Inflammatory Markers and Depression in Adults Aged 55 and Older

Can the onset of depression in adults aged 55 and older be predicted by elevated levels of proinflammatory cytokines — namely IL-6, TNFα, and CRP?

Inflammation, as measured by serum levels of IL-6 and TNFα, is predictive of the onset of depression in adults aged 55 years and older, according to study results recently published in Psychoneuroendocrinology.

It has been hypothesized that depression is associated with “psych-neuro-endocrine dysfunction” characterized by “impaired cellular immunity and elevated levels of proinflammatory cytokines” — most notably interleukin 6 (IL-6), tumor necrosis factor (TNFα) and acute phase reactive proteins (eg C reactive protein [CRP]), said study authors.

To address the lack of longitudinal studies and inconsistent findings with regards to this hypothesis, investigators for the current study conducted a longitudinal study to determine whether 3 inflammatory markers — IL-6, TNFα, and CRP — could predict depression onset later in life. Study data was extracted from the Singapore Longitudinal Ageing Study (SLAS), an ongoing population-based cohort study of older adults (≥55 years) living in Singapore, which included data collected at baseline and at 3- to 5- year follow-ups. Data from 2761 individuals were used in analyses; of those, 1420 were depression-free baseline. Mean age at enrollment was 66.3±7.8 years; 62.8% were women; 90.1% were of Chinese descent; and 5.7% were of Malay descent.

Investigators analyzed SLAS data on baseline serum levels of IL-6, TNFα, and CRP, and also created an additional overall “inflammation score” composited from levels of these 3 cytokines. Depressive symptoms at baseline and during periodic follow-ups were assessed using the 15-item Geriatric Depression Scale. Sociodemographic and lifestyle factors captured in the SLAS survey report were also analyzed.

The primary outcome for the current study was depression at follow-up; logistic regression models were used to assess the impact of inflammatory markers on depression risk. Models were adjusted for sociodemographic and lifestyle factors and medical history.

The baseline prevalence of depression was 6.8%. At follow-up, the prevalence rates of depression were significantly elevated in patients with high vs low CRP (15.7% vs 9.5%, respectively; P <.001); patients with high vs low IL-6 (21.3% vs 9.5%, respectively; P <.001); and patients with high vs low TNFα (22.2% vs 4.7%, respectively; P <.001).

In fully adjusted regression models, having a high overall inflammation score was significantly predictive of incident depression at follow-up (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.19-1.35). This association was driven by a significant association between depression and high levels of IL-6 (OR, 3.17; 95% CI, 2.33-4.31) and TNF-a (OR, 2.16; 95% CI, 1.65-2.82).

Although the relationship between CRP levels and depression was significant in unadjusted models, the researchers found that the association did not persist in fully-adjusted calculations. After excluding patients with depression at baseline, inflammation remained a major predictor of depression at follow-up. Specifically, IL-6 (OR, 3.44; 95% CI, 2.48-4.78), TNFα (OR, 2.51; 95% CI, 1.91-3.32), and combined inflammation score (OR, 1.28; 95% CI, 1.20-1.38) were significantly associated with subsequent risk of depression in fully-adjusted models. However, as in the total cohort, the relationship between CRP and incident depression risk was significant in unadjusted models but no longer significant in fully-adjusted analyses.

Results from this analysis align with prior findings that inflammatory cytokines may play a role in the pathogenesis of depression. Further study in a larger cohort — and with a more extensive panel of inflammatory markers — is necessary to better explore these associations.

“Our findings add to mounting evidence in support of the inflammation hypothesis in depression, by demonstrating the temporal plausibility that inflammation may lead to the development of depression, at least in the elderly,” said study authors. “As the association between diverse inflammatory markers and depression is heterogeneous, future research needs to explore the specific associations between different inflammatory markers, other moderating and mediating factors, and depression subtypes.”


Shi R, Gwee X, Chua DQ, et al. Inflammatory markers and incident depression: Evidence in a population-based prospective study. Psychoneuroendocrinology. Published online May 23, 2022. doi:10.1016/j.psyneuen.2022.105806