Fever induced by clozapine has an incidence of between 0.5% to 55%, and is a frequent side effect that usually occurs during the first 4 weeks of treatment.¹ In clozapine users, fever may be a warning symptom of life-threatening complications, though benign causes of fever are far more frequent than adverse drug reactions.² A thorough understanding of the causes of clozapine-induced fever may help improve and optimize clinical decision making. In a study published in Schizophrenia Research, researchers explored the clinical determinants of fever among clozapine users and the impact of these determinants on treatment.

For this study, the researchers searched MEDLINE, Web of Sciences, Cochrane Library, and PsycINFO databases from inception to February 2019 to identify all English- and French-language studies on clozapine-induced fever. The term “clozapine” was combined with one of the following keywords: fever, hyperthermia, body temperature, pyrexia, febrile, heat, and thermoregulation. For each medical condition associated with fever, researchers extracted information on its frequency, time to onset after initiation of clozapine treatment, fever characteristics, related symptoms, lab tests and exams used for diagnosis, course, lethality, and discontinuation of the drug. In total, researchers extracted data from 73 articles published between 1993 and 2018, the majority of which were case reports (n=40).²

The incidence of severe neutropenia was 0.9%, with more than 38% of cases having occurred within the first month of clozapine treatment.² Clozapine-induced agranulocytosis can be prevented by obtaining a weekly white blood count. Following the discontinuation of white blood count monitoring during chronic clozapine treatment, the risk for agranulocytosis decreased, but never disappeared. Researchers advise clinicians to monitor white blood counts if patients are diagnosed with agranulocytosis and have fever following discontinuation of clozapine.

Clozapine can induce neuroleptic malignant syndrome and heat stroke to cause fever in some users. The incidence of clozapine-induced neuroleptic malignant syndrome was 0.2% during clozapine initiation, with fever presenting in 50% to 90% of cases.² The researchers suggested that patients diagnosed with neuroleptic malignant syndrome stop using clozapine immediately. There were only 2 cases of heat stroke associated with clozapine use, both of which occurred during a heatwave. Both patients survived after temporarily discontinuing clozapine.


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The risk of infection — particularly pneumonia — was higher among patients who used clozapine compared with those who did not use antipsychotics. Of all antipsychotics, clozapine was associated with the highest risk of pneumonia, with clozapine users being 2 times more likely to develop pneumonia than nonusers, especially during the first month of exposure.² The researchers considered pneumonia to be the most frequent and potentially lethal infectious complication associated with clozapine use, attributing its frequency to the increased risk of aspiration pneumonia with sedation, increased saliva production, difficulty swallowing, and concomitant benzodiazepine use.

The researchers recommend that chest radiography and urinalyses be performed in clozapine users without an identified cause of fever, and that clozapine be continued with dosage adjustment by therapeutic drug monitoring. Clinicians may also reduce clozapine dosage by half to prevent intoxication, especially when inflammation is present.²

Clozapine-induced fever is defined when fever is the only clinical symptom with no detectable cause other than clozapine use.² Retrospective chart reviews demonstrated that the frequency of clozapine-induced fever following initiation of clozapine treatment ranged from 14% to 50%.² Fever began between 5 and 15 days after clozapine initiation and lasted for 3 to 5 days.² The researchers suggest continuing clozapine in these users but consider temporarily stopping clozapine and restarting treatment with slower titration to reduce fever.

Clozapine-induced lupus typically occurred during the first weeks of treatment and was characterized by fever, joint pain, and muscle pain. Clozapine was discontinued in 3 cases, but continued in 1 case because the benefit/risk ratio was considered greater than discontinuation despite joint pain.² The researchers recommend close monitoring of renal function in cases where clozapine is continued in clozapine-induced lupus.

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The researchers suspected that rapid titration was a contributing factor to clozapine-induced myocarditis, with the first case presenting in a patient who was titrated extremely fast to 500 mg per day of clozapine within a 7-day period.² Clozapine-induced myocarditis began during the first 3 weeks following clozapine initiation, with approximately 87% of cases having occurred within 30 days.² Myocarditis was associated with a high mortality rate of between 15% and 24%, with fever being the most frequent symptom reported in at least 2 of 3 patients.² The researchers recommend that clozapine users diagnosed with myocarditis discontinue treatment immediately.

According to the researchers, the incidence of clozapine-induced serositis was extremely low, but in reported cases, serositis began within 8 to 70 days after clozapine initiation.² Fever or other flu-like symptoms were observed in 32% of these cases, and inflammation of other organs was reported in 41% of cases.² Clozapine was discontinued in 20 of 22 patients, and no deaths were reported.

In all reported cases of clozapine-induced pneumonitis and alveolitis, symptoms including fever, cough, and fatigue appeared within the first 3 weeks of treatment.² The symptoms disappeared in all cases when clozapine was discontinued.

Fever was present in 89% of reported cases of clozapine-induced hepatitis, which developed at a mean of 34 days following clozapine initiation.² The researchers recommend that clozapine treatment be continued with close monitoring of white blood count, transaminases levels, and other hepatitis symptoms, but clozapine should be discontinued immediately following the confirmed diagnosis of clozapine-induced hepatitis.

Fever was present in 75% of clozapine-induced pancreatitis cases.² The mean onset of symptoms was 18 days following clozapine initiation, and all cases occurred within 5 weeks. Sodium valproate may increase the risk of developing clozapine-induced pancreatitis, though other risk factors should be considered, including alcohol abuse, hyperglycemia, and hypertriglyceridemia.² The researchers recommend the immediate discontinuation of clozapine following the diagnosis of clozapine-induced pancreatitis.

Fever was present in all cases of clozapine-induced nephritis, which had a mean delay of 28 days between initiation and onset, and began within 3 weeks in 73% of cases.² No fatalities were reported, though researchers suggest the immediate discontinuation of clozapine in confirmed cases of clozapine-induced nephritis.

Cases of clozapine-induced colitis generally occurred within the first 30 days of clozapine initiation, and presented symptoms of spiking fever, abdominal pain, and intense watery or bloody diarrhea.² The researchers recommend stopping clozapine following the diagnosis of associated colitis.

Researchers found a few reports of fever associated with dermatological lesions, which were limited by their heterogeneity. There were only 3 cases in which dermatological lesions were associated with fever, and clozapine was discontinued in all 3 cases.²

Approximately 58% of pulmonary thromboembolism cases occurred within the first month of clozapine treatment, where fever was associated with other symptoms including fatigue, tachycardia, and elevated C-reactive protein.² Fatality was reported in 25% of cases.² The researchers recommend stopping clozapine in the event of thromboembolism recurrence.

The anticholinergic properties of clozapine may induce severe constipation known as ischemic bowel necrosis, which is characterized by fever, abdominal pain, and distention.² In cases of necrotizing colitis, the researchers recommend partial colectomy and temporary discontinuation of clozapine.

The researchers concluded that discontinuation of clozapine should not be automatically considered in the event of fever, especially during the early phase of treatment initiation.² However, they suggest that clinicians should make it a priority to eliminate agranulocytosis, neuroleptic malignant syndrome, and myocarditis, and perform lab tests that include white blood count, C-reactive protein, troponin, and serum creatine-kinase concentrations. Results from a 2017 case study published in In Vivo revealed that measuring troponin regularly during clozapine initiation may prevent fever and the risk of myocarditis and cardiac dysfunction.¹ Additionally, they suggest slow titration of clozapine to prevent myocarditis, and advise clinicians to wait before increasing doses of clozapine until abnormalities are resolved or normalized.

Should fever occur during clozapine maintenance treatment, the researchers advise clinicians to keep in mind that agranulocytosis and neuroleptic malignant syndrome may occur at any time over the course of treatment. Fever may also signify potentially lethal pneumonia. Furthermore, clinicians and patients should remain aware of the risk of pneumonia and clinicians should rule out infection in the case of fever and consider altering the dosage of clozapine. Fever during clozapine maintenance treatment may also require monitoring of white blood count, C-reactive protein, and serum creatine-kinase concentrations to rule out serious conditions.

References

1. Gerasimou C, Vitali GP, Vavougios GD, et al. Clozapine associated with autoimmune reaction, fever and low level cardiotoxicity – a case reportIn Vivo. 2017;31(1):141-144.

2. Verdoux H, Quiles C, de Leon J. Clinical determinants of fever in clozapine users and implications for treatment management: A narrative review [published online August 1, 2019]. Schizophr Res. doi: 10.1016/j.schres.2019.07.040

This article originally appeared on Psychiatry Advisor