Overall, 179 participants were included in the discovery sample; 295, replication sample. The solid horizontal line represents the median CTQ score. The boxes above the median represent the 50th through 75th percentiles and the boxes below the median represent the 25th through 50th percentiles of the scores. The whiskers indicate the distribution of scores within 1.5 times the interquartile range. Circles represent scores outside of this range. P values were calculated using unadjusted Wilcoxon rank sum tests (α = .05). CMV indicates cytomegalovirus.
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Ford BN, Yolken RH, Aupperle RL, et al. Association of Early-Life Stress With Cytomegalovirus Infection in Adults With Major Depressive Disorder. JAMA Psychiatry. 2019;76(5):545–547. doi:10.1001/jamapsychiatry.2018.4543
Early-life stress is a well-established risk factor in the development of psychiatric disorders. Although the biological processes behind this association are unclear, there is evidence to suggest that early-life stress may lead to immune dysregulation.1 One possibility is that early-life stress may impair adaptive immunity and, therefore, increase vulnerability to initial infection and subsequent reactivation of herpesviruses. Herpesviruses are potential immune-modifying agents that persist as latent infections and can reactivate during periods of stress. Initially believed to be benign except in cases of immunosuppression, cytomegalovirus (CMV) infection has been found to be associated with a range of negative outcomes, including depression, immunosenescence, neurodegenerative disorders, and reduced lifespan.2
Given the prevalence of CMV infection (approximately 50% in the United States) and documented pathogenic effects,2 we focused on CMV as a proof-of-principle test of the association between early-life stress and infectious disease in the context of depression.
This study tested the hypothesis that early-life stress is a risk factor for CMV infection using a discovery sample of 179 volunteers (mean [SD] age, 36.2 [11.6] years; 138 women [77.1%]; 156 white patients [87.2%]) who were diagnosed with major depressive disorder based on the Structured Clinical Interview for DSM-IV, and a replication sample of 295 volunteers (mean [SD] age, 34.9 [11.1] years; 184 women [62.4%]; 248 white patients [84.2%]) who met DSM-V criteria for major depressive disorder per the Mini International Neuropsychiatric Interview. Among patients in the discovery sample, 89 (49.7%) had remitted depression, 57 (31.8%) were taking medication, and 81 (45.3%) were CMV seropositive. In the replication sample, 83 patients (28.1%) had remitted depression, 95 (32.3%) took medication, and 168 (56.0%) were CMV seropositive. Pertinent exclusion criteria for the discovery sample included major medical disorders, substance abuse within the previous 6 months or lifetime history of substance dependence, and acute or chronic illnesses (or treatments) that would impact immunity. The replication sample was drawn from a community-based study with fewer exclusion criteria.3 Serum IgG antibodies to CMV were measured using a commercially available semiquantitative enzyme-linked immunosorbent assay (IBL-America). Self-reported early-life stress was measured with the 28-item Childhood Trauma Questionnaire (CTQ). The CTQ is composed of the following Likert-type subscales: physical, sexual, and emotional abuse and physical and emotional neglect. Scores range from 5 to 25 for each subscale such that the total score ranges from 25 to 125. Higher scores are indicative of greater self-reported trauma. Approval for this study was granted by the Western institutional review board, and written informed consent was obtained from participants. Statistical analyses were performed using R version 3.3.2 in RStudio version 1.0.136. Statistical tests were 2-sided and α=.05 was considered significant.
Among the 474 total participants (mean [SD] age, 35.7 [11.3] years), 322 (67.9%) were women; 404 (85.2%) were white; 172 (36.3%) had remitted major depressive disorder; 152 (32.1%) were taking medication for major depressive disorder; and 249 (52.5%) were CMV positive. Logistic regression models controlling for age, sex, and ethnicity revealed that individuals with more early-life stress had increased odds of testing positive for CMV in both the discovery (odds ratio [OR], 1.02; 95% CI, 1.00-1.04; P =.04) and replication (OR, 1.02; 95% CI, 1.01-1.03; P =.005) samples (Table; Figure). Regarding the Childhood Trauma Questionnaire subscales, participants who affirmed more physical and sexual abuse were more likely to test positive for CMV in both discovery (physical abuse: OR, 1.10; 95% CI, 1.02-1.20; P =.02; sexual abuse: OR, 1.07; 95% CI, 1.02-1.13; P =.009) and replication samples (physical abuse: OR, 1.08; 95% CI, 1.02-1.16; P = .02; sexual abuse: OR, 1.08; 95% CI, 1.03-1.14; P = .003). Results remained significant in both samples when controlling for medication status but were only significant in the replication sample when mood status (depressed vs remitted) was added to the model. IgG titers, an indirect marker of current viral activity, were not significantly associated with Childhood Trauma Questionnaire scores.
Results of this study demonstrated that individuals with major depressive disorder who experienced more early-life stress were more likely to test positive for CMV, and this finding was replicated in a confirmation sample despite substantially different inclusion and exclusion criteria. Early CMV infection and subsequent reactivation during stressful periods may be a mechanism through which the consequences of early-life stress affect health. If substantiated, this finding has important clinical implications given that currently available pharmacological agents to control CMV infection are effective in some circumstances and that new therapeutic approaches are under development.
However, because this study is cross sectional, an alternative explanation for the results is that a childhood environment conducive to trauma also results in increased exposure to CMV. For instance, low childhood socioeconomic status, which is strongly associated with early-life stress, may increase CMV exposure through increased family size or early-age transition to larger group settings. Nevertheless, studies4,5 have reported that the association between childhood socioeconomic status and CMV infection is not attributable to increased exposure to the virus4 or adult stress levels.5
Our study adds vulnerability to CMV (and potentially to other viruses such as herpes simplex virus 1)6 to the list of consequences of early-life stress. These findings also highlight an avenue of future research that could potentially validate the proposed mechanistic link between herpesviruses and the sequalae of early-life stress and leverage this association to improve clinical outcomes.
Accepted for Publication: November 27, 2018.
Corresponding Author: Jonathan Savitz, PhD, Laureate Institute for Brain Research, 6655 S Yale Ave, Tulsa, OK 74136 (firstname.lastname@example.org).
Published Online: March 6, 2019. doi:10.1001/jamapsychiatry.2018.4543
Author Contributions: Dr Savitz had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Ford, Yolken, Aupperle, Teague, Irwin, Savitz.
Acquisition, analysis, or interpretation of data: Ford, Yolken, Aupperle, Teague, Paulus, Savitz.
Drafting of the manuscript: Ford, Yolken, Irwin, Paulus, Savitz.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Ford, Yolken, Aupperle, Paulus.
Obtained funding: Savitz.
Administrative, technical, or material support: Yolken, Teague.
Supervision: Irwin, Paulus, Savitz.
Conflict of Interest Disclosures: None reported.
Funding/Support: This research was supported by the National Institute of Mental Health (grant K23MH108707 to Dr Aupperle and grant R21MH113871 to Dr Savitz); the Laureate Institute for Brain Research, National Institute of General Medical Sciences (grant P20GM121312 to Dr Paulus); and the Brain and Behavior Research Foundation (National Alliance for Research on Schizophrenia & Depression grant YI 23850 to Dr Savitz).
Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: Dr Paulus is Associate Editor of JAMA Psychiatry but was not involved in any of the decisions regarding review of the manuscript or its acceptance.