Over the last 15 years, an increasing body of evidence has suggested a causal relationship between depression and the immunological activation and hypersecretion of pro-inflammatory cytokines, such as interleukin-1, interleukin-6 and tumor necrosis factor-alpha (TNF-alpha). However, little is known about the probable relationship of serum TNF-alpha with major depressive disorder (MDD).
To assess whether serum TNF-alpha levels could be associated with the clinical course of MDD.
TNF-alpha and C-reactive protein (CRP) serum concentrations, erythrocyte sedimentation rate, and leukocyte count were measured in 26 MDD patients and in 17 controls. The measurements were repeated following 6 weeks of antidepressant treatment with selective serotonin re-uptake inhibitors. Psychopathological improvement and the severity of depression were evaluated with the Hamilton Depression Rating Scale (HAMD) and Beck Depression Inventory (BDI).
On admission, serum TNF-alpha and leukocyte count were significantly higher in MDD patients compared to controls ( P<0.001 and P=0.005, respectively). With the antidepressant treatment, both HAMD and BDI scores decreased significantly (P<0.001 for both). Comparison of pre- and post-treatment measurements revealed that TNF-alpha, CRP, and leukocyte count decreased to levels comparable with those of the control subjects ( P<0.001, P=0.01, and P=0.01, respectively).
The results emphasized that some immunological parameters, such as CRP, leukocyte count and TNF-alpha, are significantly involved in the clinical course and treatment response in MDD. TNF-alpha in particular could be considered as a potential state marker in MDD.
"Studies were also excluded if patients suffered from a significant comorbid disease (N = 31), or if the study lacked a proper control group (N = 16), if inflammatory marker measurements had been assayed in fluids other than venous blood (N = 5) or if in vitro stimulated cytokines had been used to assess immune function (N = 3). In total, 58 articles met the inclusion criteria: 20 studies for CRP (Cizza et al., 2009; Dome et al., 2009; Frodl et al., 2012; Häfner et al., 2008; Hornig et al., 1998; Hughes et al., 2012; Joyce et al., 1992; Karlovic et al., 2012; Keri et al., 2014; Kling et al., 2007; Lanquillon et al., 2000; O'Donovan et al., 2013; Piletz et al., 2009; Rothermundt et al., 2001; Rudolf et al., 2014; Sluzewska et al., 1996; Thomas et al., 2005; Tuglu et al., 2003; Weinstein et al., 2010; Zahn et al., 2013), 31 studies for IL-6 (Basterzi et al., 2005; Carvalho et al., 2013; Dahl et al., 2014; Dhabhar et al., 2009; Dunjic-Kostic et al., 2013; Euteneuer et al., 2011; Fitzgerald et al., 2006; Fornaro et al., 2011; Frodl et al., 2012; Hennings et al., 2013; Hughes et al., 2012; Kagaya et al., 2001; Karlovic et al., 2012; Keri et al., 2014; Leo et al., 2006; Maes et al., 1997, 1995a,b; Mikova et al., 2001; Motivala et al., 2005; O'Brien et al., 2007; O'Donovan et al., 2013; Pavon et al., 2006; Pike and Irwin, 2006; Rudolf et al., 2014; Simon et al., 2008; Sluzewska et al., 1996; Voderholzer et al., 2012; Weinstein et al., 2010; Yang et al., 2007; Yoshimura et al., 2010), 31 studies for TNF-a (Dahl et al., 2014; Diniz et al., 2010b; Dome et al., 2009; Dunjic-Kostic et al., 2013; Eller et al., 2009, 2008; Euteneuer et al., 2011; Fitzgerald et al., 2006; Fornaro et al., 2013; Grassi-Oliveira et al., 2009; Hornig et al., 1998; Huang and Lee, 2007; Hughes et al., 2012; Kagaya et al., 2001; Karlovic et al., 2012; Leo et al., 2006; Li et al., 2013; Maes et al., 2012a,b; Mikova et al., 2001; Narita et al., 2006; O'Brien et al., 2007; O'Donovan et al., 2013; Pavon et al., 2006; Piletz et al., 2009; Schmidt et al., 2014; Simon et al., 2008; Sutcigil et al., 2007; Tuglu et al., 2003; Weinstein et al., 2010; Yang et al., 2007) and 14 studies for IL-1b (Dahl et al., 2014; Diniz et al., 2010a; Fornaro et al., 2013; Hernandez et al., 2008, 2013; Huang and Lee, 2007; Hughes et al., 2012; Kagaya et al., 2001; Leo et al., 2006; Pavon et al., 2006; Piletz et al., 2009; Simon et al., 2008; Thomas et al., 2005; Yang et al., 2007). Supplementary Table 2 presents the descriptive and quality data of each study and Supplementary Table 3 shows the specific inclusion and exclusion criteria used in these studies. "
[Show abstract][Hide abstract] ABSTRACT: Cumulative meta-analyses are used to evaluate the extent to which further studies are needed to confirm or refute a hypothesis. We used this approach to assess observational evidence on systemic inflammation in individuals with major depressive disorder. We identified 58 studies of four common inflammatory markers in a literature search of PubMed, Embase and PsychInfo databases in May 2014. Pooled data from the earliest eight studies already showed an association between interleukin-6 concentrations and major depression; 23 more recent studies confirmed this finding (d = 0.54, p < 0.0001). A significant association between C-reactive protein levels and major depression was noted after 14 studies and this did not change after addition of six more studies (d = 0.47, p < 0.0001). For these two inflammatory markers, there was moderate heterogeneity in study-specific estimates, subgroup differences were small, and publication bias appeared to be an unlikely explanation for the findings. Sensitivity analyses including only high-quality studies and subjects free of antidepressant medication further verified the associations. While there was a link between tumour necrosis factor-α levels and major depression (d = 0.40, p = 0.002), the cumulative effect remained uncertain due to the extensive heterogeneity in study-specific estimates and inconsistencies between subgroups. No evidence was found for the association between interleukin-1β levels and major depression (d = −0.05, p = 0.86). In conclusion, this cumulative meta-analysis confirmed higher mean levels of interleukin-6 and C-reactive protein in patients with major depression compared to non-depressed controls. No consistent association between tumour necrosis factor-α, interleukin-1β and major depression was observed. Future studies should clarify the specific immune mechanisms involved as well as continue testing anti-inflammatory therapies in patients suffering from major depression.
"Cytokines alterations in depression have also important implications with respect to the response to pharmacological treatments. On one end, different studies have demonstrated the ability of some antidepressants to reduce cytokines activation in depressed patients (Sluzewska et al., 1995; Frommberger et al., 1997; Tuglu et al., 2003; Basterzi et al., 2005). Our research group has recently demonstrated that cytokine expression in the leukocytes from depressed patients are reduced following escitalopram and nortriptyline treatment with a significant correlation between these changes and treatment response (Cattaneo et al., 2013). "
[Show abstract][Hide abstract] ABSTRACT: During the past two decades, there has been increasing interest in understanding and characterizing the role of inflammation in major depressive disorder (MDD). Indeed, several are the evidences linking alterations in the inflammatory system to Major Depression, including the presence of elevated levels of pro-inflammatory cytokines, together with other mediators of inflammation. However, it is still not clear whether inflammation represents a cause or whether other factors related to depression result in these immunological effects. Regardless, exposure to early life stressful events, which represent a vulnerability factor for the development of psychiatric disorders, act through the modulation of inflammatory responses, but also of neuroplastic mechanisms over the entire life span. Indeed, early life stressful events can cause, possibly through epigenetic changes that persist over time, up to adulthood. Such alterations may concur to increase the vulnerability to develop psychopathologies. In this review we will discuss the role of inflammation and neuronal plasticity as relevant processes underlying depression development. Moreover, we will discuss the role of epigenetics in inducing alterations in inflammation-immune systems as well as dysfunction in neuronal plasticity, thus contributing to the long-lasting negative effects of stressful life events early in life and the consequent enhanced risk for depression. Finally we will provide an overview on the potential role of inflammatory system to aid diagnosis, predict treatment response, enhance treatment matching, and prevent the onset or relapse of Major Depression.
"c o m / l o c a t e / p h b and paroxetine attenuated LPS-induced increases in TNFα in mice . Treatment of depressive subjects with SSRIs has led to reduced concentration of pro-inflammatory cytokine TNFα . Collectively, these studies suggest an association of increased pro-inflammatory cytokines with depression. "
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