Hierarchical Inflammatory Phenotypes of Depression: A Novel Approach across Five Independent Samples and 27,730 Adults

Background: Although characterizing associations between inflammation and depression may prove critical for informing theory, research, and treatment decisions, extant research has been limited by ignoring the possibility that inflammation may be simultaneously associated with depression broadly and with a subset of symptoms. This lack of direct comparison has hampered attempts to understand inflammatory phenotypes of depression and, critically, fails to consider that inflammation might be uniquely associated with both depression broadly and individual symptoms. Methods: We used moderated nonlinear factor analysis in five NHANES cohorts (N=27,730, 51% female, mean age=46 years). Results: C-reactive protein (CRP) is simultaneously associated with latent depression, appetite, and fatigue. Specifically, CRP was associated with latent depression in all five samples (rs: .044-.089; ps: <.001-.002) and was associated with both appetite (significant rs: .031-.049, significant ps: .001-.007) and fatigue (significant rs: .030-.054, significant ps: <.001-.029) in four samples. These results were largely robust to covariates. Conclusions: Methodologically, these models indicate that the PHQ-9 is scalar noninvariant as a function of CRP (i.e., identical PHQ-9 scores may represent different constructs in those with high vs. low CRP). Therefore, mean-comparisons of depression total scores and CRP might be misleading without accounting for symptom-specific associations. Conceptually, these findings indicate that studies investigating inflammatory phenotypes of depression should examine how inflammation is simultaneously related to both depression broadly and specific symptoms, and whether these relations function via different mechanisms. This has the potential to yield new theoretical insights and may lead to novel therapies for reducing inflammation-related symptoms of depression.