Inflammation: its role in schizophrenia and the potential anti-inflammatory effects of antipsychotics

Abstract

Over the last few years, inflammation has made a major comeback as a pathogenic theory of schizophrenia. Its effects on monoamine metabolism, neuroendocrine function, and synaptic plasticity have all been proposed as potential pathways mediating the link between inflammation and schizophrenia (Haroon et al. 2012). Further support for a link between activation of the immune system and schizophrenia is seen in this month's issue of Psychopharmacology, where Song et al. report high levels of interleukin (IL)1β, IL6 and tumour necrosis factor (TNF)α in drug naive-first episode schizophrenia patients when compared with healthy controls matched for age, gender, smoking status, and bodymass index (Song et al. 2013). These findings extend a growing body of literature on inflammation in schizophrenia by giving a better insight on longitudinal changes in cytokine levels in the context of treatment with antipsychotics. Recent reviews and meta-analysis of the literature show that increased blood levels of IL1β, IL6 and TNFα are consistently reported in patients at the onset of this disorder (Di Nicola et al. 2013; Miller et al. 2011; Mondelli et al. 2011). However, how much of these peripheral abnormalities reflect central inflammation and contribute to the development of schizophrenia remains still debated. Indeed, while the evidence of increased peripheral immune activation in schizophrenia has become more consistent over the years, the presence of a neuroinflammatory state in these patients has been the object of more controversy. Post-mortem studies in subjects with schizophrenia have reported mixed findings, possibly in relation also to some methodological issues; most postmortem studies have been conducted on relatively small samples, included mainly elderly subjects in whom incidental lesions are common, and have used different methods for counting astrocytes and microglia (Schnieder and Dwork 2011). Nevertheless, more recent studies quantifying microglia activation in vivo, by using positron emission tomography, have reported increased microglia activation (Doorduin et al. 2009; van Berckel et al. 2008) supporting the role of neuroinflammation in the pathophysiology of schizophrenia. Interestingly, cytokine abnormalities differ between acute and stable phases of schizophrenia, suggesting either that some cytokines could be influenced by antipsychotic treatment or that these differences may reflect different stages of illness (Miller et al. 2011). Studies on the effect of antipsychotic treatment on inflammation, and more specifically on cytokine levels, have so far given mixed findings, showing an increase, a decrease, or unchanged levels of cytokines after antipsychotic treatment (reviewed by Zajkowska and Mondelli 2013). One potential explanation for the mixed findings is that antipsychotic agents might exert different effects on the immune system, having both a direct antiinflammatory activity and an indirect pro-inflammatory activity, mediated by their effect on weight-gain and increased adiposity. Interestingly, this dual antiand pro-inflammatory action of antipsychotics is supported by the longitudinal study from Song et al., who observed a decrease in IL1β and IL6 levels in the first weeks of treatment with risperidone, followed by an increase back to baseline levels by the end of 6 months treatment, which happened alongside a steady weight gain (Song et al. 2013). The findings suggest that when V. Mondelli Institute of Psychiatry, Department of Psychological Medicine, King’s College London, London, UK