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Psychiatry International
Volume 7
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10.3390/psychiatryint7030140
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Background:
Systematic Review

Peripheral Inflammatory Biomarkers in First-Episode, Drug-Naïve Major Depressive Disorder: A Systematic Review

by
Esteban Zavaleta-Monestel
1,*,
Luis Guillermo Herrera-Jiménez
2,
José Miguel Chaverri-Fernández
2,
Sebastián Arguedas-Chacón
1,
Jeaustin Mora-Jiménez
1 and
Ricardo Millán-González
3,4
1
Health Research Department, Hospital Clínica Bíblica, San Jose 1307-1000, Costa Rica
2
Department of Pharmacy, University of Costa Rica, San Jose 11501-2060, Costa Rica
3
Department of Medicine, University of Costa Rica, San Jose 11501-2060, Costa Rica
4
Department of Psychiatry, Hospital Clínica Biblica, San Jose 1307-1000, Costa Rica
*
Author to whom correspondence should be addressed.
Psychiatry Int. 2026, 7(3), 140; https://doi.org/10.3390/psychiatryint7030140
Submission received: 12 May 2026 / Revised: 8 June 2026 / Accepted: 9 June 2026 / Published: 22 June 2026
(This article belongs to the Section Clinical Psychiatry and Psychotherapy)
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Abstract

Major depressive disorder (MDD) is clinically heterogeneous, and peripheral inflammatory biomarkers may help clarify early biological mechanisms before illness chronicity or pharmacologic treatment confound interpretation. This systematic review synthesized evidence on peripheral inflammatory biomarkers in first-episode, drug-naïve major depressive disorder (FEDN-MDD) compared with healthy controls and examined associations with clinical severity. Following PRISMA 2020, searches of PubMed/MEDLINE, Embase, PsycINFO, and Scopus from inception to 19 March 2026 identified 313 records; after screening, 16 publications were included in qualitative synthesis. Studies varied in age group, biological matrix, assay platform, and statistical reporting, precluding meta-analysis. The most frequently assessed biomarkers were IL-1β, TNF-α, IL-6, and CRP/hs-CRP. IL-6 showed the clearest recurrent tendency toward elevation in FEDN-MDD, whereas CRP/hs-CRP findings were partially positive but methodologically limited. TNF-α and IL-1β findings were mixed, and clinical correlations with depressive severity were sparse and inconsistent. Overall, the evidence supports heterogeneous early immune dysregulation in a subset of patients with FEDN-MDD rather than a single reproducible inflammatory signature. Peripheral inflammatory biomarkers should currently be considered research tools for biological stratification and mechanistic hypothesis generation, pending larger standardized longitudinal studies.
Keywords: major depressive disorder; first-episode depression; drug-naïve patients; peripheral inflammation; inflammatory biomarkers; interleukin-6; C-reactive protein; cytokines; systematic review major depressive disorder; first-episode depression; drug-naïve patients; peripheral inflammation; inflammatory biomarkers; interleukin-6; C-reactive protein; cytokines; systematic review

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MDPI and ACS Style

Zavaleta-Monestel, E.; Herrera-Jiménez, L.G.; Chaverri-Fernández, J.M.; Arguedas-Chacón, S.; Mora-Jiménez, J.; Millán-González, R. Peripheral Inflammatory Biomarkers in First-Episode, Drug-Naïve Major Depressive Disorder: A Systematic Review. Psychiatry Int. 2026, 7, 140. https://doi.org/10.3390/psychiatryint7030140

AMA Style

Zavaleta-Monestel E, Herrera-Jiménez LG, Chaverri-Fernández JM, Arguedas-Chacón S, Mora-Jiménez J, Millán-González R. Peripheral Inflammatory Biomarkers in First-Episode, Drug-Naïve Major Depressive Disorder: A Systematic Review. Psychiatry International. 2026; 7(3):140. https://doi.org/10.3390/psychiatryint7030140

Chicago/Turabian Style

Zavaleta-Monestel, Esteban, Luis Guillermo Herrera-Jiménez, José Miguel Chaverri-Fernández, Sebastián Arguedas-Chacón, Jeaustin Mora-Jiménez, and Ricardo Millán-González. 2026. "Peripheral Inflammatory Biomarkers in First-Episode, Drug-Naïve Major Depressive Disorder: A Systematic Review" Psychiatry International 7, no. 3: 140. https://doi.org/10.3390/psychiatryint7030140

APA Style

Zavaleta-Monestel, E., Herrera-Jiménez, L. G., Chaverri-Fernández, J. M., Arguedas-Chacón, S., Mora-Jiménez, J., & Millán-González, R. (2026). Peripheral Inflammatory Biomarkers in First-Episode, Drug-Naïve Major Depressive Disorder: A Systematic Review. Psychiatry International, 7(3), 140. https://doi.org/10.3390/psychiatryint7030140

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