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.