Elsevier

Psychoneuroendocrinology

Volume 50, December 2014, Pages 139-148
Psychoneuroendocrinology

Herpesviruses, inflammatory markers and incident depression in a longitudinal study of Detroit residents

https://doi.org/10.1016/j.psyneuen.2014.08.002Get rights and content

Summary

Background

Depression is predicted to become the leading cause of disability worldwide by 2030 and moreover, socioeconomic inequalities in depression persist. Herpesviruses, which are more prevalent among socioeconomically disadvantaged populations, subject to stress-induced reactivation and are associated with increased levels of pro-inflammatory cytokines implicated in the etiology of depression, may serve as novel risk factors for depression onset.

Methods

Data are from individuals in the Detroit Neighborhood Health Study tested for herpes simplex virus-1 (HSV-1) and cytomegalovirus (CMV) seropositivity/immunoglobulin G (IgG) antibody levels (N = 263) as well as interleukin-6 (IL-6) (N = 245) and C-reactive protein (CRP) (N = 236) levels and assessed for incident depression via the Patient Health Questionnaire-9. Linear and logistic regression models were used to examine associations between pathogen seropositivity/IgG antibody levels, pro-inflammatory markers and incident depression over approximately one-year of follow-up.

Results

For every one unit increase in CMV IgG antibody level, the odds of incident depression increased by 26% and individuals with IgG antibody levels in the highest quartile had over three times greater odds of incident depression (odds ratio 3.87, 95% confidence interval 1.47, 10.19), compared to those in the lower three quartiles. Neither CMV or HSV-1 seropositivity nor HSV-1 IgG antibody level were associated with IL-6 or CRP levels at Wave 1, nor were IL-6 or CRP levels associated with incident depression at Wave 2.

Conclusions

Further examination of the biological pathways linking CMV and depression are warranted.

Introduction

Lifetime prevalence of major depressive disorder is estimated to be 16.6% among U.S. adults (Kessler et al., 2005) and importantly, depression is predicted to become the leading cause of disability worldwide by 2030 (WHO, 2004). Moreover, socioeconomic inequalities in depression prevalence and incidence persist in the U.S. (Gilman et al., 2013, Pabayo et al., 2014) and have been shown to worsen in older populations (Green and Benzeval, 2013). Given that the proportion of the U.S. population over the age of 65 is projected to grow to nearly 20% over the next two decades (Vincent and Velkoff, 2010), it remains important to identify novel biological risk factors for the onset of depression, particularly those which may be most salient among socioeconomically disadvantaged populations.

The adverse effects of psychosocial stress on immune function are well-documented (Webster Marketon and Glaser, 2008) and recent studies suggest that increased incidence of severe infection may serve as an important risk factor for the onset of depression (Goodwin, 2011, Benros et al., 2013). For example, Benros et al. (2013) found that increased hospitalization for infection was associated with greater risk of subsequent mood disorders (incidence rate ratio 1.62, 95% confidence interval (CI) 1.60, 1.64) in a large, population-based study of 3.65 million Danish individuals followed for over 20 years. Similarly, Goodwin (2011) found that children whose parents reported they ever experienced, “a severe infection during the first year of life, needing antibiotics” had almost 4 times greater odds of major depression during childhood.

Debate regarding the directionality of the association between depression and inflammation (Howren et al., 2009) is ongoing, however, it has been hypothesized that infections may lead to the onset of mood disorders in part via inflammatory pathways (Dantzer et al., 2008). For example, pro-inflammatory cytokines triggered in response to infection are known to induce symptoms referred to as “sickness behavior” that overlap with those of depression such as anhedonia, sleep disturbances, loss of appetite and fatigue (Dantzer et al., 2008). Indoleamine 2, 3-dioxygenase activity is also enhanced by cell-mediated cytokines, causing tryptophan to be metabolized along the kynurenine pathway, thereby depleting the levels of plasma tryptophan available for the synthesis of serotonin-a neurotransmitter important for mood regulation (Christmas et al., 2011). Furthermore, imbalances in the metabolites of kynurenine which serve as either N-methyl-d-aspartate agonists or antagonists, may also contribute to the etiology of depression onset via altering glutamatergic neurotransmission (Christmas et al., 2011).

While acute infections elicit a short-term inflammatory response, pathogens such as herpesviruses, which once acquired are never cleared from the body and capable reactivation (Glaser, 1994), have been hypothesized to lead to increased incidence of elevated pro-inflammatory cytokines over time (De Martinis et al., 2005). Indeed, a wealth of experimental and observational studies have shown that a wide array of stressors can trigger reactivation of herpesviruses such as herpes simplex virus-1 (HSV-1) and cytomegalovirus (CMV), via down-regulation of cellular immune processes, leading to the release of viral antigens into the circulation (Glaser, 1994). Immunoglobulin G (IgG) antibodies targeted against such pathogens have been shown to increase with leukocyte viral load (Kuo et al., 2008) as well as viral shedding in urine (Stowe et al., 2001), and importantly have also been found to be correlated with increased levels of pro-inflammatory markers such as interleukin-6 (IL-6) and C-reactive protein (CRP) (Nazmi et al., 2010, Bennett et al., 2012). Elevated levels of IL-6 and CRP have, in turn, been associated with increased risk of depression onset in several longitudinal studies as highlighted in a recent meta-analysis by Valkanova et al. (2013). HSV-1 and CMV have further been linked to several chronic diseases with inflammatory etiology such as cerebrovascular disease (Elkind and Cole, 2006) with which depression commonly co-occurs or is a sequelae (Taylor et al., 2013). Taken together, we hypothesize that in addition to severe infections, chronic herpesvirus infections may also increase risk for depression onset, particularly among those undergoing increased levels of psychosocial stress.

To our knowledge, all previous studies examining the association between herpesviruses and depression have been cross-sectional (Trzonkowski et al., 2004, Miller et al., 2005, Phillips et al., 2008, Jaremka et al., 2013). Thus whether pathogens such as HSV-1 and CMV increase risk for the onset of de novo depression remains unknown. Furthermore, while it has been hypothesized that inflammatory pathways may play a key role in the etiology of depression (Trzonkowski et al., 2004, Miller et al., 2005), we are unware of any longitudinal studies that explicitly test whether pro-inflammatory cytokines mediate the association between herpesviruses and depression onset. The aims of this study are therefore to examine: (1) whether seropositivity and/or IgG antibody levels for HSV-1 and CMV are associated with incident depression over approximately one year of follow-up among those free of lifetime history of depression at baseline and (2) whether these associations are mediated by levels of the pro-inflammatory markers IL-6 and CRP at baseline, using data from The Detroit Neighborhood Health Study (DNHS), a longitudinal study of individuals 18 years of age and older, living in Detroit, MI.

Section snippets

Study population

A probability sample of 1547 individuals (aged ≥18 years) living within the Detroit city limits participated in a baseline telephone survey in Wave 1 of DNHS (2008–2009). Wave 1 survey participants were representative of the Detroit population in terms of age, gender, race, income, and educational attainment (ACS, 2009). More detailed information on sampling frame, recruitment procedures, and sample characteristics have been published previously (Uddin et al., 2010). All Wave 1 respondents were

Demographic and clinical characteristics

Demographic and clinical characteristics of participants at Wave 1 are shown in Table 1. All participants were between 19 and 91 years of age (mean 54.0 ± standard deviation (SD) 15.8), the majority of which self-reported their race as Black or African-American (81.4%). Fifty-eight percent were female, almost half reported ≤High School education (44.9%) and 61.2% of the study population reported annual income level of less than $35,000 per year. Approximately 13.3% of participants reported taking

Discussion

To our knowledge this is the first longitudinal study examining the association between herpesvirus seropositivity/IgG antibody level, inflammatory markers and incident depression. Neither CMV nor HSV-1 seropositivity at Wave 1 were associated with onset of depression at Wave 2. Among those seropositive for CMV, however, every one unit increase in IgG antibody level at Wave 1 was associated with 26% greater odds of incident depression at Wave 2 and those with CMV IgG antibody levels in the

Role of funding source

The study sponsors played no role in each of the following: the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Conflict of interest

None declared.

Contributors

Drs. Simanek and Aiello conceived the study hypotheses and study design, Dr. Simanek conducted all statistical analyses and drafted the initial manuscript, Drs. Yolken, Uddin, Galea and Aiello as well as Ms. Cheng provided feedback on the draft and revisions and all authors have reviewed and approved the final version.

Acknowledgements

We acknowledge funding for A.E.A. and R.Y. from the Stanley Medical Research Institute. We also acknowledge funding for the PI (A.E.A.) on NIH grants R01DA022720, R01DA022720-Revision, R01DA022720-S1, and R01AG040115. We gratefully acknowledge Helen Meier for coordinating the DNHS project, Fuller Torrey for manuscript review, and the many Detroit residents who chose to participate in the DNHS.

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