With data from a population-based study in older persons, we examined the relationship between plasma inflammatory markers and symptoms of depression. We found evidence of a cross-sectional and prospective independent association between IL-1ra and depressive symptoms assessed by CES-D. Several cross-sectional studies (1
) found a significant association between depression and high serum IL-1ra. In an experimental study in healthy young men (13
) positive correlations were found between IL-1ra levels and depressed mood in people with endotoxemia. In a previous prospective study of older individuals (22
) elevated levels of IL-1ra preceded the onset of depressed mood. In our study, subjects in the two highest quartiles of IL-1ra at baseline, compared with those in the lowest quartile, had a 2.32- and 2.78-fold higher risk of developing depressed mood after 6 years.
Interleukin-1ra, the pure antagonist of IL-1α and IL-1β, is a reliable marker of immune system activation. There is evidence that IL-1ra is an acute phase protein (33
). As a member of the IL-1 gene family, IL-1ra production increases under the same inflammatory conditions that stimulate IL-1α and IL-1β. However, although these molecules are produced locally, rapidly metabolized, and their serum concentrations are often below the detectable limits with standard methods, IL-1ra is produced by the liver in larger quantities and remains in the circulation for long time (34
). Therefore, IL-1ra is considered a marker of inflammation even more reliable than IL-1. Regardless of the mechanism, our findings suggest that serum IL-1ra might capture aspects on inflammation that are most relevant to the development of depressive mood. If these findings are confirmed, IL1ra might someday become a valuable clinical tool for risk assessment.
Interestingly, in our study baseline plasma levels of IL-1ra were not predictive of depressed mood at 3-year follow-up. This could partly be explained by the small mean increase in CES-D scores after 3 years (2.6 points). We could hypothesize that the influence of inflammation on the development of depressive symptoms is a slow process that takes several years to cross the threshold of clinical manifestation.
Previous epidemiological studies on the association between inflammation and depression have produced discrepant results (14
). This discrepancy between studies is probably attributable to differences in the study populations, assessments of depression, and measures of cytokines (clinical vs. population-based samples, questionnaire vs. DSM diagnosis, and choice of the inflammatory markers/technical limitations of assay). Our findings are consistent with the “cytokine hypothesis of depression” (1
). The IL-1 network molecules could communicate with the brain directly crossing the blood brain barrier (37
) or indirectly via the afferent projections of the vagus nerve (39
). This central action might account for neurochemical and neu-roendocrine features of depressive disorders (40
). Cytokines have been found to induce serotonin depletion by lowering the availability of tryptophan through activation of tryptophan-metabolizing enzyme (indoleamine 2,3-dioxygenase [IDO]) (42
To date the exact mechanisms through which inflammation plays a role in the pathophysiology of depression are still unclear. Further research in this area is needed.
One limitation of this study is the loss of participants to follow-up. Those lost had high levels of inflammatory markers at baseline. Therefore, censoring of these participants probably led to an underestimation of the relationship between inflammation and depression. Another limitation is that depressive symptoms were evaluated by the CES-D questionnaire, and the diagnosis of depression was not confirmed by a clinical psychiatric diagnosis. However, the CES-D is a commonly used scale to measure depressive symptoms and has been widely used in older population-based studies (25
). Moreover DSM affective disorders are not highly prevalent among elderly persons in the community, whereas subsyndromal chronic depression is more common (19
). Another limitation is that the study design did not allow us to detect depressive episodes that started and remitted between subsequent follow-up visits. Furthermore, the results could have been affected by the use of antidepressant drugs; some studies (45
) found that antidepressant agents have negative immuno-regulatory effect through stimulation of IL-10 release. However, when we adjusted the analysis for antidepressant medication use, the results did not change substantially. Finally, in our database there was no measure of cognition more selective than MMSE to test the confounding effect of cognitive decline on the association between inflammation and depression.
Despite this limitation, we believe that our findings suggest a potential causal role for inflammatory process in the onset of depressive symptoms in elderly patients. Accumulation of diseases and cardiovascular risk factor with age or dysregulation due to immunosenescence could slowly increase the “low-grade proinflammatory state” (18
); this could lead over time to the development of depression that worsens the prognosis of the patient. Modulation of the inflammatory process might in the future become a strategy to reduce depressive mood in elderly patients and prevent its deleterious consequences on morbidity and mortality (47