Repeated Low-Grade Infections Predict Antidepressant-Resistant Depression: A Nationwide Population-Based Cohort Study

The relationship between severe inflammation and clinical depression in the context of major medical illnesses has been addressed, but the relationship between inflammation caused by mild infections and clinical depression is unclear. We aimed to examine whether a history of repeated low-grade infections (RLGI) in medically healthy subjects (MHS) could increase their vulnerability to major depressive disorder (MDD) (ICD-9-CM) and whether RLGI could be associated with higher resistance to antidepressants in those developing MDD.

A nationwide, population-based cohort study (January 1996 to December 2011) was conducted for MHS with and without a history of RLGI. The rates of MDD during an up to 8-year follow-up period were compared between the 2 groups in 2 independent cohorts. The stratified responses to adequate antidepressant trials, including easy-to-treat (ETT) and difficult-to-treat (DTT) responses, were also compared in the MDD patients.

During the follow-up, the 2 cohorts consistently revealed that the RLGI(+) (ie, high-inflammation; n = 727) group had a significantly higher chance of developing MDD over time than the RLGI(-) (ie, low-inflammation; n = 443) group: Cox proportional hazards regression models showed that the hazard ratio associated with a history of RLGI was 1.369 to 1.911 (P < .001), after adjusting for confounding factors. The RLGI(+) group was consistently associated with a higher likelihood of DTT responses than was the RLGI(-) group (Cohort-2002: 11.5% vs 7.6%; Cohort-2004: 11.8% vs 4.3%; P < .05 by Wald χ² tests in both cohorts).

This is the first large-scale retrospective cohort study to report a reliable temporal association between a history of RLGI and subsequent diagnosis of MDD and poor responses to antidepressants in 2 independent cohorts. Our data support the view that repeated mild infections play a role in the pathophysiology of MDD and antidepressant-resistant depression.