Pro-inflammatory cytokines and treatment response to escitaloprsam in major depressive disorder

Abstract

Alterations in the immune system may have importance for the pathophysiology of depression. Several studies have linked increased production of pro-inflammatory cytokines to depression and depressive symptoms. There is growing evidence that antidepressive treatment may influence the production of pro-and anti-inflammatory cytokines. In the present study we aimed to find associations between the levels of soluble interleukin-2 receptor (sIL-2R), interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α) and the response to antidepressant treatment in patients with major depression. Our study group consisted of 100 patients (35 males and 65 females) who were treated with escitalopram 10–20 mg/day for 12 weeks. Responders and non-responders were identified according to Montgomery-Asberg's Depression Rating Scale (MADRS) scores. The levels of cytokines were measured at baseline and at 4th and 12th week of the treatment and compared to cytokine concentrations in healthy volunteers (n = 45; 19 males and 26 females). Our data indicated that a higher level of TNF-α might predict a non-response to treatment with escitalopram and that changes in concentrations of sIL-2R during the treatment were different in responders and non-responders.

Introduction

Alterations in the immune system and immune response have been studied in various psychiatric disorders including major depression (Schiepers et al 2005), bipolar disorder (O'Brien et al 2006), dysthymia (Brambilla et al 2004) and schizophrenia (Maes et al., 2002, Müller et al., 2000). There is growing evidence that major depression is associated with up-regulation of inflammatory response as reflected by increased production of pro-inflammatory cytokines, but the results are controversial for specific subgroups. Kaestner et al. (2005) have found elevated interleukin (IL)-1β and IL-1 receptor antagonist concentration in non-melancholic depressive patients as compared to melancholic type. However, Marques-Deak et al. (2007) did not notice any differences in IL-1β, IL-6 or interferon-γ (INF-γ) measured in female patients with different subtypes of major depressive disorder. A number of studies have focused on the role of cytokines in the pathogenesis and treatment of major depression (Capuron et al., 2003, Capuron and Miller, 2004), but the question about their causative involvement is still open. Animal models as well as cytokine therapy in humans suggest that pro-inflammatory cytokines may induce depressive symptoms (Anisman et al., 2002, Bonaccorso et al., 2001, Capuron and Miller, 2004, Pollak et al., 2003) and this may be modulated by antidepressants (Brustolim et al., 2006, Malek-Ahmadi and Ghandour, 2004; reviewed by Schiepers et al., 2005). Conceivably, antidepressants may exert therapeutic effects via inhibition of pro-inflammatory cytokine production (reviewed by Kenis and Maes, 2002). In a recent study with animal models of two human diseases, namely septic shock and allergic asthma, both desipramine and fluoxetine reduced inflammatory reaction and, in particular, dose-dependently inhibited release of tumor necrosis factor alpha (TNF-α) (Roumestan et al., 2007).

The effects of antidepressants on the cytokines have been also investigated in vitro in cell cultures. In healthy volunteers suppression of pro-inflammatory cytokine production was found with several antidepressants, such as moclobemide (Lin et al., 2000), clomipramine, sertraline and trazodone (Maes et al., 1999), imipramine and mianserin (Szuster-Ciesielska et al., 2003) as well as reboxetine, desipramine, fluoxetine and clomipramine (Diamond et al., 2006). In contrast, Kubera et al. (2004) found in a study with depressive patients that imipramine, venlafaxine, 5-HTP and a combination of 5-HTP and fluoxetine increased the production of IL-6, but did not affect TNF-α production. Another report indicated that circulating pro-inflammatory cytokine levels were not significantly associated with pro-inflammatory cytokine production in vitro (Cyranowski et al., 2007).

To date, a number of studies have explored the effects of antidepressants on serum cytokine concentrations in patients with depression. Micova et al. (2001) did not find significant effects of an 8-week treatment with different antidepressants on IL-6, IL-8, TNF-α, soluble IL-2 receptor (sIL-2R) and uteroglobulin levels in a sample of in-patients (n = 14). Nevertheless, they detected an association between higher serum IL-2R and non-response to treatment with antidepressants. Earlier, Maes et al. (1995) reported that sub-chronic treatment with fluoxetine or tricyclic antidepressants had no impact on plasma IL-6, sIL-6R, sIL-2R and transferring receptor in depressed in-patients (n = 17). In contrast, newer studies have demonstrated significant lowering of IL-6 levels during treatment in 25 (Maes et al., 1997) and 23 (Basterzi et al., 2005) depressed patients. On the other hand, significant increases in serum IL-1b, IL-6 and INF-γ levels were noted in 27 depressive women treated with antidepressants to remission (Marques-Deak et al., 2007). The treatment effects on serum cytokine concentrations in this study were independent from the antidepressant class (imipramine or sertraline) or subtypes of depression; however, post-treatment levels of cytokines differently depended on severity, chronicity and recurrence of depressive episodes. The opposite effects of antidepressants on cytokines were recently reported by Lee and Kim (2006), who demonstrated significant decrease in IL-12 values and increase in transforming growth factor β-1 (TGF-β1) levels after a 6 week treatment in 16 patients with major depression. In a recent study Kim et al. (2007) showed a significant decrease in IL-2, IL-6, and TGF-β1 production after treatment with antidepressants from different classes in 32 patients with major depression, whereas levels of IFN-γ, IL-4, and TNF-α did not change significantly. When the effect of individual antidepressants (bupropion, citalopram, mirtazapine, paroxetine, and venlafaxine) on cytokine network was analyzed separately, only citalopram significantly decreased TGF-β1 production. Finally, increased mRNA expressions of IL-1β, IL-6, IFN-γ and TNF-α were revealed in depressed patients, but only the expression of IFN-γ significantly diminished in those patients (n = 8) who received 3 months treatment with fluoxetine (Tsao et al., 2006).

Notably, the aforementioned studies had certain methodological limitations, such as non-standardized medication choice and treatment schedule, use of antidepressants from various classes, small group sizes and short treatment duration in most of the studies. Different or even opposite effects of antidepressants with distinct pharmacological properties on immunological profiles could also complicate interpretation of data. Therefore, in order to validate the relationship between antidepressant treatment effects and cytokine activity we used a standardized treatment and a larger sample of patients. Specifically, the aim of our study was to investigate the acute and chronic effects of selective serotonin re-uptake inhibitor, escitalopram, on serum levels of IL-8, TNF-α and sIL-2R in patients with major depression. These cytokines belong to pro-inflammatory mediators, except IL-8, which depending of concentration may also perform anti-inflammatory role (Schiepers et al., 2005). The fact that different cells could produce these cytokines may indicate their unique or distinct role in the pathogenesis of depression. Nevertheless, their roles in antidepressant treatment are less known making them good candidates for inclusion in the study. Escitalopram was chosen as an antidepressant due to its high selectivity to serotonin re-uptake protein without effects on other receptors. Additionally, we aimed to explore whether serum cytokines concentrations can predict treatment response to antidepressants.