Prospective associations between major depressive disorder, generalized anxiety disorder, fibromyalgia, and myalgic encephalomyelitis/chronic fatigue syndrome.

Background: Functional disorders (FDs) are associated with internalizing disorders (IDs). Studies investigating the nature of these associations over time are limited. We tested the direction of causation between measures of IDs (major depressive disorder [MDD], generalized anxiety disorder [GAD]) and FDs (fibromyalgia [FM] and myalgic encephalomyelitis/chronic fatigue syndrome [ME/CFS]) measured across two waves of longitudinal data (N = 108,034 and N = 73,590).

Methods: The Lifelines Cohort Study is a large prospective population-based cohort study in the northeast of the Netherlands. We tested competing causal models for the longitudinal association between IDs and FDs and, to follow-up results from the model with all IDs and FDs, tested the direction of causation between MDD and FM.

Results: FDs were more stable over time than IDs. Initial model comparisons support a bidirectional relationship between most IDs and FDs. Follow-up analyses support a unidirectional model where FM predicts MDD over time (β = 0.14, 95% confidence interval = [0.11, 0.18]), but not vice versa.

Conclusions: The cross-time associations between ME/CFS, MDD, and GAD appear bidirectional (causal in both directions). Our results are consistent with, but not demonstrative of, a causal relationship from FM to MDD. The consequences of specific FDs vary, underscoring the value of studying these conditions as distinct constructs.