Effects of antipsychotic drugs on cytokine networks

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Abstract

It has been known since the 1950s that phenothiazines have immunomodulatory effects. This review summarizes recent evidence suggesting that antipsychotic drugs, in particular chlorpromazine and the atypical compound clozapine, influence the production of cytokines. Cytokines, organized in networks of related peptides with pleiotropic functions, are pivotal humoral mediators of infection and inflammation, and they play an important role in hematopoiesis and autoimmunity. Therefore, the effects of antipsychotic drugs on cytokine networks are important for the understanding of immune-mediated side effects of these drugs, e.g. agranulocytosis. In addition, modulation of cytokine production by antipsychotic agents suggests that these drugs might be useful for the treatment of diseases which primarily involve the immune system. Moreover, because cytokines are known to have numerous effects on the CNS, they may mediate effects of antipsychotic drugs on brain functions. Finally, the influence of antipsychotic drugs on cytokine networks is an important confounding factor in studies investigating disease-related immunopathology in psychiatric disorders. This review provides a synopsis of the data published on these topics and outlines future research perspectives.

Introduction

Immunomodulatory effects of antipsychotic medication have been discovered already in the 1950s. Shortly after the introduction of chlorpromazine into clinical practice this drug was shown to protect mice from endotoxin-induced sepsis-like shock (Chedid, 1954). In parallel chlorpromazine was reported to have tuberculostatic effects in humans (Geiger and Finkelstein, 1954, Fisher and Teller, 1959, Maccagnani, 1959). In addition, side effects of chlorpromazine and other phenothiazines, such as agranulocytosis (Pisciotta, 1969), thrombocytopenia (Zucker et al., 1990), and the induction of systemic lupus erythematodes (Dubois et al., 1972, Ananth and Mimi, 1973) support the view that this class of antipsychotic drugs are potent modulators of immune functions.

The dibenzodiazepine clozapine, the prototype of atypical or second generation antipsychotic drugs, induces agranulocytosis in about 1% of patients treated (Alvir et al., 1993). Although the underlying mechanisms are not yet fully understood, an involvement of the immune system is very likely (Pisciotta et al., 1992, Pisciotta and Konings, 1994, Corzo et al., 1995, Turbay et al., 1997). In addition, clozapine induces transient fever in up to 50% of patients treated (Blum and Mauruschat, 1972, Pollmächer et al., 1996), and metabolites of clozapine have potent antiretroviral effects in vitro (Jones-Brando et al., 1997). Moreover, some cases of pancreatitis (Bergemann et al., 1999, Cerulli, 1999), parotitis (Robinson et al., 1995, Hinze-Selch et al., 1996, Southall et al., 1999) and myocarditis (Killian et al., 1999) have been reported during clozapine therapy, further supporting the idea that this drug has immunomodulatory properties.

Although chlorpromazine and clozapine differ with respect to their chemical structure, neurotransmitter binding profile and clinical effects, both drugs may influence the immune system through similar pathways: recently it was discovered that both, chlorpromazine (Bertini et al., 1993, Mengozzi et al., 1994, Tarazona et al., 1995) and clozapine (Maes et al, 1994, Pollmächer et al., 1995a, Pollmächer et al., 1996, Monteleone et al., 1997, Hinze-Selch e al., 1998) affect cytokine networks. Cytokines constitute a heterogeneous class of endogenous peptides that are released mainly by immunocompetent cells and orchestrate their interaction. They are of crucial importance for inflammation and host responses to infection (Burell, 1994, Kerksiek and Palmer, 1999), for hematopoiesis (Socolovsky et al., 1998) and autoimmune processes (Cope, 1998, Falcone et al., 1999). Therefore, it is likely that altered cytokine production during treatment with antipsychotic drugs is involved in the immune-related side effects of phenothiazines and of clozapine. On the other hand, the modulation of cytokine secretion by antipsychotic drugs indicates a therapeutic potential beyond clinical psychiatry. Moreover, cytokine release during antipsychotic treatment may be involved in the drugs' effects on the central nervous system (CNS). Cytokines signal to the brain peripheral host defense activation and mediate CNS-dependent host responses such as fever (Kluger, 1991) and neuroendocrine activation (Turnbull and Rivier, 1999) during infection and inflammation. In addition, cytokines mediate host defense-induced changes in sleep-wake behavior (Krueger et al., 1995, Pollmächer et al., 200b) suggesting that they are potent modulators of complex brain functions.

At the end of the 19th century the psychiatrist and Nobel prize laureate Wagner-Jauregg reported on beneficial effects of acute infections and experimental fever on symptoms of psychiatric disorders (Wagner, 1887). Although this issue has never been investigated systematically, there is recent evidence that cytokines released during infections indeed may positively affect psychopathology. Bauer et al. (1995) injected depressed patients with bacterial endotoxin, the major cell-wall component of gram-negative bacteria. They found, in parallel with increased circulating amounts of inflammatory cytokines, a transient improvement in depressive symptomatology. Hence, it should be considered that the effects of antipsychotic agents on cytokine production might be involved in the drugs' effects on complex brain functions, including sleep-wake behavior and psychopathology.

This idea gains further importance from an additional perspective. It has been discussed since decades that the immune system plays an etiological role in depression and schizophrenia (Yolken and Torrey, 1995). In this context it has been hypothesized that antipsychotic treatment is effective, at least in part, by counteracting preexisting immunopathology (for review see Müller and Ackenheil, 1998) which involves cytokines. However, it must also be considered that immunopathology observed in psychiatric patients might not be related to the disease process itself, but might be induced by psychotropic treatment.

The present review will begin with a short overview of cytokine networks with special reference to aspects important for the present topic. Then, the methods available to investigate the effects of antipsychotic drugs on these networks will be outlined. The effects of phenothiazines and clozapine will be described in detail, and the scanty knowledge about the effects of other antipsychotics will be summarized. Thereafter, the effects of antipsychotic drugs on cytokine networks will be discussed from four perspectives: (1) the mechanisms underlying side-effects of treatment with antipsychotics; (2) the implications for therapeutic use of antipsychotic drugs outside clinical psychiatry; (3) their possible significance for the effects of antipsychotic drugs on the CNS; and (4) the potential of antipsychotic drugs to confound the results of studies aimed at investigating disease-related immunopathology in psychiatric disorders. Finally, some perspectives of future research in these areas will be outlined.

Although this paper is based on extensive literature research in the major electronic databases up to May 2000, this is a selective review in the sense that in general only studies were included that addressed the influence of particular drugs on cytokine networks. Hence, some studies have been omitted which point to effects of medication in general, but do not allow to conclude for specific substances to be involved.

Section snippets

Cytokine networks, the immune system and the brain

The immune system (for a short overview see Haynes and Fauci, 1998) is an omnipresent functional entity composed of immunocompetent cells and humoral factors (Table 1). In addition, specialized organs (bone marrow, thymus, spleen, Peyer's patches, tonsils, lymph nodes and lymph vessels) provide a matrix for the differentiation, maturation and action of immunocompetent cells.

Independently of the basic dichotomy between cellular and humoral immunity the immune system is composed of non-specific

Methods to investigate the influence of antipsychotic drugs on cytokine networks

There are numerous experimental approaches to study the influence of antipsychotic drugs on cytokine networks. In principle, in vivo and in vitro approaches can be distinguished, and each of these can be used to study different aspects such as spontaneous and stimulated production, secretion or shedding of cytokines and their soluble receptors.

Not surprisingly, each approach has advantages and disadvantages. In vivo approaches are more relevant to the clinical situation, because dealing with

Effects of phenothiazines on cytokine production in animals

Numerous studies have investigated the effects of phenothiazines, in particular of chlorpromazine, on stimulated cytokine production in intact animals of various species. The most consistent result was an inhibition of TNF-α release induced by different stimuli. Chlorpromazine inhibited the endotoxin-induced increase in circulating TNF-α in calves (Ohtsuka et al., 1997) and mice (Bertini et al., 1989, Bertini et al., 1993, Gadhini et al., 1991, Gatti et al., 1993, Mengozzi et al., 1994, Netea

Effects of clozapine in vivo

The effects of clozapine (Blum and Mauruschat, 1972) on cytokine networks in vivo have been investigated so far exclusively in patients suffering from schizophrenia. It has been reported that clozapine increases the levels of sIL-2R, but not of sIL-6R (Maes et al, 1994, Pollmächer et al., 1995a). Shortly thereafter it was found that clozapine, in addition, increases the plasma levels of TNF-α and both sTNF-Rs (Pollmächer et al., 1996). These increases occurred within the first week of treatment

Effects of other antipsychotic drugs on cytokine networks

Olanzapine is an antipsychotic drug that was recently approved for the treatment of schizophrenia (Beasley et al., 1996). It shares with clozapine similarities in chemical structure and in the neurotransmitter receptor binding profile. Clinical data show that olanzapine has a low potential to induce extrapyramidal side effects (Stephenson and Pilowsky, 1999), suggesting that this drug, like clozapine, might classify as an atypical antipsychotic. Olanzapine induces weight gain to a comparable

Mechanisms underlying the effects of antipsychotics on cytokine networks

The mechanisms underlying the influence of antipsychotic drugs on cytokine production at the cellular and subcellular level are not known. Only with respect to chlorpromazine there have been some attempts to unravel these mechanisms. It is tempting to hypothesize that the drug's blocking effects on dopaminergic, serotoninergic, cholinergic, adrenergic, or histaminergic neurotransmitter receptors are of importance, which all are present on immunocompetent cells (Blalock, 1989). However, although

Cytokines and immunological side-effects of antipsychotics

There is no doubt that cytokines are involved in any kind of immunological process. Hence, it is very likely that the effects of antipsychotic drugs on cytokine production are linked to the drugs' immunological side effects. However, the details of this link have been hardly explored so far. Suppressed stimulated proinflammatory cytokine production in chlorpromazine-treated mice, and the concomitant increased production of the anti-inflammatory cytokine IL-10 (Tarazona et al., 1995) fit quite

Perspectives of future research about the influence of antipsychotics on cytokine networks

In our view there are four major areas that deserve intensive future research:

  • 1.

    On a descriptive level it is desirable to characterize as many psychotropic agents as possible with respect to their effects on cytokine production. To get a complete picture, those investigations ideally should measure the circulating amounts of cytokines and soluble cytokine receptors, and, in addition, characterize the drugs' effects on stimulated cytokine production of immunocompetent cells in vitro.

  • 2.

    It will be

Acknowledgments

We would like to acknowledge the support of the Volkswagenstiftung, Hannover, Germany (grant # 1/71979).

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