Altered Plasma Endocannabinoids and Oxylipins in Adolescents with Major Depressive Disorders: A Case–Control Study

<b>Background:</b> Pediatric Major Depressive Disorder (pMDD) is one of the leading causes of disability in adolescents. There is currently no single explanation that fully accounts for the cause of the disorder, but various factors, including dysregulation of the immune and stress responses, have been linked to its onset. Oxylipins and endocannabinoids, derived from metabolization of <i>n</i>-3 and <i>n</i>-6 polyunsaturated fatty acids (PUFAs), regulate inflammation and have been suggested to attenuate inflammation associated with depression. This study aims to understand whether adolescents with pMDD have altered baseline levels of oxylipins and endocannabinoids compared to healthy adolescents. <b>Methods:</b> In this case-control study, we measured 60 oxylipins and endocannabinoids in plasma from 82 adolescents with pMDD and their matching healthy controls. <b>Results:</b> A Principal Component Analysis revealed substantial variability within each group and only a moderate degree of separation between them. In a paired analysis, the lipid mediators of controls exhibited higher concentrations of <i>n</i>-6 PUFA-derived prostaglandins and thromboxanes (PGE2, PGD2, PGF2a and TXB2), <i>n</i>-3 PUFA-derived TxB3, and the endocannabinoids AEA, EPEA, and DHEA. In contrast, cases had higher concentrations of the <i>n</i>-6 PUFA-derived 6-keto-PGF1a and the <i>n</i>-3 PUFA-derived PGD3. In addition, we observed a higher percentage of oxylipins and endocannabinoids derived from DHA (5.65 ± 5.46% vs. 4.72 ± 4.94%) and AA (16.31 ± 11.10% vs. 12.76 ± 13.46%) in plasma from controls, in line with the higher DHA and AA levels observed in erythrocytes from controls compared to cases. <b>Conclusions:</b> Overall, our results show lower plasma levels of endocannabinoids and lower DHA- and AA-derived oxylipins in adolescents with pMDD, supporting their role in the pathophysiology of pMDD. To infer a causative role of the <i>n</i>-3 and <i>n</i>-6 PUFA-derived oxylipins and endocannabinoids in pMDD, an intervention study with <i>n</i>-3 PUFA supplementation and monitoring of oxylipins and endocannabinoids would be necessary.