Summary of Study ST001097

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000734. The data can be accessed directly via it's Project DOI: 10.21228/M8SX1Q This work is supported by NIH grant, U2C- DK119886.

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Study IDST001097
Study TitleMetabolomics of Metabolic Risk in Patients Taking Atypical Antipsychotics (part I)
Study TypeQuantitative NMR and TLC-GC fatty acid analysis
Study SummarySTUDY OBJECTIVE Patients with schizophrenia are known to have higher rates of metabolic disease than the general population. Contributing factors likely include lifestyle and atypical antipsychotic (AAP) use, but the underlying mechanisms are unknown. The objective of this study was to identify metabolomic variability in adult patients with schizophrenia who were taking AAPs and grouped by fasting insulin concentration, our surrogate marker for metabolic risk. DESIGN Metabolomics analysis. PARTICIPANTS Ninety-four adult patients with schizophrenia who were taking an AAP for at least 6 months, with no changes in their antipsychotic regimen for the previous 8 weeks, and who did not require treatment with insulin. Twenty age- and sex-matched nonobese (10 subjects) and obese (10 subjects) controls without cardiovascular disease or mental health diagnoses were used to match the body mass index range of the patients with schizophrenia to account for metabolite concentration differences attributable to body mass index. MEASUREMENTS AND MAIN RESULTS Existing serum samples were used to identify aqueous metabolites (to differentiate fasting insulin concentration quartiles) and fatty acids with quantitative nuclear magnetic resonance (NMR) and gas chromatography (GC) methods, respectively. To exclude metabolites from our pathway mapping analysis that were due to variability in weight, we also subjected serum samples from the nonobese and obese controls to the same analyses. Patients with schizophrenia had a median age of 47.0 (interquartile range 41.0-52.0) years. Using a false discovery rate threshold of <25%, 10 metabolites, not attributable to weight, differentiated insulin concentration quartiles in patients with schizophrenia and identified variability in one-carbon metabolism between groups. Patients with higher fasting insulin concentrations (quartiles 3 and 4) also trended toward having higher levels of saturated fatty acids compared with patients with lower fasting insulin concentrations (quartiles 1 and 2). CONCLUSION These results illustrate the utility of metabolomics to identify pathways underlying variable fasting insulin concentration in patients with schizophrenia. Importantly, no significant difference in AAP exposure was observed among groups, suggesting that current antipsychotic use may not be a primary factor that differentiates middle-aged adult patients with schizophrenia by fasting insulin concentration. This article is protected by copyright. All rights reserved. As published in Pharmacotherapy. 2018 Jun;38(6):638-650.
Institute
University of Michigan
DepartmentClinical Pharmacy
LaboratoryUniversity of Michigan NMR Metabolomics Core
Last NameStringer
First NameKathleen
Address428 Church St
EmailNMRmetabolomics@umich.edu
Phone734/647-4775
Submit Date2018-08-30
Analysis Type DetailNMR
Release Date2019-01-22
Release Version1
Kathleen Stringer Kathleen Stringer
https://dx.doi.org/10.21228/M8SX1Q
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Project:

Project ID:PR000734
Project DOI:doi: 10.21228/M8SX1Q
Project Title:Metabolomics of Metabolic Risk in Patients Taking Atypical Antipsychotics
Project Type:Quantitative NMR and TLC-GC fatty acid analysis
Project Summary:STUDY OBJECTIVE Patients with schizophrenia are known to have higher rates of metabolic disease than the general population. Contributing factors likely include lifestyle and atypical antipsychotic (AAP) use, but the underlying mechanisms are unknown. The objective of this study was to identify metabolomic variability in adult patients with schizophrenia who were taking AAPs and grouped by fasting insulin concentration, our surrogate marker for metabolic risk. DESIGN Metabolomics analysis. PARTICIPANTS Ninety-four adult patients with schizophrenia who were taking an AAP for at least 6 months, with no changes in their antipsychotic regimen for the previous 8 weeks, and who did not require treatment with insulin. Twenty age- and sex-matched nonobese (10 subjects) and obese (10 subjects) controls without cardiovascular disease or mental health diagnoses were used to match the body mass index range of the patients with schizophrenia to account for metabolite concentration differences attributable to body mass index. MEASUREMENTS AND MAIN RESULTS Existing serum samples were used to identify aqueous metabolites (to differentiate fasting insulin concentration quartiles) and fatty acids with quantitative nuclear magnetic resonance (NMR) and gas chromatography (GC) methods, respectively. To exclude metabolites from our pathway mapping analysis that were due to variability in weight, we also subjected serum samples from the nonobese and obese controls to the same analyses. Patients with schizophrenia had a median age of 47.0 (interquartile range 41.0-52.0) years. Using a false discovery rate threshold of <25%, 10 metabolites, not attributable to weight, differentiated insulin concentration quartiles in patients with schizophrenia and identified variability in one-carbon metabolism between groups. Patients with higher fasting insulin concentrations (quartiles 3 and 4) also trended toward having higher levels of saturated fatty acids compared with patients with lower fasting insulin concentrations (quartiles 1 and 2). CONCLUSION These results illustrate the utility of metabolomics to identify pathways underlying variable fasting insulin concentration in patients with schizophrenia. Importantly, no significant difference in AAP exposure was observed among groups, suggesting that current antipsychotic use may not be a primary factor that differentiates middle-aged adult patients with schizophrenia by fasting insulin concentration. This article is protected by copyright. All rights reserved. As published in Pharmacotherapy. 2018 Jun;38(6):638-650.
Institute:University of Michigan
Department:Clinical Pharmacy
Laboratory:University of Michigan NMR Metabolomics Core
Last Name:Stringer
First Name:Kathleen
Address:428 Church St
Email:NMRmetabolomics@umich.edu
Phone:734-647-4775
Funding Source:Funding for this work was supported in part by grants from the following centers: the University of Michigan Claude D. Pepper Older Americans Independence Center (National Institute on Aging [NIA] grantAGA024824); the University of Michigan’s Nutrition Obesity Research Center (grant DK089503) and Weight Management Program, and the Michigan Regional Comprehensive Metabolomics Resource Core (grant DK097153),the Michigan Center for Diabetes Translational Research(grant P30DK092926), and the A. Alfred Taubman Medical Institute and the Robert C. and Veronica Atkins Foundation. This work was also supported in part by a metabolomics supplement to a grant from the National Institute of Mental Health (NIMH; grant MH082784; Dr. Ellingrod).Dr. Stringer’s effort is supported in part by a grant from the National Institute of General Medical Sciences (NIGMS; grant GM111400). Dr. Rothberg’s effort is supported in part by DK089503.
Publications:Pharmacotherapy. 2018 Jun;38(6):638-650

Subject:

Subject ID:SU001141
Subject Type:Human
Subject Species:Homo sapiens
Taxonomy ID:9606
Age Or Age Range:30-60 years old
Weight Or Weight Range:52.3-176.6 kg
Gender:Male and female
Human Medications:To be included in the study all participants had to be taking an atypical (second generation) antipsychotic
Human Inclusion Criteria:DSM IV diagnosis of a schizophrenia spectrum diagnosis who had been taking an atypical antipsychotic for at least 6 months, with no changes in antipsychotic regimen for 8 weeks preceding the baseline visit. Twenty age and sex matched obese and nonobese participants without mental health diagnoses were included to match the BMI range of the patients with schizophrenia as BMI controls.
Human Exclusion Criteria:Current use of insulin, diagnosis of diabetes mellitus type 2 prior to antipsychotic exposure, active substance abuse diagnosis

Factors:

Subject type: Human; Subject species: Homo sapiens (Factor headings shown in green)

mb_sample_id local_sample_id Treatment
SA074768CCMB_17Non-obese control
SA074769CCMB_15Non-obese control
SA074770CCMB_05Non-obese control
SA074771CCMB_19Non-obese control
SA074772P2721_27Non-obese control
SA074773P2721_40Non-obese control
SA074774P2721_28Non-obese control
SA074775CCMB_04Non-obese control
SA074776P2721_23Non-obese control
SA074777P2721_22Non-obese control
SA074778Q077Obese control
SA074779Q025Obese control
SA074780Q897Obese control
SA074781Q005Obese control
SA074782Q308Obese control
SA074783Q160Obese control
SA074784Q442Obese control
SA074785Q632Obese control
SA074786Q504Obese control
SA074787Q610Obese control
SA074788V158Schizophrenia dx
SA074789V156Schizophrenia dx
SA074790V154Schizophrenia dx
SA074791V163Schizophrenia dx
SA074792V151Schizophrenia dx
SA074793V179Schizophrenia dx
SA074794V149Schizophrenia dx
SA074795V174Schizophrenia dx
SA074796V172Schizophrenia dx
SA074797V169Schizophrenia dx
SA074798V165Schizophrenia dx
SA074799V133Schizophrenia dx
SA074800V138Schizophrenia dx
SA074801V135Schizophrenia dx
SA074802V134Schizophrenia dx
SA074803V183Schizophrenia dx
SA074804V139Schizophrenia dx
SA074805V142Schizophrenia dx
SA074806V147Schizophrenia dx
SA074807V146Schizophrenia dx
SA074808V144Schizophrenia dx
SA074809V148Schizophrenia dx
SA074810V214Schizophrenia dx
SA074811V225Schizophrenia dx
SA074812V224Schizophrenia dx
SA074813V223Schizophrenia dx
SA074814V221Schizophrenia dx
SA074815V228Schizophrenia dx
SA074816V232Schizophrenia dx
SA074817V252Schizophrenia dx
SA074818V250Schizophrenia dx
SA074819V249Schizophrenia dx
SA074820V241Schizophrenia dx
SA074821V216Schizophrenia dx
SA074822V215Schizophrenia dx
SA074823V194Schizophrenia dx
SA074824V193Schizophrenia dx
SA074825V191Schizophrenia dx
SA074826V190Schizophrenia dx
SA074827V198Schizophrenia dx
SA074828V202Schizophrenia dx
SA074829V131Schizophrenia dx
SA074830V212Schizophrenia dx
SA074831V209Schizophrenia dx
SA074832V205Schizophrenia dx
SA074833V187Schizophrenia dx
SA074834V092Schizophrenia dx
SA074835V033Schizophrenia dx
SA074836V032Schizophrenia dx
SA074837V029Schizophrenia dx
SA074838V023Schizophrenia dx
SA074839V034Schizophrenia dx
SA074840V035Schizophrenia dx
SA074841V046Schizophrenia dx
SA074842V045Schizophrenia dx
SA074843V041Schizophrenia dx
SA074844V037Schizophrenia dx
SA074845V019Schizophrenia dx
SA074846V018Schizophrenia dx
SA074847V008Schizophrenia dx
SA074848V004Schizophrenia dx
SA074849V003Schizophrenia dx
SA074850V001Schizophrenia dx
SA074851V009Schizophrenia dx
SA074852V011Schizophrenia dx
SA074853V015Schizophrenia dx
SA074854V014Schizophrenia dx
SA074855V013Schizophrenia dx
SA074856V012Schizophrenia dx
SA074857V047Schizophrenia dx
SA074858V048Schizophrenia dx
SA074859V100Schizophrenia dx
SA074860V097Schizophrenia dx
SA074861V094Schizophrenia dx
SA074862V089Schizophrenia dx
SA074863V110Schizophrenia dx
SA074864V115Schizophrenia dx
SA074865V126Schizophrenia dx
SA074866V123Schizophrenia dx
SA074867V118Schizophrenia dx
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Collection:

Collection ID:CO001135
Collection Summary:Fasting blood samples were collected via venipuncture into an additive-free vial and allowed to coagulate at room temperature for 30 minutes. They were then centrifuged for 15 minutes at 2500 rcf to obtain serum. Samples were frozen at -80C, thawed once for sample processing related to parent study, then kept at -80C until processing for NMR and TLC-GC assays.
Sample Type:Blood (serum)
Storage Conditions:-80℃
Collection Vials:Additive-free vacutainer

Treatment:

Treatment ID:TR001155
Treatment Summary:N/A: this was an observational study

Sample Preparation:

Sampleprep ID:SP001148
Sampleprep Summary:Serum samples were subjected to a 1:1 methanol:chloroform extraction, then lyophilized. Prior to NMR the aqueous fraction samples were resuspended and filtered. Prior to fatty acid analysis the lipid fractions were resuspended and purified by TLC prior to GC analysis. This is described in more detail in the attached document.
Sampleprep Protocol ID:EllingrodSamplePrepProtocol
Processing Method:methanol:chloroform extraction, filtration
Processing Storage Conditions:4?
Extraction Method:methanol:chloroform
Extract Enrichment:ultra-filtration (3kDa filters) to remove residual protein
Extract Cleanup:N/A
Extract Storage:-80?
Sample Resuspension:500uL deuterium oxide for aqueous fraction, lipid fraction was resuspended in hexane prior to GC analysis
Sample Spiking:aqueous fraction: CaFormate 12mM, lipid faction: C17:0 methyl ester

Analysis:

Analysis ID:AN001785
Analysis Type:NMR
Num Factors:3
Num Metabolites:38
Units:uM

NMR:

NMR ID:NM000135
Analysis ID:AN001785
Instrument Name:Agilent 500/54 Premium Shielded
Instrument Type:FT-NMR
NMR Experiment Type:1D 1H
Spectrometer Frequency:500 MHz
NMR Probe:ONE-Probe
NMR Solvent:D2O
NMR Tube Size:5mm
Shimming Method:Auto shim (gradient shimming)
Pulse Sequence:1D-NOESY
Water Suppression:saturation at 80 Hz induced field strength
Pulse Width:5.5ms
Offset Frequency:around -178Hz
Chemical Shift Ref Cpd:Formate
Temperature:25
Number Of Scans:32
Baseline Correction Method:manual
Chemical Shift Ref Std:Calcium formate
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