Interest in the hypothesis that inflammation contributes to the pathogenesis of depression and its comorbidities is growing rapidly. Despite the mounting interest, research on depression and inflammation has yielded inconsistent findings, leading to speculation that these conditions may cluster only in certain subgroups of patients, like those exposed to childhood adversity. In six waves of data from a study of individuals at high risk for depression, we found strong evidence to support this view. Indeed, among subjects exposed to higher levels of childhood adversity, the transition to depression was accompanied by relative increases in both CRP and IL-6. The higher CRP levels remained evident in these subjects six months later, suggesting that childhood adversity potentiates a lingering inflammatory response, which is detectable even after the depressive episode has abated. These lingering effects appear to be bi-directional. Among subjects with a history of childhood adversity, high levels of IL-6 forecasted risks of depression six months later, even after concurrent inflammation was considered. This coupling of depression and inflammation was not apparent in subjects without childhood adversity.
These findings have several implications for our understanding and management of depression. First, they identify a subgroup of patients, those with childhood adversity, in whom depression and inflammation co-occur. From observational data like these, inferences about causality cannot be made. However, if the clustering we observed reflects a causal influence of inflammation, these patients may be promising candidates for anti-inflammatory therapies (33
). Our findings suggest that such treatments would be ineffective for patients without childhood adversity, as depression and inflammation tend to dissociate in them. Second, the lingering effects seen here suggest that childhood adversity may predispose individuals to a scarring phenomenon, whereby even brief encounters with depression leave a persisting inflammatory residue. (And vice-versa.) These findings converge with and extend studies of remitted depressed patients, in some of whom CRP remains elevated after symptom remission (34
). As a consequence of these lingering effects, childhood adversity may predispose individuals to complicated depressions, characterized by treatment non-response, residual mood symptoms, or frequent relapse (3
). The increased exposure to inflammatory mediators may also heighten these patients’ vulnerability to comorbid medical conditions, like diabetes, autoimmune disorders, and cardiovascular disease. As such, additional monitoring of adversity-exposed patients for psychiatric difficulties and medical comorbidities may be advantageous. Third, these findings suggest that even “mundane” forms of childhood adversity (36
), involving parental separation and socioeconomic difficulties, can promote clustering of depression and inflammation. The fact that such clustering arises without exposure to more severe adversity, like maltreatment, suggests that even normative childhood stressors may exert lasting influences on neural-immune crosstalk. This findings take on special relevance at present, when rates of childhood poverty and familial instability are increasing.
How might childhood adversity promote the clustering of depression and inflammation? We considered a number of explanations via statistical analysis, including adversity-related differences in the severity or duration of depressive episodes, and the contribution of putative demographic and biobehavioral confounds. None of these variables accounted for the consistent pattern of cross-level interactions. Instead, we speculate that childhood adversity fosters the emergence of a vigorous neural-immune pipeline, which amplifies cytokine signaling between the central nervous system and peripheral lymphoid structures (15
). Such a pipeline could become embedded through any of several mechanisms, including post-translation modification of proteins involved with cytokine signaling (37
), or densification of sympathetic connections that enable crosstalk between neural stress-response centers and peripheral immune compartments (38
). Also potentially relevant are epigenetic alterations to genes involved with the propagation or transduction of inflammatory signals (39
). Alternatively, the clustering could arise as a consequence of disparities in central serotonergic activity (41
), imparted through previous adversity (43
) or relevant allelic variation (44
Several limitations of this study must be considered. We observed a relatively small number of depressive episodes, and they were generally of brief duration and mild severity. Considering these clinical features and the sample’s characteristics – otherwise healthy teenagers from mostly middle-class families – the clustering we observed is even more striking. That said, to ascertain the clinical significance of these observations, research is needed on patients with severe, persistent depression. Such work could reveal whether clustering presages vulnerability to more complicated affective disorders and subsequent comorbid disease. Another weakness of the study was its failure to assess maltreatment. In the absence of such data, it remains uncertain whether the observed clustering arises from the “mundane” adversity captured by our index, versus unmeasured but co-occuring experiences with maltreatment. We view this scenario as somewhat unlikely, given prospective data showing that both impoverished and maltreated children go on to have more adult inflammation, and these effects are statistically independent (45
). A final limitation is that our adversity index was constructed in a manner that treated all exposures as equally powerful. Follow-up analyses were supportive of this approach, suggesting that each type of adversity was associated with later clustering. However, because rates of exposure to some adversities were low, we lacked the power to formally test for distinct influences. Future research with larger, more vulnerable samples is needed to address this question. Since our study was limited to adolescent females, follow-ups with broader demographic representation would also be desirable.
To summarize, these results suggest that childhood adversity potentiates a phenotype wherein depression and inflammation co-occur. This clustering has implications for our understanding of depression’s pathogenesis, the mechanisms by which it confers susceptibility to comorbidities, and possibly for targeted application of anti-inflammatory therapy. More broadly, the findings contribute to an emerging consensus that childhood social conditions are important in establishing lifecourse trajectories that eventuate in differential vulnerability to disease and disability (15