Unhealthy lifestyle may increase later depression via inflammation in older women but not men
Introduction
The inflammatory hypothesis of depression posits that inflammation may have a causative role in depression. It is supported by observations of depressive-like behaviour following cytokine administration in animals and humans, and idiopathic major depressive disorder in patients treated with cytokines such as interferon-alpha or interleukin (IL)-2 (Anisman et al., 2005, Capuron et al., 2009, Dantzer et al., 2011, Miller et al., 2009, Myint et al., 2009, Reichenberg et al., 2001). Furthermore, inflammatory mediators, including IL-6, C-reactive protein (CRP), and tumor necrosis factor are consistently elevated in depression (Dowlati et al., 2010, Hiles et al., 2012, Howren et al., 2009). Emerging evidence from randomised controlled trials suggests that anti-inflammatory medications may improve depression outcomes (Akhondzadeh et al., 2009, Raison et al., 2013). Inflammatory mediators interact with key biological systems implicated in depression, including altering neuroendocrine stress activity, neural plasticity, cognitive functioning, reactive oxygen species, and neurotransmitter metabolism and activity (Irwin and Miller, 2007, Miller et al., 2009). Thus, a causal relationship is biologically plausible.
The source of the elevated inflammatory markers in depression remains unclear. Recent theories, such as the social signal transduction theory (Slavich and Irwin, 2014) and PATHOS-D (Raison and Miller, 2013), propose that real or imagined psychosocial stressors, represented cortically, activate autonomic and hormonal inflammatory pathways and upregulate inflammatory gene expression. This upregulation produces the elevated circulating inflammatory mediators that cause cognitive, emotional and behavioural symptoms of depression. However, the source of inflammation in people with depression may be broader than this, involving factors such as nascent or apparent physical illness, including obesity, and/or aspects of lifestyle (Berk et al., 2013). Aspects of physical illness and unhealthy lifestyle, including central adiposity, low physical activity, poor diet quality, smoking and alcohol use, are frequently observed in people with depression and also have inflammatory consequences (Hamer et al., 2009a, Lopresti et al., 2013, Milaneschi et al., 2009, O'Connor et al., 2009). For instance, adipose tissue, particularly hypertrophic abdominal fat, produces inflammatory cytokines and mediators (Bastard et al., 2006, Maury and Brichard, 2010, Odegaard and Chawla, 2013) and it may be this abdominal, and not subcutaneous, fat that is associated with depression (Everson-Rose et al., 2009).
Little attention has been given to examining potential sources of inflammation in depression within longitudinal contexts. Indeed, few published studies address longitudinal evidence of whether elevations in inflammatory markers precede or follow depressive symptoms, and the evidence that is published is mixed. Meta-analysis of longitudinal studies indicate a small significant association between elevated CRP (eight studies) or IL-6 (three studies) and subsequent depressive symptoms, with moderate heterogeneity (Valkanova et al., 2013). There is also support for a bi-directional prospective relationship between inflammatory markers and depressive symptoms (Hamer et al., 2009a, Hamer et al., 2009b, Matthews et al., 2010). Given the limited and mixed evidence, further exploration of the prospective relationship is warranted, with close consideration of the influence of effect modifiers. For instance, although previous prospective studies have selectively examined women (Matthews et al., 2007, Matthews et al., 2010) or men (Boyle et al., 2007), typically gender is considered as a control variable, rather than an effect modifier. There are well-established differences in the clinical presentation of depression in men and women (Marcus et al., 2005), likely due to both social factors and biological factors, including inflammatory markers and neuroendocrine stress hormones (Edwards et al., 2006, Kudielka and Kirschbaum, 2005, Larsson et al., 2009, Marriott and Huet-Hudson, 2006, McConnell et al., 2005). Therefore, examining the prospective relationship between depression and inflammatory markers by gender is pertinent.
To our knowledge, mediation analyses have not been completed to examine whether inflammatory markers mediate the relationship between baseline health and lifestyle factors, and later depression. This approach may highlight whether physical health and lifestyle could be a source of elevated inflammatory markers observed in people with depression. The current study explores the relationship between inflammatory markers, depressive symptoms and indicators of psychosocial functioning, physical health, and unhealthy lifestyle (central adiposity, low physical activity, poor diet quality, smoking and alcohol use). There are two discrete aims. The first aim is to explore a practical question from a biomarker perspective: whether baseline levels of inflammatory markers – IL-6 and CRP – are associated with levels of depressive symptoms at follow-up, and whether the effects remain after adjusting for confounding. The second aim is to examine lifestyle, physical health or psychosocial functioning as predictors of depressive symptom outcomes at follow-up, and explore whether inflammatory markers mediate this relationship, thereby providing evidence regarding potential sources of inflammatory markers in depression.
Section snippets
Participants
Participants were drawn from the Hunter Community Study, a study of the health of older persons in the large regional centre of Newcastle, New South Wales, Australia (McEvoy et al., 2010). Participants gave informed consent to participate. All procedures were approved by the institutional ethics review board and conducted in accordance with the Declaration of Helsinki. Briefly, between December 2004 and December 2007, community-dwelling individuals from the Newcastle region were randomly
Sample description
Table 1 describes the baseline characteristics of the 1410 participants included in these analyses. They were an average of 65.6 years old (SD = 7.1); 711 (50.4%) were females, 1074 (77.9%) were married or de facto/living with a partner, and all were living in the community. By follow-up, most were still living in the community, with less than 1% in retirement or hostel facilities.
Cross sectional associations
For females, most aspects of unhealthy lifestyle and all measures of physical health and psychosocial functioning
Discussion
The current study sought to examine whether baseline levels of inflammatory markers predict later depression outcomes, and whether the effects are driven by aspects of physical health, unhealthy lifestyle and perceived psychosocial functioning. The strongest effects observed were that unhealthy lifestyle factors drive depression both directly and indirectly via inflammatory mediators. There was also evidence that the effect of psychological coping on depression outcomes is through inflammation.
Funding body agreements and policies
Funding sources for this study included: University of Newcastle's Strategic Initiatives Fund, Gladys M Brawn Senior Research Fellowship scheme, Vincent Fairfax Family Foundation, John Hunter Charitable Trust, Xtrata, and beyondblue. We also acknowledge in-kind support from the Hunter Medical Research Institute for media support during the initial recruitment of participants, and Dr Anne Crotty, Prof. Rodney Scott and Prof. Chris Levi who provided financial support towards freezing costs for
Contributors
All authors contributed to and have approved the final manuscript. Sarah Hiles conducted literature reviews, planned and conducted the statistical analyses, and wrote the first draft of the manuscript. Amanda Baker provided advice for the development of the research question and analyses, and led the editing of the manuscript. Theo de Malmanche assisted with the analysis of the blood samples and provided immunology expertise. Mark McEvoy managed data collection for the Hunter Community Study.
Conflict of interest
The authors have no conflicts of interest to declare.
Acknowledgements
This research based was conducted as part of the Hunter Community Study, The University of Newcastle. We are grateful to the men and women of the Hunter region who provided the information recorded. We acknowledge funding from the University of Newcastle's Strategic Initiatives Fund, Gladys M Brawn Senior Research Fellowship scheme, Vincent Fairfax Family Foundation and the John Hunter Charitable Trust. We also acknowledge the Hunter Medical Research Institute who provided media support during
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