Peripheral biomarkers and clinical correlates of Prolonged Grief Disorder (PGD): comparison with Major Depressive Episode and healthy controls

Background: Prolonged Grief Disorder (PGD) is recently classified mental disorder affecting bereaved individuals with unusually long and impairing dysfunction following a significant loss. Although Major Depression is a common co-occurring condition, PGD is increasingly recognized as a separate entity defined by a unique set of traumatic distress symptoms. Existing literature provides scarce and conflicting data about potential biomarkers of PGD. Aims: first aim was to examine the possible presence of peripheral markers in a sample of patients with a diagnosis of PGD (PGD group) and comparison with a group of patients with Major Depressive Episode (MDE group) and healthy controls (CTL group). We aimed to analyze the circulating concentrations of: tryptophan (TRP); serotonin (5-HT); kynurenine (KYN) and quinolinic acid (QA); plasmatic (PPP) and intraplatelet (PLT) BDNF; cortisol; superoxide dismutase (SOD) and catalase (CAT). Second aim was to examine potential correlations between the biochemical markers examined and clinical features. Methods: All subjects underwent a psychiatric assessment and concomitant biological samplings. Psychometric instruments included SCID-5, HAM-D, YMRS, ICG, IES-R and WSAS. Peripheral levels of TRP, 5-HT, KYN, QA, PPP/PLT-BDNF, SOD and CAT and nighttime and early morning urinary cortisol were analyzed. 5-HT/TRP, KYN/TRP, QA/TRP, QA/KYN and %PPP/PLT ratios were calculated too. Biological parameters under investigation were measured by means of dedicated Enzyme-linked immunosorbent assays (ELISA) and Clinical Chemistry Assays. Biochemical evaluations were performed at the Laboratory of Biochemistry of Department of Pharmacy, University of Pisa (Pisa, Italy). Results: Between-group comparisons showed interesting results. For instance, lower TRP concentrations in PGD group than in the CTL one were found. 5-HT levels, its relative 5-HT/TRP ratio and PLT-BDNF levels were significantly lower in both MDE and PGD groups than in the CTL one. MDE group showed significantly reduced SOD levels, while CAT was significantly reduced in the PGD group compared to controls. Urinary cortisol levels were significantly higher in PGD vs. CTL group. Correlations between peripheral biochemical parameters showed many significant correlations, including positive correlations between TRP and 5-HT and PLT-BDNF and negative correlations with QA and %PPP/PLT ratio. 5-HT was negatively correlated with QA, KYN/TRP and QA/TRP ratios, while a positive correlation with CAT and PPP-BDNF was shown. PLT-BDNF revealed a similar correlation profile of 5-HT. Group-specific correlations showed a positive correlation of 5-HT with CAT and PLT-BDNF in PGD, whilst positive correlation between 5-HT and PPP-BDNF and the negative one between urinary cortisol and PLT-BDNF were related to the DEP group. Correlations between biochemical and clinical parameters revealed that TRP and 5-HT levels were negatively correlated with the clinical scores; QA levels and its related QA ratios were positively correlated with the clinical scores. KYN/TRP ratio showed a similar correlation profile to that of QA. PLT-BDNF correlated negatively with all clinical scores. Results confirmed that redox enzymes showed discriminant correlations in respect to MDE or PGD diagnosis: SOD levels were indeed negatively correlated with severity of depressive symptoms, whilst CAT levels were negatively correlated with severity of prolonged grief symptoms ones. Conclusion: To the best of our knowledge, this is the first study investigating possible peripheral biomarkers and clinical correlates of PGD in comparison with major depressive episode and healthy controls. Taking into account all these considerations, it could be hypothesized that in PGD and depression different pattern of energy metabolism, cell signaling, inflammation messengers and cytokine release can occur resulting in distinct modulatory effects on redox state and antioxidant reactivity.