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Repeated Low-Grade Infections Predict Antidepressant-Resistant Depression: A Nationwide Population-Based Cohort Study
Abstract
BACKGROUND: 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. METHOD: 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. RESULTS: 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). CONCLUSIONS: 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.
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For depression, low-grade inflammatory activity seems to be related to the failure of responding to pharmacological antidepressant treatments specifically.
“For depression, low-grade inflammatory activity seems to be related to the failure of responding to pharmacological antidepressant treatments specifically [27,28].”
From Baseline Pro-Inflammatory Cytokine Levels Moderate Psychological Inflexibility in Behavioral Treatment for Chronic Pain (2022) · cites this paper as [28]
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Lasselin, J., Lekander, M., Axelsson, J., & Karshikoff, B. (2018) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2018.06.005 · Cited by 106
“Potential inflammatory mechanistic components may contribute to disease to a varying degree in different individuals, or only so in a subpopulation of patients (Jeng et al., 2018; Lotrich, 2015; Osimo et al., 2018).”
Gillespie, S. L., Anderson, C. M., Zhao, S., Tan, Y., Kline, D., Brock, G. N., Odei, J. B., O'Brien, E. C., Sims, M., Lazarus, S. A., et al. (2019) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2019.06.020 · Cited by 89
“In fact, some evidence suggests the presence of an inflammatory subtype of depression more likely to demonstrate resistance to traditional pharmacotherapies (Beijers, Wardenaar, van Loo, & Schoevers, 2019; Jeng et al., 2018), prompting pursuit of adjuvant or alternative treatment approaches among these individuals (re…”
BackgroundThe association between C-reactive protein, mood disorder, and cognitive function in UK Biobank
Milton, D. C., Ward, J., Ward, E., Lyall, D. M., Strawbridge, R. J., Smıth, D. J., & Cullen, B. (2021) · European Psychiatry · doi:10.1192/j.eurpsy.2021.6 · Cited by 37
Jeon, H. J., Ju, P., Sulaiman, A. H., Aziz, S. A., Paik, J., Tan, W., Bai, D., & Li, C. (2022) · Clinical Psychopharmacology and Neuroscience · doi:10.9758/cpn.2022.20.1.70 · Cited by 25
Self-citationLapato, D. M., Roberson‐Nay, R., Kirkpatrick, R. M., Webb, B. T., York, T. P., & Kinser, P. A. (2019) · Clinical Epigenetics · doi:10.1186/s13148-019-0769-z · Cited by 21
Karshikoff, B., Martucci, K. T., & Mackey, S. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.651083 · Cited by 17
Inflammatory Blood Signature Related to Common Psychological Comorbidity in Chronic Pain
Karshikoff, B., Wåhlén, K., Åström, J., Lekander, M., Holmström, L., & Wicksell, R. K. (2023) · Biomedicines · doi:10.3390/biomedicines11030713 · Cited by 17
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Braun, S. E., Lapato, D. M., Brown, R., Lancaster, E. E., York, T. P., Amstadter, A. B., & Kinser, P. A. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.04.005 · Cited by 8
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“For depression, low-grade inflammatory activity seems to be related to the failure of responding to pharmacological antidepressant treatments specifically [27,28].”
BackgroundHow Can Experimental Endotoxemia Contribute to Our Understanding of Pain? A Narrative Review
Benson, S., & Karshikoff, B. (2023) · NeuroImmunoModulation · doi:10.1159/000534467 · Cited by 6
Luo, J., Yang, W., Liu, Y., Ji, H., Li, X., Bai, J., Liu, T., Chen, W., Li, X., Mo, G., et al. (2025) · BMC Psychology · doi:10.1186/s40359-025-02516-3 · Cited by 3
“Similarly, patients with a his - tory of recurrent low-grade infections are more likely to develop mood disorders in later life [42].”
Bai, Y., Cheng, L., Lin, W.-C., Hsu, J.-W., Chen, L., Tu, P., Li, C., Tsai, S., Chen, L.-C., Su, T., et al. (2025) · Journal of Affective Disorders · doi:10.1016/j.jad.2025.120491 · Cited by 1
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Metadata
- Authors
- Jeng, J.-S., Li, C.-T., Chen, M.-H., Lin, W.-C., Bai, Y.-M., Tsai, S.-J., Su, T.-P., Chang, W.-H., & Sung, Y.-J.
- Affiliations
- Taipei Veterans General Hospital (TW)
- Venue
- The Journal of Clinical Psychiatry
- Publisher
- Physicians Postgraduate Press, Inc
- Published
- 2018-02-21
- Volume
- 79
- Issue
- 1
- Pages
- 17m11540
- ISSN
- 0160-6689 (ISSN-L)
- OpenAlex
- W2771475710
- Cited by
- 13
- References
- 0
- Citations by year
- 2025: 2 · 2023: 3 · 2022: 2 · 2021: 2 · 2019: 3 · 2018: 1
- FWCI
- 0.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- antidepressant-resistant depression, major depressive disorder, inflammation, infection history, antidepressant response, difficult-to-treat depression, depression pathophysiology
- MeSH terms
- Adult, Antidepressive Agents, Major Depressive Disorder, Female, Humans, Infections, Male, Retrospective Studies, Cohort Studies, Case-Control Studies, Databases, Factual, Treatment Outcome, Young Adult, Depressive Disorder, Treatment-Resistant
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