Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression Michael Maes ⁎ Maes Clinics@TRIA, 998 Rimklongsamsen Road, Piyavate Hospital, Bangkok 10310, Thailand abstract article info Article history: Received 23 May 2010 Received in revised form 11 June 2010 Accepted 14 June 2010 Available online 20 June 2010 Keywords: Cytokines Depression IDO Inflammation T cell activation Tryptophan The first findings that depression is characterized by cell-mediated immune activation and inflammation were published between 1990–1993 (Maes et al.). Recently, it was reported that – based on meta-analysis results – depression is an inflammatory disorder because the plasma levels of two cytokines are increased, i.e. interleukin-(IL)-6 and tumor necrosis factor-α (TNFα). The same meta-analysis found that plasma IL-2 and interferon-(IFN)γ levels are not altered in depression, suggesting that there is no T cell activation in that illness. The present paper reviews the body of evidence that depression is accompanied by cell-mediated immune activation. The findings include: increased serum levels of the soluble IL-2 receptor (sIL-2R) and the sCD8 molecule; increased numbers and percentages of T cells bearing T cell activation markers, such as CD2+CD25+, CD3+CD25+, and HLA-DR+; increased stimulated production of IFNγ; higher neopterin and sTNFR-1 or sTNFR-2 levels; induction of indoleamine 2,3-dioxygenase (IDO) with lowered levels of plasma tryptophan and increased levels of tryptophan catabolites along the IDO pathway (TRYCATs); and glucocorticoid resistance in immune cells. Interferon-α (IFNα)-based immunotherapy shows that baseline and IFNα-induced activation of T cells, IDO activity and TRYCAT formation are related to the development of IFNα-induced depressive symptoms. Animal models of depression show that a cell-mediated immune response is related to the development of depression-like behavior. Antidepressants and mood stabilizers suppress different aspects of cell-mediated immunity and rather specifically target IFNγ production. This review shows that inflammation and cell-mediated immune activation are key factors in depression. © 2010 Elsevier Inc. All rights reserved. 1. Introduction In 1990–1993 the first original papers were published that depression is an illness characterized by inflammation and monocytic and T cell activation (Maes et al., 1990–1991; 1991a,b; 1992a,b; 1993a). These findings in clinical depression laid the foundation for a novel hypothesis that inflammation and cell-mediated immune activation are key factors in depression (Maes et al., 1990–1991; 1991b; 1992a,b; Maes, 1993). Since 1990–1991, we have published the first reports that major depression is characterized by: a) an inflammatory response as shown by monocytic activation with increased production of interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNFα)(Maes et al., 1990–1991; 1991b; 1993a; Mikova et al., 2001); and an acute phase response (Maes et al., 1992b; 1993d,e); b) cell-mediated immune activation, with T and T helper (Th)-1-like cell activation, as demonstrated by – for example – increased serum soluble IL-2 receptor (sIL-2R) levels and interferon-γ (IFNγ) production (Maes et al., 1990–1991; 1991b; 1992a; 1993d; 1994c); and c) significant interrelationships between the acute phase or inflammatory response and cell-mediated immune activation (Maes et al., 1993e). We were the first to show that a) activation of the inflammatory response system (IRS) in depression is related to indices of hypothalamic-pituitary-adrenal-axis (HPA) hyperactivity, suggesting that HPA-hyperactivity in depression is induced by pro-inflammatory cytokines (Maes et al., 1993a,d). b) The serotonergic disturbances in depression are the consequence of cell-mediated immune activation. Thus, the lowered availability of plasma L-tryptophan to the brain in depression is a marker of immune activation indicating that lowered plasma L-tryptophan, and hence serotonin, are induced through activation of indoleamine 2,3-dioxygenase (IDO) (Maes et al., 1993b; Progress in Neuro-Psychopharmacology & Biological Psychiatry 35 (2011) 664–675 Abbreviations: IL-1β, interleukin-1β; IL-6, interleukin-6; TNF, tumor necrosis factor-α; Th, T helper; sIL-2R, soluble interleukin-2 receptor; IFNγ, interferon- gamma; IRS, inflammatory response system; HPA-axis, hypothalamic-pituitary- adrenal-axis; IDO, indoleamine 2,3-dioxygenase; O&NS, oxidative and nitrosative stress (O&NS); I&ND, the inflammatory and (neuro)degenerative; TGFβ, transforming growth factor β; sCD8, soluble CD8; APPs, acute phase proteins; IL-1RA, IL-1 receptor antagonist; DTH, delayed-type hypersensitivity; PBMC, peripheral blood mononuclear cells; DST, dexamethasone suppression test; PHA, phytohemagglutinin; Con-A, concanavalin A; TRYCATs, tryptophan catabolites; LNAA, large neutral amino acids; TCA, tricyclic antidepressant; SNRI, serotonin/noradrenaline reuptake inhibitor; 5-HTP, 5-hydroxytryptophan (5-HTP); SSRI, selective serotonin reuptake inhibitor; RIMAs, reversible inhibitor of monoamine oxidase A. ⁎ Tel.: +66 32 3 4809282. E-mail address: miermeat@yahoo.com. URL: http://www.michaelmaes.comcrc.mh@telenet.be. 0278-5846/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2010.06.014 Contents lists available at ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp