When second-generation antipsychotics (SGAs) were introduced, clinicians hoped the drugs would not have the potential to cause neuroleptic malignant syndrome (NMS).1 Since then, however, case reports have made it clear that SGAs—like first-generation antipsychotics (FGAs)—can precipitate this life-threatening neurologic emergency.
To help you protect your patients receiving SGAs, this article explains how to:
- identify those at risk
- recognize the different NMS presentations associated with each SGA
- continue antipsychotic treatment for a patient with a history of NMS.
CASE STUDY: A drug-induced disorder
Mrs. Z, age 39, has a history of multiple hospitalizations for schizoaffective disorder complicated by poor compliance and a history of benzodiazepine abuse. This time she was admitted with increased auditory hallucinations and paranoid delusions of her family trying to poison her. Despite multiple haloperidol injections (5 mg IM q4h prn), Mrs. Z continued to have hallucinations and remained agitated.
Haloperidol was discontinued and ziprasidone (20 mg IM q4h prn) was started. After 3 days, Mrs. Z became less agitated and had fewer hallucinations. The IM route was discontinued and oral ziprasidone was started at 40 mg bid, then titrated to 80 mg bid after 2 days. On the third day after titration, Mrs. Z fell twice. She hit her head in one fall, but a brain CT to rule out bleeding was normal.
The next day, Mrs. Z became more confused and developed fever, tremor, urinary incontinence, and a severe headache. She became obtunded, was intubated, and was transferred to the intensive care unit of a tertiary care center.
On admission, her temperature was 103° F (39.4° C); she had severe muscle rigidity and blood pressure of 85/60 mm Hg. Creatine phosphokinase (CPK) was 2,559 U/L (normal 24 to 170 U/L). Liver enzymes were elevated: alanine transaminase was 202 U/L (normal 13 to 50 U/L), and aspartate transaminase (AST) was 190 U/L (normal 15 to 46 U/L). At 140 μg/dL, Mrs. Z’s serum iron was within normal limits (40 to 150 μg/dL).
Neuroleptic malignant syndrome
Clinical manifestations of NMS range from typical—as defined by the DSM-IV-TR (Table 1)2,3—to atypical, without:
Table 1
DSM-IV-TR definition of NMS*
| Hyperthermia (>38° C) and |
| Muscle rigidity and |
At least 2 of the following:
|
| * Symptoms must be associated with the use of neuroleptic medication, and other central and systemic causes of hyperthermia must be excluded. |
| CPK: creatine phosphokinase; NMS: neuroleptic malignant syndrome |
| Source: DSM-IV-TR |
Many conditions resemble NMS (Table 2). Because NMS can be fatal without emergent diagnosis and treatment, maintain a high index of suspicion for this condition whenever you prescribe antipsychotics.
Table 2
NMS differential diagnosis
| Primary CNS disorders |
| CNS vasculitis |
| Infarctions |
| Infections |
| Parkinson’s disease |
| Status epilepticus |
| Trauma |
| Tumors |
| Systemic disorders |
| Acute porphyria |
| Autoimmune disorders |
| Dehydration |
| Heat stroke |
| Hyperthyroidism |
| Infections |
| Pheochromocytoma |
| Tetanus |
| Psychiatric disorders |
| Idiopathic lethal catatonia |
| Medication-related disorders |
| Anticholinergic syndrome |
| Drug intoxication |
| Levodopa syndrome |
| Malignant hyperthermia |
| Serotonin syndrome |
NMS is believed to be caused by reduced dopamine activity in the brain associated with dopamine antagonists, interruptions in nigrostriatal dopamine pathways, or withdrawal of dopaminergic medications.3 However, dopamine D2 receptor blocking potential is not directly linked to the occurrence of NMS.6 Other mechanisms include genetic susceptibility and different CNS neurotransmitter disturbances.7
NMS develops in an estimated 0.02% to 2.5% of patients treated with antipsychotics.8-10 The syndrome appears to occur slightly less frequently with SGAs than with FGAs.6,10
Risk factors. NMS can develop at any age, in men and women, and in patients with psychiatric or medical illness.11,12 In addition to antipsychotics, other medications—including antiemetics and sedatives—can cause NMS. The syndrome has been triggered when Parkinson’s disease patients stop taking or reduce the dose of a dopamine agonist or switch from 1 dopamine agonist to another.13,14
Symptoms usually develop during the first 2 weeks of pharmacotherapy but may start after the initial dose or during long-term stable therapy.15 Although some studies found NMS development to be dose-independent, multiple cases have demonstrated an association with dose changes. Death occurs from dysautonomic manifestations and systemic complications.
An elevated risk for NMS may exist in patients with:
- mood disorders
- preexisting catatonia16
- complicated medical and neurologic disorders, such as encephalitis or mental retardation17
- poor functional and physiologic status3
- concurrent lithium treatment
- IM injection of an antipsychotic
- use of a high-potency antipsychotic, such as haloperidol
- psychomotor agitation.
Other potential risk factors include dehydration, adolescent age, male gender, low serum iron concentrations, relatively high antipsychotic dosages, and mental retardation or prior structural brain injury.18-20
NMS and SGAs
We reviewed 88 reports of NMS cases associated with 6 SGAs: olanzapine, clozapine, risperidone, ziprasidone, quetiapine, and aripiprazole. In this article, we cite representative cases only; readers interested in the full literature search can find this evidence and its references in the Case Reports Table.