Intolerable fever: A previously unreported side-effect of quetiapine

To the Editor

We present a case of quetiapine-induced fever, a previously unreported finding outside of the neuroleptic malignant syndrome, in a patient with schizophrenia who was fully rehabilitated and working within the community whilst on this medication. While much has been written about atypical antipsychotic medications causing neuroleptic malignant syndrome (Carroll and Surber, 2009; Gortney et al., 2009; Trollor et al., 2009) there are a paucity of data describing an isolated fever.

A 45-year-old male with treatment-resistant schizophrenia was referred to our institution for evaluation of persistent pyrexia. He was noted as having fevers of 38–40°C during routine observations in the psychiatric unit. He was admitted after revocation of a community treatment order secondary to medication non-compliance. His history was notable for an episode of fever after a single dose of olanzapine during an acute psychotic episode.

On further questioning, the patient had been experiencing drenching sweats following commencement of quetiapine. Despite good control of his psychotic symptoms, he was unable to tolerate quetiapine and thus self-ceased the medication, leading to a recurrence of overt psychosis with auditory hallucinations, delusions of grandeur and paranoia. In view of his symptomatic status his quetiapine was recommenced on the day of admission.

Physical examination was unremarkable apart from a body mass index (BMI) of 35. Importantly, there were no features to suggest neuroleptic malignant syndrome. Multiple investigations were performed to exclude an infective process including: full blood examination, three sets of blood cultures, viral serology and autoimmune screen. These were all normal. Imaging studies including abdominal ultrasound, CT chest, abdomen and pelvis and trans-thoracic and trans-oesophageal echocardiography were also normal. However, the patient continued to have pyrexia. His previous sensitivity to olanzapine led us to believe that the quetiapine could be responsible for the fever.

After careful discussion with the patient, family and psychiatric team, it was decided to stop the quetiapine. Given his excellent symptom control in the community this was not a decision undertaken lightly.

Following discontinuation of quetiapine, the fever abated and the patient was commenced on risperidone without further pyrexia. Unfortunately, he had suboptimal symptom control on risperidone and was not compliant with this therapy, leading to further symptom relapse.

Drug fever is defined as “a disorder characterized by fever coinciding with administration of a drug and disappearing after the discontinuation of the drug, when no other cause for the fever is evident after a careful physical examination and laboratory investigation” (Mackowiak and LeMaistre, 1987). Our case therefore satisfies the criterion for a drug-induced fever.

Quetiapine is a dibenzothiazepine atypical antipsychotic. It has been proposed that this drug’s antipsychotic activity is mediated through a combination of dopamine type 2 (D₂) and serotonin type 2 (5-HT₂) antagonism (Lemke and Williams, 2002). Leukopenia is a well-recognised complication of quetiapine treatment (Alexander and Tibrewal, 2010) but pyrexia associated with quetiapine has not been described previously.

The mechanism behind the side-effects of atypical antipsychotics is poorly understood. Clozapine remains one of the most thoroughly investigated atypical antipsychotic drugs and many mechanisms for potential modes of action and adverse sequelae have been postulated. These include increased cytokine production (Pollmächer et al., 1996; Schmitt et al., 2005), the formation of antibodies against haematopoietic precursors as well as binding of drug or metabolite to the neutrophil cell membrane leading to T-cell mediated destruction (Flanagan and Dunk, 2008). Whether similar mechanisms exist for quetiapine is unknown.

This case is important as it is the first time quetiapine-induced fever has been described in the absence of neuroleptic malignant syndrome. It also highlights a major challenge in medicine – treating a patient with a disabling condition who cannot tolerate the recommended therapy. The armamentarium available to treat schizophrenia is dominated by atypical antipsychotic medication, with few drugs available to those who cannot tolerate this drug class. Fever is often regarded as a minor side-effect by physicians, however to patients, it can be disabling.

Knowledge of side-effects of antipsychotic medication is critical to allow effective treatment decisions to be made and avoid unnecessary investigations that may also be potentially harmful.