Grief-Related Psychopathology from Complicated Grief to DSM-5-TR Prolonged Grief Disorder: A Systematic Review of Biochemical Findings

Prolonged Grief Disorder (PGD) is marked by enduring and disruptive grief symptoms following the death of a significant other. Although PGD has been recognized as a distinct psychopathological entity within the trauma dimension in the DSM-5-TR, its neurobiological underpinnings remain not fully defined. A systematic literature review was conducted up to September 2025 following PRISMA 2020 guidelines. PubMed, Scopus, Embase and Web of Science were searched using a comprehensive strategy combining MeSH terms and free-text keywords. Eligible studies included human participants, validated grief assessment tools and biomarker assessments. Out of 2140 initial records, 12 studies published between 1989 and 2022 met inclusion criteria. Investigated neuro-psycho-endocrine systems included the hypothalamic-pituitary-adrenal (HPA) axis, catecholamines, oxytocin, endocannabinoids and immune/inflammatory markers. Key findings in pathological grief reactions included altered cortisol rhythms, elevated oxytocin levels, increased pro-inflammatory cytokines and immune system dysregulation. Results are limited by heterogeneity in study designs, small sample sizes, inconsistent use of diagnostic criteria prior to DSM-5-TR and lack of control for psychiatric comorbidities. This review highlights emerging biological correlates of PGD, particularly those involving the stress response, reward-attachment networks and immune/inflammatory pathways. Further standardized, longitudinal research is essential to gain a more defined picture of PGD, to clarify causal mechanisms and to guide targeted therapeutic interventions.