Research report
Immune–inflammatory markers in patients with seasonal affective disorder: effects of light therapy

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Abstract

Background: There is increasing evidence that an activation of the immune–inflammatory system is involved in the pathophysiology of depressive disorders. The purposes of this study were to (1) compare immune–inflammatory markers in patients with seasonal affective disorder (SAD) with those in matched normal controls; and (2) examine the effects of light therapy on the immune–inflammatory markers in patients with SAD. Methods: Plasma concentrations of interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R) and soluble IL-2 receptor (sIL-2R) were measured in 15 patients with SAD and 15 age- and sex-matched normal controls. Of the 15 patients, 14 had repeated blood sampling for these variables following 2 weeks of light therapy. Results: We found that patients with SAD had significantly increased IL-6 levels compared to normal controls (P<0.0005). There was a trend toward increased sIL-2R in patients with SAD (P=0.09). There was no significant difference in sIL-6R level between the two diagnostic groups (P=0.18), but the product term (IL-6×sIL-6R) was significantly higher in patients with SAD than that in normal control controls (P<0.0003). Furthermore, all 14 patients who completed the study improved with 2 weeks of light therapy and nine of them (64%) had 50% reduction in score of the Hamilton Depression Rating Scale–SAD version post-treatment compared to baseline. However, the initially increased immune markers in SAD patients were not significantly altered by the therapeutic light therapy. Limitations: This study was limited to a small sample size and other immune inflammatory markers should be measured for further evidence of immune activation in seasonal depression. Conclusions: Our results of increased IL-6, IL-6×sIL-6R, and sIL-2R in patients with SAD suggest an activation of the immune–inflammatory system in winter depression, which is not altered by 2 weeks of successful light therapy.

Introduction

Of pro-inflammatory cytokines, interleukin 6 (IL-6) has been the most studied in depression. This pleiotropic cytokine is a major immune and inflammatory mediator. It regulates the synthesis of acute phase proteins and induces proliferation and differentiation of B cells. It is also involved in T-cell activation and induces prostaglandin secretion (Kushner, 1991). IL-6 exerts its action through the interaction with a membrane receptor (i.e. interleukin 6 receptor, IL-6R) and a signal-transducing protein (i.e. gp 130) (Bock et al., 1992). Shedding of membrane receptors generates a soluble form of IL-6R (Mullberg et al., 1993). A parallel increase in plasma concentrations of IL-6 and sIL-6R has been reported in depressed patients in two studies (Maes et al., 1995, Sluzewska et al., 1996), suggesting an activation of immune–inflammatory response in depression. Since it is known that sIL-6R can augment the biological activity of IL-6 (Bock et al., 1992), the parallel increase of plasma IL-6 and sIL-6R in patients with major depression would be expected to induce a further enhancement in the biological activity of IL-6 per se (Maes et al., 1995). Evidence in support of this comes from the observation that in the presence of sIL-6R, the concentrations of IL-6 required for its biological activity were lower than that required in the absence of sIL-6R (Bock et al., 1992). However, another two studies simultaneously measuring plasma IL-6 and sIL-6R levels in patients with major depression and normal controls showed that IL-6, but not sIL-6R, was significantly increased in depressed patients compared to normal controls (Maes et al., 1997, Song et al., 1998). The reason for the discrepancy in the results of plasma sIL-6R levels between the studies is unclear.

In addition to increased IL-6, studies of immune–inflammatory markers in depression consistently showed increased plasma concentrations of soluble interleukin 2 receptor (sIL-2R) (Maes et al., 1990, Maes et al., 1991, Nassberger and Traskman-Bendz, 1993, Sluzewska et al., 1994, Maes et al., 1995, Sluzewska et al., 1996). Since activated T cells release a soluble form of IL-2 receptor into the blood and sIL-2R concentrations appear to correlate with IL-2 secretion (Caruso et al., 1993), increased sIL-2R level is considered as an indication of T-cell activation (Caruso et al., 1993). The findings of increased plasma sIL-2R in depressed patients would, therefore, suggest an increase in the numbers of activated T cells in acute depression. Consistent with this, Maes et al. (1992) have shown that patients with major depression had significantly increased numbers of CD25+ bearing cells and cells with class II MHC HLA-DR molecules (i.e. interleukin-2 receptor bearing cells) when compared to controls.

Seasonal affective disorder (SAD) is a clinical subtype of recurrent major depression that occurs with a seasonal pattern (Rosenthal et al., 1984). It is a very common psychiatric disorder affecting up to 5–10% of the general population (Rosen et al., 1990). Besides the personal distress, patients with SAD have considerable impairment in occupational and social function (Allen et al., 1993). Winter depression is the most common type of SAD in which patients experience symptoms of clinical depression during the fall and winter, with full remission to normal mood during the spring and summer seasons. A significant proportion of patients with winter depression responds to daily exposure to bright artificial light, known as light therapy (Rosenthal et al., 1988, Terman et al., 1989, Magnusson and Kristbjarnarson, 1991, Eastman et al., 1998, Lewy et al., 1998, Terman et al., 1998). As yet, the pathophysiology of SAD and the therapeutic mechanism of light are still unknown. Given that depressive symptoms (Allen et al., 1993, Tam et al., 1997) and the treatment response to antidepressants (Lam et al., 1995, Ruhrmann et al., 1998) are shared between seasonal and non-seasonal depressions, one may expect that an alteration in immune–inflammatory markers such as IL-6, sIL-6R, and sIL-2R is also involved in seasonal depression and its treatment. The purposes of this study were therefore to determine (1) if there is an increase in plasma levels of IL-6, sIL-6 and sIL-2R in patients with SAD compared to normal controls; and (2) if light therapy has an immunomodulatory effect on these variables in patients with SAD.

Section snippets

Subjects

We studied a total of 15 patients with SAD (9 males and 6 females) and 15 healthy subjects (8 males and 7 females). All study subjects were physically healthy and were drug free for at least 2 weeks prior to blood sampling and none had taken fluoxetine in the preceding 8 weeks. We excluded those subjects with chronic illnesses known to affect the immune status and with acute infectious or allergic reactions for at least 2 weeks prior to the study. The DSM-IV diagnosis of recurrent major

Results

There was no significant difference in sex between patients with SAD and normal controls (χ2=0.13, df=1, P=0.71). There was also no significant difference in age between the patients with SAD (mean age 35.3 years, S.D.=8.8) and normal controls (mean age 35.3 years, S.D.=7.9) (t=0.02, df=28, P=0.98). Repeated measures ANOVA on data of IL-6, sIL-6R, IL-6×sIL-6 and sIL-2R showed a significant group effect (F=14.9, df=1,28, P<0.002) and a significant cytokine×group effect (F=8.9, df=3,84, P<0.001).

Discussion

The major findings of the present study included that 1) patients with SAD had significantly increased IL-6 levels and the product term of sIL-6×IL-6, as well as a trend toward increased plasma sIL-2R levels, and 2) the initially increased immune markers in SAD patients were not significantly altered by 2 weeks of successful light therapy.

This is the first report that plasma IL-6 concentrations are significantly increased in patients with SAD. This finding is consistent with previous reports

Acknowledgments

The authors would like to thank Dr. Heather A. Robertson, Ms Arvinder Grewal, Mr. Frank C. Chi for their assistance. A preliminary report of these data was presented at the 54th Annual Meeting, Society of Biological Psychiatry, Washington DC, USA, May 13–15, 1999. This research is partially supported by National Scientific Council of Taiwan, (Grant NSC-88-2314-B-038-116 to Dr. S.-J. Leu).

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