Does Olanzapine (an atypical antipsychotic) cause hyperthermia (fever)?

From the Guidelines

Olanzapine can cause fever as a side effect, particularly as part of neuroleptic malignant syndrome (NMS), a rare but serious adverse effect of antipsychotic medications. Fever may occur as part of NMS, which typically presents with high fever, muscle rigidity, altered mental status, and autonomic instability 1. The incidence of NMS has been difficult to determine, with estimates ranging from 0.02% to 3%, and experts suggest considering NMS in the differential diagnosis of patients presenting with fever and altered mental status who are taking or may have taken an antipsychotic 1.

Key Considerations

• NMS affects patients of all ages, with an apparent predominance in young adults and male patients (2:1) 1.
• Coadministration of psychotropic agents seems to be an especially high risk factor for precipitating NMS; in one study, more than half of people with reported NMS cases were taking concomitant psychotropic agents 1.
• Other risk factors include dehydration, physical exhaustion, preexisting organic brain disease, and the use of long-acting depot antipsychotics 1.
• If a patient taking olanzapine develops a fever, especially if accompanied by confusion, muscle stiffness, sweating, or irregular heartbeat, they should seek immediate medical attention as this could indicate a serious reaction requiring prompt intervention.

Treatment and Management

• Treatment often involves discontinuing the precipitating agent and providing supportive care, which may include treatment of agitation (eg, benzodiazepines), amelioration of hyperthermia, and management of the autonomic instability (eg, IV fluids and other agents to address abnormal vital signs) 1.
• Approximately one-quarter of patients are treated with intubation, mechanical ventilation, and admission to an ICU, and the mortality rate is approximately 11% 1.
• Clinical diagnostic criteria for serotonin syndrome have been proposed, with Hunter criteria being most commonly used, and the adult dosage of serotonin2A antagonists may be considered, with cyproheptadine being most commonly used 1.

From the FDA Drug Label

1. 3 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including olanzapine Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia).
2. 4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with olanzapine exposure DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis.

Olanzapine may cause fever as part of two rare but potentially life-threatening conditions:

• Neuroleptic Malignant Syndrome (NMS), characterized by hyperpyrexia, muscle rigidity, and autonomic instability.
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), which may present with fever, eosinophilia, and systemic complications. These conditions require immediate medical attention and discontinuation of olanzapine 2, 2.

From the Research

Olanzapine-Induced Fever

• Olanzapine, a second-generation antipsychotic, has been implicated as a cause of drug-induced fever in the absence of neuroleptic malignant syndrome 3.
• A case study reported a patient who developed isolated fever following olanzapine monotherapy, which subsided after discontinuation of olanzapine 3.
• The mechanisms of fever development during treatment with olanzapine may include blockade of dopaminergic receptors and elevated cytokines concentration 3.

Neuroleptic Malignant Syndrome (NMS)

• NMS is a rare but life-threatening idiosyncratic side effect resulting from neuroleptic drugs, including olanzapine 4, 5, 6.
• Olanzapine-induced NMS can occur even in the absence of recent dosage adjustments or titration 4.
• Symptoms of NMS include fever, muscle rigidity, diaphoresis, drooling, urinary incontinence, and high blood pressure 4, 5, 6.

Atypical Presentations

• Atypical cases of NMS associated with olanzapine may present without rigidity 6.
• Such cases may support a spectrum concept of NMS or the theory that NMS secondary to atypical antipsychotics differs from that caused by conventional neuroleptics 6.
• Olanzapine-induced fever can occur in the absence of NMS, and should not be confused with incomplete neuromalignant syndrome 7.