Effects of clozapine and olanzapine on cytokine systems are closely linked to weight gain and drug-induced fever
Introduction
The second generation antipsychotic drugs clozapine and olanzapine are dibenzodiazepines that share similar structures and receptor binding profiles (Bymaster et al., 1996). The side effect profile, in contrast, is only partly similar: Whilst weight gain is very common in both treatments, drug-induced fever and agranulocytosis are very frequent or occasional side effects with clozapine but are not reported or reported very rarely with olanzapine (Pollmächer et al., 1996, Allison et al., 1999, Tollefson et al., 2001, Tham and Dickson, 2002, Su et al., 2007).
Inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), have been implicated in weight gain (Zimmermann et al., 2003) on the one hand and drug-induced fever (Conti et al., 2004) and agranulocytosis (Turbay et al., 1997) on the other: TNF-α plasma levels have been shown to be elevated in obese patients and to decline with weight loss (Dandona et al., 1998, Bruun et al., 2002). Also, soluble tumor necrosis factor receptors 1 and 2 (sTNFR-1, sTNFR-2) levels were correlated with weight in obese patients (Hauner et al., 1998, Bulló et al., 2002, Ziccardi et al., 2002) as well as in the general population (Himmerich et al., 2006b). Similarly, weight gain with clozapine was associated with an increase of TNF-α, sTNFR-1 and sTNFR-2 levels (Hinze-Selch et al., 2000a). In a small study, weight gain with olanzapine was associated with significant increases of sTNFR-1 and sTNFR-2, but not of TNF-α (Schuld et al., 2000). A more recent study reported a decrease of TNF-α (Baptista et al., 2007). Furthermore, interleukin-6 (IL-6) has been shown to be increased in obese men compared to lean controls and to decline after weight loss (Bastard et al., 2000, Ziccardi et al., 2002, Bruun et al., 2003). Treatment with clozapine (Pollmächer et al., 1996, Maes et al., 1997) but not olanzapine (Schuld et al., 2000) was associated with increased IL-6 levels. In addition, IL-6 and other cytokines have 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 (Conti et al., 2004). Likewise, soluble interleukin-2 receptors (sIL-2R) were increased in several types of fever (Erken et al., 1996, Mansueto et al., 1997). Treatment with clozapine (Maes et al., 1994, Pollmächer et al., 1995, Maes et al., 1997) but not olanzapine (Schuld et al., 2000) was associated with increased plasma levels of sIL-2R. Furthermore, an involvement of TNF-α in the pathophysiology of clozapine induced agranulocytosis has been suggested (Turbay et al., 1997). Thus, both drugs are associated with an increase of inflammatory cytokines and weight. In contrast, drug-induced fever and agranulocytosis commonly occur only with clozapine.
Leptin, an anorexigenic protein hormone produced by adipocytes in relation to the amount of total body fat, plays a crucial role in weight regulation by signaling the size of adipose tissue to the hypothalamus (Harvey and Ashford, 2003). Leptin is increased in obese subjects and decreases with weight loss and vice versa (Hebebrand et al., 1997; van Dielen et al., 2002). Weight gain induced by clozapine (Brömel et al., 1998, Kraus et al., 1999, Hägg et al., 2001, Wehmeier et al., 2005) and olanzapine (Kraus et al., 1999, Melkersson et al., 2000, McIntyre et al., 2003) was also associated with an increase of plasma leptin. In addition, leptin appears to be part of the immune response system. For example, it acts on monocytes by inducing the synthesis of eicosanoids and cytokines. Furthermore, leptin levels were elevated during infection and inflammation (Otero et al., 2005).
All information on the effects of antipsychotic drugs on cytokines and leptin was gained from un-randomized pre–post comparisons and cross sectional studies. In this randomized, double-blind study, we aimed to test the hypothesis that weight gain, a side effect frequently occurring with both clozapine and olanzapine, and drug-induced fever being rather unique to clozapine, reflect in differential immunoendocrine secretion patterns of both drugs.
Section snippets
Patients
Inpatients between 18 and 65 years, who met DSM-IV criteria for schizophrenia, schizophreniform disorder or schizoaffective disorder were screened. Inclusion criteria included a Brief Psychiatric Rating Scale (BPRS)0–6 score of ≥24. Patients with a serious, unstable physical illness, uncorrected hypothyroidism, narrow-angle glaucoma, leukopenia, history of one or more seizures, current jaundice, substance use disorder, or any concomitant medication with primary activity on the central nervous
Patient demographics
Thirty-seven patients were screened and 30 patients randomized (18 females). Four patients discontinued the study prematurely (Fig. 1). Patients’ demographic and clinical data at baseline are shown in Table 1. Except for one patient in the olanzapine group, all patients had been treated with an antipsychotic medication before the wash-out period; type and frequency of antipsychotics used were comparable in both groups (predominantly: risperidone, haloperidol). None of the patients had received
Discussion
This is, to our knowledge, the first randomized double-blind study comparing immunomodulatory effects of antipsychotic drugs, namely clozapine and olanzapine. There are three main findings from this study:
- 1.
Both drugs activated cytokine systems, but in different ways. Clozapine activated cytokine systems to a greater extent than olanzapine. With both treatments, cytokines showed maximum plasma levels after about 3 weeks of treatment. There was no linear increase of plasma levels.
- 2.
BMI and skinfold
Role of the funding sources
The study was funded by the Lilly Deutschland GmbH, Bad Homburg, Germany. Lilly was not involved in the interpretation of data, writing the manuscript, or in the decision to submit the paper for publication.
Conflict of interest
Alexander Schacht, Peter M. Wehmeier and Ralf W. Dittmann are full-time employees of Lilly Deutschland GmbH. Ralf W. Dittmann is stockholder of Eli Lilly and Company. Michael Kluge, Andreas Schuld, Hubertus Himmerich, Mira Dalal, Dunja Hinze-Selch, Thomas Kraus and Thomas Pollmächer have nothing to disclose.
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