Pro-inflammatory cytokines are elevated in adolescent females with emotional disorders not treated with SSRIs

Abstract

Background

Adults with major depressive disorder (MDD) show elevated levels of IL-6 and TNF-alpha. Studies of adolescents with MDD or anxiety disorders (AD) are few and present conflicting results.

Methods

We studied plasma cytokines in a clinical sample of adolescent females with MDD and/or clinical AD (n = 60, mean age 16.8 years), compared to healthy controls (n = 44; mean age 16.5 years).

Results

The clinical sample showed significantly higher values of IL-2 (Z = − 4.09, p > 0.0001), IL1-beta (Z = − 2.40, p < 0.05) and IL-10 (Z = − 2.38, p < 0.05) as compared to controls. The subgroup of the clinical sample not treated with SSRIs had a significant difference of IL-6 (Z = − 2.26, p < 0.05) in addition to the difference of IL-2 and IL1-beta, but showed no difference of IL-10 as compared to the controls. SSRI treatment was related to IL-6, explaining 26% of the variance in the clinical sample after controlling for BMI and symptom severity. In the clinical sample, levels of IL-6 and IFN-gamma were positively correlated with self-assessed symptoms of anxiety and/or depression (corr.coeff 0.35 resp 0.40 at p < 0.05).

Limitations

The cross-sectional design does not allow for conclusions on causality. The sample sizes were relatively small and a large drop-out in the clinical sample may have influenced the representativity.

Discussion

The study suggests that pro-inflammatory cytokines are part of the pathophysiology of emotional disorders in adolescent females and that SSRIs have anti-inflammatory properties. The findings prompt further studies on the specific mechanisms involved and may contribute to the development of more effective treatment and prevention.

Introduction

The importance of the immune system in the pathophysiology of emotional disorders is being elucidated in current research. Immune system dysregulation is related to major depressive disorder (MDD) in adults and according to recent meta analyses the most robust findings are higher concentrations of the pro-inflammatory cytokines TNF-α and IL-6 in depressed subjects compared with controls (Dowlati et al., 2010). Increased levels of pro-inflammatory cytokines have also been found in some anxiety disorders such as obsessive compulsive disorder (Konuk et al., 2007) and post-traumatic stress disorder (Gill et al., 2009).

Studies on systemic cytokines in adolescents with major depressive disorder and/or anxiety disorders have been few and present conflicting results (Brambilla et al., 2004, Gabbay et al., 2009a, Gabbay et al., 2009b, Pervanidou et al., 2007). This may be explained by the fact that the samples have been small and consisted of both boys and girls and of mixed levels of puberty. A predominance of mood disorders in females as compared to males emerges at the onset of puberty (Angold et al., 1998) and sex differences in immunity during puberty may be implicated in the pathophysiology of depression (Pitychoutis and Papadopoulou-Daifoti, 2010). Furthermore, the use of selective serotonin reuptake inhibitors (SSRIs) has not been systematically addressed in the studies on systemic cytokines in adolescents with emotional disorders, which may be yet an explanation to the conflicting results. In adults, IL-6 levels decrease with SSRI treatment in patients with major depression (Basterzi et al., 2005) and non-steroid anti-inflammatory drugs have been suggested in treatment of depression (Davis et al., 2011).

We and others have previously shown that adolescent female psychiatric patients with anxiety and/or depression show decreased vagal function as estimated by reduced heart rate variability (HRV) compared with healthy controls (Bosch et al., 2009, Henje Blom et al., 2010, Tonhajzerova et al., 2009, Tonhajzerova et al., 2010). In adults associations between decreased HRV and panic anxiety, generalized anxiety and depression have been found (Thayer, 2009, Thayer and Lane, 2000, Thayer et al., 1996). Decreased HRV has also been associated with increased pro-inflammatory cytokines in patients with coronary heart disease (CHD) (Thayer and Sternberg, 2006) and decreased vagal function has been shown to characterize the risk factors of inflammation and negative affect for CHD (Janszky et al., 2004).

Our primary aim was to study systemic cytokines in post pubertal adolescent females with anxiety disorders and/or MDD, with or without ongoing SSRI-treatment compared to healthy controls. Since depression is highly co-morbid with anxiety disorders in adolescence (Costello et al., 2002, Costello et al., 2003), and it is clinically difficult to define a sample with MDD without co-morbid anxiety in this age group we chose to study a sample including adolescent females with MDD and/or some kind of anxiety disorder. We hypothesized that concentrations of pro-inflammatory cytokines would be elevated in the clinical sample as previously described in adults and that patients treated with SSRIs would show lower levels of pro-inflammatory cytokines compared to untreated. We also wanted to investigate whether HRV was related to pro-inflammatory cytokines in the clinical sample.