This is a broad meta-analysis of the relations of both depression and stressors to immunological assays. The number of study samples (greater than 180) and measures (greater than 40) is much more extensive than any so far. Analyses are done by both fixed and random effects. By a fixed-effects analysis, both major depression and naturally occurring acute stressors are associated with (1) an overall leukocytosis, (2) mild reductions in absolute NK-cell counts and relative T-cell proportions, (3) marginal increases in CD4/CD8 ratios, and (4) moderate decreases in T- and NK-cell function. However, the degree of heterogeneity of the studies' results raises questions about their robustness. Therefore, we also did the first random effects analysis to estimate what is likely to appear in future studies. For depression, the analysis showed the immunological correlates included (1) an overall leukocytosis, manifesting as a relative neutrophilia and lymphoenia; (2) increased CD4/CD8 ratios; (3) increased circulating haptoglobin, PGE(2), and IL-6 levels; (4) reduced NK-cell cytotoxicity; and (5) reduced lymphocyte proliferative response to mitogen. For stressors, the random effects analysis showed that future studies are likely to find the following effects: (1) an overall leukocytosis, manifesting as an absolute lymphocytosis; (2) alterations in cytotoxic lymphocyte levels, CD4/CD8 ratios, and natural killer cell cytotoxicity with the direction of change depending on the chronicity of the stressor; (3) a relative reduction of T-cell levels; (3) increased EBV antibody titers; (4) reduced lymphocyte proliferative response and proportion of IL-2r bearing cells following mitogenic stimulation; and (5) increased leukocyte adhesiveness. The random-effects analysis revealed that for both major depression and naturally occurring stressors the following effects are shared: leukocytosis, increased CD4/CD8 ratios, reduced proliferative response to mitogen, and reduced NK cell cytotoxicity. The implications for these findings for disease susceptibility and the pathophysiology of these conditions is discussed.

The relationship of depression and stressors to immunological assays: a meta-analytic review.

1. This paper reviews recent findings on cellular and humoral immunity and inflammatory markers in depression. 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)-1 beta and IL-6 by peripheral blood mononuclear cells. 3. It is hypothesized that increased monocytic production of interleukins (Il-1 beta 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-adrenal-axis hyperactivity, disorders in serotonin metabolism, and to the vegetative symptoms (i.e. the sickness behavior) of severe depression.

Evidence for an immune response in major depression: a review and hypothesis

Contemporary models of major depression emphasize the role of hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity and of dysfunctions in the turnover of serotonin (5-HT) or catecholamines in the etiopathogenesis of major depression. Contemporary models of major depression do not incorporate the effects of the inflammatory response system (IRS), even though the IRS powerfully influences HPA-axis activity, 5-HT and catecholaminergic turnover and even though activation of the IRS may induce depression-like behavior in animals and humans. There is now evidence that major depression is accompanied by a moderate activation of the IRS (reviews: Maes, 1993; 1995; 1997; Maes, Smith, & Scharpe, 1995c; Holden, Pakula, & Mooney, 1997; Maes & Smith, 1997; Connor & Leonard, 1998; Maier & Watkins, 1998). In this paper we propose a concise IRS model of major depression.

Major depression and activation of the inflammatory response system.

It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic (fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well defined triggers.

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Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

Summary Evidence suggests that a high concentration of C-reactive protein (CRP) is a cardiovascular risk factor and an important correlate of cognitive disorders and depression. Recently, population-based studies examining the association between CRP and stroke, cognitive impairment, or depression have been done but have not yet been systematically reviewed. Here we present a systematic review of the associations between CRP and stroke, cognitive impairment, and depression. Hospital or clinic-based studies were excluded because the inferences might not be easily applicable to the general population. 19 eligible studies of CRP were selected: seven for stroke, six for cognitive disorders, and six for depression. Raised CRP concentrations were associated with history of stroke and increased risk of incident stroke. Meta-analysis of studies with long follow-up (>8 years) showed that the risk for stroke in healthy individuals with the highest quartile of CRP concentrations increased nearly 70% compared to those with the lowest quartile. High concentrations of CRP were predictive of cognitive decline and dementia. The relations of CRP to depression were all cross-sectional and were not consistent. We conclude that high concentrations of CRP are associated with increased risk of stroke and cognitive impairment. The association between CRP and depression should be studied prospectively.

Relation of C-reactive protein to stroke, cognitive disorders, and depression in the general population: systematic review and meta-analysis

MAES, MICHAEL, SIMON SCHARPE, EUGENE BOSMANS, MAURITS VANDEWOUDE, EDUARD SUY, WIM UYTTENBROECK, WALTER COOREMAN, CARINE VANDERVORST and JEF RAUS Disturbances in Acute Phase Plasma Proteins during Melancholia Additional Evidence for an Inflammatory Process during that Illness. Prog. Neuro-Psychopharmacol & Biol Psychiat 1992,16(4)501–515. 
1.	
1. Leukocyte enumeration through flow cytometry has revealed that severe depression may be accompanied by a systemic immune activation, indicative of an Inflammatory response The latter condition allegedly involves an important modification of acute phase plasma protein (APP) equilibrium

2.	
2. In order to elucidate whether the state of severe depression is represented by alterations in APPs, the authors measured: α, antitrypsin (α1,AT), α2, macroglobulln (α2,M), haptoglobin (Hp), α, acid glycoprotein (α1,S), transferrin (Tf), complement component 4 (C4) and C-reactive protein (CRP). Interleukin-1-β (II-1B) and lnterleukin-6 (II-6) circulating levels were determined

3.	
3. Hyperhaptoglobinemia and hypotransferinemia are hallmarks for major depression and depression per se, respectively, The disorders in Hp and Tf circulating levels are highly sensitive to (83%) and specific for (100%) melancholia as opposed to the healthy state.

4.	
4. Disorders in both APPs are significantly related to the absolute number of blood monocytes.

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5. The authors observed a trend towards lower α2M and higher α,S values in severely depressed subjects. Severity of depression was significantly related to Hp and α1S (both positively) and to α2M and Tf (both negatively) values.

6.	
6. No significant intercategory differences in C4 could be established, whilst only a few subjects exhibited measurable CRP, II-1β and II-6 circulating levels.

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7. Our findings may support the hypothesis that depression Is accompanied by an inflammatory response

Walter Cooreman

Papers

Disturbances in acute phase plasma proteins during melancholia: additional evidence for the presence of an inflammatory process during that illness.