title: Role of cytokine changes in clozapine-induced fever: A cohort prospective study.
abstract: OBJECTIVE
  Clozapine-associated fever is common but the specific cytokine changes and treatment durations that may cause fever remain unknown. We investigated the association between inflammatory cytokine changes and clozapine-induced fever in patients who were treated with clozapine.
  
  
  METHODS
  Forty-three patients with schizophrenia or schizoaffective disorder, diagnosed by using the Chinese Version of the Mini International Neuropsychiatric Interview, were treated with clozapine for the first time (first-time use group, n = 22) or for more than 6 months (long-term use group, n = 21). The Positive and Negative Syndrome Scale, tympanic temperature, and levels of tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ), interleukin-2 (IL-2), and interleukin-6 (IL-6) were determined at baseline and weeks 1, 2, 3, 4, and 6. A multiple linear regression with generalized estimating equation methods was used to analyze the association between the changes in the cytokine levels and clozapine-induced fever in the different groups.
  
  
  RESULTS
  The IL-6 level changes were significantly different between the two groups (P = 0.04). In the first-time use group, the fever rate was increased (47.1%) compared with the long-term use group (5.6%, P = 0.005). Moreover, in these patients, the TNF-α, INF-γ, IL-2, and IL-6 levels were significantly (P < 0.001) different from patients who did not develop a fever. An interaction effect with the different treatment duration groups and fever development was only significant for IL-6 (P < 0.001).
  
  
  CONCLUSIONS
  Patients who were treated with clozapine for the first time have an increased rate of developing a fever, and IL-6 might have a specific role in the interaction effect between treatment duration and fever development.
authors.affiliation: Department of Internal Medicine, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan.
authors.forename: Yuan-Pin
authors.initials: YP
authors.lastname: Hung
authors.affiliation: Department of Psychiatry, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan.|Department of BioMedical Engineering, National Cheng Kung University Hospital, College of Medicine, Tainan, Taiwan.
authors.forename: Carol S-M
authors.initials: CS
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan.
authors.forename: Chia-Nan
authors.initials: CN
authors.lastname: Yen
authors.affiliation: Department of Psychiatry, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan.
authors.forename: Hsun-Cheng
authors.initials: HC
authors.lastname: Chang
authors.affiliation: Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, Tainan, Taiwan.|Addiction Research Center, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Po See
authors.initials: PS
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, Tainan, Taiwan.|Addiction Research Center, National Cheng Kung University, Tainan, Taiwan.
authors.forename: I Hui
authors.initials: IH
authors.lastname: Lee
authors.affiliation: Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, Tainan, Taiwan.|Addiction Research Center, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Kao Chin
authors.initials: KC
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, Tainan, Taiwan.|Addiction Research Center, National Cheng Kung University, Tainan, Taiwan.|Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Department of Psychiatry, National Cheng Kung University Hospital, Dou-Liou Branch, Yunlin, Taiwan.
authors.forename: Yen Kuang
authors.initials: YK
authors.lastname: Yang
authors.affiliation: Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, Tainan, Taiwan.|Addiction Research Center, National Cheng Kung University, Tainan, Taiwan.|Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Allied Health Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan.
authors.forename: Ru-Band
authors.initials: RB
authors.lastname: Lu
authors.affiliation: Department of Psychiatry, National Cheng Kung University Hospital, College of Medicine, Tainan, Taiwan.
authors.forename: Tzu-Yun
authors.initials: TY
authors.lastname: Wang
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects; D003024:Clozapine / Q000009:adverse effects*; D005260:Female; D005334:Fever / Q000097:blood / Q000139:chemically induced*; D006801:Humans; D007371:Interferon-gamma / Q000097:blood*; D007376:Interleukin-2 / Q000097:blood*; D015850:Interleukin-6 / Q000097:blood*; D008297:Male; D011446:Prospective Studies; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D007376:Interleukin-2; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D003024:Clozapine
keywords: clozapine; clozapine adverse effect; cytokines; drug-induced fever; immune modulation