Clinical heterogeneity in major depressive disorder underlies comorbidity with functional disorders.

The comorbidities between MDD and functional disorders (FDs), such as fibromyalgia (FM), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and irritable bowel syndrome (IBS) remain largely unexplored. We analyzed data from 10,563 lifetime MDD cases (mean age = 50.5 (SD = 11.9), 71.8% female) from the Lifelines Cohort Study. Lifetime MDD symptoms from DSM-5 criterion A were assessed in 2018. Current FDs were assessed according to diagnostic criteria between 2014 and 2017. First, we modeled the effect of 12 disaggregated MDD symptoms on FM, ME/CFS, and IBS diagnoses using multiple logistic regression. Most, but not all, MDD symptoms were associated with FD diagnoses, suggesting that some features of MDD are particularly important to the comorbidity between MDD and FDs. Next, we used Latent Class Analysis to classify MDD cases based on their symptoms to explore whether MDD - FD comorbidities were associated with specific symptom profiles. We found that a five-class solution provided the best balance of model fit and entropy. Two classes, termed severe typical and anhedonia/weight gain, associated with increased prevalence of all FDs. The severe typical class was equally associated with FM and ME/CFS, while the anhedonia/weight gain class was differentially associated with pairs of FDs suggesting that features of the anhedonia/weight gain class are uniquely related to different FDs with varying magnitudes of effect and, possibly, different mechanisms. The comorbidity between MDD and FDs does not appear to result from a single mechanism. Identification of the mechanisms that underlie the association between MDD and FDs is a priority for future work.