Taiwanese Journal of Psychiatry

: 2019  |  Volume : 33  |  Issue : 4  |  Page : 225--226

Enhanced treatment response of clozapine after febrile infection

Yu-Ming Chen, Tiao-Lai Huang 
 Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital; Department of Psychiatry, Chang Gung University College of Medicine, Kaohsiung, Taiwan

Correspondence Address:
Tiao-Lai Huang
123, Ta-Pei Road, Niao-Sung, Kaohsiung 833

How to cite this article:
Chen YM, Huang TL. Enhanced treatment response of clozapine after febrile infection.Taiwan J Psychiatry 2019;33:225-226

How to cite this URL:
Chen YM, Huang TL. Enhanced treatment response of clozapine after febrile infection. Taiwan J Psychiatry [serial online] 2019 [cited 2022 Jan 27 ];33:225-226
Available from: http://www.e-tjp.org/text.asp?2019/33/4/225/273857

Full Text

Clozapine is often considered as a “gold-standard” medication for treatment-resistant psychosis [1]. But clozapine has many adverse effects including agranulocytosis, seizures, myocarditis, diabetes, and neuroleptic malignant syndrome [2]. The development of fever is also common in patients treated with clozapine [3].

Fever as a treatment for psychotic symptoms was broadly used in the early 20th century, termed pyrotherapy or pyretotherapy. Initially, the Nobel Prize winner Wagner-Jauregg reported a beneficial effect for patients with neurosyphilis after fever attack through inoculating blood from malaria patients [4]. But the trend has been decreased after the discovery of penicillin and the introduction of convulsion therapies such as electroconvulsive therapy and insulin coma therapy.

Here, we present a 49-year-old female patient with schizoaffective disorder who showed an increased response to clozapine after she recovered from fever and pneumonia. Both of her psychotic symptoms and mood condition were improved.

 Case Report

This 49-year-old female patient had a medical history of bipolar disorder since 18 years ago. She was hospitalized because of the decreased need for sleep, elevated mood, irritability, grandiosity, auditory hallucination, and referential delusion. The initial Positive and Negative Syndrome Scale scores were 97, and the Young Mania Rating Scale scores 45. The patient presented herself with persisted persecutory delusion and poor response to 20 mg/day of olanzapine. Therefore, we shifted olanzapine to clozapine on hospitalization day 20. We titrated clozapine upward gradually from 25 to 100 mg/day in five days and prescribed 1,000 mg/day of valproate as a mood stabilizer. After 14 days, she developed hospital-acquired pneumonia with high-grade fever and septic shock. Although the patient's valproate level (serum levels = 104 μg/mL) was only slightly greater than the therapeutic level, she presented herself with obvious valproate intoxication symptoms including toxic hepatitis, central nervous system depression, drowsiness, intermittent psychomotor agitation, hyperthermia, hypotension, and respiratory depression. Naranjo scores were eight, indicating probable adverse drug reaction of valproate. Valproate intoxication was highly suspected. She did not have sialorrhea and choking symptom after her receiving clozapine during hospitalization. Therefore, the possibility of developing aspiration pneumonia due to clozapine was relatively low.

We discontinued all psychiatric drugs, and the patient was transferred to the intensive care unit for closed observation. She received antibiotic and supportive therapy. Fever was subsided gradually, and her condition became stabilized; thus, she was transferred back to the psychiatric ward. We added back 50 mg/day of clozapine and 700 mg/day of valproate gradually (rechecked valproate serum level = 6,807 μg/mL). Although clozapine dose was reduced compared to the initial dose, she showed less psychotic symptoms and an increased response to clozapine. After 10 days, her irritability and elevated mood were also improved. Rechecked the Positive and Negative Syndrome Scale scores were 45, and the Young Mania Rating Scale scores 20.


Although the effect of fever on developing psychosis has been reported [5], little attention has been given to the therapeutic effect of fever on psychotic symptoms. In this case, the patient showed improved psychotic symptoms and a better response to clozapine after she recovered from febrile pneumonia. Fever episode is to play a rôle in the resolution of psychotic and mood symptoms. Although she also took valproate and benzodiazepine, the disease course suggests the rôle of fever in improving psychosis. This result is consistent with other reports with decreased psychotic symptoms after a fever attack [6].

Despite the beneficial effect of fever on psychotic symptoms, the physiological mechanisms of this phenomenon are not much clarified. Wagner-Jauregg supposed that this finding can be explained by the different influence of bacterial toxins or bacterial proteins. But this hypothesis was not further studied [7]. In the 1950s, the effect of fever on the hypothalamic–pituitary–adrenal axis (HPA-axis) has been studied, revealing that fever can stimulate the HPA axis directly to discharge adrenocorticotropic hormone and cortisol, being considered responsible for the treatment effect of fever to improve neurosyphilis [8]. The focus of recent study has been on the influence of neurotransmitters. Oruch et al. indicated that blockade of dopamine induces neuroleptic malignant syndrome [9]. Singh et al. found that fever induced by sulforaphane (a phytochemical derived from vegetables) can increase the biosynthesis of heat shock proteins, in improving the behaviors of autism patients [10]. But little attention has been directed toward a mechanism of treatment potential of fever for improving psychotic symptoms.

The readers are cautioned not to overinterpret the clinical observation because this clinical report has three major limitations:

We could not exclude the augmentation effect of clozapine from other infection-associated factors such as weakness, lethargy, and endotoxin. Fever is probably not the only principal factor. The previous case reports and research have mostly focused on therapeutic effect of fever on psychotic symptoms. Further surveys of influences of infection-associated symptoms on psychosis and mood are needed for clarification of possible pathophysiology.The observation period in the patient in this case report is only 10 days, which is too short for a definite observation. Although she showed stable mood after discharge, a longer observation period is important for confirming augmentation effect of fever.While few studies have been published concerning the benefit of fever on relieving psychosis, further research to understand possible biopsychological mechanism should be conducted.

On the other hand, another interesting topic to be considered is to examine the potential noninfectious pyogenic agent (like the aforementioned sulforaphane) as a reserve or adjunctive treatment for refractory psychosis.

In summary, the patient in our report showed an increased response to clozapine after she recovered from fever and severe sepsis. The febrile condition is potentially to play a rôle in reducing psychotic symptoms. The real mechanism between fever and improvement of psychotic symptoms is needed to be further clarified in future studies. This study was approved by the institutional review board of Chang Gung Memorial Hospital for publication without the need of obtaining the informed consent from the patient (protocol number = 201601169B0 and approval date = October 11, 2016).

 Financial Support And Sponsorship

This study was supported by a clinical research grant from Chang Gung Memorial Hospital (CMRPG8F1462), Taiwan.

 Conflicts Of Interest

All authors declare no conflicts of interest in writing this case report.


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