No increase in inflammation in late-life major depression screened to exclude physical illness

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Abstract

Depression is a common and debilitating disorder in the elderly. Late-life depression (LLD) has been associated with inflammation and elevated levels of proinflammatory cytokines including interleukin (IL)-1β, tumor necrosis factor-alpha, and IL-6, but often depressed individuals have comorbid medical conditions that are associated with immune dysregulation. To determine whether depression has an association with inflammation independent of medical illness, 1120 adults were screened to identify individuals who had clinically significant depression but not medical conditions associated with systemic inflammation. In total, 66 patients with LLD screened to exclude medical conditions associated with inflammation were studied in detail along with 26 age-matched controls (HC). At baseline, circulating cytokines were low and similar in LLD and HC individuals. Furthermore, cytokines did not change significantly after treatment with either an antidepressant (escitalopram 20 mg/day) or an antidepressant plus a COX-2 inhibitor or placebo, even though depression scores improved in the non-placebo treatment arms. An analysis of cerebrospinal fluid in a subset of individuals for IL-1β using an ultrasensitive digital enzyme-linked immunosorbent assay revealed low levels in both LLD and HC at baseline. Our results indicate that depression by itself does not result in systemic or intrathecal elevations in cytokines and that celecoxib does not appear to have an adjunctive antidepressant role in older patients who do not have medical reasons for having inflammation. The negative finding for increased inflammation and the lack of a treatment effect for celecoxib in this carefully screened depressed population taken together with multiple positive results for inflammation in previous studies that did not screen out physical illness support a precision medicine approach to the treatment of depression that takes the medical causes for inflammation into account.

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Crosstalk between inflammatory pathways and neurocircuits in the brain can lead to behavioural responses, such as avoidance and alarm, that are likely to have provided early humans with an evolutionary advantage in their interactions with pathogens and predators. However, in modern times, such interactions between inflammation and the brain appear to drive the development of depression and may contribute to non-responsiveness to current antidepressant therapies. Recent data have elucidated the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression. Here, we detail our current understanding of these pathways and discuss the therapeutic potential of targeting the immune system to treat depression.

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Author and article information

Contributors

Yvette I. Sheline:

ORCID: http://orcid.org/0000-0002-6929-9659

sheline@pennmedicine.upenn.edu

Journal

Journal ID (nlm-ta): Transl Psychiatry

Journal ID (iso-abbrev): Transl Psychiatry

Title: Translational Psychiatry

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2158-3188

Publication date (Electronic): 24 March 2022

Publication date PMC-release: 24 March 2022

Publication date Collection: 2022

Volume: 12

Electronic Location Identifier: 118

Affiliations

[1 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Department of Pathology and Laboratory Medicine, , Perelman School of Medicine, University of Pennsylvania, ; Philadelphia, PA USA

[2 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, ; Philadelphia, PA USA

[3 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Center for Neuromodulation in Depression and Stress (CNDS), Perelman School of Medicine, University of Pennsylvania, ; Philadelphia, PA USA

[4 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Institute for Translational Medicine and Therapeutics (ITMAT), Perelman School of Medicine, University of Pennsylvania, ; Philadelphia, PA USA

[5 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Department of Biostatistics, , Epidemiology and Informatics, University of Pennsylvania, ; Philadelphia, PA USA

[6 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Department of Medicine, , Perelman School of Medicine, University of Pennsylvania, ; Philadelphia, PA USA

[7 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Departments of Psychiatry, Radiology, Neurology, , Perelman School of Medicine, University of Pennsylvania, ; Philadelphia, PA USA

Author information

Thomas Brooks http://orcid.org/0000-0002-6980-0079

Walid Makhoul http://orcid.org/0000-0003-0035-5795

Carsten Skarke http://orcid.org/0000-0001-5145-3681

Yvette I. Sheline http://orcid.org/0000-0002-6929-9659

Article

Publisher ID: 1883

DOI: 10.1038/s41398-022-01883-4

PMC ID: 8948274

PubMed ID: 35332134

SO-VID: bdea8429-5944-4069-8cb0-34bcbc0e5883

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 31 January 2022

Date revision received : 18 February 2022

Date accepted : 2 March 2022

Funding

Funded by: FundRef https://doi.org/10.13039/100000025, U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH);

Award ID: R01 MH098260-02

Award Recipient : Carsten Skarke Yvette I. Sheline

Funded by: FundRef https://doi.org/10.13039/100000002, U.S. Department of Health & Human Services | National Institutes of Health (NIH);

Award ID: P30-CA016520

Award Recipient : Eline T. Luning Prak

Funded by: FundRef https://doi.org/10.13039/100006108, U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS);

Award ID: 5UL1TR000003

Award Recipient : Thomas Brooks

Funded by: U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)