Altered glucocorticoid immunoregulation in treatment resistant depression

doi:10.1016/S0306-4530(02)00009-4

Psychoneuroendocrinology

Volume 28, Issue 1, January 2003, Pages 49-65

https://doi.org/10.1016/S0306-4530(02)00009-4 Get rights and content

Abstract

Alterations in cellular immune function are associated with depression and have been related to changes in endocrine function. We carried out a study to: (i) reliably assess the hypothalamic–pituitary–adrenal (HPA) axis function in treatment resistant depression (TRP); (ii) evaluate whether depression was associated with changes on T-cell proliferation and cytokine production; and (iii) assessed the sensitivity of lymphocytes to glucocorticoids (GC)s in vitro. Thirty-six pharmacologically treated inpatients diagnosed with TRP and 31 healthy controls took part in the study. Salivary cortisol was measured hourly from 0800 to 2200 h both before and after dexamethasone (DEX) intake and the patients were classified into HPA axis suppressors and nonsuppressors. The following were measured in vitro: (a) phytohemagglutinin-induced T-cell proliferation; (b) cytokine production (interleukin-2 and tumor necrosis factor-α, TNF-α); and (c) lymphocyte sensitivity to both cortisol and DEX. Basal morning cortisol levels from patients and controls did not differ nor did their T-cell proliferation and cytokine production. Ten out of 36 patients were classified as nonsuppressors and presented a significantly higher post-DEX salivary cortisol levels than suppressors, 82.0 vs 8.9 nM/l/h (p <0.001). Cells of nonsuppressors produced significantly less TNF-α compared to suppressors, 299.8 vs 516.9 pg/ml (p < 0.05). Remarkably, GC-induced suppression of lymphocyte proliferation and cytokine production were generally less marked in depressives compared with controls. Our data indicate that alterations in immune function and steroid regulation associated with depression are not related to elevated basal levels of cortisol and suggest that lymphocyte steroid resistance may be associated with TRP.

Introduction

Major depression is often associated with alterations in hypothalamic–pituitary–adrenal (HPA) regulation, including increased plasma cortisol levels, enlarged anterior pituitary and adrenals, as well as failure to suppress cortisol levels following dexamethasone (DEX) administration (Gold et al., 1988). In addition to neuroendocrine changes, several studies have linked depression with altered immune function consisting of blunted mitogen-induced lymphocyte proliferation (Schleifer et al., 1984), reduced natural killer (NK) cell activity (Bauer et al., 1995), or even increased immunological activity in depression (Maes et al., 1993). To a considerable extent, it appears these results are inconsistent and may be related to symptom characteristics, including the severity of depression (Maes et al., 1992), chronicity of illness (Anisman et al., 1999) and presence of typical versus atypical features of the psychopathology (Ravindran et al., 1998).

There is also some evidence that immune function may be differentially sensitive to steroid influences in depression and may be ‘resistant’ to steroid effects (Wodarz et al., 1991, Kok et al., 1995). For instance, it has been shown that DEX reduced T-cell proliferation in HPA axis suppressors and control subjects, whereas no such changes were observed for nonsuppressors (Lowy et al., 1989). These data indicate that ‘resistance’ to steroid effects on lymphocyte blastogenesis is observed in depressed patients that exhibit altered HPA feedback inhibition. In addition, Kok et al. (1995) have shown that cortisol stimulates production of immunoglobulins (IgG and IgM) in vitro in healthy controls, while only IgG production was increased in depressed patients. Lymphocyte function in depression may, therefore, be differentially sensitive to steroid effects. However, the mechanisms underlying the altered GC immunoregulation in depression still remain unclear.

Glucocorticoid immunoregulation is orchestrated by specific binding of GCs on two distinct cytoplasmic receptors, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). Although the MR has a higher affinity for circulating GCs than the GR, most (if not all) effects on the immune system are mediated via GRs (McEwen et al., 1997). The presence of these receptors indicates that the immune system is prepared for HPA activation and the subsequent elevation in endogenous GCs. However, it has been suggested that chronically elevated cortisol levels may produce a state of steroid resistance enabling lymphocytes to respond with less intensity to GCs. For instance, recent work produced by our (Bauer et al., 2000) and other’s laboratories (Wodarz et al., 1991) revealed that chronic stress and depression were associated with significant elevations in cortisol levels and reduced lymphocyte sensitivity to GCs in vitro. These data suggest that chronic elevations in cortisol may underlie GR resistance in humans but this has been poorly explored in depression so far. In addition, it has not been investigated whether treatment resistant depression (TRD) may be associated to steroid resistance.

There is considerable evidence that cytokines have a significant impact on GR expression and function. Glucocorticoid resistance has been described in patients with acute or chronic inflammatory diseases such as sepsis, asthma, rheumatoid arthritis, ulcerative colitis, and AIDS, all of which are diseases that have high comorbidity with affective disorders (Pariante and Miller, 2001). There is some evidence suggesting that local concentrations of cytokines produced during an inflammatory response may produce acquired GR resistance (Pariante et al., 1999). Of note for the pathogenesis of GR resistance in major depression is that major depression has been associated with increased levels of pro-inflammatory cytokines [interleukin (IL)-1 and IL-6] and acute phase proteins (Maes et al., 1993). However, only a few studies have assessed the immunity of TRD patients (Maes et al., 1997b, Kubera et al., 1999).

Therefore, we carried out a study to: (i) reliably assess the HPA axis function in pharmacologically treated TRD in order to discriminate discrete DEX suppression test (DST) groups; (ii) evaluate whether TRD was associated with changes on T-cell proliferation, and production of IL-2 (pivotal for growth and expansion of T cells) and TNF-α (promoter of pro-inflammatory cytokines, IL-1 and IL-6); in addition, (iii) we investigated whether lymphocytes differed in sensitivity to GCs and so examined whether TRD was associated with altered GC immunoregulation. This was achieved by exploring lymphocyte sensitivity to DEX (selective GR agonist) and cortisol (which binds to both GR and MR) in vitro.

Section snippets

Subjects and exclusion criteria

After receiving ethical approval from the Bethlem Royal Hospital Committee (King’s College, London), written informed consent was obtained from all subjects. Thirty-six depressed inpatients (15 males; 21 females, mean age=48.8, range 21–74) were categorized according to DSM-IV criteria (American Psychiatric Association, 1994) as major depression with typical features. All patients were classified as drug resistant according to their failure to previously respond to five different types of

Demographic and clinical data

Table 1 lists the demographic and clinical information from depressives (DST suppressors and nonsuppressors) and healthy controls. There were no significant differences in the sex ratio between the diagnostic categories. Beck scores were found to be very low among the controls, confirming they were not depressed. Patients presented mean HAM-D scores of 21.0±0.9. The mean length of the current depressive episode was ca 42 months; the mean number of previous episodes of depression was 5.7.

HPA axis function in major depression

In the present study, we did not observe elevated cortisol levels in pharmacologically treated TRD patients. This is in contrast with an extensive literature that indicates elevated cortisol levels in major depression (Gold et al., 1988). It is possible, however, that the uninterrupted use of antidepressant treatments prior to our investigation altered the HPA axis function in these patients. Indeed, tricyclic antidepressants and lithium are known to up-regulate GRs in rodents and hence

Acknowledgements

The authors would like to acknowledge the excellent technical assistance of the nursing staff of the Affective Disorders Research Unit (Bethlem Royal Hospital). They thank Professor Luiz Glock (PUCRS) for statistical assistance. The work presented in this manuscript was supported by grants from the Neuroendocrinology Charitable Trust (UK), The Wellcome Trust (UK) and CNPq (Brazil).

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Altered glucocorticoid immunoregulation in treatment resistant depression

Abstract

Introduction

Section snippets

Subjects and exclusion criteria

Demographic and clinical data

HPA axis function in major depression

Acknowledgements

Brain Behav. Immun.

Life Sci.

J. Neuroimmun.

Psychiat. Res.

Immunopharmacology

Psychoneuroendocrinology

Biol. Psychiat.

Psychoneuroendocrinology

Psychiat. Res.

Int. J. Immunopharmac.

Biol. Psychiat.

Cytokine

Psychoneuroendocrinology

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Psychiat. Res.

Brain Res. Rev.

Biol. Psychiat.

Prog. Neuropsychopharmac. Biol. Psychiat.

Immun. Today

J. Affect. Disord.

J. Affect. Disord.

Diagnostic and Statistical Manual of Mental Disorders

Endocrine and cytokine correlates of major depression and dysthimia with typical or atypical features

Mol. Psychiat.