Did antismoking therapy make him sick?

Presentation: unconscious on the street

Emergency medical personnel bring Mr. M, age 66, to the ER after passers-by find him supine on the sidewalk. On arrival, he is comatose as confirmed by a Glasgow Coma Scale score of 8 (eye opening 3, verbal response 2, motor response 3). Systolic blood pressure is 108 mm Hg on palpation, pulse is 135 beats per minute, and temperature is 105 °F. Minor abrasions cover his face and arms, and his hands and feet are rigid.

Mr. M has lived at a board-and-care facility for 30 years. The facility’s operator tells us that Mr. M has had schizophrenia for 40 years and has been taking:

• olanzapine, 7.5 mg each morning and 10 mg at bedtime
  
• chlorpromazine, 50 mg nightly
  
• lithium carbonate, 300 mg tid
  
• and benztropine, 2 mg bid.
  

Three weeks ago, Mr. M was hospitalized for 6 days with pneumonia. In 3 months, he will undergo surgery for prostate cancer. He is taking no medication for the prostate cancer.

Creatine phosphokinase (CPK) is 2,939 IU/L, indicating neuroleptic malignant syndrome (NMS). Other laboratory test results suggest diabetes or renal failure (Table 1). Lumbar puncture shows protein at 91 mg/dL, glucose at 74 mg/dL, and red- and white-blood-cell counts at 0 and 1, respectively. CSF Gram’s stain and brain CT are unremarkable. ECG is normal except for sinus tachycardia. Serum lithium is normal (1.1 mmol/L).

Mr. M undergoes tracheal intubation and receives ceftazidime, dose unknown, because chest radiograph shows lower lung opacities, suggesting aspiration. He receives morphine, 2 to 4 mg hourly as needed, to calm him during intubation. He is then transferred to the intensive care unit.

Table 1

Diabetes, renal failure, or NMS? The story behind Mr. M’s laboratory values

The authors’ observations

NMS, a potentially fatal side effect of antipsychotics, is characterized by rigidity, hyperthermia, and autonomic instability¹—as seen with Mr. M.

The patient’s rigidity, elevated creatine kinase, and face and arm abrasions could suggest a seizure. Mr. M’s EEG is negative, however, and he has no history of seizures or head trauma, so seizure is ruled out.

Researchers have associated bupropion with a small risk of developing seizures. Richmond and Zwar² reported a 0.1% risk with bupropion, ≥300 mg/d, but Mr. M was taking 150 mg/d. Dunner et al³ estimated the risk of developing seizure while taking standard-release bupropion—the form Mr. M used—at 0.06%, but patients in this study who developed seizures typically had a past seizure disorder or head trauma.

The combination of hyperthermia, tachycardia, altered mental status, and positive chest X-ray suggest pneumonia, which was addressed with antibiotics. Pneumonia, however, does not solely account for Mr. M’s fever, rigidity, and profoundly increased CPK. These findings suggest NMS.

The Glasgow Coma Scale (GCS) is used to quantitatively rate degree of responsiveness in critically ill or injured patients (Table 2). Total scores range from 3 to 15 based on the patient’s best eye, motor, and verbal responses. Total score ≤8 indicates a probable coma. Serial GCS scores can measure clinical course in comatose patients.

Table 2

Using Glasgow Coma Scale to determine level of consciousness

Treatment: slow progress

In the ICU, we diagnose NMS and stop all psychotropics, fearing that interactions between any of them might be causing NMS. We give midazolam, 1 to 2 mg hourly as needed for agitation, and continue morphine, 2 to 4 mg hourly as needed for pain. We stop ceftazidime after ruling out aspiration risk.

On day 2 of hospitalization, we call the neurology and consultation-liaison (C-L) psychiatry services. The C-L psychiatrist attempts a mental status examination, but Mr. M is too frail and sedated to communicate. Neurologic exam shows increased foot rigidity, and follow-up studies show negative EEG, normal head and neck MRIs and MRAs, a peak in CPK at 5,487 IU/L, and normal chest films.

We taper and discontinue midazolam and morphine, and Mr. M’s consciousness improves as the dosages decrease. We add lorazepam, 1 mg tid, to address Mr. M’s agitation. He also starts physical therapy to address potential movement problems caused by laying static for 3 days. By day 7, he is extubated and transferred to the general medical unit.

On day 9, Mr. M’s recall and concentration are diminished, and he cannot follow a 3-step command. His Mini-Mental State Examination (MMSE) score of 17 points to a cognitive impairment.

By day 12, residual psychosis is increasing Mr. M’s confusion, paranoia, and agitation. Despite this complication, he is able to work with his occupational and physical therapists.

By day 20, Mr. M becomes more paranoid, with tangential and loose associations. To address these symptoms, we stop lorazepam and start aripiprazole, 15 mg each morning. Because aripiprazole is a partial dopamine agonist and antagonist, it is less likely than other antipsychotics to cause recurrence of NMS symptoms.

Four days later, Mr. M is medically cleared for transfer to the county psychiatric hospital. Creatinine and CPK elevations, metabolic acidosis, and anemia have resolved.

Treatment: new facility, new drugs

On initial evaluation at the psychiatric hospital, Mr. M is cooperative and aware of person, place, and time. His thought processes range from tangential to disorganized, and his paranoia persists.

The attending psychiatrist stops aripiprazole and starts risperidone, 1 mg bid, possibly because he is less familiar with aripiprazole—a newer antipsychotic— than with risperidone. Laboratory results within 3 days of starting risperidone show normal serum levels, blood counts, liver enzymes, and CPK.

On day 2 at the psychiatric hospital, Mr. M’s behavior worsens; he frequently disrobes in front of others, yells at staff, and requires verbal redirection. His MMSE score has fallen to 15. The attending psychiatrist modifies risperidone to 2 mg nightly and adds donepezil, 10 mg each morning, to try to reverse his cognitive decline.

By day 8, Mr. M is more cooperative and his behavior improves. He is transferred back to his board-and-care facility on risperidone and donepezil at the above dosages.

The following month, Mr. M presents to his outpatient psychiatrist with improved cognitive function, but he is still delusional. The psychiatrist stops risperidone and donepezil and resumes olanzapine, 7.5 mg each morning and 10 mg nightly, and chlorpromazine, 50 mg nightly, to try to restore the patient’s pre-NMS function.

Mr. M undergoes successful prostate cancer surgery before his 3-month psychiatry follow-up, at which the psychiatrist adds lithium carbonate, 300 mg tid, for residual irritability. Serum lithium levels are normal; bupropion is not restarted.

One year after presentation, Mr. M is minimally delusional but functioning well. No symptoms suggesting NMS recurrence have been reported.

The authors’ observations

Though the precise mechanism is unknown, NMS has been linked with use of FGAs such as chlorpromazine, which can trigger excessive dopamine blockade.⁴ Studies increasingly associate SGAs such as olanzapine, risperidone, and aripiprazole with NMS onset.^4-6 Mood stabilizers such as lithium carbonate also have been implicated, especially when used with antipsychotics.^6-9 No association between antibiotics and NMS has been found.

For years, Mr. M has been taking FGAs and concomitant olanzapine and lithium carbonate without developing NMS symptoms until now. Since discharge, he has been free of NMS symptoms despite taking two SGAs (aripiprazole and risperidone) at different times and later resuming chlorpromazine, olanzapine, and lithium carbonate.

Of note, bupropion—the last psychotropic added before NMS onset—has not been restarted. The literature does not link bupropion to NMS, although one case report¹⁰ suggests an association between fluoxetine and NMS after the patient had taken several antipsychotic/antidepressant combinations.

As a dopamine agonist, bupropion should protect against NMS. Case reports,^11,12 however, have described patients who developed NMS after antipsychotics were discontinued, and stopping an antipsychotic essentially mimics bupropion’s action by eliminating the dopamine blockade. Additionally, bupropion’s norepinephrine modulation could have precipitated NMS by dysregulating the sympathetic nervous system.¹³

Mr. M’s board-and-care operator indicated that the patient’s tobacco consumption decreased—from about a pack to a half-pack of cigarettes daily—after bupropion was added. Alternatively, the effects of pneumonia could have curtailed Mr. M’s smoking. Because nicotine increases metabolism of neuroleptics,^14,15 decreased nicotine consumption might have increased dopamine blockade to the point of causing NMS.

Other possibilities. Mr. M’s pneumonia might have caused dehydration, which can also lead to NMS.

Bupropion also reportedly alters metabolism of chlorpromazine and other phenothiazine antipsychotics by inhibiting the cytochrome P-450 2D6 isoenzyme. This pharmacokinetic interaction could have precipitated Mr. M’s NMS episode independent of an antipsychotic dosage increase.¹⁶

Because this case is so complex, pinpointing a specific cause for Mr. M’s apparent NMS symptoms is difficult. Be aware that combining psychotropics can lead to NMS. Patients who present with mental status changes, hyperthermia, rigidity, and/or increased creatine kinase while taking psychotropics should be promptly evaluated and managed.

Treating NMS

A review of NMS treatment by Davis et al¹⁷ suggests that you:

• consider NMS in the differential diagnosis of an acutely delirious patient who has used antipsychotics, no matter how long he or she has been taking the medication(s) or how stable the dosage
  
• check for other signs of NMS—such as rigidity or autonomic instability—during the physical examination.
  
• consider NMS as a possible cause of dysarthria, diaphoresis, dysphagia, sialorrhea, and myoclonus, although these are less common signs of the disorder
  
• include CPK levels, chemistry panel, CBC, and liver enzyme assessment in the early evaluation of laboratory results. Consider performing a urine drug screen to check for illicit substance use. Head CT results might also help confirm NMS diagnosis.
  

If sedation becomes necessary, use benzodiazepines cautiously. Serial CPKs and daily reassessment of clinical degree of rigidity are essential; continued rigidity may indicate use of dopamine agonists and dantrolene.¹⁷

Related resources

• Neuroleptic Malignant Syndrome Information Service. Archive of articles addressing NMS diagnosis and treatment, and listing of psychotropics associated with NMS. www.nmsis.org.
  

• Aripiprazole • Abilify
  
• Benztropine • Cogentin
  
• Bupropion SR • Wellbutrin, Zyban
  
• Ceftazidime • various
  
• Chlorpromazine • Thorazine
  
• Dantrolene • Dantrium
  
• Donepezil • Aricept
  
• Lithium carbonate • various
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Risperidone • Risperdal
  

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

Presentation: unconscious on the street

Emergency medical personnel bring Mr. M, age 66, to the ER after passers-by find him supine on the sidewalk. On arrival, he is comatose as confirmed by a Glasgow Coma Scale score of 8 (eye opening 3, verbal response 2, motor response 3). Systolic blood pressure is 108 mm Hg on palpation, pulse is 135 beats per minute, and temperature is 105 °F. Minor abrasions cover his face and arms, and his hands and feet are rigid.

Mr. M has lived at a board-and-care facility for 30 years. The facility’s operator tells us that Mr. M has had schizophrenia for 40 years and has been taking:

• olanzapine, 7.5 mg each morning and 10 mg at bedtime
  
• chlorpromazine, 50 mg nightly
  
• lithium carbonate, 300 mg tid
  
• and benztropine, 2 mg bid.
  

Three weeks ago, Mr. M was hospitalized for 6 days with pneumonia. In 3 months, he will undergo surgery for prostate cancer. He is taking no medication for the prostate cancer.

Creatine phosphokinase (CPK) is 2,939 IU/L, indicating neuroleptic malignant syndrome (NMS). Other laboratory test results suggest diabetes or renal failure (Table 1). Lumbar puncture shows protein at 91 mg/dL, glucose at 74 mg/dL, and red- and white-blood-cell counts at 0 and 1, respectively. CSF Gram’s stain and brain CT are unremarkable. ECG is normal except for sinus tachycardia. Serum lithium is normal (1.1 mmol/L).

Mr. M undergoes tracheal intubation and receives ceftazidime, dose unknown, because chest radiograph shows lower lung opacities, suggesting aspiration. He receives morphine, 2 to 4 mg hourly as needed, to calm him during intubation. He is then transferred to the intensive care unit.

Table 1

Diabetes, renal failure, or NMS? The story behind Mr. M’s laboratory values

The authors’ observations

NMS, a potentially fatal side effect of antipsychotics, is characterized by rigidity, hyperthermia, and autonomic instability¹—as seen with Mr. M.

The patient’s rigidity, elevated creatine kinase, and face and arm abrasions could suggest a seizure. Mr. M’s EEG is negative, however, and he has no history of seizures or head trauma, so seizure is ruled out.

Researchers have associated bupropion with a small risk of developing seizures. Richmond and Zwar² reported a 0.1% risk with bupropion, ≥300 mg/d, but Mr. M was taking 150 mg/d. Dunner et al³ estimated the risk of developing seizure while taking standard-release bupropion—the form Mr. M used—at 0.06%, but patients in this study who developed seizures typically had a past seizure disorder or head trauma.

The combination of hyperthermia, tachycardia, altered mental status, and positive chest X-ray suggest pneumonia, which was addressed with antibiotics. Pneumonia, however, does not solely account for Mr. M’s fever, rigidity, and profoundly increased CPK. These findings suggest NMS.

The Glasgow Coma Scale (GCS) is used to quantitatively rate degree of responsiveness in critically ill or injured patients (Table 2). Total scores range from 3 to 15 based on the patient’s best eye, motor, and verbal responses. Total score ≤8 indicates a probable coma. Serial GCS scores can measure clinical course in comatose patients.

Table 2

Using Glasgow Coma Scale to determine level of consciousness

Treatment: slow progress

In the ICU, we diagnose NMS and stop all psychotropics, fearing that interactions between any of them might be causing NMS. We give midazolam, 1 to 2 mg hourly as needed for agitation, and continue morphine, 2 to 4 mg hourly as needed for pain. We stop ceftazidime after ruling out aspiration risk.

On day 2 of hospitalization, we call the neurology and consultation-liaison (C-L) psychiatry services. The C-L psychiatrist attempts a mental status examination, but Mr. M is too frail and sedated to communicate. Neurologic exam shows increased foot rigidity, and follow-up studies show negative EEG, normal head and neck MRIs and MRAs, a peak in CPK at 5,487 IU/L, and normal chest films.

We taper and discontinue midazolam and morphine, and Mr. M’s consciousness improves as the dosages decrease. We add lorazepam, 1 mg tid, to address Mr. M’s agitation. He also starts physical therapy to address potential movement problems caused by laying static for 3 days. By day 7, he is extubated and transferred to the general medical unit.

On day 9, Mr. M’s recall and concentration are diminished, and he cannot follow a 3-step command. His Mini-Mental State Examination (MMSE) score of 17 points to a cognitive impairment.

By day 12, residual psychosis is increasing Mr. M’s confusion, paranoia, and agitation. Despite this complication, he is able to work with his occupational and physical therapists.

By day 20, Mr. M becomes more paranoid, with tangential and loose associations. To address these symptoms, we stop lorazepam and start aripiprazole, 15 mg each morning. Because aripiprazole is a partial dopamine agonist and antagonist, it is less likely than other antipsychotics to cause recurrence of NMS symptoms.

Four days later, Mr. M is medically cleared for transfer to the county psychiatric hospital. Creatinine and CPK elevations, metabolic acidosis, and anemia have resolved.

Treatment: new facility, new drugs

On initial evaluation at the psychiatric hospital, Mr. M is cooperative and aware of person, place, and time. His thought processes range from tangential to disorganized, and his paranoia persists.

The attending psychiatrist stops aripiprazole and starts risperidone, 1 mg bid, possibly because he is less familiar with aripiprazole—a newer antipsychotic— than with risperidone. Laboratory results within 3 days of starting risperidone show normal serum levels, blood counts, liver enzymes, and CPK.

On day 2 at the psychiatric hospital, Mr. M’s behavior worsens; he frequently disrobes in front of others, yells at staff, and requires verbal redirection. His MMSE score has fallen to 15. The attending psychiatrist modifies risperidone to 2 mg nightly and adds donepezil, 10 mg each morning, to try to reverse his cognitive decline.

By day 8, Mr. M is more cooperative and his behavior improves. He is transferred back to his board-and-care facility on risperidone and donepezil at the above dosages.

The following month, Mr. M presents to his outpatient psychiatrist with improved cognitive function, but he is still delusional. The psychiatrist stops risperidone and donepezil and resumes olanzapine, 7.5 mg each morning and 10 mg nightly, and chlorpromazine, 50 mg nightly, to try to restore the patient’s pre-NMS function.

Mr. M undergoes successful prostate cancer surgery before his 3-month psychiatry follow-up, at which the psychiatrist adds lithium carbonate, 300 mg tid, for residual irritability. Serum lithium levels are normal; bupropion is not restarted.

One year after presentation, Mr. M is minimally delusional but functioning well. No symptoms suggesting NMS recurrence have been reported.

The authors’ observations

Though the precise mechanism is unknown, NMS has been linked with use of FGAs such as chlorpromazine, which can trigger excessive dopamine blockade.⁴ Studies increasingly associate SGAs such as olanzapine, risperidone, and aripiprazole with NMS onset.^4-6 Mood stabilizers such as lithium carbonate also have been implicated, especially when used with antipsychotics.^6-9 No association between antibiotics and NMS has been found.

For years, Mr. M has been taking FGAs and concomitant olanzapine and lithium carbonate without developing NMS symptoms until now. Since discharge, he has been free of NMS symptoms despite taking two SGAs (aripiprazole and risperidone) at different times and later resuming chlorpromazine, olanzapine, and lithium carbonate.

Of note, bupropion—the last psychotropic added before NMS onset—has not been restarted. The literature does not link bupropion to NMS, although one case report¹⁰ suggests an association between fluoxetine and NMS after the patient had taken several antipsychotic/antidepressant combinations.

As a dopamine agonist, bupropion should protect against NMS. Case reports,^11,12 however, have described patients who developed NMS after antipsychotics were discontinued, and stopping an antipsychotic essentially mimics bupropion’s action by eliminating the dopamine blockade. Additionally, bupropion’s norepinephrine modulation could have precipitated NMS by dysregulating the sympathetic nervous system.¹³

Mr. M’s board-and-care operator indicated that the patient’s tobacco consumption decreased—from about a pack to a half-pack of cigarettes daily—after bupropion was added. Alternatively, the effects of pneumonia could have curtailed Mr. M’s smoking. Because nicotine increases metabolism of neuroleptics,^14,15 decreased nicotine consumption might have increased dopamine blockade to the point of causing NMS.

Other possibilities. Mr. M’s pneumonia might have caused dehydration, which can also lead to NMS.

Bupropion also reportedly alters metabolism of chlorpromazine and other phenothiazine antipsychotics by inhibiting the cytochrome P-450 2D6 isoenzyme. This pharmacokinetic interaction could have precipitated Mr. M’s NMS episode independent of an antipsychotic dosage increase.¹⁶

Because this case is so complex, pinpointing a specific cause for Mr. M’s apparent NMS symptoms is difficult. Be aware that combining psychotropics can lead to NMS. Patients who present with mental status changes, hyperthermia, rigidity, and/or increased creatine kinase while taking psychotropics should be promptly evaluated and managed.

Treating NMS

A review of NMS treatment by Davis et al¹⁷ suggests that you:

• consider NMS in the differential diagnosis of an acutely delirious patient who has used antipsychotics, no matter how long he or she has been taking the medication(s) or how stable the dosage
  
• check for other signs of NMS—such as rigidity or autonomic instability—during the physical examination.
  
• consider NMS as a possible cause of dysarthria, diaphoresis, dysphagia, sialorrhea, and myoclonus, although these are less common signs of the disorder
  
• include CPK levels, chemistry panel, CBC, and liver enzyme assessment in the early evaluation of laboratory results. Consider performing a urine drug screen to check for illicit substance use. Head CT results might also help confirm NMS diagnosis.
  

If sedation becomes necessary, use benzodiazepines cautiously. Serial CPKs and daily reassessment of clinical degree of rigidity are essential; continued rigidity may indicate use of dopamine agonists and dantrolene.¹⁷

Related resources

• Neuroleptic Malignant Syndrome Information Service. Archive of articles addressing NMS diagnosis and treatment, and listing of psychotropics associated with NMS. www.nmsis.org.
  

• Aripiprazole • Abilify
  
• Benztropine • Cogentin
  
• Bupropion SR • Wellbutrin, Zyban
  
• Ceftazidime • various
  
• Chlorpromazine • Thorazine
  
• Dantrolene • Dantrium
  
• Donepezil • Aricept
  
• Lithium carbonate • various
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Risperidone • Risperdal
  

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

Presentation: unconscious on the street

Emergency medical personnel bring Mr. M, age 66, to the ER after passers-by find him supine on the sidewalk. On arrival, he is comatose as confirmed by a Glasgow Coma Scale score of 8 (eye opening 3, verbal response 2, motor response 3). Systolic blood pressure is 108 mm Hg on palpation, pulse is 135 beats per minute, and temperature is 105 °F. Minor abrasions cover his face and arms, and his hands and feet are rigid.

Mr. M has lived at a board-and-care facility for 30 years. The facility’s operator tells us that Mr. M has had schizophrenia for 40 years and has been taking:

• olanzapine, 7.5 mg each morning and 10 mg at bedtime
  
• chlorpromazine, 50 mg nightly
  
• lithium carbonate, 300 mg tid
  
• and benztropine, 2 mg bid.
  

Three weeks ago, Mr. M was hospitalized for 6 days with pneumonia. In 3 months, he will undergo surgery for prostate cancer. He is taking no medication for the prostate cancer.

Creatine phosphokinase (CPK) is 2,939 IU/L, indicating neuroleptic malignant syndrome (NMS). Other laboratory test results suggest diabetes or renal failure (Table 1). Lumbar puncture shows protein at 91 mg/dL, glucose at 74 mg/dL, and red- and white-blood-cell counts at 0 and 1, respectively. CSF Gram’s stain and brain CT are unremarkable. ECG is normal except for sinus tachycardia. Serum lithium is normal (1.1 mmol/L).

Mr. M undergoes tracheal intubation and receives ceftazidime, dose unknown, because chest radiograph shows lower lung opacities, suggesting aspiration. He receives morphine, 2 to 4 mg hourly as needed, to calm him during intubation. He is then transferred to the intensive care unit.

Table 1

Diabetes, renal failure, or NMS? The story behind Mr. M’s laboratory values

The authors’ observations

NMS, a potentially fatal side effect of antipsychotics, is characterized by rigidity, hyperthermia, and autonomic instability¹—as seen with Mr. M.

The patient’s rigidity, elevated creatine kinase, and face and arm abrasions could suggest a seizure. Mr. M’s EEG is negative, however, and he has no history of seizures or head trauma, so seizure is ruled out.

Researchers have associated bupropion with a small risk of developing seizures. Richmond and Zwar² reported a 0.1% risk with bupropion, ≥300 mg/d, but Mr. M was taking 150 mg/d. Dunner et al³ estimated the risk of developing seizure while taking standard-release bupropion—the form Mr. M used—at 0.06%, but patients in this study who developed seizures typically had a past seizure disorder or head trauma.

The combination of hyperthermia, tachycardia, altered mental status, and positive chest X-ray suggest pneumonia, which was addressed with antibiotics. Pneumonia, however, does not solely account for Mr. M’s fever, rigidity, and profoundly increased CPK. These findings suggest NMS.

The Glasgow Coma Scale (GCS) is used to quantitatively rate degree of responsiveness in critically ill or injured patients (Table 2). Total scores range from 3 to 15 based on the patient’s best eye, motor, and verbal responses. Total score ≤8 indicates a probable coma. Serial GCS scores can measure clinical course in comatose patients.

Table 2

Using Glasgow Coma Scale to determine level of consciousness

Treatment: slow progress

In the ICU, we diagnose NMS and stop all psychotropics, fearing that interactions between any of them might be causing NMS. We give midazolam, 1 to 2 mg hourly as needed for agitation, and continue morphine, 2 to 4 mg hourly as needed for pain. We stop ceftazidime after ruling out aspiration risk.

On day 2 of hospitalization, we call the neurology and consultation-liaison (C-L) psychiatry services. The C-L psychiatrist attempts a mental status examination, but Mr. M is too frail and sedated to communicate. Neurologic exam shows increased foot rigidity, and follow-up studies show negative EEG, normal head and neck MRIs and MRAs, a peak in CPK at 5,487 IU/L, and normal chest films.

We taper and discontinue midazolam and morphine, and Mr. M’s consciousness improves as the dosages decrease. We add lorazepam, 1 mg tid, to address Mr. M’s agitation. He also starts physical therapy to address potential movement problems caused by laying static for 3 days. By day 7, he is extubated and transferred to the general medical unit.

On day 9, Mr. M’s recall and concentration are diminished, and he cannot follow a 3-step command. His Mini-Mental State Examination (MMSE) score of 17 points to a cognitive impairment.

By day 12, residual psychosis is increasing Mr. M’s confusion, paranoia, and agitation. Despite this complication, he is able to work with his occupational and physical therapists.

By day 20, Mr. M becomes more paranoid, with tangential and loose associations. To address these symptoms, we stop lorazepam and start aripiprazole, 15 mg each morning. Because aripiprazole is a partial dopamine agonist and antagonist, it is less likely than other antipsychotics to cause recurrence of NMS symptoms.

Four days later, Mr. M is medically cleared for transfer to the county psychiatric hospital. Creatinine and CPK elevations, metabolic acidosis, and anemia have resolved.

Treatment: new facility, new drugs

On initial evaluation at the psychiatric hospital, Mr. M is cooperative and aware of person, place, and time. His thought processes range from tangential to disorganized, and his paranoia persists.

The attending psychiatrist stops aripiprazole and starts risperidone, 1 mg bid, possibly because he is less familiar with aripiprazole—a newer antipsychotic— than with risperidone. Laboratory results within 3 days of starting risperidone show normal serum levels, blood counts, liver enzymes, and CPK.

On day 2 at the psychiatric hospital, Mr. M’s behavior worsens; he frequently disrobes in front of others, yells at staff, and requires verbal redirection. His MMSE score has fallen to 15. The attending psychiatrist modifies risperidone to 2 mg nightly and adds donepezil, 10 mg each morning, to try to reverse his cognitive decline.

By day 8, Mr. M is more cooperative and his behavior improves. He is transferred back to his board-and-care facility on risperidone and donepezil at the above dosages.

The following month, Mr. M presents to his outpatient psychiatrist with improved cognitive function, but he is still delusional. The psychiatrist stops risperidone and donepezil and resumes olanzapine, 7.5 mg each morning and 10 mg nightly, and chlorpromazine, 50 mg nightly, to try to restore the patient’s pre-NMS function.

Mr. M undergoes successful prostate cancer surgery before his 3-month psychiatry follow-up, at which the psychiatrist adds lithium carbonate, 300 mg tid, for residual irritability. Serum lithium levels are normal; bupropion is not restarted.

One year after presentation, Mr. M is minimally delusional but functioning well. No symptoms suggesting NMS recurrence have been reported.

The authors’ observations

Though the precise mechanism is unknown, NMS has been linked with use of FGAs such as chlorpromazine, which can trigger excessive dopamine blockade.⁴ Studies increasingly associate SGAs such as olanzapine, risperidone, and aripiprazole with NMS onset.^4-6 Mood stabilizers such as lithium carbonate also have been implicated, especially when used with antipsychotics.^6-9 No association between antibiotics and NMS has been found.

For years, Mr. M has been taking FGAs and concomitant olanzapine and lithium carbonate without developing NMS symptoms until now. Since discharge, he has been free of NMS symptoms despite taking two SGAs (aripiprazole and risperidone) at different times and later resuming chlorpromazine, olanzapine, and lithium carbonate.

Of note, bupropion—the last psychotropic added before NMS onset—has not been restarted. The literature does not link bupropion to NMS, although one case report¹⁰ suggests an association between fluoxetine and NMS after the patient had taken several antipsychotic/antidepressant combinations.

As a dopamine agonist, bupropion should protect against NMS. Case reports,^11,12 however, have described patients who developed NMS after antipsychotics were discontinued, and stopping an antipsychotic essentially mimics bupropion’s action by eliminating the dopamine blockade. Additionally, bupropion’s norepinephrine modulation could have precipitated NMS by dysregulating the sympathetic nervous system.¹³

Mr. M’s board-and-care operator indicated that the patient’s tobacco consumption decreased—from about a pack to a half-pack of cigarettes daily—after bupropion was added. Alternatively, the effects of pneumonia could have curtailed Mr. M’s smoking. Because nicotine increases metabolism of neuroleptics,^14,15 decreased nicotine consumption might have increased dopamine blockade to the point of causing NMS.

Other possibilities. Mr. M’s pneumonia might have caused dehydration, which can also lead to NMS.

Bupropion also reportedly alters metabolism of chlorpromazine and other phenothiazine antipsychotics by inhibiting the cytochrome P-450 2D6 isoenzyme. This pharmacokinetic interaction could have precipitated Mr. M’s NMS episode independent of an antipsychotic dosage increase.¹⁶

Because this case is so complex, pinpointing a specific cause for Mr. M’s apparent NMS symptoms is difficult. Be aware that combining psychotropics can lead to NMS. Patients who present with mental status changes, hyperthermia, rigidity, and/or increased creatine kinase while taking psychotropics should be promptly evaluated and managed.

Treating NMS

A review of NMS treatment by Davis et al¹⁷ suggests that you:

• consider NMS in the differential diagnosis of an acutely delirious patient who has used antipsychotics, no matter how long he or she has been taking the medication(s) or how stable the dosage
  
• check for other signs of NMS—such as rigidity or autonomic instability—during the physical examination.
  
• consider NMS as a possible cause of dysarthria, diaphoresis, dysphagia, sialorrhea, and myoclonus, although these are less common signs of the disorder
  
• include CPK levels, chemistry panel, CBC, and liver enzyme assessment in the early evaluation of laboratory results. Consider performing a urine drug screen to check for illicit substance use. Head CT results might also help confirm NMS diagnosis.
  

If sedation becomes necessary, use benzodiazepines cautiously. Serial CPKs and daily reassessment of clinical degree of rigidity are essential; continued rigidity may indicate use of dopamine agonists and dantrolene.¹⁷

Related resources

• Neuroleptic Malignant Syndrome Information Service. Archive of articles addressing NMS diagnosis and treatment, and listing of psychotropics associated with NMS. www.nmsis.org.
  

• Aripiprazole • Abilify
  
• Benztropine • Cogentin
  
• Bupropion SR • Wellbutrin, Zyban
  
• Ceftazidime • various
  
• Chlorpromazine • Thorazine
  
• Dantrolene • Dantrium
  
• Donepezil • Aricept
  
• Lithium carbonate • various
  
• Lorazepam • Ativan
  
• Olanzapine • Zyprexa
  
• Risperidone • Risperdal
  

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