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      Immunology of Major Depression



      S. Karger AG

      Inflammation, Major depression, Psychoneuroimmunology

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          High levels of several proinflammatory components of the immune system, such as interleukin-6, C-reactive protein, tumor necrosis factor (TNF)-α, or neopterin in patients suffering from major depression (MD) point to the involvement of an inflammatory process in the pathophysiology of MD. The direct and indirect effects of cytokines on neurotransmitter storage and release - mediated by microglia cells and astrocytes - are discussed. The tryptophan/kynurenine metabolism is one of the indirect mechanisms because the enzyme indoleamine 2,3-dioxygenase - a key enzyme of this metabolism in the central nervous system - is driven by pro- and anti-inflammatory cytokines and degrades serotonin. Moreover, neuroactive kynurenines such as kynurenic acid and quinolinic acid act on the glutamatergic neurotransmission as N-methyl-<smlcap>D</smlcap>-aspartate antagonists and agonists, respectively. Alterations of the serotonergic, noradrenergic and glutamatergic neurotransmission have been shown with low-level neuroinflammation and may be involved in symptom generation. Epidemiological and clinical studies show a role for inflammation as a risk factor for MD. A large-scale epidemiological study in MD clearly demonstrates that severe infections and autoimmune disorders are lifetime risk factors for MD. The vulnerability-stress-inflammation model matches with this view as stress may increase proinflammatory cytokines and even contribute to a lasting proinflammatory state. Further support comes from the therapeutic benefit of anti-inflammatory medications such as the cyclo-oxygenase-2 inhibitors, TNF-α antagonists and others, and the anti-inflammatory and immunomodulatory intrinsic effects of antidepressants.

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          Most cited references 75

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          The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine.

          Signs of an inflammatory process, in particular increased pro-inflammatory cytokines and increased levels of prostaglandine E(2) (PGE(2)), have repeatedly been described in major depression (MD). As cyclooxygenase-2 (COX-2) inhibitors inhibit the PGE(2) production and the production of pro-inflammatory cytokines, we performed a therapeutic trial with the COX-2 inhibitor celecoxib. In a prospective, double-blind, add-on study, 40 patients suffering from an acute depressive episode were randomly assigned to either reboxetine and celecoxib or to reboxetine plus placebo. After a wash-out period, 20 patients received 4-10 mg reboxetine plus placebo and 20 received reboxetine plus 400 mg celecoxib for 6 weeks. The treatment effect was calculated by analysis of variance. There were no significant differences between groups in age, sex, duration or severity of disease or psychopathology, or reboxetine dose or plasma levels. Over 6 weeks, both groups of patients showed significant improvement in scores of the Hamilton Depression Scale. However, the celecoxib group showed significantly greater improvement compared to the reboxetine-alone group. Additional treatment with celecoxib has significant positive effects on the therapeutic action of reboxetine with regard to depressive symptomatology. Moreover, the fact that treatment with an anti-inflammatory drug showed beneficial effects on MD indicates that inflammation is related to the pathomechanism of the disorder, although the exact mechanisms remain to become elucidated.
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            Cytokine production and treatment response in major depressive disorder.

            In a controlled study, such immunological parameters as whole blood production of the cytokines interleukin-6 (IL-6) and tumor-necrosis factor-alpha (TNF-alpha) were assessed in 24 inpatients with a major depressive disorder (MDD) both before and again under treatment. After a 6-week treatment period with amitriptyline, patients were classified as responders or nonresponders according to their psychopathological outcome as evaluated by the Hamilton and the Montgomery-Asberg Depression Rating Scales. Pre-treatment levels of c-reactive protein (CRP) were significantly higher in both patient subgroups than in the control subjects. In comparison to the controls, unstimulated pretreatment production of IL-6 was significantly decreased in the responders; whereas it was significantly increased in the nonresponder subgroup. Post-treatment values did not differ significantly among the patient and control groups. Pretreatment levels of TNF-alpha were increased in both patient subgroups, with a significant decrease during treatment only in the responder subgroup. Pretreatment levels of IL-6/10(5) mononuclear cells and the ratio between lymphocytes and monocytes acted as independent variables with regard to the clinical response. Our data indicate that unstimulated secretion of TNF-alpha is related to the psychopathological improvement; whereas, IL-6 levels might dichotomize the patients into subsequent responders and nonresponders already at admission.
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              Inhibition of astroglial nuclear factor κB reduces inflammation and improves functional recovery after spinal cord injury

              In the central nervous system (CNS), the transcription factor nuclear factor (NF)-κB is a key regulator of inflammation and secondary injury processes. After trauma or disease, the expression of NF-κB–dependent genes is highly activated, leading to both protective and detrimental effects on CNS recovery. We demonstrate that selective inactivation of astroglial NF-κB in transgenic mice expressing a dominant negative (dn) form of the inhibitor of κBα under the control of an astrocyte-specific promoter (glial fibrillary acidic protein [GFAP]–dn mice) leads to a dramatic improvement in functional recovery 8 wk after contusive spinal cord injury (SCI). Histologically, GFAP mice exhibit reduced lesion volume and substantially increased white matter preservation. In parallel, they show reduced expression of proinflammatory chemokines and cytokines, such as CXCL10, CCL2, and transforming growth factor–β2, and of chondroitin sulfate proteoglycans participating in the formation of the glial scar. We conclude that selective inhibition of NF-κB signaling in astrocytes results in protective effects after SCI and propose the NF-κB pathway as a possible new target for the development of therapeutic strategies for the treatment of SCI.

                Author and article information

                S. Karger AG
                February 2014
                14 February 2014
                : 21
                : 2-3
                : 123-130
                Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University of Munich, Munich, Germany
                Author notes
                *Prof. Dr. med. Dipl.-Psych. Norbert Müller, Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University, Nussbaumstrasse 7, DE-80336 Munich (Germany), E-Mail Norbert.Mueller@med.uni-muenchen.de
                356540 Neuroimmunomodulation 2014;21:123-130
                © 2014 S. Karger AG, Basel

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                Tables: 1, Pages: 8
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