Inflammatory markers in major depression and melancholia

Abstract

Background: There is evidence that patients with major depression (MD) also suffer an inflammatory immune reaction. However, the results remain ambiguous. This could be due to the psychiatrically heterogeneous patient samples investigated in many published studies. Since melancholic depression is psychopathologically and possibly etiologically different from non-melancholic MD, we focused on investigating immune parameters in these two subgroups. Methods: 43 in-patients suffering from acute major depression were diagnosed, sub-classified according to DSM IV criteria, and compared to 43 matched healthy controls. Cell counts were determined by morphology, and acute phase proteins [c-reactive protein (CRP), α₂-macroglobulin (A2M), haptoglobin (HP)] were measured by laser nephelometry. Cytokine production (IL-1β) upon mitogen stimulation was measured by ELISA in a whole blood assay. Results: Non-melancholic patients showed increased monocyte counts and A2M serum concentrations in the acute stage of disease and after 2 and 4 weeks of treatment. Melancholic patients demonstrated a decreased monocyte count upon admission and after 4 weeks of treatment. HP levels and IL-1β production were unchanged in all studied subjects. Limitations: Medication of the patients varied. The differentiation between melancholic and non-melancholic depression was performed clinically and was not performed using any standardized instrument. Conclusion: Melancholic and non-melancholic patients show different immune patterns. This differentiation might clarify immunological findings in MD and point towards etiological factors that are involved in the development of various subtypes of MD.

Introduction

Alterations in the immune system of patients suffering from major depression (MD) have been reported throughout the last 2 decades. Several studies demonstrated evidence for inflammatory reactions in acute major depression (for review: Maes, 1995). Due to its crucial role in acute inflammatory reactions of the body, the monocyte–macrophage system has received the most attention.

During immune responses, monocytes (similarly to macrophages) do not just exert local effects. Cytokines produced by monocytes (e.g. interleukin-1β) exert far-reaching effects on the body. They increase body temperature and stimulate hepatocytes so that acute phase proteins are produced (e.g. C-reactive protein, haptoglobin and α₂-macroglobulin). These proteins activate the complement system and opsonize exogenous organisms such as bacteria.

Several studies have shown that monocyte counts are increased amongst patients suffering from major depression (Maes et al., 1992b, Maes et al., 1994b; Seidel et al., 1996; Castilla-Cortazar et al., 1998). However, other investigations revealed unchanged (Irwin et al., 1987; Darko et al., 1988; Maes et al., 1989, Maes et al., 1993a, Maes et al., 1994a; Anesi et al., 1994) or even decreased (McAdams and Leonard, 1993) monocyte counts in patients with MD compared to healthy controls.

Interleukin-1β (IL-1β) is a monokine involved in the early inflammatory immune response. The production of IL-1β upon mitogen stimulation was reported to be increased in patients with minor and major depression (Maes et al., 1991, Maes et al., 1993c). In contrast, Weizman et al. (1994) showed a decreased production of IL-1β in depressed patients.

C-reactive protein (CRP) is one of the most frequently measured acute phase proteins in clinical medicine. Several studies reported increased serum levels of CRP in patients suffering from MD (Legros et al., 1985; Seidel et al., 1995; Sluzewska et al., 1996a, Sluzewska et al., 1996b, Sluzewska et al., 1997; Berk et al., 1997), while in other investigations, no differences in CRP serum levels between patients with MD and healthy controls could be found (Joyce et al., 1992; Maes et al., 1992a).

Haptoglobin (HP) is the most frequently studied acute phase protein in MD and has provided the most consistent results. Several groups demonstrated increased HP serum levels in MD (Joyce et al., 1992; Maes et al., 1992a, Maes et al., 1992c, Maes et al., 1993a, Maes et al., 1993b, Maes et al., 1994c, Maes et al., 1997c; Song et al., 1994; Seidel et al., 1995).

Another acute phase protein, α₂-macroglobulin (A2M), was found to be significantly higher in patients with acute MD and after 6 weeks of clinical treatment compared to healthy controls (Seidel et al., 1995). Maes et al. (1992a) reported normal A2M in MD with a trend towards lower levels in melancholia.

Obviously, there is a lack of consistency in the responses of the investigated immune parameters. One reason for this might be that the diagnostic group of MD classified according to DSM III-R and DSM IV criteria is simply too heterogeneous. Few researchers have attempted to deal with this problem. Some have tried to determine associations between immune parameters and severity of depression (Maes et al., 1989; Joyce et al., 1992; Maes et al., 1993b, Maes et al., 1994a

The DSM IV classification category of ‘major depression’ covers different kinds of depression. These subtypes do not just differ quantitatively; they also differ concerning the quality of symptoms. In melancholic depression, the nature of disturbed affect is distinct from that experienced in non-melancholic major depression. Vegetative symptoms are prominent and the circadian rhythm is affected. Since melancholic depression is considered to be the most ‘biological’ form of depression, we wondered whether there might be a distinct immune pattern in this subtype of depression. If so, this discrimination might help to clarify the divergent results reported in earlier studies.

Bearing all this in mind, we undertook a study that included subjects suffering from MD either with or without melancholic features and normal controls. The patients were studied in an acute stage of disease and followed-up during clinical improvement after 2 and 4 weeks of treatment. We focused on monocytes, the related monokine IL-1β, and the acute phase proteins, CRP, A2M and HB.