Appetite changes reveal depression subgroups with distinct endocrine, metabolic, and immune states


There exists little human neuroscience research to explain why some individuals lose their appetite when they become depressed, while others eat more. Answering this question may reveal much about the various pathophysiologies underlying depression. The present study combined neuroimaging, salivary cortisol, and blood markers of inflammation and metabolism collected prior to scanning. We compared the relationships between peripheral endocrine, metabolic, and immune signaling and brain activity to food cues between depressed participants experiencing increased (N = 23) or decreased (N = 31) appetite and weight in their current depressive episode and healthy control participants (N = 42). The two depression subgroups were unmedicated and did not differ in depression severity, anxiety, anhedonia, or body mass index. Depressed participants experiencing decreased appetite had higher cortisol levels than subjects in the other two groups, and their cortisol values correlated inversely with the ventral striatal response to food cues. In contrast, depressed participants experiencing increased appetite exhibited marked immunometabolic dysregulation, with higher insulin, insulin resistance, leptin, CRP, IL-1RA, and IL-6, and lower ghrelin than subjects in other groups, and the magnitude of their insulin resistance correlated positively with the insula response to food cues. These findings provide novel evidence linking aberrations in homeostatic signaling pathways within depression subtypes to the activity of neural systems that respond to food cues and select when, what, and how much to eat. In conjunction with prior work, the present findings strongly support the existence of pathophysiologically distinct depression subtypes for which the direction of appetite change may be an easily measured behavioral marker.

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This research was supported by the National Institute of Mental Health (K01MH096175-01) grant to WKS, and NARSAD Young Investigator Award to WKS. WKS also receives funding from a National Institute of General Medical Sciences Center Grant (1P20GM121312). We also wish to thank the University of Oklahoma Integrative Immunology Center for assistance with running immunoassays.

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Correspondence to W. Kyle Simmons.

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WKS and WCD are employees of Janssen Research and Development, LLC., of Johnson and Johnson, and WCD holds equity in Johnson and Johnson. WCD and WKS are co-inventors on a patent regarding appetite change in depression. The remaining authors declare that they have no conflict of interest.

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