Viewpoint

A primer on common analytic concerns in psychoneuroimmunology: Alternatives and paths forward

Childhood adversity and depression have been linked with heightened inflammation. However, few longitudinal studies examine how dimensions of maltreatment (i.e., abuse and neglect) differentially impact pathways to heightened inflammation and internalizing symptoms. The present study examined effects of abuse and neglect on (1) internalizing symptoms through inflammation, and (2) on inflammation through internalizing symptoms across 3 years of adolescence in the context of the COVID-19 pandemic. In a sample of 78 adolescents, significant indirect effects revealed that childhood abuse, not neglect, significantly predicted future internalizing symptoms, which predicted future heighted C-reactive protein (CRP). Using prospective longitudinal data, these findings emphasize the importance of examining distinct forms of maltreatment in understanding the developmental pathways connecting early adversity, internalizing symptoms, and inflammation.

Psychoneuroimmunology and immunopsychiatry are quickly approaching a critical point where the clinical translatability of their evidence base will be tested. To maximize chances for translational success, we believe researchers must adopt causal inference techniques that augment the causal relevance of estimates given theorized causal structures. To illustrate the utility of incorporating causal inference perspectives into psychoneuroimmunology, we applied directed acyclic graphs and a combination of empirical and simulated data to demonstrate the consequences of controlling for adiposity when testing the association between inflammation and depression under the plausible causal structure of increases in adipose tissue leading to greater inflammation that in turn promotes depression. Effect size estimates were pulled from a dataset combining the Midlife in the United States 2 (MIDUS-2) and MIDUS Refresher datasets. Data were extracted and used to simulate data reflecting an adiposity → inflammation → depression causal structure. Next, a Monte Carlo simulation study with 1,000 iterations and three sample size scenarios (Ns = 100, 250, and 500) was conducted testing whether controlling for adiposity when estimating the relation between inflammation and depression influenced the precision of this estimate. Across all simulation scenarios, controlling for adiposity reduced precision of the inflammation → depression estimate, suggesting that researchers primarily interested in quantifying inflammation → depression associations should not control for adiposity. This work thus underscores the importance of incorporating causal inference approaches into psychoneuroimmunological research.

This study examined whether C-reactive protein (CRP), a marker of low-grade systemic inflammation, mediates the association between vascular risk factor (VRF) burden and depressive symptoms.

We drew on the prospective design of the UK Biobank to include participants with longitudinal data on VRF burden, CRP, and depressive symptoms. Total, direct, and indirect effects were estimated using regression-based mediation models while controlling for confounding by sociodemographic factors, baseline CRP, and baseline depression. Sensitivity analyses probed the robustness of results to unmeasured confounding.

We analyzed data from 10,470 participants from the UK Biobank (mean age = 56.75 years at baseline). Net of covariates, VRFs at baseline were associated with higher depressive symptoms at follow-up (total effect = 0.099; 95% CI, 0.002–0.163). CRP mediated this association (indirect effect = 0.010; 95% CI, 0.004–0.017), accounting for 10.0% (95% CI, 0.3%–30.0%) of the total effect of VRF burden on depressive symptoms. Exploratory analyses suggested that the total and indirect effects pertained to somatic depressive symptoms (tiredness and appetite).

These results suggest that inflammation-promoting effects of VRFs may contribute to depressive symptoms in mid- and later life. However, the mediating pathway via CRP explains only a small part of the association between VRFs and depression after accounting for important covariates and may pertain to specific depressive symptoms. Future studies leveraging similar longitudinal designs are needed to further disentangle the time-varying effects between VRFs, inflammation, and certain depressive symptoms while addressing important confounders.