Pharmacotherapeutic Management of Depression in Patients With Cancer: A Review of Mechanistic and Clinical Evidence.
Sepideh Hajivalizadeh, Kimia Farahmand, Kimia Kazemzadeh, Ghazaleh Hajivalizadeh, Ahmad Shamabadi
Cancer reports (Hoboken, N.J.) May 1, 2026 Peer reviewed DOI: 10.1002/cnr2.70587 via PubMed
Summary
Depression frequently co-occurs with cancer, but standard antidepressants often work poorly. This review proposes a new approach based on the unique biology of cancer-related depression, which involves inflammation, stress hormone dysregulation, serotonin pathway disruption, and glutamate toxicity. Drugs that directly target inflammation (celecoxib) or glutamate (ketamine) show early promise. Atypical antidepressants like mirtazapine and the psychedelic psilocybin also show preliminary benefits, while standard SSRIs and tricyclics have mixed results. A personalized, mechanism-based treatment strategy is needed instead of a one-size-fits-all model.
Study at a glance
| Design | narrative review |
|---|---|
| Population | patients with cancer and depression |
| Key finding | A personalized, mechanism-informed approach targeting inflammation, HPA axis hyperactivity, and glutamate excitotoxicity is essential for managing depression in cancer patients, as conventional antidepressants show inconsistent efficacy. |
Abstract
Depression is a prevalent comorbidity in cancer, yet conventional treatments show inconsistent efficacy. This review sought to provide a mechanism-based framework for managing cancer-related depression by exploring its unique pathophysiology and evaluating promising pharmacotherapies based on their alignment with these biological pathways. This narrative review synthesized evidence on promising pharmacotherapies based on their ability to target the core biological mechanisms of cancer-related depression, including pro-inflammatory cytokine activity, hypothalamic-pituitary-adrenal axis hyperactivity, serotonin pathway disruption via indolamine-2,3-dioxygenase activation, and glutamate excitotoxicity. Interventions directly targeting inflammation (e.g., celecoxib) and glutamate modulation (e.g., ketamine) demonstrated encouraging early evidence. The effect of ketamine can also be due to its anti-inflammatory properties. Atypical antidepressants, such as mirtazapine, and the serotonergic psychedelic psilocybin also showed promising but preliminary benefits. In contrast, conventional selective serotonin reuptake inhibitors and tricyclic antidepressants yielded conflicting results. Other agents, including the psychostimulant methylphenidate, showed utility for specific symptoms like fatigue. A personalized, mechanism-informed approach targeting the core pathophysiological cascade of inflammation, hypothalamic-pituitary-adrenal axis hyperactivity, and glutamate excitotoxicity is essential for effectively managing depression in patients with cancer. This represents a necessary paradigm shift away from a one-size-fits-all treatment model.