any brain region. Symptoms include:

• impaired social interaction
• inability to control one’s movements
• alogia
• amnesia.

Episodes typically start with a blank stare followed by automatisms. The actions and movements often are unorganized or confused. Motor symptoms typically last for 1 to 2 minutes and confusion persists for another 1 to 2 minutes.⁸ In rare cases, a patient may become agitated or engage in behaviors such as undressing. Complex partial seizures may cause a person to run in apparent fear, cry out, or repeat a phrase.⁹ Electroencephalogram, CT, MRI, or positron-emission tomography scan could reveal any intracranial focus of complex partial seizures.

We suspect PCP or embalming fluid intoxication and initiate supportive therapy.

EVALUATION: Still confused

Initial baseline labs include a urine drug screen (UDS), chest radiography, ECG, and head CT. Mr. C’s UDS is positive for cannabis. A specific PCP assay is negative. White blood cell count (WBC) is 22,000/μL with high neutrophil count (88%), creatine kinase (CK) is 458 U/L, and urinalyis reveals protein 75 mg/dL and ketone 50 mg/dL. Head CT is negative for any acute process (click here for detailed description of Mr. C�s hospital course while in the ED).

During psychiatric evaluation 7 hours after presentation, Mr. C’s speech is loose and somewhat pressured, but intelligible. He cannot follow commands. Mr. C is delusional and appears to be hallucinating. He can repeat 3 words immediately but not after 3 minutes. We start Mr. C on divalproex, 1,500 mg/d, haloperidol, 6 mg/d, and IV lorazepam, 2 mg as needed for agitation. Although mildly disoriented, he gradually becomes less agitated.

The authors’ observations

At this point further evaluation is needed. Mr. C’s elevated WBC count could explain his fluctuating symptoms. He cannot provide further history and his family denies any past psychiatric episodes. Thyroid-stimulating hormone, B12, and folate levels are within normal limits. A negative LP rules out meningitic infection. We give Mr. C a diagnosis of psychosis NOS (Table 2).¹⁰

Table 2

DSM-IV-TR criteria for psychotic disorder, not otherwise specified

TREATMENT: Medication choices

After 8 hours in the ED, Mr. C is transferred to the medical unit, where he becomes agitated and complains of auditory and visual hallucinations. He receives divalproex, 750 mg, haloperidol, 3 mg, and IM diphenhydramine, 50 mg, to calm him. He remains agitated but not violent until bedtime. At midnight he is agitated and violent and receives another dose of haloperidol and IM diphenhydramine with IV lorazepam, 2 mg. These medications calm him and he is able to sleep until morning.

Morning labs reveal CK is 674 U/L and WBC decreased to 13,200/μL. Mr. C denies any distress but after the fourth dose of haloperidol, he develops dystonia of his arms so we discontinue this medication. We start aripiprazole, 10 mg/d gradually increased to 30 mg/d, and Mr. C receives 1 injection of diphenhydramine. He responds well to the treatment.

The next few hours are uneventful but then Mr. C becomes verbally abusive to his relatives and sitter; physical restraints are ordered and he receives IM ziprasidone, 20 mg, and IV lorazepam, 2 mg. He remains awake and babbling. His perception continues to wax and wane and his words are jumbled. He remains calm until the next morning (click here for detailed description of Mr. C�s hospital course while on the medical unit).

After 4 days on the medical unit Mr. C is transferred to the psychiatry unit, where he is angry, belligerent, and hostile, but not placed in restraints. His symptoms resolve in 2 days without any further episodes of violent behavior.

OUTCOME: Solving the puzzle

When Mr. C becomes cooperative, he gives a detailed history. He repeats his suspicion of smoking adulterated marijuana, but during detailed questioning, he admits to using alprazolam, which he purchased illegally, to sleep for the past 6 to 7 months. He started with 1 or 2 “footballs” (1 to 2 mg) and gradually increased to 3 or 4 “bars” (6 to 8 mg) each day. Mr. C could no longer afford the drug and last took alprazolam 6 days before his symptoms began. He says that after stopping alprazolam he felt anxious and could not sleep. His girlfriend adds that he was irritable and “he had not been acting himself” several days before admission. She says he complained of hearing the voice of God, particularly when he was not taking alprazolam.

Mr. C’s hand wounds heal and his vitals are normal during his 1-week stay on the psychiatric unit. His interactions with staff and peers improve. Aripiprazole is tapered and discontinued; divalproex is reduced to 1,000 mg/d. Mr. C is discharged 11 days after presentation and prescribed divalproex, 1,000 mg/d, with instructions to taper the drug over several days to prevent withdrawal seizures before stopping it in 1 week.

Mr. C does not return for his follow-up appointment; however, in a telephone follow-up 6 months later, he denies experiencing withdrawal symptoms after discharge. Mr. C is now undergoing drug rehabilitation.

The authors’ observations

Benzodiazepine withdrawal symptoms occur 7 to 10 days after abrupt cessation (Table 3).¹⁰ Symptoms are similar to those of alcohol withdrawal and include tachycardia, hypertension, clouding of consciousness, and auditory and visual hallucinations.¹¹ Serious reactions to benzodiazepine withdrawal include seizures and death.¹²

Because of the high prevalence of poly-substance misuse, obtain a detailed substance use history in patients undergoing benzodiazepine withdrawal to determine the likelihood of polysubstance withdrawal.¹³ A cross-tolerant sedative such as clonazepam could prevent withdrawal symptoms as the dose is gradually decreased. Long-acting benzodiazepines such as clonazepam or diazepam are recommended.¹⁴

In Mr. C’s case, minor withdrawal symptoms, such as disturbed sleep and irritability, began 3 to 4 days after discontinuing benzodiazepines¹⁵ and preceded development of psychosis. Withdrawal symptoms usually resolve after 2 weeks.¹⁶ Mr. C responded only partially to IV lorazepam because he did not receive the total replacement dose. Had we known he was experiencing benzodiazepine withdrawal, Mr. C could have been managed with detoxi"cation of the primary drug, alprazolam, with diazepam substitution and tapering over 3 weeks.¹⁷

Table 3

Criteria for sedative, hypnotic, or anxiolytic withdrawal

Related Resource

• Vikander B, Koechling UM, Borg S, et al. Benzodiazepine tapering: a prospective study. Nord J Psychiatry. 2010; 64(4):273-282.

Drug Brand Names

• Alprazolam • Xanax
• Aripiprazole • Abilify
• Chlordiazepoxide • Librium
• Diazepam • Valium
• Diphenhydramine • Diphenhydramine injection
• Divalproex • Depakote
• Haloperidol • Haldol
• Lorazepam • Ativan
• Ziprasidone • Geodon

Acknowledgements

The authors wish to thank Reena Kumar, MD, and Sonja Gennuso, fourth-year medical student at Louisiana State University Health Sciences Center, Shreveport, for their help in preparing this manuscript.

Disclosure

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

Table 1

Mr. C’s hospital course in the emergency department

Table 2

Mr. C’s hospital course on the medical unit

CASE: New-onset mania

Ms. Z, age 69, is admitted to our hospital’s medical unit after developing manic symptoms. Her medical history includes hemodialysis-dependent chronic kidney disease, Parkinson’s disease stabilized by carbidopa/levodopa, 75/300 mg/d, for 4 years, diet-controlled type 2 diabetes mellitus, hypertension, hyperlipidemia, myelodysplasia, and acid reflux. She experiences mild anxiety, which has been stable for many years with escitalopram, 10 mg/d, but has no history of alcohol or drug abuse and no family history of psychiatric illness.

The staff at her assisted living facility reports that 8 days ago Ms. Z was mildly irritable and argumentative regarding her medications and 7 days ago began to refuse all medications. Six days ago she refused dialysis, reportedly because she was angry at the staff. One day later, the staff noticed Ms. Z had developed manic symptoms, including decreased need for sleep (only 2 hours a night), talkativeness, counting things and spelling words rapidly out loud, and making explicit drawings of men. Ms. Z refused her next 2 dialysis treatments and her manic symptoms worsened. She explained that all her medical problems had been “cured.” She inaccurately exclaimed that she can urinate, even though she is anuric, and that she can walk after not having done so for 5 years.

During our interview, Ms. Z is disheveled and exhibits pressured speech, often interrupting the interviewer. Her affect is euphoric and expansive. She perseverates on patenting her cures for diabetes and Parkinson’s disease, endorses hypersexuality, and denies hallucinations. Folstein Mini-Mental State Exam score is 18/28; however, Ms. Z refuses to participate in elements of cognitive testing, including writing a sentence, drawing pentagons, or drawing a clock, all of which would reveal her tremor. We note no disorientation or waxing and waning of attention or consciousness. She is fully oriented to person, place, time, and purpose and can perform serial 7s and spell a word backwards.

The authors’ observations

A number of factors suggest that Ms. Z’s manic symptoms likely are caused by a medical problem (Table 1).¹ She has no family history and only minimal personal history of psychiatric illness, and new-onset bipolar disorder in a 69-year-old woman is unusual.² Given Ms. Z’s acute change in mental status and numerous medical problems, we consider delirium. Because Ms. Z does not exhibit disorientation or waxing and waning of attention or consciousness, we feel delirium is unlikely to be the primary diagnosis.

Table 1

Criteria for mood disorder due to a general medical condition

EVALUATION: Clues to the cause

Physical exam reveals stable vital signs, and resting tremor and mild cogwheel rigidity in her right upper extremity consistent with Parkinson’s disease. Laboratory results show elevated blood urea nitrogen (65 mg/dL) and creatinine (8 mg/dL) and stably low white cell count (2.9/μL) and platelets (118x10³/μL), which are consistent with her known myelodysplasia. Results for urinalysis, B12, folate, thyroid-stimulating hormone, electrolytes, glucose, liver function, antinuclear antibodies, and rapid plasma reagin are unremarkable. Ms. Z’s elevated blood urea nitrogen and creatinine are expected because she recently refused dialysis. We consider that uremia could be causing her manic symptoms; however, with only 2 case reports of uremia-induced mania in the literature over the past century, we want to rule out other potential causes.^3,4

A CT of Ms. Z’s brain is normal. The neurology service performs an EEG and results show mild disorganization with a predominantly posterior rhythm of 8 to 9 Hz symmetrically, occasional periods of slowing, and no epileptiform activity or evidence of encephalopathy; these findings are consistent with end-stage renal disease.

The authors’ observations

Although mood disorder due to a general medical condition—in this case, mania secondary to uremia—was our primary consideration, at this point we could not rule out subclinical delirium. In delirium, we would expect EEG to show diffuse slowing of background rhythm, which we did not see with Ms. Z. However, occasional periods of slowing indicate that delirium was a possible factor.

Parkinson’s disease is known to be a rare predisposing factor for mania—possibly related to potential manicogenic properties of dopaminergic medications⁵—but this would not explain new-onset mania in the context of uremia in a patient whose carbidopa/levodopa dose had been stable for several years. It is possible that Ms. Z’s refusal of dialysis could have led to build-up of carbidopa/levodopa in her blood, thereby contributing to mania; however, when she began feeling irritable, she refused several of her medications, including carbidopa/levodopa. Therefore, it is unlikely that carbidopa/levodopa accumulated to toxic levels.

We carefully evaluated Ms. Z’s complete medication list to determine if other drugs could be contributing factors. She has been taking escitalopram for anxiety for several years. Although Ms. Z had no personal or family history of bipolar disorder and no past hypomania or agitation associated with this medication, we discontinue escitalopram in case it was contributing to her manic symptoms. Ms. Z also receives amlodipine, 5 mg/d for hypertension; atorvastatin, 20 mg/d, for hyperlipidemia; pantoprazole, 40 mg/d, for acid reflux; metoprolol, 100 mg/d, for hypertension; aspirin, 81 mg/d, for cardioprotection; and fish oil, 2000 mg/d, for cardioprotection. We do not feel that any of these medications significantly contribute to her current state.

TREATMENT: Restarting dialysis

We start Ms. Z on olanzapine, 5 mg/d, for manic symptoms 1 day after admission, and resume dialysis treatments 1 day later. Because of concerns that olanzapine could worsen her myelodysplasia, we switch to aripiprazole, titrating up to 30 mg/d, 4 days later. After 2 dialysis treatments, her manic symptoms begin to resolve.

The authors’ observations

A number of factors suggest that uremia likely is causing Ms. Z’s manic symptoms. Her symptoms suddenly developed shortly after her first missed dialysis treatment, but gradually resolved after re-initiating dialysis. It is possible that antipsychotics relieved her manic symptoms, but this does not detract from the factors that make a causal relationship between uremia and mania likely.

Manic symptoms have been reported to be precipitated by a variety of medical problems, including metabolic disturbances, infections such as human immunodeficiency virus brain infection, neurologic disorders, brain neoplasms, or traumatic brain injuries (Table 2).^6,7 End-stage renal disease frequently is associated with psychiatric manifestations—including depression, psychosis, delirium, and dementia—but mania is not a typical presentation. It is possible that this condition occurs more often but is not recognized.

Table 2

Common causes of secondary mania

Kidney disease and psychotropics

We considered the effect of dialysis on psychotropics when selecting pharmacotherapy for Ms. Z’s manic symptoms. Haloperidol is not renally cleared so no dosage adjustment is necessary;⁸ however, this potent dopamine D2-blocker could have worsened Ms. Z’s parkinsonism. Lithium is contraindicated in acute renal failure. Valproic acid clearance is reduced in renal failure, but because it is cleared by hemodialysis, dosage adjustment is not recommended for dialysis patients.⁸ However, Ms. Z’s myelodysplasia is a contraindication for valproic acid as well as carbamazepine. With atypical antipsychotics as our primary options, we noted that olanzapine, quetiapine, or aripiprazole do not require dosage adjustments for dialysis patients.^8,9 Of these, we eventually chose aripiprazole because we felt that it was least likely to exacerbate Ms. Z’s myelodysplasia.¹⁰

How uremia might cause mania

The pathophysiology of uremia-induced mania remains speculative. Possible factors include:

• Chronic renal failure can cause an elevation in plasma free tryptophan, a serotonin (5-HT) precursor.¹¹ Postmortem examination of brains of patients who died in uremic coma show elevated 5-HT.¹² Moreover, cerebrospinal fluid of patients with chronic renal failure has shown increased 5-hydroxyindoleacetic acid, the major 5-HT metabolite.¹³ Increased 5-HT could cause mania in some uremic patients, similar to how serotonergic medications can precipitate mania in some patients.
• Circulating ß-endorphin levels are increased in renal failure.¹⁴ ß-endorphins increase animal locomotor activity, which is the basis of an animal model of mania.^15,16 Therefore, uremia-induced mania could be partly related to elevated ß-endorphin levels.

This case demonstrates that mania could be a psychiatric manifestation of end-stage renal disease. Clinicians should be aware of this possibility, and further study should examine underlying pathophysiologic changes in uremia and other secondary causes of mania that might lead to such a mood state.

OUTCOME: Lasting improvement

At discharge 17 days after admission, Ms. Z is back to her baseline mental state. Her aripiprazole dose is tapered to 20 mg/d with no return of manic symptoms. After 10 weeks, aripiprazole is discontinued, with no recurrence of mania.

Related Resource

• Arora M, Daughton J. Mania in the medically ill. Curr Psychiatry Rep. 2007;9(3):232-235.

Drug Brand Names

• Amlodipine • Norvasc
• Aripiprazole • Abilify
• Atorvastatin • Lipitor
• Carbamazepine • Tegretol
• Carbidopa/levodopa • Sinemet
• Escitalopram • Lexapro
• Haloperidol • Haldol
• Isoniazid • Nydrazid
• Lithium • Eskalith, Lithobid
• Metoprolol • Lopressor
• Olanzapine • Zyprexa
• Pantoprazole • Protonix
• Quetiapine • Seroquel
• Valproic acid • Depakote
• Zidovudine • Retrovir

Disclosure

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

CASE: New-onset mania

Ms. Z, age 69, is admitted to our hospital’s medical unit after developing manic symptoms. Her medical history includes hemodialysis-dependent chronic kidney disease, Parkinson’s disease stabilized by carbidopa/levodopa, 75/300 mg/d, for 4 years, diet-controlled type 2 diabetes mellitus, hypertension, hyperlipidemia, myelodysplasia, and acid reflux. She experiences mild anxiety, which has been stable for many years with escitalopram, 10 mg/d, but has no history of alcohol or drug abuse and no family history of psychiatric illness.

The staff at her assisted living facility reports that 8 days ago Ms. Z was mildly irritable and argumentative regarding her medications and 7 days ago began to refuse all medications. Six days ago she refused dialysis, reportedly because she was angry at the staff. One day later, the staff noticed Ms. Z had developed manic symptoms, including decreased need for sleep (only 2 hours a night), talkativeness, counting things and spelling words rapidly out loud, and making explicit drawings of men. Ms. Z refused her next 2 dialysis treatments and her manic symptoms worsened. She explained that all her medical problems had been “cured.” She inaccurately exclaimed that she can urinate, even though she is anuric, and that she can walk after not having done so for 5 years.

During our interview, Ms. Z is disheveled and exhibits pressured speech, often interrupting the interviewer. Her affect is euphoric and expansive. She perseverates on patenting her cures for diabetes and Parkinson’s disease, endorses hypersexuality, and denies hallucinations. Folstein Mini-Mental State Exam score is 18/28; however, Ms. Z refuses to participate in elements of cognitive testing, including writing a sentence, drawing pentagons, or drawing a clock, all of which would reveal her tremor. We note no disorientation or waxing and waning of attention or consciousness. She is fully oriented to person, place, time, and purpose and can perform serial 7s and spell a word backwards.

The authors’ observations

A number of factors suggest that Ms. Z’s manic symptoms likely are caused by a medical problem (Table 1).¹ She has no family history and only minimal personal history of psychiatric illness, and new-onset bipolar disorder in a 69-year-old woman is unusual.² Given Ms. Z’s acute change in mental status and numerous medical problems, we consider delirium. Because Ms. Z does not exhibit disorientation or waxing and waning of attention or consciousness, we feel delirium is unlikely to be the primary diagnosis.

Table 1

Criteria for mood disorder due to a general medical condition

EVALUATION: Clues to the cause

Physical exam reveals stable vital signs, and resting tremor and mild cogwheel rigidity in her right upper extremity consistent with Parkinson’s disease. Laboratory results show elevated blood urea nitrogen (65 mg/dL) and creatinine (8 mg/dL) and stably low white cell count (2.9/μL) and platelets (118x10³/μL), which are consistent with her known myelodysplasia. Results for urinalysis, B12, folate, thyroid-stimulating hormone, electrolytes, glucose, liver function, antinuclear antibodies, and rapid plasma reagin are unremarkable. Ms. Z’s elevated blood urea nitrogen and creatinine are expected because she recently refused dialysis. We consider that uremia could be causing her manic symptoms; however, with only 2 case reports of uremia-induced mania in the literature over the past century, we want to rule out other potential causes.^3,4

A CT of Ms. Z’s brain is normal. The neurology service performs an EEG and results show mild disorganization with a predominantly posterior rhythm of 8 to 9 Hz symmetrically, occasional periods of slowing, and no epileptiform activity or evidence of encephalopathy; these findings are consistent with end-stage renal disease.

The authors’ observations

Although mood disorder due to a general medical condition—in this case, mania secondary to uremia—was our primary consideration, at this point we could not rule out subclinical delirium. In delirium, we would expect EEG to show diffuse slowing of background rhythm, which we did not see with Ms. Z. However, occasional periods of slowing indicate that delirium was a possible factor.

Parkinson’s disease is known to be a rare predisposing factor for mania—possibly related to potential manicogenic properties of dopaminergic medications⁵—but this would not explain new-onset mania in the context of uremia in a patient whose carbidopa/levodopa dose had been stable for several years. It is possible that Ms. Z’s refusal of dialysis could have led to build-up of carbidopa/levodopa in her blood, thereby contributing to mania; however, when she began feeling irritable, she refused several of her medications, including carbidopa/levodopa. Therefore, it is unlikely that carbidopa/levodopa accumulated to toxic levels.

We carefully evaluated Ms. Z’s complete medication list to determine if other drugs could be contributing factors. She has been taking escitalopram for anxiety for several years. Although Ms. Z had no personal or family history of bipolar disorder and no past hypomania or agitation associated with this medication, we discontinue escitalopram in case it was contributing to her manic symptoms. Ms. Z also receives amlodipine, 5 mg/d for hypertension; atorvastatin, 20 mg/d, for hyperlipidemia; pantoprazole, 40 mg/d, for acid reflux; metoprolol, 100 mg/d, for hypertension; aspirin, 81 mg/d, for cardioprotection; and fish oil, 2000 mg/d, for cardioprotection. We do not feel that any of these medications significantly contribute to her current state.

TREATMENT: Restarting dialysis

We start Ms. Z on olanzapine, 5 mg/d, for manic symptoms 1 day after admission, and resume dialysis treatments 1 day later. Because of concerns that olanzapine could worsen her myelodysplasia, we switch to aripiprazole, titrating up to 30 mg/d, 4 days later. After 2 dialysis treatments, her manic symptoms begin to resolve.

The authors’ observations

A number of factors suggest that uremia likely is causing Ms. Z’s manic symptoms. Her symptoms suddenly developed shortly after her first missed dialysis treatment, but gradually resolved after re-initiating dialysis. It is possible that antipsychotics relieved her manic symptoms, but this does not detract from the factors that make a causal relationship between uremia and mania likely.

Manic symptoms have been reported to be precipitated by a variety of medical problems, including metabolic disturbances, infections such as human immunodeficiency virus brain infection, neurologic disorders, brain neoplasms, or traumatic brain injuries (Table 2).^6,7 End-stage renal disease frequently is associated with psychiatric manifestations—including depression, psychosis, delirium, and dementia—but mania is not a typical presentation. It is possible that this condition occurs more often but is not recognized.

Table 2

Common causes of secondary mania

Kidney disease and psychotropics

We considered the effect of dialysis on psychotropics when selecting pharmacotherapy for Ms. Z’s manic symptoms. Haloperidol is not renally cleared so no dosage adjustment is necessary;⁸ however, this potent dopamine D2-blocker could have worsened Ms. Z’s parkinsonism. Lithium is contraindicated in acute renal failure. Valproic acid clearance is reduced in renal failure, but because it is cleared by hemodialysis, dosage adjustment is not recommended for dialysis patients.⁸ However, Ms. Z’s myelodysplasia is a contraindication for valproic acid as well as carbamazepine. With atypical antipsychotics as our primary options, we noted that olanzapine, quetiapine, or aripiprazole do not require dosage adjustments for dialysis patients.^8,9 Of these, we eventually chose aripiprazole because we felt that it was least likely to exacerbate Ms. Z’s myelodysplasia.¹⁰

How uremia might cause mania

The pathophysiology of uremia-induced mania remains speculative. Possible factors include:

• Chronic renal failure can cause an elevation in plasma free tryptophan, a serotonin (5-HT) precursor.¹¹ Postmortem examination of brains of patients who died in uremic coma show elevated 5-HT.¹² Moreover, cerebrospinal fluid of patients with chronic renal failure has shown increased 5-hydroxyindoleacetic acid, the major 5-HT metabolite.¹³ Increased 5-HT could cause mania in some uremic patients, similar to how serotonergic medications can precipitate mania in some patients.
• Circulating ß-endorphin levels are increased in renal failure.¹⁴ ß-endorphins increase animal locomotor activity, which is the basis of an animal model of mania.^15,16 Therefore, uremia-induced mania could be partly related to elevated ß-endorphin levels.

This case demonstrates that mania could be a psychiatric manifestation of end-stage renal disease. Clinicians should be aware of this possibility, and further study should examine underlying pathophysiologic changes in uremia and other secondary causes of mania that might lead to such a mood state.

OUTCOME: Lasting improvement

At discharge 17 days after admission, Ms. Z is back to her baseline mental state. Her aripiprazole dose is tapered to 20 mg/d with no return of manic symptoms. After 10 weeks, aripiprazole is discontinued, with no recurrence of mania.

Related Resource

• Arora M, Daughton J. Mania in the medically ill. Curr Psychiatry Rep. 2007;9(3):232-235.

Drug Brand Names

• Amlodipine • Norvasc
• Aripiprazole • Abilify
• Atorvastatin • Lipitor
• Carbamazepine • Tegretol
• Carbidopa/levodopa • Sinemet
• Escitalopram • Lexapro
• Haloperidol • Haldol
• Isoniazid • Nydrazid
• Lithium • Eskalith, Lithobid
• Metoprolol • Lopressor
• Olanzapine • Zyprexa
• Pantoprazole • Protonix
• Quetiapine • Seroquel
• Valproic acid • Depakote
• Zidovudine • Retrovir

Disclosure

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

CASE: New-onset mania

Ms. Z, age 69, is admitted to our hospital’s medical unit after developing manic symptoms. Her medical history includes hemodialysis-dependent chronic kidney disease, Parkinson’s disease stabilized by carbidopa/levodopa, 75/300 mg/d, for 4 years, diet-controlled type 2 diabetes mellitus, hypertension, hyperlipidemia, myelodysplasia, and acid reflux. She experiences mild anxiety, which has been stable for many years with escitalopram, 10 mg/d, but has no history of alcohol or drug abuse and no family history of psychiatric illness.

The staff at her assisted living facility reports that 8 days ago Ms. Z was mildly irritable and argumentative regarding her medications and 7 days ago began to refuse all medications. Six days ago she refused dialysis, reportedly because she was angry at the staff. One day later, the staff noticed Ms. Z had developed manic symptoms, including decreased need for sleep (only 2 hours a night), talkativeness, counting things and spelling words rapidly out loud, and making explicit drawings of men. Ms. Z refused her next 2 dialysis treatments and her manic symptoms worsened. She explained that all her medical problems had been “cured.” She inaccurately exclaimed that she can urinate, even though she is anuric, and that she can walk after not having done so for 5 years.

During our interview, Ms. Z is disheveled and exhibits pressured speech, often interrupting the interviewer. Her affect is euphoric and expansive. She perseverates on patenting her cures for diabetes and Parkinson’s disease, endorses hypersexuality, and denies hallucinations. Folstein Mini-Mental State Exam score is 18/28; however, Ms. Z refuses to participate in elements of cognitive testing, including writing a sentence, drawing pentagons, or drawing a clock, all of which would reveal her tremor. We note no disorientation or waxing and waning of attention or consciousness. She is fully oriented to person, place, time, and purpose and can perform serial 7s and spell a word backwards.

The authors’ observations

A number of factors suggest that Ms. Z’s manic symptoms likely are caused by a medical problem (Table 1).¹ She has no family history and only minimal personal history of psychiatric illness, and new-onset bipolar disorder in a 69-year-old woman is unusual.² Given Ms. Z’s acute change in mental status and numerous medical problems, we consider delirium. Because Ms. Z does not exhibit disorientation or waxing and waning of attention or consciousness, we feel delirium is unlikely to be the primary diagnosis.

Table 1

Criteria for mood disorder due to a general medical condition

EVALUATION: Clues to the cause

Physical exam reveals stable vital signs, and resting tremor and mild cogwheel rigidity in her right upper extremity consistent with Parkinson’s disease. Laboratory results show elevated blood urea nitrogen (65 mg/dL) and creatinine (8 mg/dL) and stably low white cell count (2.9/μL) and platelets (118x10³/μL), which are consistent with her known myelodysplasia. Results for urinalysis, B12, folate, thyroid-stimulating hormone, electrolytes, glucose, liver function, antinuclear antibodies, and rapid plasma reagin are unremarkable. Ms. Z’s elevated blood urea nitrogen and creatinine are expected because she recently refused dialysis. We consider that uremia could be causing her manic symptoms; however, with only 2 case reports of uremia-induced mania in the literature over the past century, we want to rule out other potential causes.^3,4

A CT of Ms. Z’s brain is normal. The neurology service performs an EEG and results show mild disorganization with a predominantly posterior rhythm of 8 to 9 Hz symmetrically, occasional periods of slowing, and no epileptiform activity or evidence of encephalopathy; these findings are consistent with end-stage renal disease.

The authors’ observations

Although mood disorder due to a general medical condition—in this case, mania secondary to uremia—was our primary consideration, at this point we could not rule out subclinical delirium. In delirium, we would expect EEG to show diffuse slowing of background rhythm, which we did not see with Ms. Z. However, occasional periods of slowing indicate that delirium was a possible factor.

Parkinson’s disease is known to be a rare predisposing factor for mania—possibly related to potential manicogenic properties of dopaminergic medications⁵—but this would not explain new-onset mania in the context of uremia in a patient whose carbidopa/levodopa dose had been stable for several years. It is possible that Ms. Z’s refusal of dialysis could have led to build-up of carbidopa/levodopa in her blood, thereby contributing to mania; however, when she began feeling irritable, she refused several of her medications, including carbidopa/levodopa. Therefore, it is unlikely that carbidopa/levodopa accumulated to toxic levels.

We carefully evaluated Ms. Z’s complete medication list to determine if other drugs could be contributing factors. She has been taking escitalopram for anxiety for several years. Although Ms. Z had no personal or family history of bipolar disorder and no past hypomania or agitation associated with this medication, we discontinue escitalopram in case it was contributing to her manic symptoms. Ms. Z also receives amlodipine, 5 mg/d for hypertension; atorvastatin, 20 mg/d, for hyperlipidemia; pantoprazole, 40 mg/d, for acid reflux; metoprolol, 100 mg/d, for hypertension; aspirin, 81 mg/d, for cardioprotection; and fish oil, 2000 mg/d, for cardioprotection. We do not feel that any of these medications significantly contribute to her current state.

TREATMENT: Restarting dialysis

We start Ms. Z on olanzapine, 5 mg/d, for manic symptoms 1 day after admission, and resume dialysis treatments 1 day later. Because of concerns that olanzapine could worsen her myelodysplasia, we switch to aripiprazole, titrating up to 30 mg/d, 4 days later. After 2 dialysis treatments, her manic symptoms begin to resolve.

The authors’ observations

A number of factors suggest that uremia likely is causing Ms. Z’s manic symptoms. Her symptoms suddenly developed shortly after her first missed dialysis treatment, but gradually resolved after re-initiating dialysis. It is possible that antipsychotics relieved her manic symptoms, but this does not detract from the factors that make a causal relationship between uremia and mania likely.

Manic symptoms have been reported to be precipitated by a variety of medical problems, including metabolic disturbances, infections such as human immunodeficiency virus brain infection, neurologic disorders, brain neoplasms, or traumatic brain injuries (Table 2).^6,7 End-stage renal disease frequently is associated with psychiatric manifestations—including depression, psychosis, delirium, and dementia—but mania is not a typical presentation. It is possible that this condition occurs more often but is not recognized.

Table 2

Common causes of secondary mania

Kidney disease and psychotropics

We considered the effect of dialysis on psychotropics when selecting pharmacotherapy for Ms. Z’s manic symptoms. Haloperidol is not renally cleared so no dosage adjustment is necessary;⁸ however, this potent dopamine D2-blocker could have worsened Ms. Z’s parkinsonism. Lithium is contraindicated in acute renal failure. Valproic acid clearance is reduced in renal failure, but because it is cleared by hemodialysis, dosage adjustment is not recommended for dialysis patients.⁸ However, Ms. Z’s myelodysplasia is a contraindication for valproic acid as well as carbamazepine. With atypical antipsychotics as our primary options, we noted that olanzapine, quetiapine, or aripiprazole do not require dosage adjustments for dialysis patients.^8,9 Of these, we eventually chose aripiprazole because we felt that it was least likely to exacerbate Ms. Z’s myelodysplasia.¹⁰

How uremia might cause mania

The pathophysiology of uremia-induced mania remains speculative. Possible factors include:

• Chronic renal failure can cause an elevation in plasma free tryptophan, a serotonin (5-HT) precursor.¹¹ Postmortem examination of brains of patients who died in uremic coma show elevated 5-HT.¹² Moreover, cerebrospinal fluid of patients with chronic renal failure has shown increased 5-hydroxyindoleacetic acid, the major 5-HT metabolite.¹³ Increased 5-HT could cause mania in some uremic patients, similar to how serotonergic medications can precipitate mania in some patients.
• Circulating ß-endorphin levels are increased in renal failure.¹⁴ ß-endorphins increase animal locomotor activity, which is the basis of an animal model of mania.^15,16 Therefore, uremia-induced mania could be partly related to elevated ß-endorphin levels.

This case demonstrates that mania could be a psychiatric manifestation of end-stage renal disease. Clinicians should be aware of this possibility, and further study should examine underlying pathophysiologic changes in uremia and other secondary causes of mania that might lead to such a mood state.

OUTCOME: Lasting improvement

At discharge 17 days after admission, Ms. Z is back to her baseline mental state. Her aripiprazole dose is tapered to 20 mg/d with no return of manic symptoms. After 10 weeks, aripiprazole is discontinued, with no recurrence of mania.

Related Resource

• Arora M, Daughton J. Mania in the medically ill. Curr Psychiatry Rep. 2007;9(3):232-235.

Drug Brand Names

• Amlodipine • Norvasc
• Aripiprazole • Abilify
• Atorvastatin • Lipitor
• Carbamazepine • Tegretol
• Carbidopa/levodopa • Sinemet
• Escitalopram • Lexapro
• Haloperidol • Haldol
• Isoniazid • Nydrazid
• Lithium • Eskalith, Lithobid
• Metoprolol • Lopressor
• Olanzapine • Zyprexa
• Pantoprazole • Protonix
• Quetiapine • Seroquel
• Valproic acid • Depakote
• Zidovudine • Retrovir

Disclosure

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

HISTORY: Visual disturbances

Ms. G, age 30, has schizoaffective disorder and presents with worsening auditory hallucinations, paranoid delusions, and thought broadcasting and insertion, which is suspected to be related to a change from olanzapine to aripiprazole. She complains of visual disturbances—a hallucination of flashing lights—that she describes as occurring “all the time, like salt-and-pepper dancing, and sometimes splotches.” Her visual symptoms are worse when she closes her eyes and in dimly lit environments, but occur in daylight as well. Her vision is otherwise unimpaired.

The visual disturbances started with Ms. G’s first psychotic break at age 23 and have persisted continuously. She reports that at first, the spots were more intense, like an incessant strobe light. These symptoms are aggravated by sleep deprivation and anger and improve only with topiramate, 100 mg/d, which was prescribed a year earlier after a neurologic consultation but discontinued because of cognitive side effects.

Ms. G also complains of dull, aching, continuous headaches in the center of her forehead, which do not wake her, are not worse in the morning, and do not vary with the intensity of her visual symptoms. The headaches are incorporated into her system of delusions; she believes they “drain the electricity from her head” and make her feel better. She denies a history of migraines. Ms. G has a history of experiencing well-formed visual hallucinations, such as the devil, but has not had them for several years.

She had 5 to 10 episodes over the last 2 years that she describes as seizures—“an earthquake, a huge whooshing noise,” accompanied by heart palpitations that occur with stress, in public, in bright lights, or whenever she feels vulnerable. These episodes are not associated with loss of consciousness, incontinence, amnesia, or post-ictal confusion and she can stop them with relaxation techniques such as deep breathing and reminding herself to calm down. The last episode was 2 months ago and seemed unrelated to her visual phenomena. She also complains of occasional paresthesias in her extremities but denies dizziness, presyncope, or blurry or double vision.

Ms. G is obese and has no history of head injury or birth defects. Her family history is negative for epilepsy; however, her mother has bipolar disorder and father has schizophrenia. Her medications are phentermine, 37.5 mg/d for short-term management of obesity, oxcarbazepine, 600 mg/d for supposed partial seizures, sertraline, 100 mg/d for depression, aripiprazole, 10 mg/d, and nizatidine, 150 mg/d, for gastroesophageal reflux disease. She does not use alcohol, cigarettes, or illicit drugs. Ms. G obtained a master’s degree in health communications and works as a research assistant at a local medical school.

The authors’ observations

Visual hallucinations are not distortions of reality but original false perceptions that co-occur with real perceptions.¹ They vary from simple, elemental hallucinations involving flashes of light or geometric figures to more complex elaborations such as seeing crawling insects or a flock of angels.² Hallucinations can originate anywhere in the visual system from the lens to the visual cortex and can be vascular, toxic, electrophysiologic, structural, or neurochemical manifestations of neurologic, psychiatric, or ophthalmologic disorders. Depending on the hallucination’s etiology, treatment varies from emergent ophthalmologic examination and retinal surgery to antipsychotic therapy to simple observation. Photopsia is a perception of flashing lights, and its etiology varies; causes can be categorized as emergent or nonemergent.

Emergent causes of photopsia typically have a sudden onset, often can be diagnosed from associated symptoms or medical history, and must be recognized quickly to prevent permanent vision loss. Posterior vitreous detachment and retinal tearing can manifest as flashes of light, floaters, or blurred vision in the peripheral visual field that are worse in dim illumination and localizable by the patient. Retinal detachment can cause photopsia, floaters, or a “curtain” or “shadow” moving over the visual field, which may be accompanied by central or peripheral vision loss.³ Severe myopia is a risk factor for retinal detachment.

New-onset photopsia can suggest cytomegaloviral retinitis in an immune-compromised patient, and ocular-vascular crisis in a patient with sickle cell disease. New-onset or recurrent photopsia with bilateral blurred vision, ataxia, vertigo, dysarthria, or drop attacks may be caused by vertebrobasilar artery insufficiency (VBAI). Photopsia has been reported as the presenting symptom in carotid artery dissection.⁴ Photopsia correlated with eye movement implicates the retina or optic nerve. All of these etiologies except for VBAI should be referred to an ophthalmologist for indirect ophthalmoscopy and evaluation.

Nonemergent causes of photopsia include:

• drug toxicity
• migraine headache
• thyroid ophthalmopathy
• arteriovenous malformations
• seizures
• psychiatric disorders.

Digoxin, cocaine, paclitaxel, and clomiphene may have ocular side effects, including photopsia. The first symptoms of digitalis toxicity often are visual and include photopsia, yellow or green discoloration of the visual field, halos, and the appearance of frost over objects.⁵ Signs of cocaine intoxication can include visual hallucinations such as photopsia, shadows, moving objects, and insects crawling and co-occurring euphoria, hypervigilance, impaired judgment, and autonomic changes such as tachycardia, pupillary dilation, hypertension, and nausea.⁶ High-dose paclitaxel infusion has been reported to cause photopsia.⁷ Clomiphene can cause flickering lights and shimmering that persists after discontinuing the medication.⁸

Migraine with aura, which includes photopsia 39% of the time,⁹ often involves an expanding central visual disturbance or scotoma, and usually is confined to 1 visual field but may involve both. The aura typically lasts 10 to 20 minutes and often is followed by headache. Patients often report a history of episodic stereotyped auras and headache. Ocular examination is normal.

Ophthalmic migraine, also known as ocular or retinal migraine, is thought to be caused by transient vasospasm of the choroidal or retinal arteries and can be precipitated by postural changes, exercise, and oral contraceptives. It manifests as a gradual visual disturbance in a mosaic scotomata pattern that enlarges, producing total unilateral visual loss lasting from minutes to an hour, and—misleadingly—can be associated with minimal or no headache. Ocular examination is normal, and a personal or family history of migraine confirms the diagnosis.

Seizure activity in the occipital cortex and adjacent association areas can produce static light and stars. In a prospective study of 18 patients with occipital epilepsy, visual seizures lasted from a few seconds to 3 minutes—although rarely 20 to 150 minutes—and occurred in multiple clusters a day or week.¹⁰ All but 2 patients had secondary generalized tonic-clonic convulsions. Occipital seizures often are misdiagnosed as the visual aura of migraine, particularly when elementary visual hallucinations are followed by post-ictal headache and vomiting.¹¹ Lights with a color or a spherical shape suggest occipital epilepsy. Consider ordering an electroencephalogram (EEG) if the clinical diagnosis is unclear.

EXAMINATION: No obvious cause

During a mental status exam, Ms. G is pleasant, cooperative, alert, and oriented to person, place, and time. Her speech is fluent, her affect is full, and she describes her mood as a “sensitive, overwhelmed state.” Her thoughts occasionally are tangential, and she perseverates on guilty, embarrassed, and paranoid thoughts. She has auditory hallucinations and experiences photopsia during the interview, but denies other visual hallucinations. She shows no deficits in attention, concentration, memory, language, calculations, visuospatial abilities, or general fund of knowledge.

Her physical exam shows pupils that are equal, round, and reactive to light with normal extraocular movements, intact visual fields, 20/20 visual acuity in both eyes with glasses, and sharp optic disc margins with no retinal abnormalities apparent on funduscopic exam. The rest of her physical and neurologic exam is normal. Her complete blood count, electrolytes, kidney, liver function tests, urinalysis, and serum toxicology screens are normal. She has no history of immunodeficiency.

An MRI performed a year earlier showed mild diffuse congestion of a left maxillary sinus but no other intracranial abnormalities, and a waking EEG with sphenoidal electrodes was normal.

The authors’ observations

Evaluation of patients with photopsia includes taking a history and performing an eye examination including visual acuity testing, visual field testing, and funduscopic examination. The appearance, location, and duration of photopsia may help narrow the differential diagnosis and identify emergent cases (Table 1 and Table 2). Seizure activity associated with flashing lights suggests occipital epilepsy. A history of hypertension, diabetes, or polymyalgia rheumatica points to vascular causes, and hyperthyroidism suggests that flashing lights may be phosphenes of Graves’ disease. Myopia or eye trauma could indicate vitreous traction. Prescription medications and illicit drug use may point to a toxic etiology.¹²

Table 1
Diagnoses suggested by photopsia phenomena

Table 2
Photopsia differential diagnosis: Look for co-occurring symptoms

OUTCOME: Diagnosis of exclusion

Ms. G’s visual disturbance resembles vitreous detachment or classic migraine; however, the onset is not sudden, her funduscopic exam is normal, and she has no discrete episodes with concomitant headache. Ms. G’s improvement with topiramate is inconsistent with an ophthalmic origin because such photopsia should not improve with medication. It is consistent with recurrent seizures or status epilepticus of the occipital cortex; however, she did not experience multiple discrete episodes a day or generalized seizures experienced by most occipital seizure patients, and her EEG and clinical history are not consistent with seizures. Because we cannot rule out occipital lobe epilepsy, we refer Ms. G for repeat EEG and routine ophthalmologic exam, both of which are normal.

Perceptual disturbances are common in schizoaffective disorder and schizophrenia,^13-15 which we consider the most likely etiology of Ms. G’s photopsia, given her normal neurologic and ophthalmologic examinations. We switch her from aripiprazole to ziprasidone, 40 mg/d, discontinue phentermine, and taper and discontinue oxcarbazepine.

Related resources

• Ophthalmology Web. www.ophthalmologyweb.com.
• Aleman A, Larøi F. Hallucinations: the science of idiosyncratic perception. Washington, DC: American Psychological Association; 2008.

Drug Brand Names

• Aripiprazole • Abilify
• Clomiphene • Clomid, Serophene
• Digoxin • Lanoxin
• Nizatidine • Axid
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Paclitaxel • Onxol, Taxol
• Phentermine • Adipex-P, Inoamin
• Sertraline • Zoloft
• Topiramate • Topamax
• Ziprasidone • Geodon

Disclosure

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

HISTORY: Visual disturbances

Ms. G, age 30, has schizoaffective disorder and presents with worsening auditory hallucinations, paranoid delusions, and thought broadcasting and insertion, which is suspected to be related to a change from olanzapine to aripiprazole. She complains of visual disturbances—a hallucination of flashing lights—that she describes as occurring “all the time, like salt-and-pepper dancing, and sometimes splotches.” Her visual symptoms are worse when she closes her eyes and in dimly lit environments, but occur in daylight as well. Her vision is otherwise unimpaired.

The visual disturbances started with Ms. G’s first psychotic break at age 23 and have persisted continuously. She reports that at first, the spots were more intense, like an incessant strobe light. These symptoms are aggravated by sleep deprivation and anger and improve only with topiramate, 100 mg/d, which was prescribed a year earlier after a neurologic consultation but discontinued because of cognitive side effects.

Ms. G also complains of dull, aching, continuous headaches in the center of her forehead, which do not wake her, are not worse in the morning, and do not vary with the intensity of her visual symptoms. The headaches are incorporated into her system of delusions; she believes they “drain the electricity from her head” and make her feel better. She denies a history of migraines. Ms. G has a history of experiencing well-formed visual hallucinations, such as the devil, but has not had them for several years.

She had 5 to 10 episodes over the last 2 years that she describes as seizures—“an earthquake, a huge whooshing noise,” accompanied by heart palpitations that occur with stress, in public, in bright lights, or whenever she feels vulnerable. These episodes are not associated with loss of consciousness, incontinence, amnesia, or post-ictal confusion and she can stop them with relaxation techniques such as deep breathing and reminding herself to calm down. The last episode was 2 months ago and seemed unrelated to her visual phenomena. She also complains of occasional paresthesias in her extremities but denies dizziness, presyncope, or blurry or double vision.

Ms. G is obese and has no history of head injury or birth defects. Her family history is negative for epilepsy; however, her mother has bipolar disorder and father has schizophrenia. Her medications are phentermine, 37.5 mg/d for short-term management of obesity, oxcarbazepine, 600 mg/d for supposed partial seizures, sertraline, 100 mg/d for depression, aripiprazole, 10 mg/d, and nizatidine, 150 mg/d, for gastroesophageal reflux disease. She does not use alcohol, cigarettes, or illicit drugs. Ms. G obtained a master’s degree in health communications and works as a research assistant at a local medical school.

The authors’ observations

Visual hallucinations are not distortions of reality but original false perceptions that co-occur with real perceptions.¹ They vary from simple, elemental hallucinations involving flashes of light or geometric figures to more complex elaborations such as seeing crawling insects or a flock of angels.² Hallucinations can originate anywhere in the visual system from the lens to the visual cortex and can be vascular, toxic, electrophysiologic, structural, or neurochemical manifestations of neurologic, psychiatric, or ophthalmologic disorders. Depending on the hallucination’s etiology, treatment varies from emergent ophthalmologic examination and retinal surgery to antipsychotic therapy to simple observation. Photopsia is a perception of flashing lights, and its etiology varies; causes can be categorized as emergent or nonemergent.

Emergent causes of photopsia typically have a sudden onset, often can be diagnosed from associated symptoms or medical history, and must be recognized quickly to prevent permanent vision loss. Posterior vitreous detachment and retinal tearing can manifest as flashes of light, floaters, or blurred vision in the peripheral visual field that are worse in dim illumination and localizable by the patient. Retinal detachment can cause photopsia, floaters, or a “curtain” or “shadow” moving over the visual field, which may be accompanied by central or peripheral vision loss.³ Severe myopia is a risk factor for retinal detachment.

New-onset photopsia can suggest cytomegaloviral retinitis in an immune-compromised patient, and ocular-vascular crisis in a patient with sickle cell disease. New-onset or recurrent photopsia with bilateral blurred vision, ataxia, vertigo, dysarthria, or drop attacks may be caused by vertebrobasilar artery insufficiency (VBAI). Photopsia has been reported as the presenting symptom in carotid artery dissection.⁴ Photopsia correlated with eye movement implicates the retina or optic nerve. All of these etiologies except for VBAI should be referred to an ophthalmologist for indirect ophthalmoscopy and evaluation.

Nonemergent causes of photopsia include:

• drug toxicity
• migraine headache
• thyroid ophthalmopathy
• arteriovenous malformations
• seizures
• psychiatric disorders.

Digoxin, cocaine, paclitaxel, and clomiphene may have ocular side effects, including photopsia. The first symptoms of digitalis toxicity often are visual and include photopsia, yellow or green discoloration of the visual field, halos, and the appearance of frost over objects.⁵ Signs of cocaine intoxication can include visual hallucinations such as photopsia, shadows, moving objects, and insects crawling and co-occurring euphoria, hypervigilance, impaired judgment, and autonomic changes such as tachycardia, pupillary dilation, hypertension, and nausea.⁶ High-dose paclitaxel infusion has been reported to cause photopsia.⁷ Clomiphene can cause flickering lights and shimmering that persists after discontinuing the medication.⁸

Migraine with aura, which includes photopsia 39% of the time,⁹ often involves an expanding central visual disturbance or scotoma, and usually is confined to 1 visual field but may involve both. The aura typically lasts 10 to 20 minutes and often is followed by headache. Patients often report a history of episodic stereotyped auras and headache. Ocular examination is normal.

Ophthalmic migraine, also known as ocular or retinal migraine, is thought to be caused by transient vasospasm of the choroidal or retinal arteries and can be precipitated by postural changes, exercise, and oral contraceptives. It manifests as a gradual visual disturbance in a mosaic scotomata pattern that enlarges, producing total unilateral visual loss lasting from minutes to an hour, and—misleadingly—can be associated with minimal or no headache. Ocular examination is normal, and a personal or family history of migraine confirms the diagnosis.

Seizure activity in the occipital cortex and adjacent association areas can produce static light and stars. In a prospective study of 18 patients with occipital epilepsy, visual seizures lasted from a few seconds to 3 minutes—although rarely 20 to 150 minutes—and occurred in multiple clusters a day or week.¹⁰ All but 2 patients had secondary generalized tonic-clonic convulsions. Occipital seizures often are misdiagnosed as the visual aura of migraine, particularly when elementary visual hallucinations are followed by post-ictal headache and vomiting.¹¹ Lights with a color or a spherical shape suggest occipital epilepsy. Consider ordering an electroencephalogram (EEG) if the clinical diagnosis is unclear.

EXAMINATION: No obvious cause

During a mental status exam, Ms. G is pleasant, cooperative, alert, and oriented to person, place, and time. Her speech is fluent, her affect is full, and she describes her mood as a “sensitive, overwhelmed state.” Her thoughts occasionally are tangential, and she perseverates on guilty, embarrassed, and paranoid thoughts. She has auditory hallucinations and experiences photopsia during the interview, but denies other visual hallucinations. She shows no deficits in attention, concentration, memory, language, calculations, visuospatial abilities, or general fund of knowledge.

Her physical exam shows pupils that are equal, round, and reactive to light with normal extraocular movements, intact visual fields, 20/20 visual acuity in both eyes with glasses, and sharp optic disc margins with no retinal abnormalities apparent on funduscopic exam. The rest of her physical and neurologic exam is normal. Her complete blood count, electrolytes, kidney, liver function tests, urinalysis, and serum toxicology screens are normal. She has no history of immunodeficiency.

An MRI performed a year earlier showed mild diffuse congestion of a left maxillary sinus but no other intracranial abnormalities, and a waking EEG with sphenoidal electrodes was normal.

The authors’ observations

Evaluation of patients with photopsia includes taking a history and performing an eye examination including visual acuity testing, visual field testing, and funduscopic examination. The appearance, location, and duration of photopsia may help narrow the differential diagnosis and identify emergent cases (Table 1 and Table 2). Seizure activity associated with flashing lights suggests occipital epilepsy. A history of hypertension, diabetes, or polymyalgia rheumatica points to vascular causes, and hyperthyroidism suggests that flashing lights may be phosphenes of Graves’ disease. Myopia or eye trauma could indicate vitreous traction. Prescription medications and illicit drug use may point to a toxic etiology.¹²

Table 1
Diagnoses suggested by photopsia phenomena

Table 2
Photopsia differential diagnosis: Look for co-occurring symptoms

OUTCOME: Diagnosis of exclusion

Ms. G’s visual disturbance resembles vitreous detachment or classic migraine; however, the onset is not sudden, her funduscopic exam is normal, and she has no discrete episodes with concomitant headache. Ms. G’s improvement with topiramate is inconsistent with an ophthalmic origin because such photopsia should not improve with medication. It is consistent with recurrent seizures or status epilepticus of the occipital cortex; however, she did not experience multiple discrete episodes a day or generalized seizures experienced by most occipital seizure patients, and her EEG and clinical history are not consistent with seizures. Because we cannot rule out occipital lobe epilepsy, we refer Ms. G for repeat EEG and routine ophthalmologic exam, both of which are normal.

Perceptual disturbances are common in schizoaffective disorder and schizophrenia,^13-15 which we consider the most likely etiology of Ms. G’s photopsia, given her normal neurologic and ophthalmologic examinations. We switch her from aripiprazole to ziprasidone, 40 mg/d, discontinue phentermine, and taper and discontinue oxcarbazepine.

Related resources

• Ophthalmology Web. www.ophthalmologyweb.com.
• Aleman A, Larøi F. Hallucinations: the science of idiosyncratic perception. Washington, DC: American Psychological Association; 2008.

Drug Brand Names

• Aripiprazole • Abilify
• Clomiphene • Clomid, Serophene
• Digoxin • Lanoxin
• Nizatidine • Axid
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Paclitaxel • Onxol, Taxol
• Phentermine • Adipex-P, Inoamin
• Sertraline • Zoloft
• Topiramate • Topamax
• Ziprasidone • Geodon

Disclosure

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

HISTORY: Visual disturbances

Ms. G, age 30, has schizoaffective disorder and presents with worsening auditory hallucinations, paranoid delusions, and thought broadcasting and insertion, which is suspected to be related to a change from olanzapine to aripiprazole. She complains of visual disturbances—a hallucination of flashing lights—that she describes as occurring “all the time, like salt-and-pepper dancing, and sometimes splotches.” Her visual symptoms are worse when she closes her eyes and in dimly lit environments, but occur in daylight as well. Her vision is otherwise unimpaired.

The visual disturbances started with Ms. G’s first psychotic break at age 23 and have persisted continuously. She reports that at first, the spots were more intense, like an incessant strobe light. These symptoms are aggravated by sleep deprivation and anger and improve only with topiramate, 100 mg/d, which was prescribed a year earlier after a neurologic consultation but discontinued because of cognitive side effects.

Ms. G also complains of dull, aching, continuous headaches in the center of her forehead, which do not wake her, are not worse in the morning, and do not vary with the intensity of her visual symptoms. The headaches are incorporated into her system of delusions; she believes they “drain the electricity from her head” and make her feel better. She denies a history of migraines. Ms. G has a history of experiencing well-formed visual hallucinations, such as the devil, but has not had them for several years.

She had 5 to 10 episodes over the last 2 years that she describes as seizures—“an earthquake, a huge whooshing noise,” accompanied by heart palpitations that occur with stress, in public, in bright lights, or whenever she feels vulnerable. These episodes are not associated with loss of consciousness, incontinence, amnesia, or post-ictal confusion and she can stop them with relaxation techniques such as deep breathing and reminding herself to calm down. The last episode was 2 months ago and seemed unrelated to her visual phenomena. She also complains of occasional paresthesias in her extremities but denies dizziness, presyncope, or blurry or double vision.

Ms. G is obese and has no history of head injury or birth defects. Her family history is negative for epilepsy; however, her mother has bipolar disorder and father has schizophrenia. Her medications are phentermine, 37.5 mg/d for short-term management of obesity, oxcarbazepine, 600 mg/d for supposed partial seizures, sertraline, 100 mg/d for depression, aripiprazole, 10 mg/d, and nizatidine, 150 mg/d, for gastroesophageal reflux disease. She does not use alcohol, cigarettes, or illicit drugs. Ms. G obtained a master’s degree in health communications and works as a research assistant at a local medical school.

The authors’ observations

Visual hallucinations are not distortions of reality but original false perceptions that co-occur with real perceptions.¹ They vary from simple, elemental hallucinations involving flashes of light or geometric figures to more complex elaborations such as seeing crawling insects or a flock of angels.² Hallucinations can originate anywhere in the visual system from the lens to the visual cortex and can be vascular, toxic, electrophysiologic, structural, or neurochemical manifestations of neurologic, psychiatric, or ophthalmologic disorders. Depending on the hallucination’s etiology, treatment varies from emergent ophthalmologic examination and retinal surgery to antipsychotic therapy to simple observation. Photopsia is a perception of flashing lights, and its etiology varies; causes can be categorized as emergent or nonemergent.

Emergent causes of photopsia typically have a sudden onset, often can be diagnosed from associated symptoms or medical history, and must be recognized quickly to prevent permanent vision loss. Posterior vitreous detachment and retinal tearing can manifest as flashes of light, floaters, or blurred vision in the peripheral visual field that are worse in dim illumination and localizable by the patient. Retinal detachment can cause photopsia, floaters, or a “curtain” or “shadow” moving over the visual field, which may be accompanied by central or peripheral vision loss.³ Severe myopia is a risk factor for retinal detachment.

New-onset photopsia can suggest cytomegaloviral retinitis in an immune-compromised patient, and ocular-vascular crisis in a patient with sickle cell disease. New-onset or recurrent photopsia with bilateral blurred vision, ataxia, vertigo, dysarthria, or drop attacks may be caused by vertebrobasilar artery insufficiency (VBAI). Photopsia has been reported as the presenting symptom in carotid artery dissection.⁴ Photopsia correlated with eye movement implicates the retina or optic nerve. All of these etiologies except for VBAI should be referred to an ophthalmologist for indirect ophthalmoscopy and evaluation.

Nonemergent causes of photopsia include:

• drug toxicity
• migraine headache
• thyroid ophthalmopathy
• arteriovenous malformations
• seizures
• psychiatric disorders.

Digoxin, cocaine, paclitaxel, and clomiphene may have ocular side effects, including photopsia. The first symptoms of digitalis toxicity often are visual and include photopsia, yellow or green discoloration of the visual field, halos, and the appearance of frost over objects.⁵ Signs of cocaine intoxication can include visual hallucinations such as photopsia, shadows, moving objects, and insects crawling and co-occurring euphoria, hypervigilance, impaired judgment, and autonomic changes such as tachycardia, pupillary dilation, hypertension, and nausea.⁶ High-dose paclitaxel infusion has been reported to cause photopsia.⁷ Clomiphene can cause flickering lights and shimmering that persists after discontinuing the medication.⁸

Migraine with aura, which includes photopsia 39% of the time,⁹ often involves an expanding central visual disturbance or scotoma, and usually is confined to 1 visual field but may involve both. The aura typically lasts 10 to 20 minutes and often is followed by headache. Patients often report a history of episodic stereotyped auras and headache. Ocular examination is normal.

Ophthalmic migraine, also known as ocular or retinal migraine, is thought to be caused by transient vasospasm of the choroidal or retinal arteries and can be precipitated by postural changes, exercise, and oral contraceptives. It manifests as a gradual visual disturbance in a mosaic scotomata pattern that enlarges, producing total unilateral visual loss lasting from minutes to an hour, and—misleadingly—can be associated with minimal or no headache. Ocular examination is normal, and a personal or family history of migraine confirms the diagnosis.

Seizure activity in the occipital cortex and adjacent association areas can produce static light and stars. In a prospective study of 18 patients with occipital epilepsy, visual seizures lasted from a few seconds to 3 minutes—although rarely 20 to 150 minutes—and occurred in multiple clusters a day or week.¹⁰ All but 2 patients had secondary generalized tonic-clonic convulsions. Occipital seizures often are misdiagnosed as the visual aura of migraine, particularly when elementary visual hallucinations are followed by post-ictal headache and vomiting.¹¹ Lights with a color or a spherical shape suggest occipital epilepsy. Consider ordering an electroencephalogram (EEG) if the clinical diagnosis is unclear.

EXAMINATION: No obvious cause

During a mental status exam, Ms. G is pleasant, cooperative, alert, and oriented to person, place, and time. Her speech is fluent, her affect is full, and she describes her mood as a “sensitive, overwhelmed state.” Her thoughts occasionally are tangential, and she perseverates on guilty, embarrassed, and paranoid thoughts. She has auditory hallucinations and experiences photopsia during the interview, but denies other visual hallucinations. She shows no deficits in attention, concentration, memory, language, calculations, visuospatial abilities, or general fund of knowledge.

Her physical exam shows pupils that are equal, round, and reactive to light with normal extraocular movements, intact visual fields, 20/20 visual acuity in both eyes with glasses, and sharp optic disc margins with no retinal abnormalities apparent on funduscopic exam. The rest of her physical and neurologic exam is normal. Her complete blood count, electrolytes, kidney, liver function tests, urinalysis, and serum toxicology screens are normal. She has no history of immunodeficiency.

An MRI performed a year earlier showed mild diffuse congestion of a left maxillary sinus but no other intracranial abnormalities, and a waking EEG with sphenoidal electrodes was normal.

The authors’ observations

Evaluation of patients with photopsia includes taking a history and performing an eye examination including visual acuity testing, visual field testing, and funduscopic examination. The appearance, location, and duration of photopsia may help narrow the differential diagnosis and identify emergent cases (Table 1 and Table 2). Seizure activity associated with flashing lights suggests occipital epilepsy. A history of hypertension, diabetes, or polymyalgia rheumatica points to vascular causes, and hyperthyroidism suggests that flashing lights may be phosphenes of Graves’ disease. Myopia or eye trauma could indicate vitreous traction. Prescription medications and illicit drug use may point to a toxic etiology.¹²

Table 1
Diagnoses suggested by photopsia phenomena

Table 2
Photopsia differential diagnosis: Look for co-occurring symptoms

OUTCOME: Diagnosis of exclusion

Ms. G’s visual disturbance resembles vitreous detachment or classic migraine; however, the onset is not sudden, her funduscopic exam is normal, and she has no discrete episodes with concomitant headache. Ms. G’s improvement with topiramate is inconsistent with an ophthalmic origin because such photopsia should not improve with medication. It is consistent with recurrent seizures or status epilepticus of the occipital cortex; however, she did not experience multiple discrete episodes a day or generalized seizures experienced by most occipital seizure patients, and her EEG and clinical history are not consistent with seizures. Because we cannot rule out occipital lobe epilepsy, we refer Ms. G for repeat EEG and routine ophthalmologic exam, both of which are normal.

Perceptual disturbances are common in schizoaffective disorder and schizophrenia,^13-15 which we consider the most likely etiology of Ms. G’s photopsia, given her normal neurologic and ophthalmologic examinations. We switch her from aripiprazole to ziprasidone, 40 mg/d, discontinue phentermine, and taper and discontinue oxcarbazepine.

Related resources

• Ophthalmology Web. www.ophthalmologyweb.com.
• Aleman A, Larøi F. Hallucinations: the science of idiosyncratic perception. Washington, DC: American Psychological Association; 2008.

Drug Brand Names

• Aripiprazole • Abilify
• Clomiphene • Clomid, Serophene
• Digoxin • Lanoxin
• Nizatidine • Axid
• Olanzapine • Zyprexa
• Oxcarbazepine • Trileptal
• Paclitaxel • Onxol, Taxol
• Phentermine • Adipex-P, Inoamin
• Sertraline • Zoloft
• Topiramate • Topamax
• Ziprasidone • Geodon

Disclosure

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

CASE: Feeling detached

Ms. A, age 23, presents to our clinic complaining of feeling detached for the past 4 years. She says she feels “fuzzy all the time, like I lost touch with reality 4 years ago and really miss it.” She complains of “confused thinking,” excessive tiredness and weakness, depression, and anxiety. She says, “It feels like I’m watching my life on television; I don’t feel any emotions.” These symptoms began immediately after a college party, which the police stopped because of underage drinking. She says, “I don’t know why, but that party set it off, and it feels like I am in a dream all the time.”

For the last 4 years, Ms. A has been working as a waitress and is now engaged. She presents to our clinic because the treatments she has been receiving are ineffective and she wants to feel her emotions again, especially before her wedding.

Ms. A has no history of mania, depression, or psychosis. She says she was an anxious child and suffered from anorexia nervosa between age 13 and 14. She experienced occasional panic attacks beginning in high school that were triggered by feeling overwhelmed or frustrated with not feeling normal. During these panic attacks, Ms. A experienced tightness in her chest and dizziness. She denies suicidal or homicidal ideation or attempts.

At age 18, she was sexually assaulted. Ongoing stressors include living in a dangerous neighborhood, having her car broken into, her father’s disapproval of her fiancé, and wanting to get married. She drank heavily in college, but has used alcohol infrequently since then.

Ms. A’s father has a history of anxiety. She describes him as domineering and her mother as very emotional and always wanting to be her friend. Ms. A says she struggles with relationships, employment, and plans for advancement, all of which are moderately to severely affected by her depersonalization symptoms. During the initial appointment, we diagnose Ms. A with generalized anxiety disorder, panic disorder, and major depressive disorder (MDD).

Which diagnoses would you include among the differential diagnosis?

1. posttraumatic stress disorder (PTSD)
2. MDD with psychotic features
3. depersonalization disorder
4. schizophrenia, undifferentiated type
5. psychosis not otherwise specified

The authors’ observations

Depersonalization symptoms can occur in a variety of situations, including:

• mentally healthy persons suffering from acute stressors, fatigue, or drug use
• neuropsychiatric conditions such as epilepsy
• migraine
• anxiety disorders
• depressive disorders
• schizophrenia.¹

Transient depersonalization symptoms are common and have been found in 2.4% of the general population.² Community surveys using standardized diagnostic interviews reveal 1-month prevalence rates of 1.6% to 1.9% in 2 UK samples.^3,4 Depersonalization symptoms are brief and less debilitating than depersonalization disorder.

Depersonalization rarely presents as a primary disorder, when symptoms persist chronically. Rating scales (Table 1)^5-7 and DSM-IV-TR criteria (Table 2) can help assess symptom severity and differentiate transient symptoms from a disorder. Psychiatric conditions that commonly are comorbid with depersonalization disorder appear in Table 3.⁸ Triggers for a first episode of depersonalization disorder include:

Table 1

Assessing for depersonalization: 3 rating scales

• psychological stressors (31%)
• substance abuse (25%)
• physical stressor (12%)
• situational stressor (17%)
• social and/or relationship problems (10%)
• trauma (6%)
• panic/anxiety (2%).⁸

Although Ms. A experiences depersonalization—constant numbness and emptiness—when she thinks about the sexual assault, she does not meet criteria for PTSD because she denies re-experiencing the assault, hyperarousal, and avoidance behaviors.

Ms. A meets all 4 DSM-IV-TR criteria for depersonalization disorder (Table 2). She experiences persistent feelings of detachment, which cause her considerable distress. Her reality testing is intact and these experiences are not due to a general medical condition, another mental disorder, or direct physiological effects of a substance.

Table 2

DSM-IV-TR criteria for depersonalization disorder

Which medications would you consider for Ms. A?

1. benzodiazepine plus a tricyclic antidepressant (TCA)
2. selective serotonin reuptake inhibitor (SSRI) plus a benzodiazepine
3. trazodone plus bupropion
4. atypical antipsychotic plus a benzodiazepine and a TCA

TREATMENT: Insufficient response

Ms. A’s previous psychiatrist prescribed various SSRIs and selective serotonin-norepinephrine reuptake inhibitors, including sertraline, escitalopram, citalopram, paroxetine, and venlafaxine, for depression and anxiety with little or no benefit. When she presented at our clinic, Ms. A was taking clonazepam, 0.25 mg as needed, and fluvoxamine, 50 mg/d, which she said helped her anxiety a little, but not depersonalization symptoms. She received supportive psychotherapy provided during biweekly 30-minute medication management visits.

We add aripiprazole, 2.5 mg/d, to augment fluvoxamine’s antidepressant effect and reduce her anxiety and dissociative symptoms. At the next visit 5 weeks later, she reports her depersonalization symptoms gradually lessened from 10 to 6 on a 10-point self-report scale.

We discontinue fluvoxamine after 5 weeks because it no longer significantly contributes to her recovery. We add amantadine, 100 mg/d, based on the belief that dopamine augmentation might help reduce her symptoms. Ms. A reports improved depersonalization symptoms over the next 4 weeks (5/10). However, a week later she says she feels her anxiety is worsening the depersonalization symptoms. We start buspirone, 7.5 mg/d titrated to 15 mg/d over 4 weeks, Ms. A reports feeling worse so we discontinue the drug.

Next Ms. A complains of excessive sleepiness, which seems to be related to amantadine, so we discontinue it. We start bupropion, 150 mg/d and titrate it to 450 mg/d, which we hope will reduce her fatigue, anxiety, depersonalization, and depression. Bupropion’s effect on norepinephrine and dopamine reuptake and a study of autonomic blunting in depersonalization⁹ justify our selection.

After 3 months, Ms. A stops taking aripiprazole because it is too costly. The following month she presents with severe anxiety and low-to-moderate depression. Clonazepam and bupropion are discontinued and replaced with diazepam, 20 mg/d, and clomipramine, 25 mg/d at bedtime titrated to 75 mg/d. Our decision is guided by a study on the efficacy of clomipramine in treating depersonalization¹⁰ and our desire to aggressively treat her anxiety and depression. After 2 weeks, Ms. A says her anxiety and depression have resolved completely but the depersonalization symptoms persist. We restart amantadine, 100 mg as needed, for anorgasmia.

Because of her persistent complaints of depersonalization, after discussion with Ms. A, we decide to return to what had helped her at the beginning of treatment and restart aripiprazole, 2.5 mg/d. Four months later, she reports her depersonalization symptoms have resolved completely. At this time, her regimen consists of clomipramine, 50 mg at bedtime, diazepam, 10 mg at bedtime, and aripiprazole, 2.5 mg/d.

Which neurotransmitter systems have been implicated in depersonalization disorder?

1. HPA axis
2. serotonin system
3. norepinephrine-dopamine system
4. dopamine-serotonin system
5. all of the above

The authors’ observations

The neurobiology of emotion processing is still unclear but some evidence indicates that the amygdala, anterior cingulate cortex, and medial prefrontal cortex might be involved in emotion regulation and integration.

Depersonalization disorder is associated with HPA axis dysregulation and patients with depersonalization disorder have a lower basal cortisol level compared with patients with MDD.^11,12 Simeon et al⁹ found a marked basal norepinephrine decline with increasing depersonalization severity.

Various SSRIs,^13,14 TCAs,^10,15,16 citalopram-olanzapine combination, naltrexone, citalopram-clonazepam combination,¹⁷ and fluoxetine-buspirone combination¹⁸ have been studied as treatment for depersonalization disorder. We present the first case report of aripiprazole to treat depersonalization disorder. A previous study¹⁹ of quetiapine—a low potency blocker of dopamine D2 receptors, which also has a high affinity for serotonin 5-HT2A receptors—suggested a potential role in improving emotional numbing symptoms in depersonalization/derealization disorder. The authors hypothesized that quetiapine may facilitate dopamine and serotonin neurotransmissions in the anterior limbic cortex and prefrontal cortex, which are involved in emotional experiences.

Other treatment options

The kappa opioid system also is implicated in depersonalization. Enadoline, a selective k-opioid agonist, has been shown to cause depersonalization symptoms in healthy subjects.²⁰ High doses of opioid antagonists, such as naltrexone, have been used successfully to treat depersonalization symptoms in patients with borderline personality disorder,²¹ PTSD,²² and depersonalization disorder.²³

Ketamine—which can produce depersonalization—increases glutamate transmission, which suggests that drugs that affect the glutamate system might be targets for future investigation. Similarly, smoking marijuana can induce depersonalization, which indicates that cannabinoid receptors might be another area for research. Hallucinogens, such as lysergic acid diethylamide, psilocybin, and dimethyltryptamine, can produce temporary depersonalization. These drugs are 5-HT2 agonists (HT2A, HT2C), which gives weight to using 5-HT2 antagonists to treat depersonalization.

Psychodynamic approaches based on self-constancy—cohesiveness and stability of self-representation—may be helpful, especially in patients with acute symptoms.²⁴ Cognitive-behavioral therapy may be effective and could be divided into 2 phases:

Table 3

Depersonalization comorbidity: Common disorders

• nonspecific interventions such as activity scheduling, graded exposure to avoidance behaviors, and negative automatic thought charts
• techniques to facilitate controlled re-experiencing of emotions and refocusing of attention away from the self and the depersonalization experience.²⁵

Measures such as relaxation techniques, breathing exercises, yoga, tai chi, and meditation also might help decrease anxiety.

OUTCOME: Why did it work?

Ms. A responded partially to the diazepam-clomipramine combination but experienced a full response only after we added aripiprazole. We are not certain whether her response was caused by aripiprazole, a delayed action of clomipramine, or a spontaneous remission. Aripiprazole, 2.5 mg/d, was the first medication we added when Ms. A presented to our clinic and she had reported a partial response to the drug. Aripiprazole was also the last medication added before she experienced response, which lasted for at least 5 months, after which Ms. A was lost to follow-up.

The authors’ observations

We believe that aripiprazole might rebalance serotonin/dopamine neurotransmission for some patients with depersonalization disorder. We theorize that aripiprazole’s blockade of serotonin 2A receptors may enhance dopamine release in certain areas of the brain, possibly improving cognitive and affective symptoms. Depersonalization may be a symptom of worsening psychiatric illness and justifies the use of intensive pharmacologic and psychological therapy.

Related resource

• Simeon D. Feeling unreal: Depersonalization disorder and loss of self. New York, NY: Oxford University Press; 2006.

Drug brand names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Bupropion • Wellbutrin
• Buspirone • BuSpar
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clonazepam • Klonopin
• Diazepam • Valium
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Ketamine • Ketalar
• Naltrexone • ReVia
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Sertraline • Zoloft
• Trazodone • Desyrel
• Venlafaxine • Effexor

Disclosure

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

CASE: Feeling detached

Ms. A, age 23, presents to our clinic complaining of feeling detached for the past 4 years. She says she feels “fuzzy all the time, like I lost touch with reality 4 years ago and really miss it.” She complains of “confused thinking,” excessive tiredness and weakness, depression, and anxiety. She says, “It feels like I’m watching my life on television; I don’t feel any emotions.” These symptoms began immediately after a college party, which the police stopped because of underage drinking. She says, “I don’t know why, but that party set it off, and it feels like I am in a dream all the time.”

For the last 4 years, Ms. A has been working as a waitress and is now engaged. She presents to our clinic because the treatments she has been receiving are ineffective and she wants to feel her emotions again, especially before her wedding.

Ms. A has no history of mania, depression, or psychosis. She says she was an anxious child and suffered from anorexia nervosa between age 13 and 14. She experienced occasional panic attacks beginning in high school that were triggered by feeling overwhelmed or frustrated with not feeling normal. During these panic attacks, Ms. A experienced tightness in her chest and dizziness. She denies suicidal or homicidal ideation or attempts.

At age 18, she was sexually assaulted. Ongoing stressors include living in a dangerous neighborhood, having her car broken into, her father’s disapproval of her fiancé, and wanting to get married. She drank heavily in college, but has used alcohol infrequently since then.

Ms. A’s father has a history of anxiety. She describes him as domineering and her mother as very emotional and always wanting to be her friend. Ms. A says she struggles with relationships, employment, and plans for advancement, all of which are moderately to severely affected by her depersonalization symptoms. During the initial appointment, we diagnose Ms. A with generalized anxiety disorder, panic disorder, and major depressive disorder (MDD).

Which diagnoses would you include among the differential diagnosis?

1. posttraumatic stress disorder (PTSD)
2. MDD with psychotic features
3. depersonalization disorder
4. schizophrenia, undifferentiated type
5. psychosis not otherwise specified

The authors’ observations

Depersonalization symptoms can occur in a variety of situations, including:

• mentally healthy persons suffering from acute stressors, fatigue, or drug use
• neuropsychiatric conditions such as epilepsy
• migraine
• anxiety disorders
• depressive disorders
• schizophrenia.¹

Transient depersonalization symptoms are common and have been found in 2.4% of the general population.² Community surveys using standardized diagnostic interviews reveal 1-month prevalence rates of 1.6% to 1.9% in 2 UK samples.^3,4 Depersonalization symptoms are brief and less debilitating than depersonalization disorder.

Depersonalization rarely presents as a primary disorder, when symptoms persist chronically. Rating scales (Table 1)^5-7 and DSM-IV-TR criteria (Table 2) can help assess symptom severity and differentiate transient symptoms from a disorder. Psychiatric conditions that commonly are comorbid with depersonalization disorder appear in Table 3.⁸ Triggers for a first episode of depersonalization disorder include:

Table 1

Assessing for depersonalization: 3 rating scales

• psychological stressors (31%)
• substance abuse (25%)
• physical stressor (12%)
• situational stressor (17%)
• social and/or relationship problems (10%)
• trauma (6%)
• panic/anxiety (2%).⁸

Although Ms. A experiences depersonalization—constant numbness and emptiness—when she thinks about the sexual assault, she does not meet criteria for PTSD because she denies re-experiencing the assault, hyperarousal, and avoidance behaviors.

Ms. A meets all 4 DSM-IV-TR criteria for depersonalization disorder (Table 2). She experiences persistent feelings of detachment, which cause her considerable distress. Her reality testing is intact and these experiences are not due to a general medical condition, another mental disorder, or direct physiological effects of a substance.

Table 2

DSM-IV-TR criteria for depersonalization disorder

Which medications would you consider for Ms. A?

1. benzodiazepine plus a tricyclic antidepressant (TCA)
2. selective serotonin reuptake inhibitor (SSRI) plus a benzodiazepine
3. trazodone plus bupropion
4. atypical antipsychotic plus a benzodiazepine and a TCA

TREATMENT: Insufficient response

Ms. A’s previous psychiatrist prescribed various SSRIs and selective serotonin-norepinephrine reuptake inhibitors, including sertraline, escitalopram, citalopram, paroxetine, and venlafaxine, for depression and anxiety with little or no benefit. When she presented at our clinic, Ms. A was taking clonazepam, 0.25 mg as needed, and fluvoxamine, 50 mg/d, which she said helped her anxiety a little, but not depersonalization symptoms. She received supportive psychotherapy provided during biweekly 30-minute medication management visits.

We add aripiprazole, 2.5 mg/d, to augment fluvoxamine’s antidepressant effect and reduce her anxiety and dissociative symptoms. At the next visit 5 weeks later, she reports her depersonalization symptoms gradually lessened from 10 to 6 on a 10-point self-report scale.

We discontinue fluvoxamine after 5 weeks because it no longer significantly contributes to her recovery. We add amantadine, 100 mg/d, based on the belief that dopamine augmentation might help reduce her symptoms. Ms. A reports improved depersonalization symptoms over the next 4 weeks (5/10). However, a week later she says she feels her anxiety is worsening the depersonalization symptoms. We start buspirone, 7.5 mg/d titrated to 15 mg/d over 4 weeks, Ms. A reports feeling worse so we discontinue the drug.

Next Ms. A complains of excessive sleepiness, which seems to be related to amantadine, so we discontinue it. We start bupropion, 150 mg/d and titrate it to 450 mg/d, which we hope will reduce her fatigue, anxiety, depersonalization, and depression. Bupropion’s effect on norepinephrine and dopamine reuptake and a study of autonomic blunting in depersonalization⁹ justify our selection.

After 3 months, Ms. A stops taking aripiprazole because it is too costly. The following month she presents with severe anxiety and low-to-moderate depression. Clonazepam and bupropion are discontinued and replaced with diazepam, 20 mg/d, and clomipramine, 25 mg/d at bedtime titrated to 75 mg/d. Our decision is guided by a study on the efficacy of clomipramine in treating depersonalization¹⁰ and our desire to aggressively treat her anxiety and depression. After 2 weeks, Ms. A says her anxiety and depression have resolved completely but the depersonalization symptoms persist. We restart amantadine, 100 mg as needed, for anorgasmia.

Because of her persistent complaints of depersonalization, after discussion with Ms. A, we decide to return to what had helped her at the beginning of treatment and restart aripiprazole, 2.5 mg/d. Four months later, she reports her depersonalization symptoms have resolved completely. At this time, her regimen consists of clomipramine, 50 mg at bedtime, diazepam, 10 mg at bedtime, and aripiprazole, 2.5 mg/d.

Which neurotransmitter systems have been implicated in depersonalization disorder?

1. HPA axis
2. serotonin system
3. norepinephrine-dopamine system
4. dopamine-serotonin system
5. all of the above

The authors’ observations

The neurobiology of emotion processing is still unclear but some evidence indicates that the amygdala, anterior cingulate cortex, and medial prefrontal cortex might be involved in emotion regulation and integration.

Depersonalization disorder is associated with HPA axis dysregulation and patients with depersonalization disorder have a lower basal cortisol level compared with patients with MDD.^11,12 Simeon et al⁹ found a marked basal norepinephrine decline with increasing depersonalization severity.

Various SSRIs,^13,14 TCAs,^10,15,16 citalopram-olanzapine combination, naltrexone, citalopram-clonazepam combination,¹⁷ and fluoxetine-buspirone combination¹⁸ have been studied as treatment for depersonalization disorder. We present the first case report of aripiprazole to treat depersonalization disorder. A previous study¹⁹ of quetiapine—a low potency blocker of dopamine D2 receptors, which also has a high affinity for serotonin 5-HT2A receptors—suggested a potential role in improving emotional numbing symptoms in depersonalization/derealization disorder. The authors hypothesized that quetiapine may facilitate dopamine and serotonin neurotransmissions in the anterior limbic cortex and prefrontal cortex, which are involved in emotional experiences.

Other treatment options

The kappa opioid system also is implicated in depersonalization. Enadoline, a selective k-opioid agonist, has been shown to cause depersonalization symptoms in healthy subjects.²⁰ High doses of opioid antagonists, such as naltrexone, have been used successfully to treat depersonalization symptoms in patients with borderline personality disorder,²¹ PTSD,²² and depersonalization disorder.²³

Ketamine—which can produce depersonalization—increases glutamate transmission, which suggests that drugs that affect the glutamate system might be targets for future investigation. Similarly, smoking marijuana can induce depersonalization, which indicates that cannabinoid receptors might be another area for research. Hallucinogens, such as lysergic acid diethylamide, psilocybin, and dimethyltryptamine, can produce temporary depersonalization. These drugs are 5-HT2 agonists (HT2A, HT2C), which gives weight to using 5-HT2 antagonists to treat depersonalization.

Psychodynamic approaches based on self-constancy—cohesiveness and stability of self-representation—may be helpful, especially in patients with acute symptoms.²⁴ Cognitive-behavioral therapy may be effective and could be divided into 2 phases:

Table 3

Depersonalization comorbidity: Common disorders

• nonspecific interventions such as activity scheduling, graded exposure to avoidance behaviors, and negative automatic thought charts
• techniques to facilitate controlled re-experiencing of emotions and refocusing of attention away from the self and the depersonalization experience.²⁵

Measures such as relaxation techniques, breathing exercises, yoga, tai chi, and meditation also might help decrease anxiety.

OUTCOME: Why did it work?

Ms. A responded partially to the diazepam-clomipramine combination but experienced a full response only after we added aripiprazole. We are not certain whether her response was caused by aripiprazole, a delayed action of clomipramine, or a spontaneous remission. Aripiprazole, 2.5 mg/d, was the first medication we added when Ms. A presented to our clinic and she had reported a partial response to the drug. Aripiprazole was also the last medication added before she experienced response, which lasted for at least 5 months, after which Ms. A was lost to follow-up.

The authors’ observations

We believe that aripiprazole might rebalance serotonin/dopamine neurotransmission for some patients with depersonalization disorder. We theorize that aripiprazole’s blockade of serotonin 2A receptors may enhance dopamine release in certain areas of the brain, possibly improving cognitive and affective symptoms. Depersonalization may be a symptom of worsening psychiatric illness and justifies the use of intensive pharmacologic and psychological therapy.

Related resource

• Simeon D. Feeling unreal: Depersonalization disorder and loss of self. New York, NY: Oxford University Press; 2006.

Drug brand names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Bupropion • Wellbutrin
• Buspirone • BuSpar
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clonazepam • Klonopin
• Diazepam • Valium
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Ketamine • Ketalar
• Naltrexone • ReVia
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Sertraline • Zoloft
• Trazodone • Desyrel
• Venlafaxine • Effexor

Disclosure

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

CASE: Feeling detached

Ms. A, age 23, presents to our clinic complaining of feeling detached for the past 4 years. She says she feels “fuzzy all the time, like I lost touch with reality 4 years ago and really miss it.” She complains of “confused thinking,” excessive tiredness and weakness, depression, and anxiety. She says, “It feels like I’m watching my life on television; I don’t feel any emotions.” These symptoms began immediately after a college party, which the police stopped because of underage drinking. She says, “I don’t know why, but that party set it off, and it feels like I am in a dream all the time.”

For the last 4 years, Ms. A has been working as a waitress and is now engaged. She presents to our clinic because the treatments she has been receiving are ineffective and she wants to feel her emotions again, especially before her wedding.

Ms. A has no history of mania, depression, or psychosis. She says she was an anxious child and suffered from anorexia nervosa between age 13 and 14. She experienced occasional panic attacks beginning in high school that were triggered by feeling overwhelmed or frustrated with not feeling normal. During these panic attacks, Ms. A experienced tightness in her chest and dizziness. She denies suicidal or homicidal ideation or attempts.

At age 18, she was sexually assaulted. Ongoing stressors include living in a dangerous neighborhood, having her car broken into, her father’s disapproval of her fiancé, and wanting to get married. She drank heavily in college, but has used alcohol infrequently since then.

Ms. A’s father has a history of anxiety. She describes him as domineering and her mother as very emotional and always wanting to be her friend. Ms. A says she struggles with relationships, employment, and plans for advancement, all of which are moderately to severely affected by her depersonalization symptoms. During the initial appointment, we diagnose Ms. A with generalized anxiety disorder, panic disorder, and major depressive disorder (MDD).

Which diagnoses would you include among the differential diagnosis?

1. posttraumatic stress disorder (PTSD)
2. MDD with psychotic features
3. depersonalization disorder
4. schizophrenia, undifferentiated type
5. psychosis not otherwise specified

The authors’ observations

Depersonalization symptoms can occur in a variety of situations, including:

• mentally healthy persons suffering from acute stressors, fatigue, or drug use
• neuropsychiatric conditions such as epilepsy
• migraine
• anxiety disorders
• depressive disorders
• schizophrenia.¹

Transient depersonalization symptoms are common and have been found in 2.4% of the general population.² Community surveys using standardized diagnostic interviews reveal 1-month prevalence rates of 1.6% to 1.9% in 2 UK samples.^3,4 Depersonalization symptoms are brief and less debilitating than depersonalization disorder.

Depersonalization rarely presents as a primary disorder, when symptoms persist chronically. Rating scales (Table 1)^5-7 and DSM-IV-TR criteria (Table 2) can help assess symptom severity and differentiate transient symptoms from a disorder. Psychiatric conditions that commonly are comorbid with depersonalization disorder appear in Table 3.⁸ Triggers for a first episode of depersonalization disorder include:

Table 1

Assessing for depersonalization: 3 rating scales

• psychological stressors (31%)
• substance abuse (25%)
• physical stressor (12%)
• situational stressor (17%)
• social and/or relationship problems (10%)
• trauma (6%)
• panic/anxiety (2%).⁸

Although Ms. A experiences depersonalization—constant numbness and emptiness—when she thinks about the sexual assault, she does not meet criteria for PTSD because she denies re-experiencing the assault, hyperarousal, and avoidance behaviors.

Ms. A meets all 4 DSM-IV-TR criteria for depersonalization disorder (Table 2). She experiences persistent feelings of detachment, which cause her considerable distress. Her reality testing is intact and these experiences are not due to a general medical condition, another mental disorder, or direct physiological effects of a substance.

Table 2

DSM-IV-TR criteria for depersonalization disorder

Which medications would you consider for Ms. A?

1. benzodiazepine plus a tricyclic antidepressant (TCA)
2. selective serotonin reuptake inhibitor (SSRI) plus a benzodiazepine
3. trazodone plus bupropion
4. atypical antipsychotic plus a benzodiazepine and a TCA

TREATMENT: Insufficient response

Ms. A’s previous psychiatrist prescribed various SSRIs and selective serotonin-norepinephrine reuptake inhibitors, including sertraline, escitalopram, citalopram, paroxetine, and venlafaxine, for depression and anxiety with little or no benefit. When she presented at our clinic, Ms. A was taking clonazepam, 0.25 mg as needed, and fluvoxamine, 50 mg/d, which she said helped her anxiety a little, but not depersonalization symptoms. She received supportive psychotherapy provided during biweekly 30-minute medication management visits.

We add aripiprazole, 2.5 mg/d, to augment fluvoxamine’s antidepressant effect and reduce her anxiety and dissociative symptoms. At the next visit 5 weeks later, she reports her depersonalization symptoms gradually lessened from 10 to 6 on a 10-point self-report scale.

We discontinue fluvoxamine after 5 weeks because it no longer significantly contributes to her recovery. We add amantadine, 100 mg/d, based on the belief that dopamine augmentation might help reduce her symptoms. Ms. A reports improved depersonalization symptoms over the next 4 weeks (5/10). However, a week later she says she feels her anxiety is worsening the depersonalization symptoms. We start buspirone, 7.5 mg/d titrated to 15 mg/d over 4 weeks, Ms. A reports feeling worse so we discontinue the drug.

Next Ms. A complains of excessive sleepiness, which seems to be related to amantadine, so we discontinue it. We start bupropion, 150 mg/d and titrate it to 450 mg/d, which we hope will reduce her fatigue, anxiety, depersonalization, and depression. Bupropion’s effect on norepinephrine and dopamine reuptake and a study of autonomic blunting in depersonalization⁹ justify our selection.

After 3 months, Ms. A stops taking aripiprazole because it is too costly. The following month she presents with severe anxiety and low-to-moderate depression. Clonazepam and bupropion are discontinued and replaced with diazepam, 20 mg/d, and clomipramine, 25 mg/d at bedtime titrated to 75 mg/d. Our decision is guided by a study on the efficacy of clomipramine in treating depersonalization¹⁰ and our desire to aggressively treat her anxiety and depression. After 2 weeks, Ms. A says her anxiety and depression have resolved completely but the depersonalization symptoms persist. We restart amantadine, 100 mg as needed, for anorgasmia.

Because of her persistent complaints of depersonalization, after discussion with Ms. A, we decide to return to what had helped her at the beginning of treatment and restart aripiprazole, 2.5 mg/d. Four months later, she reports her depersonalization symptoms have resolved completely. At this time, her regimen consists of clomipramine, 50 mg at bedtime, diazepam, 10 mg at bedtime, and aripiprazole, 2.5 mg/d.

Which neurotransmitter systems have been implicated in depersonalization disorder?

1. HPA axis
2. serotonin system
3. norepinephrine-dopamine system
4. dopamine-serotonin system
5. all of the above

The authors’ observations

The neurobiology of emotion processing is still unclear but some evidence indicates that the amygdala, anterior cingulate cortex, and medial prefrontal cortex might be involved in emotion regulation and integration.

Depersonalization disorder is associated with HPA axis dysregulation and patients with depersonalization disorder have a lower basal cortisol level compared with patients with MDD.^11,12 Simeon et al⁹ found a marked basal norepinephrine decline with increasing depersonalization severity.

Various SSRIs,^13,14 TCAs,^10,15,16 citalopram-olanzapine combination, naltrexone, citalopram-clonazepam combination,¹⁷ and fluoxetine-buspirone combination¹⁸ have been studied as treatment for depersonalization disorder. We present the first case report of aripiprazole to treat depersonalization disorder. A previous study¹⁹ of quetiapine—a low potency blocker of dopamine D2 receptors, which also has a high affinity for serotonin 5-HT2A receptors—suggested a potential role in improving emotional numbing symptoms in depersonalization/derealization disorder. The authors hypothesized that quetiapine may facilitate dopamine and serotonin neurotransmissions in the anterior limbic cortex and prefrontal cortex, which are involved in emotional experiences.

Other treatment options

The kappa opioid system also is implicated in depersonalization. Enadoline, a selective k-opioid agonist, has been shown to cause depersonalization symptoms in healthy subjects.²⁰ High doses of opioid antagonists, such as naltrexone, have been used successfully to treat depersonalization symptoms in patients with borderline personality disorder,²¹ PTSD,²² and depersonalization disorder.²³

Ketamine—which can produce depersonalization—increases glutamate transmission, which suggests that drugs that affect the glutamate system might be targets for future investigation. Similarly, smoking marijuana can induce depersonalization, which indicates that cannabinoid receptors might be another area for research. Hallucinogens, such as lysergic acid diethylamide, psilocybin, and dimethyltryptamine, can produce temporary depersonalization. These drugs are 5-HT2 agonists (HT2A, HT2C), which gives weight to using 5-HT2 antagonists to treat depersonalization.

Psychodynamic approaches based on self-constancy—cohesiveness and stability of self-representation—may be helpful, especially in patients with acute symptoms.²⁴ Cognitive-behavioral therapy may be effective and could be divided into 2 phases:

Table 3

Depersonalization comorbidity: Common disorders

• nonspecific interventions such as activity scheduling, graded exposure to avoidance behaviors, and negative automatic thought charts
• techniques to facilitate controlled re-experiencing of emotions and refocusing of attention away from the self and the depersonalization experience.²⁵

Measures such as relaxation techniques, breathing exercises, yoga, tai chi, and meditation also might help decrease anxiety.

OUTCOME: Why did it work?

Ms. A responded partially to the diazepam-clomipramine combination but experienced a full response only after we added aripiprazole. We are not certain whether her response was caused by aripiprazole, a delayed action of clomipramine, or a spontaneous remission. Aripiprazole, 2.5 mg/d, was the first medication we added when Ms. A presented to our clinic and she had reported a partial response to the drug. Aripiprazole was also the last medication added before she experienced response, which lasted for at least 5 months, after which Ms. A was lost to follow-up.

The authors’ observations

We believe that aripiprazole might rebalance serotonin/dopamine neurotransmission for some patients with depersonalization disorder. We theorize that aripiprazole’s blockade of serotonin 2A receptors may enhance dopamine release in certain areas of the brain, possibly improving cognitive and affective symptoms. Depersonalization may be a symptom of worsening psychiatric illness and justifies the use of intensive pharmacologic and psychological therapy.

Related resource

• Simeon D. Feeling unreal: Depersonalization disorder and loss of self. New York, NY: Oxford University Press; 2006.

Drug brand names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Bupropion • Wellbutrin
• Buspirone • BuSpar
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clonazepam • Klonopin
• Diazepam • Valium
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Ketamine • Ketalar
• Naltrexone • ReVia
• Olanzapine • Zyprexa
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Sertraline • Zoloft
• Trazodone • Desyrel
• Venlafaxine • Effexor

Disclosure

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

CASE: Self-reported TBI

When charged with raping a 19-year-old woman, Mr. P, age 32, pleads not guilty by reason of insanity (NGRI). He has a self-reported history of traumatic brain injury (TBI) and claims that since suffering a blow to the head 8 years before the rape, he has experienced episodes of personality changes, psychosis, and violent behavior. Mr. P is adamant that any wrongdoing on his part was beyond his control, and he argues that consequences of the brain injury, such as hallucinations and aggressive behavior, had recently emerged. The court asks that a forensic psychiatrist evaluate Mr. P.

An only child, Mr. P was raised by his mother in an inner city area. His father was dependent on alcohol and cocaine and abandoned the family shortly after Mr. P’s birth. Mr. P abuses alcohol, as evidenced by previous driving under the influence charges, but denies illicit drug use. He graduated from high school with average grades and denies a history of disciplinary action at school or home. Although Mr. P was charged with misdemeanors in his late teens, the sexual assault is his first felony charge. Mr. P describes himself as a “charmer.”

After high school, Mr. P worked full-time in construction, where he claims he suffered a traumatic blow to the head. Despite this injury, he continued to work and socialize and never sought treatment at a mental health clinic.

The authors’ observations

Although defendants may legitimately suffer from TBI and resultant complications, many individuals capitalize on a history of minor head injury to support their NGRI defense.¹ Forensic psychiatrists must retain a healthy degree of clinical suspicion for malingering in defendants who claim NGRI as a result of complications from brain injury, especially when the injury and complications are not documented and simply patient-reported.

TBI is a CNS injury that occurs when an outside force traumatically injures the brain and can cause a variety of physical, cognitive, emotional, and behavioral effects ( Table 1 ).² Cognitive deficits include:

• impaired attention
• disrupted insight
• poor judgment
• thought disorders.

Reduced processing speed, distractibility, and deficits in executive functions such as abstract reasoning, planning, problem solving, and multitasking have been documented. Memory loss—the most common cognitive impairment among head-injured people—occurs in 20% to 79% of people with closed head trauma, depending on injury severity.³ People who have suffered TBI may have difficulty understanding or producing spoken or written language, or with more subtle aspects of communication, such as body language.

TBI may cause emotional or behavioral problems and personality changes. Mood and affect changes are common. TBI predisposes patients to obsessive-compulsive disorder, substance abuse, dysthymia, clinical depression, bipolar disorder, phobias, panic disorder, and schizophrenia.⁴ Frontal lobe injuries have been correlated with disinhibition and inappropriate or childish behavior, and temporal lobe injuries with irritability and aggression.⁵

Table 1

TBI symptoms correspond to area of injury

TBI and the insanity defense

The M’Naghten Rule of 1843 requires that for an insanity defense, the defendant must have a mental disease or defect that causes him not to know the nature and quality or the wrongfulness of his act.⁶ TBI is an abnormal condition of the mind leading to a mental disease that can substantially affect control of emotions and behaviors.

Nevertheless, TBI-induced criminality remains controversial.⁷ Theories on the etiology of impulse dyscontrol resulting from TBI have suggested structural damage to the brain and altered neurotransmitters. In TBI, the amygdala—which is located within the anterior temporal lobe and adjoins emotions to thoughts—often is injured. Damage to this structure leads to poor impulse control and violent behavior. Damage to specific neurotransmitter systems that causes elevated norepinephrine and dopamine levels and reduced serotonin levels have also been implicated as a cause of impulse dyscontrol in TBI patients.⁸

In theory, TBI patients potentially could have enough cognitive impairment to have a substantial lack of appreciation of the criminality or wrongfulness of an act. TBI-related impulsivity and cognitive impairment can lead to recklessness and negligence.⁹ The U.S. Supreme Court has acknowledged that CNS dysfunction affects judgment, reality testing, and self-control.¹⁰

EVALUATION: Vague answers

To determine whether Mr. P’s defense is plausible, the forensic psychiatrist must pay attention to the details of the patient’s presentation and history. During the interview, Mr. P quickly shifts from cooperative to obstinate and restricted. He ruminates on the head injury causing him to suffer auditory hallucinations, which he claims he always obeys. Mr. P refuses to provide details of the hallucinations, however, and answers most questions about the head injury or his defense with vague answers, including “I don’t know.”

Because of Mr. P’s reluctance to share information, his lack of psychiatric symptoms other than those he self-reports, and the presence of potential secondary gain from an NGRI defense, the psychiatrist begins to suspect malingering.

The authors’ observations

Malingering is a condition—not a diagnosis—characterized by intentional production of false or grossly exaggerated physical or psychological symptoms motivated by external incentives.¹¹ The presence of external incentives distinguishes malingering from psychiatric illnesses such as factitious and somatoform disorders, in which there is no apparent external incentive. Malingering of psychiatric symptoms occurs in up to 20% of forensic patients, 5% of military recruits, and 1% of mental health patients.⁵ Stimuli for malingering range from seeking food and shelter to avoiding criminal responsibility ( Table 2 ). Malingering is more common in individuals being evaluated for criminal responsibility than for competence to stand trial. The 3 categories of malingering are:

Table 2

Common external incentives for malingering

• pure malingering—feigning a nonexistent disorder
• partial malingering—consciously exaggerating real symptoms

• false imputation—ascribing real symptoms to a cause the individual knows is unrelated to the symptoms.¹²

Determining if a defendant with a history of TBI is malingering requires a multi-step approach that encompasses the clinical interview, a thorough review of collateral data, and focused psychological testing. In interviews, psychiatrists detect approximately 50% of lies, which is no better than would be discovered by chance.¹³ If you suspect a patient is malingering, combine a structured clinical interview with collateral sources such as old hospital records, treatment history, insurance records, police reports, and interviews with close family and friends.

TBI patients’ poor cognition, memory deficits, and inattention will prove challenging. Malingering patients who attempt to capitalize on a pre-existing TBI to evade responsibility for a current criminal charge may grossly exaggerate or even fake intellectual deficits. Be patient with such defendants and remain aware that such people will give vague or hedging answers to straightforward questions, often accompanied by “I don’t know.” Prolonging the interview may be helpful because it may fatigue a defendant who is faking.¹²

Some patients who malinger after sustaining a TBI will attempt to feign psychotic symptoms. Table 3 ¹⁴ illustrates criteria for assessing a patient suspected of malingering psychosis and Table 4 ¹⁴ highlights atypical psychotic symptoms that suggest feigning illness. Malingering of psychosis can be both assessed in the interview and through testing.

Table 3

Criteria for malingered psychosis

Table 4

Atypical psychotic symptoms that suggest malingering

Psychological testing

Several standardized diagnostic instruments can be used to help determine whether a patient is feigning or exaggerating psychotic symptoms or cognitive impairments ( Table 5 ). Testing for a patient such as Mr. P—who attributes any criminal wrongdoing to psychosis and also cites limited cognition as a reason for trouble in the interview—would include personality tests, tests to assess exaggerations of psychosis, and cognitive tests.

In the forensic setting, the preferred personality test is the MMPI-2.¹⁵ It consists of 567 items, with 10 clinical scales and several validity scales. The F scale, “faking good” or “faking bad,” detects people who are answering questions with the goal of appearing better or worse than they actually are. The Personal Assessment Inventory (PAI)¹⁶ is a 344-item test with a 4-point response format. The 22 scales cover a range of important axis I and II psychopathology.

SIRS¹⁷ is the gold standard in detecting malingered psychiatric illness; it includes questions about rare symptoms and uncommon symptom pairing. M-FAST¹⁸ was developed to provide a brief, reliable screen for malingered mental illness. It has shown good validity and high correlation with the SIRS and MMPI-2.

Tests of exaggerated cognitive impairment are extremely important in evaluating patients who claim to suffer from complications following TBI. TOMM¹⁹ —a 50-item recognition test designed to discriminate between true memory-impaired patients and malingerers—is the most studied and valid of such tests. Defendants’ scores that meet the recommended criteria for detecting malingering—≥5 errors on the retention trial—were found to also report a history of head injury.¹

Although not as well validated, the Portland Digit Recognition Test (PDRT)²⁰ is an alternative to the TOMM. This test is a forced-choice measure of recognition designed for assessing the possibility of malingering in individuals claiming mental illness because of head injury. The Victoria Symptoms Validity Test (VSVT)²¹ is used in outpatient and inpatient settings and also uses a forced-choice model to assess possible exaggeration or feigning of cognitive impairments. Finally, the Word Memory Test (WMT)²² is a neuropsychological assessment that evaluates the effort participants put forth.

Table 5

Standardized diagnostic instruments for detecting malingering

OUTCOME: Unsupported claims

Mr. P’s hospital records reveal a very minor head trauma that resulted in no structural brain abnormalities on imaging tests. Collateral interviews with Mr. P’s family and close friends fail to support the defendant’s claim that after the accident he began to experience behavioral changes and periods of psychosis. Mr. P’s SIRS and TOMM scores indicate malingering, and the psychiatrist did not support his NGRI defense.

Related resource

• Williamson DJ. Neurocognitive impairment: feigned, exaggerated, or real? Current Psychiatry. 2007;6(8):19-37.

Disclosure

Dr. Nasrallah receives research grant/research support from Forest Pharmaceuticals, GlaxoSmithKline, Janssen, Otsuka America Pharmaceuticals, Pfizer Inc., Roche, sanofi-aventis, and Shire, is on the advisory board of Abbott Laboratories, AstraZeneca, Janssen, Novartis, Pfizer Inc., and Merck, and is on the speakers’ bureau for Abbott Laboratories, AstraZeneca, Janssen, Novartis, Pfizer Inc., and Merck.

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

CASE: Self-reported TBI

When charged with raping a 19-year-old woman, Mr. P, age 32, pleads not guilty by reason of insanity (NGRI). He has a self-reported history of traumatic brain injury (TBI) and claims that since suffering a blow to the head 8 years before the rape, he has experienced episodes of personality changes, psychosis, and violent behavior. Mr. P is adamant that any wrongdoing on his part was beyond his control, and he argues that consequences of the brain injury, such as hallucinations and aggressive behavior, had recently emerged. The court asks that a forensic psychiatrist evaluate Mr. P.

An only child, Mr. P was raised by his mother in an inner city area. His father was dependent on alcohol and cocaine and abandoned the family shortly after Mr. P’s birth. Mr. P abuses alcohol, as evidenced by previous driving under the influence charges, but denies illicit drug use. He graduated from high school with average grades and denies a history of disciplinary action at school or home. Although Mr. P was charged with misdemeanors in his late teens, the sexual assault is his first felony charge. Mr. P describes himself as a “charmer.”

After high school, Mr. P worked full-time in construction, where he claims he suffered a traumatic blow to the head. Despite this injury, he continued to work and socialize and never sought treatment at a mental health clinic.

The authors’ observations

Although defendants may legitimately suffer from TBI and resultant complications, many individuals capitalize on a history of minor head injury to support their NGRI defense.¹ Forensic psychiatrists must retain a healthy degree of clinical suspicion for malingering in defendants who claim NGRI as a result of complications from brain injury, especially when the injury and complications are not documented and simply patient-reported.

TBI is a CNS injury that occurs when an outside force traumatically injures the brain and can cause a variety of physical, cognitive, emotional, and behavioral effects ( Table 1 ).² Cognitive deficits include:

• impaired attention
• disrupted insight
• poor judgment
• thought disorders.

Reduced processing speed, distractibility, and deficits in executive functions such as abstract reasoning, planning, problem solving, and multitasking have been documented. Memory loss—the most common cognitive impairment among head-injured people—occurs in 20% to 79% of people with closed head trauma, depending on injury severity.³ People who have suffered TBI may have difficulty understanding or producing spoken or written language, or with more subtle aspects of communication, such as body language.

TBI may cause emotional or behavioral problems and personality changes. Mood and affect changes are common. TBI predisposes patients to obsessive-compulsive disorder, substance abuse, dysthymia, clinical depression, bipolar disorder, phobias, panic disorder, and schizophrenia.⁴ Frontal lobe injuries have been correlated with disinhibition and inappropriate or childish behavior, and temporal lobe injuries with irritability and aggression.⁵

Table 1

TBI symptoms correspond to area of injury

TBI and the insanity defense

The M’Naghten Rule of 1843 requires that for an insanity defense, the defendant must have a mental disease or defect that causes him not to know the nature and quality or the wrongfulness of his act.⁶ TBI is an abnormal condition of the mind leading to a mental disease that can substantially affect control of emotions and behaviors.

Nevertheless, TBI-induced criminality remains controversial.⁷ Theories on the etiology of impulse dyscontrol resulting from TBI have suggested structural damage to the brain and altered neurotransmitters. In TBI, the amygdala—which is located within the anterior temporal lobe and adjoins emotions to thoughts—often is injured. Damage to this structure leads to poor impulse control and violent behavior. Damage to specific neurotransmitter systems that causes elevated norepinephrine and dopamine levels and reduced serotonin levels have also been implicated as a cause of impulse dyscontrol in TBI patients.⁸

In theory, TBI patients potentially could have enough cognitive impairment to have a substantial lack of appreciation of the criminality or wrongfulness of an act. TBI-related impulsivity and cognitive impairment can lead to recklessness and negligence.⁹ The U.S. Supreme Court has acknowledged that CNS dysfunction affects judgment, reality testing, and self-control.¹⁰

EVALUATION: Vague answers

To determine whether Mr. P’s defense is plausible, the forensic psychiatrist must pay attention to the details of the patient’s presentation and history. During the interview, Mr. P quickly shifts from cooperative to obstinate and restricted. He ruminates on the head injury causing him to suffer auditory hallucinations, which he claims he always obeys. Mr. P refuses to provide details of the hallucinations, however, and answers most questions about the head injury or his defense with vague answers, including “I don’t know.”

Because of Mr. P’s reluctance to share information, his lack of psychiatric symptoms other than those he self-reports, and the presence of potential secondary gain from an NGRI defense, the psychiatrist begins to suspect malingering.

The authors’ observations

Malingering is a condition—not a diagnosis—characterized by intentional production of false or grossly exaggerated physical or psychological symptoms motivated by external incentives.¹¹ The presence of external incentives distinguishes malingering from psychiatric illnesses such as factitious and somatoform disorders, in which there is no apparent external incentive. Malingering of psychiatric symptoms occurs in up to 20% of forensic patients, 5% of military recruits, and 1% of mental health patients.⁵ Stimuli for malingering range from seeking food and shelter to avoiding criminal responsibility ( Table 2 ). Malingering is more common in individuals being evaluated for criminal responsibility than for competence to stand trial. The 3 categories of malingering are:

Table 2

Common external incentives for malingering

• pure malingering—feigning a nonexistent disorder
• partial malingering—consciously exaggerating real symptoms

• false imputation—ascribing real symptoms to a cause the individual knows is unrelated to the symptoms.¹²

Determining if a defendant with a history of TBI is malingering requires a multi-step approach that encompasses the clinical interview, a thorough review of collateral data, and focused psychological testing. In interviews, psychiatrists detect approximately 50% of lies, which is no better than would be discovered by chance.¹³ If you suspect a patient is malingering, combine a structured clinical interview with collateral sources such as old hospital records, treatment history, insurance records, police reports, and interviews with close family and friends.

TBI patients’ poor cognition, memory deficits, and inattention will prove challenging. Malingering patients who attempt to capitalize on a pre-existing TBI to evade responsibility for a current criminal charge may grossly exaggerate or even fake intellectual deficits. Be patient with such defendants and remain aware that such people will give vague or hedging answers to straightforward questions, often accompanied by “I don’t know.” Prolonging the interview may be helpful because it may fatigue a defendant who is faking.¹²

Some patients who malinger after sustaining a TBI will attempt to feign psychotic symptoms. Table 3 ¹⁴ illustrates criteria for assessing a patient suspected of malingering psychosis and Table 4 ¹⁴ highlights atypical psychotic symptoms that suggest feigning illness. Malingering of psychosis can be both assessed in the interview and through testing.

Table 3

Criteria for malingered psychosis

Table 4

Atypical psychotic symptoms that suggest malingering

Psychological testing

Several standardized diagnostic instruments can be used to help determine whether a patient is feigning or exaggerating psychotic symptoms or cognitive impairments ( Table 5 ). Testing for a patient such as Mr. P—who attributes any criminal wrongdoing to psychosis and also cites limited cognition as a reason for trouble in the interview—would include personality tests, tests to assess exaggerations of psychosis, and cognitive tests.

In the forensic setting, the preferred personality test is the MMPI-2.¹⁵ It consists of 567 items, with 10 clinical scales and several validity scales. The F scale, “faking good” or “faking bad,” detects people who are answering questions with the goal of appearing better or worse than they actually are. The Personal Assessment Inventory (PAI)¹⁶ is a 344-item test with a 4-point response format. The 22 scales cover a range of important axis I and II psychopathology.

SIRS¹⁷ is the gold standard in detecting malingered psychiatric illness; it includes questions about rare symptoms and uncommon symptom pairing. M-FAST¹⁸ was developed to provide a brief, reliable screen for malingered mental illness. It has shown good validity and high correlation with the SIRS and MMPI-2.

Tests of exaggerated cognitive impairment are extremely important in evaluating patients who claim to suffer from complications following TBI. TOMM¹⁹ —a 50-item recognition test designed to discriminate between true memory-impaired patients and malingerers—is the most studied and valid of such tests. Defendants’ scores that meet the recommended criteria for detecting malingering—≥5 errors on the retention trial—were found to also report a history of head injury.¹

Although not as well validated, the Portland Digit Recognition Test (PDRT)²⁰ is an alternative to the TOMM. This test is a forced-choice measure of recognition designed for assessing the possibility of malingering in individuals claiming mental illness because of head injury. The Victoria Symptoms Validity Test (VSVT)²¹ is used in outpatient and inpatient settings and also uses a forced-choice model to assess possible exaggeration or feigning of cognitive impairments. Finally, the Word Memory Test (WMT)²² is a neuropsychological assessment that evaluates the effort participants put forth.

Table 5

Standardized diagnostic instruments for detecting malingering