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Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are classified as major mental disorders and together account for the second-highest global disease burden, and half of these patients experience symptom onset in adolescence. Several studies have reported both similar and unique features regarding the risk factors and clinical symptoms of these three disorders. However, it is still unclear whether these disorders have similar or unique metabolic characteristics in adolescents. We conducted a metabolomics analysis of plasma samples from adolescent healthy controls (HCs) and patients with MDD, BD, and SCZ. We identified differentially expressed metabolites between patients and HCs. Based on the differentially expressed metabolites, correlation analysis, metabolic pathway analysis, and potential diagnostic biomarker identification were conducted for disorders and HCs. Our results showed significant changes in plasma metabolism between patients with these mental disorders and HCs; the most distinct changes were observed in SCZ patients. Moreover, the metabolic differences in BD patients shared features with those in both MDD and SCZ, although the BD metabolic profile was closer to that of MDD than to SCZ. Additionally, we identified the metabolites responsible for the similar and unique metabolic characteristics in multiple metabolic pathways. The similar significant differences among the three disorders were found in fatty acid, steroid-hormone, purine, nicotinate, glutamate, tryptophan, arginine, and proline metabolism. Interestingly, we found unique characteristics of significantly altered glycolysis, glycerophospholipid, and sphingolipid metabolism in SCZ; lysine, cysteine, and methionine metabolism in MDD and BD; and phenylalanine, tyrosine, and aspartate metabolism in SCZ and BD. Finally, we identified five panels of potential diagnostic biomarkers for MDD-HC, BD-HC, SCZ-HC, MDD-SCZ, and BD-SCZ comparisons. Our findings suggest that metabolic characteristics in plasma vary across psychiatric disorders and that critical metabolites provide new clues regarding molecular mechanisms in these three psychiatric disorders., (© 2024. The Author(s).)

Major depressive disorder (MDD) is a highly heterogeneous psychiatric disorder. The pathogenesis of MDD remained unclear, and it may be associated with exposure to different stressors. Most previous studies have focused on molecular changes in a single stress-induced depression model, which limited the identification of the pathogenesis of MDD. The depressive-like behaviors were induced by four well-validated stress models in rats, including chronic unpredictable mild stress, learned helplessness stress, chronic restraint stress and social defeat stress. We applied proteomic and metabolomic to investigate molecular changes in the hippocampus of those four models and revealed 529 proteins and 98 metabolites. Ingenuity Pathways Analysis (IPA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified differentially regulated canonical pathways, and then we presented a schematic model that simulates AKT and MAPK signaling pathways network and their interactions and revealed the cascade reactions. Further, the western blot confirmed that p-AKT, p-ERK12, GluA1, p-MEK1, p-MEK2, p-P38, Syn1, and TrkB, which were changed in at least one depression model. Importantly, p-AKT, p-ERK12, p-MEK1 and p-P38 were identified as common alterations in four depression models. The molecular level changes caused by different stressors may be dramatically different, and even opposite, between four depression models. However, the different molecular alterations converge on a common AKT and MAPK molecular pathway. Further studies of these pathways could contribute to a better understanding of the pathogenesis of depression, with the ultimate goal of helping to develop or select more effective treatment strategies for MDD., (© 2023. The Author(s).)

Adolescent depression is a common and serious mental disorder with unique characteristics that are distinct from adult depression. The adult non-human primate stress-induced model of depressive-like behavior is an excellent model for the study of mechanisms; however, an adolescent nonhuman primate model is still lacking. Ten male adolescent cynomolgus monkeys were divided into a chronic unpredictable mild stress (CUMS, n = 5) group and a control (CON, n = 5) group by age and weight-matched pairs. The CUMS group was exposed to multiple unpredictable mild stressors for five cycles over 55 days. At baseline, there were no differences between CUMS and CON groups. At endpoint, the CUMS group demonstrated significantly higher depressive-like behavior (huddle posture), and significantly lower locomotion compared with the CON group. Furthermore, depressive-like behavior increased from baseline to endpoint in the CUMS group, but not changed in the CON group. In the attempt for apple test, the CUMS group made significantly fewer attempts for the apple than the CON group. In the human intruder test, the CUMS group showed significantly higher anxiety-like behaviors in the stare phase than the CON group. Hair cortisol level was significantly higher in the CUMS group than the CON group at endpoint, and was also elevated from baseline to endpoint. Metabolic profiling of plasma at endpoint identified alterations in metabolite pathways which overlapped with those of adolescent depression patients. CUMS can induce depressive-like and anxiety-like behaviors, hypercortisolemia, and metabolic perturbations in adolescent cynomolgus monkeys. This is a promising model to study the mechanisms underlying adolescent depression.