Cytokine function in medication-naive first episode psychosis: A systematic review and meta-analysis

Abstract

This systematic review sets out to give a comprehensive overview of the cytokine profile at the onset of psychosis un-confounded by medication. We aim to provide insight into the early pathophysiological process of psychosis and areas for future research of potential biomarkers able to chart the extent of illness or effectiveness of treatment.

Following PRISMA guidelines, a systematic primary search identified 4638 citations, 4651 studies were retrieved and screened, and 23 studies met the inclusion criteria (published in English before June 2013, patients with neuroleptic naive first episode psychosis, and assessed circulating cytokines). These reported 570 patients, 683 healthy control subjects, and 20 cytokine/cytokine receptors. Papers that contained sufficient stratified data were included in a random-effects pooled effect size meta-analysis.

Highly significant effect sizes were found for elevated IL-1β, sIL-2r, IL-6, and TNF-α. Non-significant effect size estimates were obtained for IL-2, IL-4, and IFN-γ.

Thus, we found significant elevation in pro-inflammatory cytokine levels in the serum of patients with medication-naive first episode psychosis. This adds to the evidence of a pro-inflammatory immune deregulation in schizophrenia and suggests these cytokines should be the focus for further research in biomarkers of progress and extent of illness. Future studies should focus on the medication-naive group at the early stages of illness with numbers large enough to allow for the control of other potential confounding factors.

Introduction

Schizophrenia is currently understood as a debilitating neurodevelopmental disorder that appears at a critical period in early adulthood (Gilmore and Murray, 2006, van Os and Kapur, 2009). In recent times, there has been an increased interest into the study of prodromal stages of this disorder and the evolution to clinically significant psychosis (Malla et al., 2002). However, the underlying pathophysiological cause of schizophrenia in its early stages is essentially unknown. The vast majority of biological research into the pathogenesis of schizophrenia has focused on neurotransmitter abnormalities in established disorder (Aghajanian and Marek, 2000, Jones et al., 2005). There is also evidence for genetic predisposition (Craddock and Owen, 2005), viral infections (Bradbury and Miller, 1985), and obstetric complication (Gilmore and Murray, 2006). Increasing evidence, however, also suggests a role of immunological processes. Indeed, schizophrenia has been associated with an abnormal activation of the immune system for many years (Dameshek, 1930, Schwarz, 2007, Miller et al., 2011, Müller, 2011).

The immune response is a highly coordinated process involving an array of cell types, normally protecting the body from harm, such as from pathogens or cancerous cells, while maintaining tolerance to harmless or beneficial organisms. The first arm is our “innate” defence mechanism, which is older in evolutionary terms and considered to be a first line defence. Its cellular components include neutrophils, basophils, eosinophils, monocytes macrophages, dendritic cells, and natural killer (NK) cells. These recognize and promote defence against pathogens but lack the sophistication to adapt compared to other more recent additions to the immune system. The innate humoral component is made up of acute phase proteins and the compliment cascade, which allow phagocytic cells to clear pathogens from an organism and various cytokines. The second arm of our immune system is the “adaptive” system, which is often considered more highly advanced and organized. This arm acts on memory, re-exposure, and the ability to be conditioned. The prime cellular components of the adaptive system include T cells and B cells. T cells comprise key components of the T helper 1 (Th1) system and the T helper 2 system (Th2). The Th1 system is polarised towards the production of pro-inflammatory cytokines such as interleukin 2 (IL-2), interferon Υ (IF-Υ), and tumor necrosis factor (TNF-α). The Th2 system promotes the generation and maintenance of antibody-mediated immune responses and the production of anti-inflammatory cytokines such as interleukin 4 (IL-4), interleukin 10 (IL-10) and interleukin 13 (IL-13). The humoral component of the adaptive system includes these various circulating cytokines and specific antibodies. A more recently recognized addition to the adaptive immune system includes regulatory T cells (“suppressor” T cells) and other specialised T helper cells (e.g., Th17 and Th22)(Meredith et al., 2005).

There is also considerable “cross talk” between the two major arms of the immune system (Upthegrove and Barnes, 2014). Cytokines are the key signalling molecules that coordinate the innate and adaptive arms of the immune system, and they can exert effects peripherally and in the brain. Recently, changes in cytokines levels, their receptors and cytokine activity modifiers have been found in blood and cerebrospinal fluid (CSF) of schizophrenic patients. Evidence includes the presence of antibodies in serum, an altered distribution of T-cell subsets and altered serum levels of Th1- and Th2-related cytokines (Müller and Schwarz, 2010, Upthegrove and Barnes, 2014). It had been initially proposed that patients with psychosis may have an impaired production of Th1 cytokines and an overactivation of the Th2 system, leading to a dysfunction in the normal Th1/Th2 balance (Müller, 2011). In contrast, some investigations point to an overactivation of the Th1 activity in schizophrenia (Kim et al., 2004). It would therefore appear that an imbalance between Th1 and Th2 cytokines may play a role in schizophrenia, but the data reported are variable, inconsistent or even contradictory. Likely contributing factors to this disarray include studies sampling patients at different stage of illness, differing illness course, acutely unwell or in remission. Use of illicit drugs, differences in age, gender, smoking, body mass, and recent infections will also have significant impact yet are not controlled for (Upthegrove and Barnes, 2014). Most significantly, however, is the role of antipsychotic medication, as we now know its ability to impact the immune system is clear (Drzyzga et al., 2006). For instance, studies in vitro confirm that the antipsychotic drug effects on immune cell function is widespread and often occurs very shortly after initial exposure—indicating some direct effects of the drugs upon immune cell subsets. However, mixed results and differing effects are evident, including either stimulatory or inhibitory actions, particularly with regard to interferon (INF-Υ). It is of further interest that recent studies in vitro suggest that, in part, the efficacy of some antipsychotics arises through the suppression of cytokine-mediated microglial activity (Bian et al., 2008), for instance, aripiprazole suppressing the apoptosis of rodent oligodendrocytes by IFN-γ-activated microglia and the inhibition of tumor necrosis factor-alpha (TNF-α) secretion from IFN-γ-activated microglia (Seki et al., 2013).

Some newer clinical studies have begun to take account of confounding factors, yet antipsychotic medication has not been controlled for regularly, and therefore it is not clear whether results presented are at least in part a product of medication effects (Potvin et al.,2008). In studies investigating first episode psychosis, the vast majority have sampled patients on medication, or in a drug-free status variously defined as neuroleptic naive, free of medication for a period of time, or recently commenced on medication. In a comprehensive meta-analysis, Miller et al. (2011) explored cytokine function in first episode psychosis, with significant results, yet their analysis included groups with mixed neuroleptic exposure and naive status combined.

Therefore, in order to re-assess recent advances and conclusions, we performed a review of studies investigating serum cytokine levels in a medication-naive status and first episode psychosis. The present review article aimed to give a comprehensive and up-to-date overview of the cytokine profile at the onset of first episode psychosis un-confounded by medication. We hope to provide insights into early pathophysiological processes moderating progression of illness and potentially forward avenues of research to identify biomarkers able to judge the extent of disease or the effectiveness of treatment.