اثر افسردگی بر روی پروفایل سایتوکاین در داروی ساده روان پریشی

Abstract Schizophrenia is accompanied by alterations in immuno-inflammatory pathways, including abnormalities in cytokine profile. The immune assessment of patients in a first episode of psychosis (FEP) and particularly in drug naïve patients is very important to further elucidate this association. The objectives of this study are to delineate the cytokine profile (IL-2, IL-10, IL-4, IL-6, IFNγ, TNFα and IL-17) in FEP patients (n = 55) versus healthy controls (n = 57) and to examine whether the presence of depressive symptoms in FEP is accompanied by a specific cytokine profile. We found increased levels of IL-6, IL-10 and TNFα in FEP patients when compared to healthy controls. FEP patients with depression showed higher IL-4 and TNFα levels versus those without depression. Cytokine levels were not correlated to the total PANSS and the positive or negative subscale scores. Our results suggest that FEP is accompanied by a cytokine profile indicative of monocytic and T regulatory cell (Treg) activation. Depression in FEP is accompanied by monocytic and Th-2 activation, whereas FEP without depression is characterized by Treg activation only. In conclusion, depression emerged as a key component explaining the cytokines imbalance in FEP that is responsible for a large part of the immune–inflammatory abnormalities described.

Psychosis is a core symptom of schizophrenia, a severe neurodevelopmental disorder, with large economical and social impact (Insel, 2010). Abnormal immune–inflammatory responses, including increased levels of pro-inflammatory cytokines are found in patients with schizophrenia (Potvin et al., 2008 and Miller et al., 2011). In 1995, the immune–inflammatory theory of schizophrenia proposed that activated immune–inflammatory pathways, particularly activated macrophages and T-lymphocytes, may explain the higher offspring schizophrenia risk associated with gestational infections through the neurotoxic effects of pro-inflammatory cytokines and their detrimental consequences (Smith and Maes, 1995). More recently, several reviews addressed the role of activated immune–inflammatory pathways in the neurodevelopmental pathophysiology of schizophrenia (Anderson et al., 2013a and Meyer, 2013). Cytokines are proteins involved in the activation, coordination and suppression of immune responses. Their neuromodulatory actions appear to be critical for the regulation of neuroplasticity, cell resilience and apoptosis (Boulanger and Shatz, 2004, Golan et al., 2004 and Bauer et al., 2007). Macrophages are activated during innate immune response in two functional distinct states (M1 and M2), producing different cytokines. M1 macrophages produce pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-12 and tumor necrosis factor (TNF)α, stimulating cell-mediated response. M2 macrophages produce negative immunoregulatory cytokines, such as IL-10 and transforming growth factor (TGF)β (Seruga et al., 2008 and Maes et al., 2012b). During the adaptive immune response, T lymphocytes differentiate into T helper (Th)1, Th17, T regulatory (Treg) and Th2 cells. Naïve cells are driven towards Th1 and Th2 phenotypes by M1 and M2 macrophages, respectively (Seruga et al., 2008 and Maes et al., 2012b). A Th1-shift cytokine profile indicates immune activation, whereas a Th2-shift may indicate negative immunoregulatory effects and activated humoral immunity (Maes et al., 2012b). A recent meta-analysis showed that schizophrenia is accompanied by increased levels of pro-inflammatory cytokines indicating M1 activation and increased levels of Th1-like cytokines, indicating T cell activation (Miller et al., 2011). There are, however, few studies that have examined the associations between psychosis and levels of monocytic cytokines, Th1, Th2, Th17 and Treg cytokines simultaneously. Meta-analyses (Potvin et al., 2008 and Miller et al., 2011) demonstrated a notable heterogeneity of results in existing studies, possibly as a consequence of several confounding factors, such as use of medications and clinical features. The acute or (sub)chronic use of antipsychotic drugs, which have significant immune-regulatory effects (Maes et al., 2000, MacDowell et al., 2013 and Tourjman et al., 2013), is one of those factors that may modify the levels of cytokines measured. Therefore, the analysis of the immune state in drug naïve patients is of paramount importance to examine the levels of monocytic, Th1, Th2, Th17 and Treg cytokines. Upthegrove et al. (2014) recently published a meta-analysis examining patients with drug naïve first episode psychosis (FEP). They found an elevation in pro-inflammatory cytokine (and receptor) levels in the serum of FEP patients with higher levels of IL-1β, soluble IL-2 receptor (sIL-2R), IL-6 and TNF-α, a profile suggesting M1 and Th1 activation. The immune–inflammatory profile of patients with psychosis seems to be modulated by clinical characteristics. For example, a more disordered immune–inflammatory profile may be found in patients with a more severe course of the disorder (Noto et al., 2011, Asevedo et al., 2013 and Noto et al., 2013). Another important clinical factor is the presence of depressive symptoms in patients with psychosis. The prevalence of depression in schizophrenia may be as high as 61% (Gozdzik-Zelazny et al., 2011) and in FEP the prevalence may be as high as 80% (Upthegrove et al., 2010 and Sonmez et al., 2014). Despite being different disorders, schizophrenia and depression shared some clinical and biological characteristics. Both present cognitive and neurostructural changes suggestive of neuroprogressive processes. There is consistent evidence that depression is an immune–inflammatory disorder accompanied by increases in macrophage (M1), Th1, Th2 and Th17-like cytokines and lowered levels of Treg cytokines (Leonard and Maes, 2012 and Noto et al., 2014a). Both schizophrenia and depression share significant overlaps in immune–inflammatory pathways, including increased levels of pro-inflammatory cytokines and Th1 cytokines (Maes et al., 1990, Leonard and Maes, 2012, Anderson et al., 2013a and Noto et al., 2014a). They also shared other biological pathways, such as activation of oxidative and nitrosative stress, decreased antioxidant levels, and activation of the tryptophan catabolite pathway through induction of indoleamine-2,3-dioxygenase (IDO). The association between both disorders is related with poor quality of life, impairments in social and vocational functioning, and higher rates of relapse. It may cause a worse outcome and increased suicide, even at early stages (Conley et al., 2007, Challis et al., 2013, Noto et al., 2013, Bjorkenstam et al., 2014 and Schennach et al., 2015). At the FEP symptoms as loss of self-confidence, feelings of guilt and suicidal thoughts are one of the most prevalent (an der Heiden et al., 2005). Based on these findings it was hypothesized that schizophrenia is primed for an increased expression of depression via activated immune–inflammatory pathways (Anderson et al., 2013b). The aims of the present study were to examine whether a) FEP is characterized by a specific cytokine profile indicating macrophage, Th1, Th2, Th17 or Treg activation (IL-2, IL-10, IL-4, IL-6, IFNγ, TNFα and IL-17); and b) the presence of depressive symptoms in FEP individuals may be related to a specific cytokine profile.