Profiling of Lipidomics Before and After Antipsychotic Treatment in First-Episode Psychosis

Leppik, Liisa; Parksepp, Madis; Janno, Sven; Koido, Kati; Haring, Liina; Vasa, Eero; Zilmer, Mihkel

doi:10.2139/ssrn.3220097

Cited by 5 publications

(6 citation statements)

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“…Particularly, our targeted metabolomic pro les contained the amino acids Asn and Cys, which have also been reported in other SCZ studies[6, 82-84]. Many lyso-PCs have also been detected to be enriched in the SCZ samples in multiple lipidomic studies [9,12,61,85]. Despite the availability of these datasets, a link between the dysregulated metabolites and a putative pathological SCZ mechanism is still missing.…”

Section: Discussionsupporting

confidence: 56%

Integrative metabolomics-genomics analysis identifies key networks in a stem cell-based model of schizophrenia.

Edenhofer

Spathopoulou

Fenkart

et al. 2022

Preprint

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Schizophrenia is a neuropsychiatric disorder, caused by a combination of genetic and environmental factors. Recently, metabolomic studies based on patients’ biofluids and post-mortem brain specimens have revealed altered levels of distinct metabolites between healthy individuals and patients with schizophrenia (SCZ). However, a putative link between dysregulated metabolites and distorted neurodevelopment has not been assessed and access to patients’ material is restricted. In this study, we aimed to investigate a presumed correlation between transcriptomics and metabolomics in a SCZ model using patient-derived induced pluripotent stem cells (iPSCs). iPSCs were differentiated towards cortical neurons and samples were collected longitudinally at defined developmental stages, such as neuroepithelium, radial glia, young and mature neurons. Samples were subsequently analyzed by bulk RNA-sequencing and targeted metabolomics. The transcriptomic analysis revealed dysregulations in several extracellular matrix-related genes in the SCZ samples observed in early neurogenesis, including members of the collagen superfamily. At the metabolic level, several lipid and amino acid discrepancies were correlated to the SCZ phenotype. By employing a novel in silico analysis, we correlated the transcriptome with the metabolome through the generation of integrative networks. The network comparison between SCZ and healthy controls revealed a number of consistently affected pathways in SCZ, related to early stages of cortical development, indicating abnormalities in membrane composition, lipid homeostasis and amino acid imbalances. Ultimately, our study suggests a novel approach of correlating in vitro metabolic and transcriptomic data obtained from a patient-derived iPSC model. This type of analysis will offer novel insights in cellular and genetic mechanisms underlying the pathogenesis of complex neuropsychiatric disorders, such as schizophrenia.

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Section: Discussionsupporting

confidence: 56%

Integrative metabolomics-genomics analysis identifies key networks in a stem cell-based model of schizophrenia.

Edenhofer

Spathopoulou

Fenkart

et al. 2022

Preprint

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“…Therefore, changes in lipids have been associated with the pathophysiology of schizophrenia. Specifically, alterations related to fatty acids and ketone bodies 55 , 56 , phospholipids 57 , 58 sphingolipids 59 , total lipids, triglycerides and cholesterol esters were observed in schizophrenia patients 60 – 62 .…”

Section: Resultsmentioning

confidence: 97%

“…Regarding antipsychotics, studies have suggested that these drugs may compensate for or reverse lipid pathway dysregulation related to the early stage of the disorder 55,59,63 . Furthermore, fatty acid metabolism and cholesterol biosynthesis have been identified by gene expression studies as key elements in antipsychotic treatment response 64,65 .…”

Section: Resultsmentioning

confidence: 99%

Ubiquitin–proteasome system, lipid metabolism and DNA damage repair are triggered by antipsychotic medication in human oligodendrocytes: implications in schizophrenia

Seabra

Almeida

Reis‐de‐Oliveira

et al. 2020

Sci Rep

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Schizophrenia is a chronic, severe and disabling psychiatric disorder, whose treatment is based on psychosocial interventions and the use of antipsychotic drugs. While the effects of these drugs are well elucidated in neuronal cells, they are still not so clear in oligodendrocytes, which play a vital role in schizophrenia. Thus, we aimed to characterize biochemical profiles by proteomic analyses of human oligodendrocytes (MO3.13) which were matured using a protocol we developed and treated with either haloperidol (a typical antipsychotic), clozapine (an atypical antipsychotic) or a clozapine + d-serine co-treatment, which has emerged lately as an alternative type of treatment. this was accomplished by employing shotgun proteomics, using nanoeSi-Lc-MS/MS labelfree quantitation. Proteomic analysis revealed biochemical pathways commonly affected by all tested antipsychotics were mainly associated to ubiquitination, proteasome degradation, lipid metabolism and DNA damage repair. Clozapine and haloperidol treatments also affected proteins involved with the actin cytoskeleton and with EIF2 signaling. In turn, metabolic processes, especially the metabolism of nitrogenous compounds, were a predominant target of modulation of clozapine + d-serine treatment. in this context, we seek to contribute to the understanding of the biochemical and molecular mechanisms involved in the action of antipsychotics on oligodendrocytes, along with their possible implications in schizophrenia. Abbreviations ACC Anterior cingulate cortex ACN Acetonitrile ACTB Beta-actin CNPase 2′,3′-Cyclic-nucleotide-3-phosphodiesterase COPS8 COP9 signalosome complex subunit 8 DIA Data-independent acquisition DLPFC Dorsolateral prefrontal cortex DMEM Dulbecco's modified eagle medium DTT Dithiothreitol eIF2 Eukaryotic initiation factor-2

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“…The applied two targeted methodologies (AbsoluteIDQ p180 and aTRAQ) have already been used in metabolomics research of cancer 36 , 37 , cardiometabolic diseases 38 , 39 , neuroscience 40 , pharmacology and toxicology 41 . It is the first time that such methods have been applied in venom analysis.…”

Section: Discussionmentioning

confidence: 99%

Identification and quantification of honeybee venom constituents by multiplatform metabolomics

Klupczynska

Plewa

Dereziński

et al. 2020

Sci Rep

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Honeybee (Apis mellifera) venom (HBV) has been a subject of extensive proteomics research; however, scarce information on its metabolite composition can be found in the literature. The aim of the study was to identify and quantify the metabolites present in HBV. To gain the highest metabolite coverage, three different mass spectrometry (MS)-based methodologies were applied. In the first step, untargeted metabolomics was used, which employed high-resolution, accurate-mass Orbitrap MS. It allowed obtaining a broad overview of HBV metabolic components. Then, two targeted metabolomics approaches, which employed triple quadrupole MS, were applied to quantify metabolites in HBV samples. The untargeted metabolomics not only confirmed the presence of amines, amino acids, carbohydrates, and organic acids in HBV, but also provided information on venom components from other metabolite classes (e.g., nucleosides, alcohols, purine and pyrimidine derivatives). The combination of three MS-based metabolomics platforms facilitated the identification of 214 metabolites in HBV samples, among which 138 were quantified. The obtaining of the wide free amino acid profiles of HBV is one of the project’s achievements. Our study contributed significantly to broadening the knowledge about HBV composition and should be continued to obtain the most comprehensive metabolite profile of HBV.

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Profiling of Lipidomics Before and After Antipsychotic Treatment in First-Episode Psychosis

Cited by 5 publications

References 0 publications

Integrative metabolomics-genomics analysis identifies key networks in a stem cell-based model of schizophrenia.

Integrative metabolomics-genomics analysis identifies key networks in a stem cell-based model of schizophrenia.

Ubiquitin–proteasome system, lipid metabolism and DNA damage repair are triggered by antipsychotic medication in human oligodendrocytes: implications in schizophrenia

Identification and quantification of honeybee venom constituents by multiplatform metabolomics

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