Table 1
Factors that increase risk of neuroleptic malignant syndrome*
| Abrupt antipsychotic cessation |
| Ambient heat |
| Catatonia |
| Dehydration |
| Exhaustion |
| Genetic predisposition |
| Greater dosage increases |
| Higher neuroleptic doses, especially with typical and atypical IM agents |
| Low serum iron |
| Malnutrition |
| Mental retardation |
| Pre-existing EPS or parkinsonism |
| Previous NMS episode |
| Psychomotor agitation |
| * Infection or concurrent organic brain disease are predisposing factors, but their association with NMS is less clear. |
| EPS: extrapyramidal symptoms |
| Source: References: 4-7, 14-15. |
TREATMENT: MEDICATION CHANGE
Upon admission, quetiapine is increased to 75 mg in the morning and 125 mg at bedtime—still well below the dosage at which quetiapine increases the risk of NMS (Table 2). Trazodone is decreased to 100 mg/d because of quetiapine’s sedating properties. Citalopram and tolterodine are stopped for fear that either agent would aggravate her psychosis. We continue all other drugs as previously prescribed. Her paranoia begins to subside.
Three days later, Ms. G’s is increasingly confused and agitated, and her temperature rises to 101.3°F. Physical exam shows increased muscle rigidity. She is given lorazepam, 1 mg, and transferred to the emergency room for evaluation.
In the ER, Ms. G’s temperature rises to 102.3°F. Other vital signs include:
- heart rate, 112 to 120 beats per minute
- respiratory rate, 18 to 20 breaths per minute
- oxygen saturation, 98% in room air
- blood pressure, 131/61 mm Hg while seated and 92/58 mm Hg while standing.
CNS or systemic infection and myocardial infarction are considered less likely because of her reactive pupils, lack of nuchal rigidity, troponin 3. Additionally, CSF shows normal glucose and protein levels, ALT and AST are 217 and 261 U/L, respectively, and chest x-ray shows no acute cardiopulmonary abnormality.
Ms. G is admitted to the medical intensive care unit and given IV fluids. All psychotropic and antiparkinson medications are stopped for 12 hours. Ms. G is then transferred to the general medical service for continued observation and IV hydration.
Six hours later, lorazepam, 0.5 mg every 8 hours, is resumed to control Ms. G’s anxiety. Carbidopa/levodopa is resumed at the previous dosage; all other medications remain on hold.
Renal damage is not apparent, but repeat chest x-ray taken 2 days after admission to the ER shows right middle lobe pneumonia, which resolved with antibiotics.
Six days after entering the medical unit, Ms. G is no longer agitated or paranoid. She is discharged that day and continued on lorazepam, 1 mg every 8 hours as needed to control her anxiety and prevent paranoia, and carbidopa/levidopa 8-1/2 25/100-mg tablets daily for her parkinsonism. Trazodone, 100 mg nightly, is continued for 3 days to help her sleep, as is amoxicillin/clavulanate, 500 mg every 8 hours, in case an underlying infection exists. Quetiapine, citalopram, and tolterodine are discontinued; all other medications are resumed as previously prescribed.
Table 2
Antipsychotic-related NMS risk increases at these dosages
| Agent | Dosage (mg/d) |
|---|---|
| Aripiprazole | >30 |
| Chlorpromazine | >400 |
| Clozapine | 318+/-299 |
| Olanzapine | 9.7+/-2.3 |
| Quetiapine | 412.5+/-317 |
| Risperidone | 4.3+/-3.1 |
| Ziprasidone | >20 |
| Source: References 4, 6, and 15. | |
The authors’ observations
Ms. G’s NMS symptoms surfaced 3 days after her quetiapine dosage was increased, suggesting that the antipsychotic may have caused this episode.
We ruled out antiparkinson agent withdrawal malignant syndrome—usually caused by abrupt cessation of Parkinson’s medications. Ms. G’s carbidopa/levodopa had not been adjusted before the symptoms emerged, and she did not worsen after the agent was stopped temporarily. Her brief pneumonia episode, however, could have caused symptoms that mimicked this withdrawal syndrome.
Antiparkinson agent withdrawal malignant syndrome symptoms resemble those of NMS.9,10 Worsening parkinsonism, dehydration, and infection increase the risk.10 Some research suggests that leukocytosis or elevated inflammation-related cytokines may accelerate withdrawal syndrome.10
The authors’ observations
Ms. G’s case illustrates the difficulty of treating psychosis in a patient at risk for NMS.
Of the 68 patients in the Ananth et al study with atypical antipsychotic-induced NMS, 11 were rechallenged after an NMS episode with the same agent and 8 were switched to another atypical. NMS recurred in 4 of these 19 patients.4
Ms. G was stable on lorazepam at discharge, but we would consider rechallenging with quetiapine or another antipsychotic if necessary. NMS recurs in 30% to 50%11 of patients after antipsychotic rechallenge, but waiting 2 weeks to resume antipsychotic therapy appears to reduce this risk.12 Benzodiazepines and electroconvulsive therapy are acceptable—though unproven—second-line therapies if antipsychotic rechallenge is deemed too risky,11,13 such as in some patients with a previous severe NMS episode; evidence of stroke, Parkinson’s or other neurodegenerative disease; or multiple acute medical problems.