A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression

Abstract

Schizophrenia, bipolar disorder and major depressive disorder (MDD) have all been associated with aberrant blood cytokine levels; however, neither the pattern of cytokine alterations nor the impact of clinical status have been compared across disorders. We performed a meta-analysis of blood cytokines in acutely and chronically ill patients with these major psychiatric disorders. Articles were identified by searching the PubMed, PsycInfo and Web of Science, and the reference lists of these studies. Sixty-eight studies met the inclusion criteria (40 schizophrenia, 10 bipolar disorder and 18 MDD) for acutely ill patients. Forty-six studies met the inclusion criteria (18 schizophrenia, 16 bipolar disorder and 12 MDD) for chronically ill patients. Levels of two cytokines (interleukin- 6 (IL-6), tumor necrosis factor-α (TNF-α)), one soluble cytokine receptor (sIL-2R), and one cytokine receptor antagonist (IL-1RA) were significantly increased in acutely ill patients with schizophrenia, bipolar mania and MDD compared with controls (P < 0.01). Following treatment of the acute illness, IL-6 levels significantly decreased in both schizophrenia and MDD (P < 0.01); sIL-2R levels increased in schizophrenia; and IL-1RA levels in bipolar mania decreased. In chronically ill patients, the levels of IL-6 were significantly increased in schizophrenia, euthymic (but not depressed) bipolar disorder and MDD compared with controls (P < 0.01). The levels of IL-1β and sIL-2R were significantly increased in both chronic schizophrenia and euthymic bipolar disorder. Overall, there were similarities in the pattern of cytokine alterations in schizophrenia, bipolar disorder and MDD during acute and chronic phases of illness, raising the possibility of common underlying pathways for immune dysfunction. Effects of treatment on cytokines were more robust for schizophrenia and MDD, but were more frequently studied than for acute mania. These findings have important implications for our understanding of the pathophysiology and treatment of major psychiatric disorders.

Inflammation Effects on Motivation and Motor Activity: Role of Dopamine

“…Indeed, recent studies have indicated that high inflammation (plasma CRP concentrations 43 mg/l, as defined by the American Heart Association; Ridker, 2003) is consistently found in 20-40% of patients with MDD, with higher concentrations observed in patients who are resistant to standard antidepressant therapies Haroon et al, 2016;Raison et al, 2013a;Raison et al, 2013b;Rapaport et al, 2016). Similar increases in inflammatory cytokines and acute-phase reactants have also been reported in patients with bipolar disorder and schizophrenia, including meta-analyses (Goldsmith et al, 2016b;Miller et al, 2011;Potvin et al, 2008). Increased inflammatory cytokine concentrations in the cerebrospinal fluid (CSF) of patients with unipolar and bipolar depression, and schizophrenia have also been observed (Garver et al, 2003;Levine et al, 1999;Schwieler et al, 2015;Soderlund et al, 2011;Soderlund et al, 2009).…”

“…A significant proportion of patients with psychiatric disorders exhibit a chronic, low-grade inflammation, as measured by increased peripheral and central inflammatory cytokines, inflammatory mediators, and acute-phase reactants (for review, see Barbosa et al, 2014, Felger and Lotrich, 2013b, Goldsmith et al, 2016band Haroon et al, 2012. Findings from numerous laboratories have consistently indicated that innate immune activation and the release of inflammatory cytokines preferentially affect reward circuitry and basal ganglia DA to contribute to reduced motivation and motor slowing (Brydon et al, 2008;Capuron et al, 2007;Capuron et al, 2012;Eisenberger et al, 2010;Felger and Miller, 2012;Harrison et al, 2015b;Majer et al, 2008).…”

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…IL-6 is a key component of the inflammatory response in the brain, a profound stimulator of acute phase proteins from the liver and has been implicated in the etiology of neuropsychiatric disorders such as depression (Dowlati et al, 2010;Howren et al, 2009;Miller and Raison, 2016;Valkanova et al, 2013) and schizophrenia (Goldsmith et al, 2016). IL-6 has mixed effects on the glutamate system attributable to the more chronic and nuanced nature of its effects.…”

How to: Measuring blood cytokines in biological psychiatry using commercially available multiplex immunoassays

“…Nevertheless, when an immune challenge becomes chronic or unregulated, as occurs in patients who are receiving chronic cytokine treatments or those exposed to chronic medical illness or psychological stress, the cytokines may contribute to the development of clinically relevant behavioral symptoms and neuropsychiatric diseases, including major depression (Raison and Miller, 2013). In support of this hypothesis, depressive symptoms have been shown to be associated with increased serum and plasma concentrations of TNF, IL-6 and C-reactive protein (Dowlati et al, 2010;Goldsmith et al, 2016;Strawbridge et al, 2015;Valkanova et al, 2013). Most importantly, recent longitudinal studies have extended these cross-sectional observations by reporting that increased inflammatory markers in non-depressed individuals predict the later development of major depression (Gimeno et al, 2009;Pasco et al, 2010;van den Biggelaar et al, 2007).…”