Anhedonia is a core symptom of major depressive disorder (MDD) and is associated with worse treatment outcomes. While its narrow definition as a hedonic or consummatory deficit evolved to encompass anticipatory and motivational reward facets, it remains unclear where reward deficits manifest. Since evidence that metabolic hormones influence reward processing accumulates, investigating their role in alleviating reward deficits may provide crucial insights. To address these gaps, we conducted a study with 103 participants, including 52 patients with MDD and 51 healthy control participants (HCPs). After overnight fasting, blood samples were collected to determine the concentration of ghrelin, glucose, insulin, and triglycerides in serum/plasma. Participants then completed a taste test with repeated ratings of wanting and liking for snacks before and after tasting, allowing to gradually move from reward anticipation to consummation. Patients with MDD showed decreased wanting (p = .046) but not liking for food rewards during visual anticipation. However, these group differences disappeared once patients inspected and tasted the food as patients increased wanting relative to HCPs (p = .004), providing strong evidence against the hypothesis of a consummatory deficit (Bayes Factors > 9). In contrast to a narrow definition of anhedonia, higher scores on the Snaith-Hamilton Pleasure Scale (SHAPS) were more strongly associated with reduced anticipatory food wanting (p = .010), not liking, and more pronounced increases in wanting with reward proximity (p = .037). Across groups and phases, acyl ghrelin was associated with higher wanting and liking ratings, while poor glycemic control was associated with anhedonia. Overall, our study demonstrates that MDD and its cardinal symptom, anhedonia, are associated with a reduced anticipation of rewards rather than an impaired ability to experience pleasure. Since ghrelin was associated with elevated reward ratings, targeting the gut-brain axis could be a promising avenue for treating reward deficits.

JK works as a study therapist in a multicenter phase IIb study by Beckley Psychtech Ltd on 5-MeO-DMT in patients with MDD, unrelated to this investigation. JK did not receive any financial compensation from the company. MW is a member of the following advisory boards and gave presentations to the following companies: Bayer AG, Germany; Boehringer Ingelheim, Germany; Novartis, Perception Neuroscience, HMNC and Biologische Heilmittel Heel GmbH, Germany. MW has further conducted studies with institutional research support from HEEL and Janssen Pharmaceutical Research for a clinical trial (IIT) on ketamine in patients with MDD, unrelated to this investigation. MW did not receive any financial compensation from the companies mentioned above. All other authors report no biomedical financial interests or other potential conflicts of interest.

https://clinicaltrials.gov/study/NCT05318924

The study was funded by DFG KR 4555/7-1, KR 4555/9-1, KR 4555/10-1, and & WA 2673/15-1.

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The Ethics Committee/IRB of the University of Tuebingen, Faculty of Medicine, gave ethical approval for this work.

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All data produced in the present study are available upon reasonable request to the authors.