Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder

Abstract

Background

The neurobiology of bipolar disorder is not completely understood. Cytokines have received increasing attention as potential mediators of the interaction with immune, neuroendocrine system and specific pathways involved in mood, energy, and activity control. Previous reports have suggested the association of mania and bipolar depression with a proinflammatory state. However, they did not compare cytokine levels in all phases of bipolar disorder.

Methods

Sixty-one bipolar patients were recruited for assessment of serum cytokine levels. Of these, 14 were in euthymic state, 23 and 24 were in manic and depressive episodes, respectively. A healthy comparison group included 25 healthy volunteers. Cytokines involved in Th1/Th2 balance, such as TNF-α, IL-2, IL-4, IL-6, IL-10, IFN-γ, were examined by flow cytometry.

Results

During mania, proinflammatory cytokines, IL-2, IL-4 and IL-6, were increased in comparison with healthy subjects. Patients in depressive episode showed only increased IL-6 levels. There were no significant differences in cytokine levels between patients in remission and healthy subjects, except for IL-4. Mood symptoms showed a positive correlation with IL-6 and IL-2.

Discussion

These findings suggest that mania, and to a less extent, depression are associated with a proinflammatory state. These changes seem to be related to mood state, as changes in cytokine profile were more pronounced during acute episodes than in euthymia. This study provides further support to investigate the immune system as a target for future treatment development.

Introduction

Bipolar disorder (BD) is a highly prevalent and disabling condition; however the pathophysiology remains largely unknown. In the last decade, the importance of cytokines in neuronal survival was recognized (Brietzke and Kapczinski, 2008), along with the orchestrated action of neurotransmitters, hormones, and neurotrophins (Post, 2007). Recent studies have described impairments in neuroplasticity and neuronal survival in BD (Schloesser et al., 2007). In addition, cytokines can interact with the neuroendocrine system and in specific pathways involved in mood, energy, and activity control (Irwin and Miller, 2007, Pasic et al., 2003). Regardless of their etiology, chronic inflammatory responses in individuals with mood disorders may result in downstream biological damage and contribute to the elevated cardiac and other medical morbidities associated with BD (McEwen, 2003, Simon et al., 2008, Kapczinski et al., 2008).

Despite a growing body of evidence of the involvement of cytokines in psychiatric and neurodegenerative disorders, findings are still limited in BD. There are reports suggesting an association of mania and depression with a proinflammatory state. However, these findings present some inconsistencies, which could be related to sample heterogeneity regarding mood symptoms, length of illness and effect of medications. As far as we know, previous studies have not compared cytokine levels in all phases of BD. Some studies reported increased proinflammatory cytokines and hyperactivity of T helper cell 1 in BD, with significantly higher TNF-α levels in bipolar patients during manic (Kim et al., 2007, Ortíz-Domingues et al., 2007, O'Brien et al., 2006) or depressive episodes when compared with normal controls (Ortíz-Domingues et al., 2007, O'Brien et al., 2006). Kim et al. (2007) reported increased production of interleukin-6 (IL-6) and TNF-α during mania when compared with nonbipolar subjects. Among such patients, IL-6 levels returned to the baseline after 6 weeks of treatment with mood stabilizers, but TNF-α level continued high. Accordingly, the authors suggest that IL-6 could be a manic state marker, while TNF-α could be an enduring change (Kim et al., 2007). In another recent study, O'Brien et al. (2006) described that both mania and bipolar depression are associated with increased production of proinflammatory cytokines IL-6, IL-8 and TNF-α, even with the use of mood stabilizers or antipsychotic medication. No difference was observed in the concentration of anti-inflammatory cytokine IL-10 or in cortisol concentrations between manic subjects and controls. In addition, Ortíz-Domingues et al. reported increased TNF-α and reduced IL-2 levels both in mania and depression and increased IL-6 in mania and IL-4 in depression. A single study that has examined IFN-γ levels during euthymia in BD showed decreased levels in comparison with controls, but did not include those with mood episodes (Boufidou et al., 2004).

There are several methods to assess cytokine levels. Usually they are measured using ELISA kits, but other methods such as flow cytometry have been proposed. Actually, previous studies showed that flow cytometry can adequately replace ELISA and PCR in basic research as well as in immune diagnostics (Hemdan, 2008).

Therefore, this study was designed to examine which changes in cytokine levels are associated with mood episodes and which are more enduring changes, being present during euthymic periods. The levels of cytokines involved in Th1/Th2 balance, such as TNF-α, IL-2, IL-4, IL-6, IL-10, IFN-γ, were compared between depressive, manic and euthymic phases of BD. The understanding of inflammatory mechanisms of BD could potentially open avenues for new treatment options and for the investigation of the use of anti-inflammatory medications in BD (Brietzke and Kapczinski, 2008, Nery et al., 2008).