# Depression as a Prodromal Symptom of Pancreatic Cancer: A Narrative Review

## TL;DR

Depression may appear before pancreatic cancer is diagnosed, possibly due to biological changes linked to the tumor.

## Contribution

This review suggests depression could be a prodromal symptom of pancreatic cancer, not just a psychological reaction.

## Key findings

- 10–20% of pancreatic cancer patients show depressive symptoms months before diagnosis.
- Depression is linked to tumor-related processes like cytokine activity and the kynurenine pathway.
- Depression correlates with worse treatment adherence, quality of life, and survival in cancer patients.

## Abstract

Depression is frequently observed in patients with pancreatic ductal adenocarcinoma (PDAC) and may appear even months before the cancer is diagnosed. This narrative review summarizes clinical, epidemiological and biological evidence suggesting that depression could represent a prodromal or paraneoplastic manifestation of pancreatic cancer, rather than only an emotional reaction to illness. Understanding this association may help clinicians recognize early warning signs and improve patient care, prognosis, and quality of life. This review primarily focused on PDAC; evidence in other pancreatic tumor histotypes is limited to isolated reports.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, typically diagnosed at an advanced stage. The identification of prodromal symptoms could support earlier detection. Among these, depression is frequently reported, raising the question of whether it may represent not only a reactive response but also a paraneoplastic manifestation. Methods: We conducted a narrative review of clinical, epidemiological and biological literature published between 1988 and 2025. Searches were performed in PubMed/MEDLINE, Scopus, and Web of Science using predefined keywords related to pancreatic cancer, depression, prodromal symptoms, cytokines, and the kynurenine pathway. Eligible studies included clinical cohorts, population-based analyses, biological investigations, and case reports exploring the temporal or mechanistic link between depression and PDAC. Results: A substantial proportion of patients (10–20%) exhibit depressive symptoms in the months preceding the clinical diagnosis of pancreatic cancer. In several cases, depression occurs independent of weight loss and new-onset diabetes. Biological evidence highlights the involvement of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), NF-κB signaling, and activation of the tryptophan–kynurenine pathway (IDO), suggesting a link between tumor-related processes and mood alterations. These mechanistic findings are actually hypothesis-generating, deriving mainly from small clinical cohorts and preclinical models. Clinically, depression is associated with reduced adherence to treatment, poorer quality of life, and shorter survival. However, no specific depressive phenotype has been identified. Conclusions: Depression may represent a potential prodromal symptom of pancreatic cancer, reflecting systemic biological processes as well as psychological reactions. Its utility as a standalone marker remains limited; future studies should integrate psychiatric, clinical and biological biomarker assessments to enhance early clinical diagnosis.