Cytokine levels in major depression are related to childhood trauma but not to recent stressors
Introduction
Depressive disorders are the second leading cause of disability worldwide (Ferrari et al., 2013). Accumulating evidence indicates that major depressive disorder (MDD) is associated with immune activation and increased inflammatory response (Dantzer et al., 2008). Important mediators of these processes are pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6. Meta-analyses confimed that groups of MDD patients exhibit higher serum levels of IL-6 compared to groups of healthy control (HC) subjects (Dowlati et al., 2010, Haapakoski et al., 2015), while for TNF-α, both increased (Dowlati et al., 2010) and similar (Haapakoski et al., 2015) levels have been reported in MDD patients versus HC.
Despite the robust association of MDD with increased pro-inflammatory activity, individual MDD patients' values show great inter-individual heterogeneity, leading to the idea that increased inflammatory markers might only be present in a certain subgroup of MDD patients (Raison and Miller, 2011).
An important risk factor associated with MDD is psychological stress. Stressful life events have been shown to increase the risk for depression and most depressive episodes are indeed preceded by stressful events (Hammen, 2005). Especially early life stress, such as childhood maltreatment, has been shown to increase the risk of depression (in a dose-response relationship) up to decades after its occurrence (Chapman et al., 2004, Danese et al., 2009, Widom et al., 2007).
On the other hand, psychological stress is not only associated with MDD, but also with increased inflammatory activity, as demonstrated by the accumulating evidence from naturalistic and experimental studies (Slavich and Irwin, 2014). In addition, especially maltreatment in childhood has been shown to cause long lasting effects on peripheral inflammation in later life, e.g. resulting in increased pro-inflammatory cytokine levels of IL-6 and TNF-α (Baumeister et al., 2016, Coelho et al., 2014). This chronic inflammatory state associated with childhood maltreatment was found to be independent of current clinical comorbidities such as MDD (Coelho et al., 2014) and has also been demonstrated in healthy adults with a history of childhood adversity (Hartwell et al., 2013).
There are noteworthy reports on the interplay of the three factors: stress, inflammation and MDD. A prospective longitudinal cohort study showed that a history of childhood maltreatment contributes to the co-occurrence of depression and inflammation (Danese et al., 2008). Likewise, a more recent prospective study demonstrated that the coupling of MDD and inflammation was only apparent in individuals with a history of high childhood adversity but not in individuals without the latter (Miller and Cole, 2012). Indeed, high levels of IL-6 forecasted the development of depression six months later in individuals with high childhood adversity (Miller and Cole, 2012).
Literature suggests that stress of different types and severity and at different time points in life may exert differential effects on inflammation and depression. Whereas acute psychological stress leads to transient increases in systemic inflammation, chronic psychological stress may be associated with rather chronically increased markers of inflammation (Rohleder, 2014). With regard to time of emergence of the stressor, recent evidence indicates that childhood adversity and recent stressful life events independently and additively contribute to higher levels of inflammation (Hostinar et al., 2015). Interestingly, a longitudinal study with cancer patients showed that both childhood trauma and recent life events are associated with the development of depressive symptoms, but only childhood trauma and not recent events accounted for the association between inflammatory markers with depressive symptoms (Archer et al., 2012). Studies investigating effects of different childhood trauma subtypes, e.g. emotional, physical, or sexual abuse or emotional or physical neglect, are scarce. Meta-analyses have shown inconclusive findings by either highlighting the effects of sexual abuse (Lindert et al., 2014) or, in contrast, of non-sexual and “more silent” forms of maltreatment, such as psychological abuse and neglect (Infurna et al., 2015, Norman et al., 2012) on the development of MDD. With regard to inflammation, a recent meta-analysis showed a differential association of the specific type of childhood trauma (e.g. physical and sexual abuse) with a specific pro-inflammatory profile in later life (e.g. elevated levels of TNF-α and IL-6, but not CRP) (Baumeister et al., 2016). Taken together, data on how different types of stressors might specifically contribute to the association of MDD with inflammation are equivocal and limited. Therefore, studies analyzing different types of stressors in parallel are needed to further unravel the pathogenic mechanisms underlying MDD.
With the present study, we aimed to enlarge our knowledge on the relationship of stress, inflammation, and depression by investigating the effects of various forms of (early life) stress on inflammatory markers in MDD patients. In a large sample of MDD patients, various experiences of stress and adversity were retrospectively assessed with regard to different time points (childhood, past 12 months, past month), different severities (e.g. traumatic events vs. overburdening situations), and different assessment criteria (e.g. ‘objective’ number of experienced events vs. ‘subjective’ perception of situations as stressful). As indicators of pro-inflammatory activity, we determined serum levels of the pro-inflammatory cytokines TNF-α and IL-6. Based on previous literature, we hypothesize that higher pro-inflammatory cytokine levels are associated with both early and later life stressful experiences in MDD patients. Additionally, we aim to explore whether different subtypes of childhood trauma contribute differentially to the association between depression and levels of pro-inflammatory cytokines.
Section snippets
Participants
This study was approved by the ethics committee of the medical association Westphalia-Lippe, Germany (reference 2009-019-f-S). After study procedures had been fully explained, all subjects provided written informed consent. This study was part of the “MOODINFLAME”-consortium, which was funded by the European Union (EU) under the project title “Early diagnosis, treatment and prevention of mood disorders, targeting the activated inflammatory response system” and has been conducted between 2009
Sample characteristics
The mean age of the MDD patients was 41 (±12) years, 56% were female, and 46% were current smokers. Both patients' mean body mass index (BMI; 26 ± 4) and mean waist hip ratio (WHR; 0.89 ± 0.09) indicated a trend towards being overweight (Table 1). Patients' mean IDS score (34 ± 10) indicated an overall moderate depression severity. Patients reported a duration of 48 (±78) weeks on average for the current MDD episode, having had 4 (±7) previous episodes of MDD in their lifetime and an average onset of
Discussion
We have studied whether different stressors ranging from childhood to the past month are associated with pro-inflammatory cytokine levels in MDD. This study shows a linear relationship between the severity of childhood sexual abuse and the levels of pro-inflammatory cytokines TNF-α and IL-6 in adult MDD patients. In contrast, levels of TNF-α and IL-6 were not associated with either other types of reported childhood trauma (such as emotional or physical abuse or neglect) or with more recent
Financial disclosures
This study was supported by European Union EU-FP7-HEALTH-F2-2008-222963 “MOODINFLAME” and was in part supported by the National Health and Medical Research Council Australia (APP1060524 to BTB).” Laura Große was funded by EU-FP7-PEOPLE-2009-IAPP “PSYCH-AID”. Volker Arolt received grants from the German Ministry of Science and Education, from the Münster Interdisciplinary Center of Clinical Research, and from the European Union; he is a member of the advisory board of, or has given presentations
Contributors
VA and SJ contributed substantially to the design of the study and data collection. LG, OA, SJ, and BB conducted the statistical analyses and wrote the first draft of the manuscript. CJ, GS, DS, and VA contributed to analysis and interpretation of the results, and revised the manuscript critically. All listed authors concur with the submission; have made a substantial contribution to the analysis and interpretation of the data; the drafting of the article or reviewing it critically; have given
Conflict of interest
None.
Acknowledgements
We are grateful to Professor Heinrich Schulze Mönking of the St.-Rochus-Hospital in Telgte, Germany and to Professor Thomas Reker of the LWL-Klinik in Münster, Germany for their valuable contribution to the recruitment of MDD patients. Further we thank Niklas Ahn, Rhea Balske, Kathrin Entrich, Nina Griese, Franka Hanysek, Astrid Rauch, Christina Uhlmann, Rolf Voegler, and Linda Wiegers for recruitment of patients and controls. Finally, we thank Katrin Blaschei, Christiane Schettler, and Kordula
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