Article

# Maes M. Evidence for an immune response in major depression: a review and hypothesis. Prog Neuropsychopharmacol Biol Psychiatry 19: 11-38

Department of Psychiatry, University Hospitals of Cleveland, Cleveland, OHIO, USA
(Impact Factor: 3.69). 02/1995; 19(1):11-38. DOI: 10.1016/0278-5846(94)00101-M

ABSTRACT

1.1. This paper reviews recent findings on cellular and humoral immunity and inflammatory markers in depression.2.2. It is shown that major depression may be accompanied by systemic immune activation or an inflammatory response with involvement of phagocytic (monocytes, neutrophils) cells, T cell activation, B cell proliferation, an “acute” phase response with increased plasma levels of positive and decreased levels of negative acute phase proteins, higher autoantibody (antinuclear, antiphospholipid) titers, increased prostaglandin secretion, disorders in exopeptidase enzymes, such as dipeptidyl peptidase IV, and increased production of interleukin (IL)-1β and IL-6 by peripheral blood mononuclear cells.3.3. It is hypothesized that increased monocytic production of interleukins (Il-1β and Il-6) in severe depression may constitute key phenomena underlying the various aspects of the immune and “acute” phase response, while contributing to hypothalamic-pituitary-adrenalaxis hyperactivity, disorders in serotonin metabolism, and to the vegetative symptoms (i.e. the sickness behavior) of severe depression.

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Available from: Michael Maes, Nov 11, 2015
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• "This experimental protocol was chosen on the basis of the concept that internal and external stressors interact, resulting in an illness state that causes an allostatic overload [38] [39] "
##### Article: Diene Valepotriates from Valeriana glechomifolia Prevent Lipopolysaccharide-Induced Sickness and Depressive-Like Behavior in Mice
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ABSTRACT: Valeriana glechomifolia, a native species from southern Brazil, presents antidepressant-like activity and diene valepotriates (VAL) contribute to the pharmacological properties of the genus. It is known that depression can develop on an inflammation background in vulnerable patients and antidepressants present anti-inflammatory properties. We investigated the effects of VAL (10 mg/kg, p.o.) on sickness and depressive-like behaviors as well as proinflammatory cytokines (IL-1β and TNF-α) and BDNF expression in the cortex of mice exposed to a 5 min swimming session (as a stressful stimulus) 30 min before the E. coli LPS injection (600 µg/kg, i.p.). The forced swim + LPS induced sickness and depressive-like behaviors, increased the cortical expression of IL-1β and TNF-α, and decreased BDNF expression. VAL was orally administered to mice 1 h before (pretreatment) or 5 h after (posttreatment) E. coli LPS injection. The pretreatment with VAL restored the behavioral alterations and the expression of cortical proinflammatory cytokines in LPS-injected animals but had no effects on BDNF expression, while the posttreatment rescued only behavioral alterations. Our results demonstrate for the first time the positive effects of VAL in an experimental model of depression associated with inflammation, providing new data on the range of action of these molecules.
Evidence-based Complementary and Alternative Medicine 07/2015; 2015:1-12. DOI:10.1155/2015/145914 · 1.88 Impact Factor
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• "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&apos;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&apos;Brien et al., 2007; O&apos;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. "
##### Article: Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder
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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.
Brain Behavior and Immunity 06/2015; 20. DOI:10.1016/j.bbi.2015.06.001 · 5.89 Impact Factor
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• "Abnormal immune–inflammatory responses, including increased levels of pro-inflammatory cytokines are found in patients with schizophrenia (Potvin et al., 2008; 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; Meyer, 2013). "
##### Article: Effects of depression on the cytokine profile in drug naïve first-episode psychosis
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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. Copyright © 2015 Elsevier B.V. All rights reserved.
Schizophrenia Research 02/2015; 164(1-3). DOI:10.1016/j.schres.2015.01.026 · 3.92 Impact Factor