Effects of clozapine and olanzapine on cytokine systems are closely linked to weight gain and drug-induced fever

Kluge, Michael; Schuld, Andreas; Schacht, Alexander; Himmerich, Hubertus; Dalal, Mira A.; Wehmeier, Peter M.; Hinze-Selch, D.; Kraus, Thomas; Dittmann, Ralf W.; Pollmächer, Thomas

doi:10.1016/j.psyneuen.2008.08.016

Cited by 124 publications

(82 citation statements)

References 70 publications

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“…Elevated levels of CSF IL 6 were not associated with age, sex, BMI or smoking habits or with any of the metabolic parameters measured, such as plasma levels of glucose, insulin, cholesterol and triglycerides. Further more, in line with previous studies, 32,33 treatment with olan zapine appeared not to influence IL 6, as CSF or serum levels of olanzapine did not correlate with CSF IL 6.…”

Section: Discussionsupporting

confidence: 89%

Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia — significance for activation of the kynurenine pathway

Schwieler

Larsson

Skogh

et al. 2015

jpn

188

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IntroductionThe role of immune activation in schizophrenia has received increasing interest in recent years. Epidemiological studies have shown that infections and autoimmune diseases are clin ic ally important risk factors for the development of schizo phrenia. [1][2][3] Furthermore, a recent study integrating results from a meta analysis of genome wide association studies in schizophrenia found that the most significant changes were observed in genetic loci related to the immune system. 4 Also, patients with schizophrenia show microglial activation, as re vealed by positron emission tomography. 5,6 Further, postmor tem studies using messenger RNA (mRNA) expression or im munohistochemical detection have shown increased levels of immune related compounds. 7-9 A number of investigations have focused on cytokines, but these studies have not yielded a unanimous picture, possibly because of a number of con founding factors, such as smoking and dietary habits, body mass index (BMI), type and duration of antipsychotic treat ment and drug abuse -all factors potentially affecting the Background: Accumulating evidence indicates that schizophrenia is associated with brain immune activation. While a number of reports suggest increased cytokine levels in patients with schizophrenia, many of these studies have been limited by their focus on peripheral cytokines or confounded by various antipsychotic treatments. Here, well-characterized patients with schizophrenia, all receiving olanzapine treatment, and healthy volunteers were analyzed with regard to cerebrospinal fluid (CSF) levels of cytokines. We correlated the CSF cytokine levels to previously analyzed metabolites of the kynurenine (KYN) pathway. Methods: We analyzed the CSF from patients and controls using electrochemiluminescence detection with regard to cytokines. Cell culture media from human cortical astrocytes were ana lyzed for KYN and kynurenic acid (KYNA) using high-pressure liquid chromatography or liquid chromatography/mass spectrometry. Results: We included 23 patients and 37 controls in our study. Patients with schizophrenia had increased CSF levels of interleukin (IL)-6 compared with healthy volunteers. In patients, we also observed a positive correlation between IL-6 and the tryptophan:KYNA ratio, indicating that IL-6 activates the KYN pathway. In line with this, application of IL-6 to cultured human astrocytes increased cell medium concentration of KYNA. Limitations: The CSF samples had been frozen and thawed twice before analysis of cytokines. Median age differed between patients and controls. When appropriate, all present analyses were adjusted for age. Conclusion: We have shown that IL-6, KYN and KYNA are elevated in patients with chronic schizophrenia, strengthening the idea of brain immune activation in patients with this disease. Our concurrent cell culture and clinical findings suggest that IL-6 induces the KYN pathway, leading to increased production of the N-methyl-d-aspartate receptor antagonist KYNA in patients with schizophrenia.

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Section: Discussionsupporting

confidence: 89%

Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia — significance for activation of the kynurenine pathway

Schwieler

Larsson

Skogh

et al. 2015

jpn

188

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“…Clozapine-induced-fever is a common side-effect, with an incidence of 0.5% to 55% (9, 10) and there seems to be a close correlation between fever and the first step of clozapine medication. Recent reports suggest that clozapine stimulates the production of pro-inflammatory cytokines including TNFα, IL1 and IL6 (3,4,11). These have also been implicated in causing myocardial depression by direct actions on the myocytes (12).…”

Section: Discussionmentioning

confidence: 99%

Clozapine Associated with Autoimmune Reaction, Fever and Low Level Cardiotoxicity – A Case Report

Gerasimou

Vitali

Vavougios

et al. 2017

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Clozapine is a second-generation antipsychotic drug used in treatment-resistant schizophrenia (1, 2). Despite its effectiveness, this drug is not without adverse effects, highgrade fever and cardiotoxicity being among them, through its immunomodulatory effects (3). Clozapine-induced fever has been reported by several studies and a number of plausible explanations for the induction of fever exist including the implication of the immune-modulating effect by increasing soluble tumor necrosis factor (TNF) receptor p55, p75 and soluble interleukin-2 (IL2) receptor (4, 5). IL6 has also been suggested to induce fever by elevating the set point of body core temperature via temperature-sensitive neurons in the preoptic area of the hypothalamus (6), for example as a result of pyrogenic cytokines (7). Likewise, drug-induced cardiotoxicity has many underlying mechanisms, affecting the heart directly and, in other cases, indirectly, including the enhancement of immunological reactions, cell apoptosis, formation of free radicals and alterations of hemodynamic flow. Several preclinical and clinical reports have shown the relation of a high incidence of clozapine-induced myocarditis (3,4,8) with immunological-mediated mechanisms.Here we present the case of a 31-year-old Caucasian male with refractory schizophrenia who developed benign fever, increase of C-reactive protein (CRP) and high sensitivity (Hs)-troponin levels, without presenting any other signs of myocarditis, on the 13th day under clozapine treatment, all of which declined progressively upon discontinuation of the drug. Case ReportA 31-year-old Caucasian male with no significant past medical history, besides heavy smoking and abusing marijuana, was 141

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“…To the author's knowledge, there are no pharmacogenetic studies that have investigated the role of the interleukin family of cytokines in AIWG. Instead, studies of inflammatory involvement are often serologic, and thus, rooted in serum quantification of cytokine protein levels [442][443][444] .…”

Section: Future Directionsmentioning

confidence: 99%

The role of genetic variation across IL-1β, IL-2, IL-6, and BDNF in antipsychotic-induced weight gain

Fonseka

Tiwari

Gonçalves

et al. 2015

The World Journal of Biological Psychiatry

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Effects of clozapine and olanzapine on cytokine systems are closely linked to weight gain and drug-induced fever

Cited by 124 publications

References 70 publications

Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia — significance for activation of the kynurenine pathway

Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia — significance for activation of the kynurenine pathway

Clozapine Associated with Autoimmune Reaction, Fever and Low Level Cardiotoxicity – A Case Report

The role of genetic variation across IL-1β, IL-2, IL-6, and BDNF in antipsychotic-induced weight gain

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