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Accepted manuscript

Immunopsychiatry of late life depression: role of aging-related immune/inflammatory processes in the development and progression of depression

Published online by Cambridge University Press:  13 June 2025

Antonio L Teixeira Open the ORCID record for Antonio L Teixeira [Opens in a new window] ,
Izabela G Barbosa ,
Moises E Bauer Open the ORCID record for Moises E Bauer [Opens in a new window]  and
Aline S. de Miranda
Antonio L Teixeira*
Affiliation:
Geriatric Neuropsychiatry Division, The Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Disease, The University of Texas Health Science Center at San Antonio, San Antonio, TX.
Izabela G Barbosa
Affiliation:
Medical School, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Moises E Bauer
Affiliation:
Laboratory of Immunobiology, School of Health and Life Sciences, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
Aline S. de Miranda
Affiliation:
Laboratory of Neurobiology, Department of Morphology, Institute of Biological Science, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
*
Corresponding author: Antonio L Teixeira, MD, PhD, Biggs Institute, UT Health San Antonio, Floyd Curl Dr. 8300, San Antonio, TX, United States. 78229. Email: teixeiraa@uthscsa.edu
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Abstract

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Background:

Late-life depression (LLD) arises from a complex interplay among biological, psychological, and social factors. Biologically, three main hypotheses have been proposed to explain the distinct clinical features of LLD. The vascular hypothesis supports vascular-related white matter changes in the development of LLD, while the neurodegenerative hypothesis suggests that LLD might be a prodrome of neurodegenerative diseases. The inflammatory hypothesis, which is the main focus of this review, posits that heightened inflammation underlies LLD directly or indirectly through neurodegenerative and microvascular alterations.

Methods:

This is a non-systematic review on the role played by inflammation in the pathophysiology of LLD and the related opportunities to define biomarkers and therapeutic targets. We searched PubMed from January 2010 through March 2025 for relevant English-language studies.

Results:

Patients with LLD have elevated circulating levels of inflammatory biomarkers (e.g., C-reactive protein and interleukin-6) as well as evidence of neuroinflammation. Although the exact origin of this inflammatory profile remains unclear, it is thought to be exacerbated by immune cell senescence and the presence of physical comorbidities, including cardiovascular and metabolic diseases. Pharmacological (e.g., selective serotonin receptor inhibitors) and non-pharmacological (e.g., diet, physical interventions) approaches for LLD seem to exert their therapeutic effect, at least in part, through inflammation-related mechanisms.

Conclusion:

Recognizing the unique features of LLD compared to depression in other periods of life is an important step toward its proper management. More specifically, understanding the role of inflammation in LLD holds both theoretical and practical implications, including anti-inflammatory or immune-based strategies as potential therapeutic interventions.

Keywords

DepressionLate life depressionVascular depressionNeurodegenerationNeuroinflammation
Type
Review Article
Information
Acta Neuropsychiatrica , Accepted manuscript , pp. 1 - 43
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.
Copyright
© The Author(s), 2025. Published by Cambridge University Press on behalf of Scandinavian College of Neuropsychopharmacology