Schizophrenia is a chronic, disabling, and complex mental illness, of which the pathogenesis remains elusive. To provide clues for the pathogenesis and etiology of schizophrenia, we performed serum metabolic profiling in 54 patients with schizophrenia and 54 matched healthy controls using Fourier transform-ion cyclotron resonance-mass spectrometry. Based on 94 differential metabolites identified, we discovered two dysregulated metabolic pathways in schizophrenia, including the upregulated arachidonic acid-related pathway and the downregulated aromatic amino acid-related pathway. Moreover, carnitine was identified as a promising diagnostic biomarker for schizophrenia with an area under the curve of 0.997. Given the antioxidant and pro-oxidant properties of these altered metabolites, these results pointed to an imbalance of the redox homeostasis in schizophrenia, which was further confirmed by a remarkable elevation of 8-hydroxydeoxyguanosine (8-OHdG), a reactive oxidative stress marker. Furthermore, correlation analyses demonstrated that 8-OHdG was negatively correlated with antioxidant biliverdin and positively related to oxidation products, 9-hydroxylinoleic acid and o-tyrosine, and that total antioxidant capacity was positively associated with antioxidant acetylcarnitine in schizophrenia. Our results lead to the hypothesis that the disturbed metabolic characteristics reveal enhanced oxidative stress, which in turn results in the damage of lipids, proteins, and DNA and ultimately promotes the development of schizophrenia.

Polyunsaturated fatty acids (PUFAs), especially long-chain PUFAs (LCPUFAs), are crucial for both the structural and functional integrity of cells. PUFAs have been reported to be insufficient in schizophrenia, and the resulting cell membrane impairments have been hypothesized as an etiological mechanism. However, the impact of PUFA deficiencies on the onset of schizophrenia remain uncertain. We investigated the associations between PUFAs consumption and schizophrenia incidence rates through correlational analyses and conducted Mendelian randomization analyses to reveal the causal effects. Using dietary PUFA consumption and national schizophrenia incidence rates in 24 countries, we found that incidence rates of schizophrenia were inversely correlated with arachidonic acid (AA) and ω-6 LCPUFA consumption (r_AA = −0.577, p < 0.01; r_{ω-6 LCPUFA} = −0.626, p < 0.001). Moreover, Mendelian randomization analyses revealed that genetically predicted AA and gamma-linolenic acid (GLA) were protective factors against schizophrenia (OR_AA = 0.986, OR_GLA = 0.148). In addition, no significant relationships were observed between schizophrenia and docosahexaenoic acid (DHA) or other ω-3 PUFAs. These findings show that the deficiencies of ω-6 LCPUFAs, especially AA, are associated with schizophrenia risk, which sheds novel insight into the etiology of schizophrenia and a promising diet supplementation for the prevention and treatment of schizophrenia.

Adolescent depression is a globally concerned mental health issue, the pathophysiological mechanisms of which remain elusive. Membrane lipids play a crucial role in brain development and function, potentially serving as a crossroad for the abnormalities in neurotransmitters, neuroendocrine, inflammation, oxidative stress, and energy metabolism observed in depressed adolescents. The primary aim of this study was to investigate the erythrocyte membrane lipid profile in adolescent depression. A total of 2838 erythrocyte membrane lipids were detected and quantified in 81 adolescents with depression and 67 matched healthy adolescents using ultra-high performance liquid chromatography-mass spectrometry. Depressed adolescents exhibited significantly different membrane lipid characteristics compared to healthy controls. Specifically, the levels of cholesterol, sphingomyelins, and ceramides were increased, while ether lipids were decreased in patients. Moreover, the patients showed reduced polyunsaturated fatty acids and elevated lipophilic index in membrane, suggesting diminished membrane fluidity. The higher oxidized membrane lipids and plasma malondialdehyde were observed in adolescent depression, indicating the presence of oxidative stress. Importantly, membrane lipid damage was associated with more severe depressive symptoms and worse cognitive function in patients. In addition, reduced polyunsaturated fatty acids and membrane fluidity may be partly responsible for the blunted niacin skin flushing response found in depressed adolescents. In conclusion, our results reveal impaired erythrocyte membrane lipid homeostasis in adolescents with depression, which may implicate membrane dysfunction in the brain. These findings offer new insights into the underlying molecular mechanisms of adolescent depression, highlighting the potential of counteracting membrane damage as a promising avenue for future therapeutic interventions.

Adolescent depression is a significant global health challenge, with many patients responding inadequately to antidepressant treatments. Omega-3 polyunsaturated fatty acids (ω3 PUFAs) have been proposed as a potential adjunctive treatment, but their precise mechanisms remain poorly understood. This study aimed to explore the mechanisms through which ω3 PUFAs exert their antidepressant effects and to identify potential biomarkers for their therapeutic response. A comprehensive assessment of plasma metabolomic and erythrocyte membrane lipidomic was performed on 51 depressed adolescents who were randomly assigned to received either ω3 PUFAs plus paroxetine (n = 27) or paroxetine alone (n = 24) for 12 weeks. Following ω3 PUFA supplementation, phospholipid metabolism emerged as the most significantly altered pathway. ω3 PUFAs markedly influenced the composition of membrane fatty acids, significantly increasing the ω3 PUFA content, decreasing the ω6/ω3 PUFA ratio, and increasing membrane fluidity. Notably, ω3 PUFAs reduced lipid peroxidation in both plasma and cell membranes while enhancing antioxidant capacity in the membranes. Moreover, alterations in phospholipids and membrane function were significantly correlated with improvements in depressive symptoms and cognitive function. Importantly, ω3 PUFA supplementation resulted in greater improvement in clinical symptoms compared to the non-supplemented group exclusively in the subgroup with high baseline oxidative damage levels. This study suggests that ω3 PUFAs promoted phospholipid integration and alleviated oxidative stress, which may account for their antidepressant effects. Lipid oxidation biomarkers could help identify patients likely to benefit from ω3 PUFA supplementation. These findings advance our understanding of the mechanism and clinical application of ω3 PUFAs in treating adolescent depression.

The selective expression of genes is the basis of cellular and individual phenotypic differences, serving as a mediator in the causal pathways from genotypes to phenotypes. Single-cell differential expression analysis identifies distinct transcriptomic landscapes, but fails to establish causal relationships due to the presence of confounders. On the other hand, causal inference methods in population genetics such as Mendelian randomization often overlook the heterogeneity among cells and dynamic changes along trajectory. To address these limitations, we propose the trajectory-inference-based dynamic single-cell Mendelian randomization (ti-scMR), integrating population genomes and single-cell transcriptomes to explore transcriptional features causally linked to cellular and individual phenotypes. ti-scMR leverages trajectory inference and functional principal component analysis to capture the temporal cumulative effects of gene expression, select genetic instrumental variables through single-cell expression quantitative trait locus (eQTL) mapping, and employ transcriptome-level Mendelian randomization to prioritize causal genes for cellular and individual phenotypes, specifically those that are related through affecting cellular development. We demonstrate the superiority of ti-scMR in identifying causal genes through simulations. With application in two real single-cell datasets, we discover potential causal genes on immune cell differentiation and related disease. The integration of single-cell trajectory inference, eQTL, and Mendelian randomization will make ti-scMR a powerful tool for elucidating the causal mechanisms underlying complex traits.