THE INTERRELATIONSHIP BETWEEN CARDIOMETABOLIC MULTIMORBIDITY AND LATE-LIFE DEPRESSION: FROM PATHOPHYSIOLOGY TO CLINICAL IMPLICATIONS – A NARRATIVE REVIEW

Katarzyna Andrzejewska; Wiktor Golus; Paweł Edyko; Alicja Babula; Zuzanna Przybyła; Bartosz Golis; Anna Maria Gęsińska; Hubert Woźniak; Krystian Czyżkowski; Helena Szelka

doi:10.31435/ijitss.4(48).2025.4511

Authors

Katarzyna Andrzejewska Medical University of Lodz, Kosciuszki 4, 90-419 Lodz, Poland https://orcid.org/0009-0001-6994-7505
Wiktor Golus University Clinical Hospital No. 2 of the Medical University of Lodz, Żeromskiego 113, 90-549 Łódź, Poland https://orcid.org/0009-0009-1930-9837
Paweł Edyko Central Clinical Hospital of the Medical University of Łódź, Pomorska 251, 92-213 Lodz, Poland https://orcid.org/0009-0009-6764-3434
Alicja Babula T. Marciniak Lower Silesian Specialist Hospital – Centre for Emergency Medicine, Fieldorfa 2, 54-049 Wroclaw, Poland https://orcid.org/0009-0003-0573-5022
Zuzanna Przybyła Medical University of Lodz, Kosciuszki 4, 90-419 Lodz, Poland https://orcid.org/0009-0009-4778-3106
Bartosz Golis Central Clinical Hospital of the Medical University of Łódź, Pomorska 251, 92-213 Lodz, Poland https://orcid.org/0009-0007-2968-6797
Anna Maria Gęsińska Antoni Jurasz University Hospital, Skłodowskiej-Curie 9, 85-094 Bydgoszcz, Kujawsko-Pomorskie, Poland https://orcid.org/0009-0004-4336-8873
Hubert Woźniak Copernicus Memorial Hospital, Pabianicka 62, 93-513 Łódź, Poland https://orcid.org/0009-0002-9891-3248
Krystian Czyżkowski Antoni Jurasz University Hospital, Skłodowskiej-Curie 9, 85-094 Bydgoszcz, Kujawsko-Pomorskie, Poland https://orcid.org/0009-0006-8816-1811
Helena Szelka University Clinical Hospital No. 2 of the Medical University of Lodz, Żeromskiego 113, 90-549 Łódź, Poland https://orcid.org/0009-0001-7142-341X

DOI:

https://doi.org/10.31435/ijitss.4(48).2025.4511

Keywords:

Late-Life Depression, Cardiometabolic Multimorbidity, Vascular Depression, Chronic Inflammation, Cerebrovascular Disease

Abstract

Introduction and objective: Late-life depression (LLD) is a complex mood disorder that rarely occurs in isolation, frequently co-existing with cardiometabolic multimorbidity (CMM). This comorbidity triggers a cascade of adverse consequences, including accelerated biological aging and increased mortality. The objective of this narrative review is to synthesize current knowledge on the bidirectional relationship between CMM and LLD, exploring pathophysiological mechanisms from the Vascular Depression (VaDep) hypothesis to clinical implications.

Description of the state of knowledge: Epidemiological evidence indicates a strong "dose-response" relationship, where cumulative cardiometabolic burden amplifies the risk of incident depression. The review discusses the neuroimaging correlates of VaDep, particularly white matter hyperintensities, while addressing the "neuropathological paradox" observed in postmortem studies. Key pathogenic pathways identified include chronic low-grade inflammation ("inflamm-aging"), endothelial dysfunction, and the "metabolic-brain axis," specifically in type 2 diabetes. Furthermore, the analysis highlights the role of shared genetic susceptibility and the phenomenon of "joint trajectories," where physical, cognitive, and mood decline occur synchronously.

Conclusions: LLD in the context of CMM constitutes a distinct clinical phenotype driven by systemic vascular and metabolic dysregulation. Current evidence necessitates a paradigm shift from isolated psychiatric management to an integrated, interdisciplinary approach. Aggressive control of vascular risk factors, potential anti-inflammatory strategies, and social prescribing are pivotal for breaking the vicious cycle of multimorbidity and improving long-term prognosis.

References

Aizenstein, H. J., Baskys, A., Boldrini, M., Butters, M. A., Diniz, B. S., Jaiswal, M. K., ... & Taylor, W. D. (2016). Vascular depression consensus report – a critical update. BMC Medicine, 14(1), 161. https://doi.org/10.1186/s12916-016-0720-5

Alexopoulos, G. S., Meyers, B. S., Young, R. C., Campbell, S., Silbersweig, D., & Charlson, M. (1997). 'Vascular depression' hypothesis. Archives of General Psychiatry, 54(10), 915-922. https://doi.org/10.1001/archpsyc.1997.01830220033006

Apostolos, A., et al. (2024). Depression and coronary artery disease—where we stand?. Journal of Clinical Medicine.

Berk, M., Williams, L. J., Jacka, F. N., O'Neil, A., Pasco, J. A., Moylan, S., ... & Maes, M. (2023). So depression is an inflammatory disease, but where does the inflammation come from? BMC Medicine, 11, 200. https://doi.org/10.1186/s12916-013-0063-8

Cai, W., et al. (2024). Cerebral microvascular dysfunction in type 2 diabetes and its association with cognitive decline and depression: A systematic review. Diabetes Care, 47(3), 456-468.

Fan, Y., et al. (2024). Association of cardiometabolic multimorbidity with risk of late-life depression: a nationwide twin study. BMC Medicine, 22, 123. https://doi.org/10.1186/s12916-024-03328-9

Firth, J., et al. (2021). The role of lifestyle and social prescribing in the management of depression and multimorbidity. The Lancet Psychiatry, 8(11), 1005-1018.

Halaris, A. (2013). Vascular depression in older adults: pathophysiology. Therapeutic Advances in Psychopharmacology.

Hilty, D. M., et al. (2024). Integrated care for cardiometabolic multimorbidity and depression: Evidence from randomized controlled trials. General Hospital Psychiatry, 88, 102-115.

Lee, S. H., et al. (2025). Linking cardiometabolic multimorbidity to depressive symptoms in the oldest-old: results from a cross-sectional study. BMC Geriatrics, 25(1), 112.

Liu, H., Wang, L., & Zhang, Y. (2025). Vascular depression: A comprehensive exploration of the definition, mechanisms, and clinical challenges. Journal of Stroke and Cerebrovascular Diseases, 34(2), 107567. https://doi.org/10.1016/j.jstrokecerebrovasdis.2024.107567

Loyal, M. S., et al. (2025). Longitudinal associations between late-life depression, cerebrovascular disease and cognition. Journal of Affective Disorders, 376, 59-67. https://doi.org/10.1016/j.jad.2025.01.147

Morse, D. F., et al. (2022). Global developments in social prescribing: a scoping review. BMJ Global Health, 7(5), e008524. https://doi.org/10.1136/bmgh-2022-008524

Mullins, N., et al. (2025). Understanding late-life depression: focus on inflammation and immunometabolic pathways. Current Opinion in Psychiatry, 38(1), 12-19.

Nguyen, T. T., et al. (2025). Prevalence and associated factors of depression among elderly hypertensive patients in Vietnam. Geriatrics, 10(5), 129. https://doi.org/10.3390/geriatrics10050129

Oltra, J., et al. (2023). Neuropathology of depression in non-demented older adults: A large postmortem study of 741 individuals. Acta Neuropathologica.

Penninx, B. W. J. H. (2023). Immunometabolic depression: A distinct dimension of mood disorders. Molecular Psychiatry, 28, 3654–3665.

Polyakova, M., et al. (2024). Polygenic risk scores for major depressive disorder and their interaction with vascular risk factors in predicting brain structure in older adults. Translational Psychiatry, 14(1), 45.

Salo, K. I., Scharfen, J., Wilden, I. D., Schubotz, R. I., & Holling, H. (2019). Confining the concept of vascular depression to late-onset depression: A meta-analysis of MRI-defined hyperintensity burden in major depressive disorder and bipolar disorder. Frontiers in Psychology, 10, 1241. https://doi.org/10.3389/fpsyg.2019.01241

Santos, M., Kövari, E., Hof, P. R., Gold, G., Bouras, C., & Giannakopoulos, P. (2009). The impact of vascular burden on late-life depression. Brain Research Reviews, 62(1), 19-32. https://doi.org/10.1016/j.brainresrev.2009.08.003

Sjöberg, L., Östling, S., Falk, H., Sundh, V., Waern, M., & Skoog, I. (2021). Bridging late-life depression and chronic somatic diseases: a network analysis. Translational Psychiatry, 11(1), 556. https://doi.org/10.1038/s41398-021-01686-z

Sumner, R. C., et al. (2022). Systematic review of social prescribing and older adults: where to from here? Social Science & Medicine, 305, 115082.

Taylor, W. D., Aizenstein, H. J., & Alexopoulos, G. S. (2013). The vascular depression hypothesis: mechanisms linking vascular disease with depression. Molecular Psychiatry, 18(9), 963-974. https://doi.org/10.1038/mp.2013.20

Triolo, F., Sjöberg, L., Calderón-Larrañaga, A., Murri, M. B., Vetrano, D. L., Fratiglioni, L., & Dekhtyar, S. (2023). Late-life depression and multimorbidity trajectories: the role of symptom complexity and severity. Age and Ageing, 52(2), afac315. https://doi.org/10.1093/ageing/afac315

Triolo, F., Vetrano, D. L., Sjöberg, L., Calderón-Larrañaga, A., Murri, M. B., Fratiglioni, L., & Dekhtyar, S. (2024). Somatic disease burden and depression risk in late life: a community-based study. Epidemiology and Psychiatric Sciences, 33, e13. https://doi.org/10.1017/S204579602400006X

Tsopelas, C., Stewart, R., Savva, G. M., Brayne, C., Ince, P., Thomas, A., & MRC CFAS. (2011). Neuropathological analysis of lacunes and microvascular lesions in late-onset depression. The British Journal of Psychiatry, 199(4), 303-309. https://doi.org/10.1192/bjp.bp.110.088690

van Agtmaal, M. J. M., Houben, A. J. H. M., de Kort, P. L. M., et al. (2017). The association of markers of cerebral small vessel disease and brain atrophy with incidence and course of depressive symptoms – the Maastricht Study. JAMA Psychiatry.

van Sloten, T. T., Sedaghat, S., Carnethon, M. R., Launer, L. J., & Stehouwer, C. D. (2020). Cerebral microvascular complications of type 2 diabetes: stroke, cognitive dysfunction, and depression. The Lancet Diabetes & Endocrinology, 8(4), 325-336. https://doi.org/10.1016/S2213-8587(19)30405-X

Vetrano, D. L., Palmer, K., Marengoni, A., Marzetti, E., Lattanzio, F., Roller-Wirnsberger, R., ... & Onder, G. (2020). The complex interplay between depression and multimorbidity in late life: risks and pathways. Mechanisms of Ageing and Development, 190, 111321. https://doi.org/10.1016/j.mad.2020.111321

Wang, H., et al. (2023). Dose-response relationship between physical activity and the risk of late-life depression in patients with multimorbidity. Journal of Affective Disorders, 323, 120-128.

Wei, W., Karim, H. T., Lin, C., Mizuno, A., Andreescu, C., & Aizenstein, H. J. (2018). Trajectories in cerebral blood flow following antidepressant treatment in late-life depression: support for the vascular depression hypothesis. The Journal of Clinical Psychiatry, 79(6), 18m12106. https://doi.org/10.4088/JCP.18m12106

Wang, H., et al. (2023). Dose-response relationship between physical activity and the risk of late-life depression in patients with multimorbidity. Journal of Affective Disorders, 323, 120-128.

Wotton, C. J., et al. (2023). Genetic susceptibility to cardiovascular disease and risk of incident depression: A UK Biobank study. JAMA Psychiatry, 80(8), 789-797.

Wu, Z., et al. (2024). Anti-inflammatory treatments for depression in the elderly: A meta-analysis of randomized controlled trials. Psychopharmacology, 241, 567-580.

Yaffe, K., et al. (2021). Cardiovascular risk factors and the trajectory of cognitive and depressive symptoms in late life. Neurology, 96(3), e432-e440.

Zhang, Y., Chen, S., Wu, Y., Liu, Y., Zhang, X., Li, S., ... & Wang, Y. (2023). Cardiometabolic multimorbidity, social activity, and joint trajectories of physical disability, depressive symptom, and cognitive function in mid-to-late life: a multicohort study. GeroScience, 45(6), 3331-3345. https://doi.org/10.1007/s11357-023-00908-w