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
Progress in Neuro-Psychopharmacology and Biological Psychiatry (Impact Factor: 3.69). 02/1995; 19(1):11-38. DOI: 10.1016/0278-5846(94)00101-M


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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    • "In recent decades evidence has been provided showing that in depression, the inflammatory response system is activated (Maes et al. 1997, 2012, 2014). The increased production of proinflammatory cytokines, such as interleukin 1β (IL-1β), IL-6 and tumor necrosis factor-α (TNFα), as well as interferon-ϒ (IFN ϒ ), was correlated to depressive-and/or anxiety-like behavior (Maes et al. 1995; Leonard and Maes 2012). Moreover elevated levels of same pro-inflammatory cytokines, mainly IFN ϒ , induces expression of indoleamine 2,3-dioxygenase (IDO), enzyme which enhances catabolism of tryptophan and lowers plasma tryptophan and as a consequence A C C E P T E D M A N U S C R I P T "
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    ABSTRACT: Depression is a serious psychiatric disorder affecting not only the monaminergic, glutamatergic, and GABAergic neurosystems, but also the immune system. Patients suffering from depression show disturbance in the immune parameters as well as increased susceptibility to infections. Zinc is well known as an anti-inflammatory agent, and its link with depression has been proved, zinc deficiency causing depression- and anxiety-like behavior with immune malfunction. It has been discovered that trace-element zinc acts as a neurotransmitter in the central nervous system via zinc receptor GPR39. In this study we investigated whether GPR39 knockout would cause depressive-like behavior as measured by the forced swim test, and whether these changes would coexist with immune malfunction. In GPR39 knockout mice versus a wild-type control we found: i) depressive-like behavior; ii) significantly reduced thymus weight; (iii) reduced cell viability of splenocytes; iv) reduced proliferative response of splenocytes; and v) increased IL-6 production of splenocytes after ConA stimulation and decreased IL-1b and IL-6 release after LPS stimulation. The results indicate depressive-like behavior in GPR39 KO animals with an immune response similar to that observed in depressive disorder. Here for the first time we show immunological changes under GPR39-deficient conditions.
    Full-text · Article · Dec 2015 · Journal of Neuroimmunology
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    • "It is a biological host defence mechanism characterized by increased blood flow and recruitment of innate immune cells to the site of injury. The link between increased inflammation and depression was detected in the early 1990s (Maes et al., 1990; Maes et al., 1991), leading to the formulation of the macrophage hypothesis of depression (also known as the cytokine hypothesis of depression (Maes, 1995; Smith, 1991). This model proposes that external and internal stressors trigger depressive behaviour by elevating the production of proinflammatory cytokines interleukin-1 (IL-1) and IL-6, as well as activating cell-mediated immunity . "
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    ABSTRACT: The inflammation theory of depression, proposed over 20 years ago, was influenced by early studies on T cell responses and since then has been a stimulus for numerous research projects aimed at understanding the relationship between immune function and depression. Observational studies have shown that indicators of immunity, especially C reactive protein and proinflammatory cytokines, such as interleukin 6, are associated with an increased risk of depressive disorders, although the evidence from randomized trials remains limited and only few studies have assessed the interplay between innate and adaptive immunity in depression. In this paper, we review current knowledge on the interactions between central and peripheral innate and adaptive immune molecules and the potential role of immune-related activation of microglia, inflammasomes and indoleamine-2,3-dioxygenase in the development of depressive symptoms. We highlight how combining basic immune methods with more advanced ‘omics’ technologies would help us to make progress in unravelling the complex associations between altered immune function and depressive disorders, in the identification of depression-specific biomarkers and in developing immunotherapeutic treatment strategies that take individual variability into account.
    Full-text · Article · Nov 2015 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
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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] "
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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.
    Full-text · Article · Jul 2015 · Evidence-based Complementary and Alternative Medicine
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