PHARMACOMETABOLOMICS IN BIPOLAR DISORDER

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1 PHARMACOMETABOLOMICS IN BIPOLAR DISORDER V I C K I L. E L L I N G R O D, P H A R M. D., F C C P J O H N G I D E O N S E A R L E P R O F E S S O R O F C L I N I C A L A N D T R A N S L AT I O N A L P H A R M A C Y U N I V E R S I T Y O F M I C H I G A N C O L L E G E O F P H A R M A C Y, D E P A R T M E N T O F C L I N I C A L S C I E N C E S, A N D S C H O O L O F M E D I C I N E, D E P A R T M E N T O F P S Y C H I AT R Y

2 ACKNOWLEDGEMENTS University of Michigan College of Pharmacy Zarina Kraal, MS Ryan Dougherty, BS Kristen Weise, PharmD Stephanie Flowers, PharmD, PhD Michael Bly, PhD Kathleen Stringer, PharmD University of Michigan College of Literature Arts and Science/Psychology Tyler B. Grove, BS, PhD candidate University of Michigan School of Medicine Stephan F. Taylor, MD - Psychiatry Melvin McInnis, MD Psychiatry Gregory Dalack, MD Psychiatry Robert Brook, MD. Cardiology Simon Evans, PhD - Psychiatry Sebastian Zöllner, PhD Public Health Rodica Pop-Busui, MD - MEND Michigan Clinical Research Unit (MCRU) Michigan Diabetes Research and Treatment Center (MDRTC) Michigan Institute for Clinical and Health Research (MICHR) Wayne State University College of Pharmacy Kyle J. Burghardt, Pharm.D.

3 GRANT SUPPORT NO conflicts to disclose This project was supported by: NIMH (K08MH and R01 MH082784) NIH-NCCR, GCRC/CTSA Program (UL1RR024986) Chemistry Core of the Michigan Diabetes Research and Training Center (NIH5P60 DK 20572) University of Michigan College of Pharmacy Vahlteich Award Washtenaw Community Health Organization (WCHO), the Ann Arbor Veterans Affairs Medical Center, and the Detroit-Wayne County Community Mental Health Agency (DWCCMHA). National Alliance for Research In Schizophrenia and Depression (NARSAD) Prechter Longitudinal Study and the Depression Center

4 INVESTIGATING ATYPICAL ANTIPSYCHOTIC SIDE EFFECTS

5 METABOLOMICS BACKGROUND Metabolomics aims to identify all the small molecules in a cell Uses a combination of resolution strategies GC Mass Spec or NMR Two approaches Targeted vs. untargeted Yields large amounts of data from a very small sample Facilitates bioinformatic approaches to understanding disease and treatment Important tool in personalized medicine research - discover new metabolites or sets of metabolites associated with treatment response or side effects Adapted from:

6 METABOLOMICS SPECIFIC AIM Metabolomics Study To identify significant metabolites in bipolar patients on atypical antipsychotics compared to bipolar patients on lithium monotherapy

7 METABOLOMICS SUBJECTS AND METHODS Inclusion Criteria DSM-IV diagnosis of bipolar I disorder Between the ages of years Currently symptom stable with no medication changes in the past 6 months Subjects were seen in the clinic research unit and fasted for 8 hours prior to study visit After informed consent was obtained, subjects underwent the following procedures Laboratory measures and metabolic syndrome screening Medication history interview Blood draw for metabolomic assessment

8 METABOLOMICS SUBJECT DEMOGRAPHICS Total Bipolar I Subjects (N=81) Subjects on Atypical Antipsychotic (N=49) Subjects on Lithium Monotherapy (N=32) Age (years) 45.4 ± ± 12.2 % Female % Caucasian % With Metabolic Syndrome Poster Presentation: American College of Neuropsychopharmacology December 2013

9 METABOLOMICS METHODS All serum samples taken within 3 hours of subject s normal waking time and processed within 30 minutes of the draw Used hydrophilic interaction chromatography (HILIC)- and Reversed phase based LC/MS technology in an untargeted approach on fasting serum samples Gives putative metabolite identifications and relative abundance Set of radiolabeled standards where ran with each sample for quality control All samples ran on the same day Data was normalized using radiolabeled standards and analyzed with multivariate approaches using R statistical software packages based on atypical antipsychotic use Group 1: BP subjects on atypical antipsychotics Group 2: BP subjects on lithium monotherapy

10 ANALYSIS Metabolic Signature were determined using a Partial Least Squared Discriminate Analysis (PLS-DA) plot. multivariate, supervised method that attempts to describe the overall metabolite differences (X) between subject groups (Y) To assess statistical significance, a permutation test was performed using the ratio of the between sum of the squares and the within sum of squares (B/W-ratio) for the class assignment prediction of each model was calculated. There are two variable importance measures in PLS-DA. Variable Importance in Projection (VIP) is a weighted sum of squares of the PLS loadings taking into account the amount of explained Y-variation in each dimension. The coefficient-based importance measure is based on weighted sum of the absolute regression coefficients.

11 METABOLOMICS RESULTS 415 named metabolites R2=0.75, Q2=0.3, Accuracy =0.78

12 Poster Presentation: American college of Neuropsychopharmacology December 2013 METABOLOMICS RESULTS Insulin resistance RNA metabolism Lipid metabolism Energy & fuel Cellular signaling Phthalates Tryptophan metabolism

13 Metabolomics Results Retinal is the oxidized form of Retinol and it was the highest in the bipolar subjects on atypical antipsychotics (Fishers Post-hoc tests P=0.007)

14 RETINOL AND INSULIN RESISTANCE Mechanisms linking obesity with cardiovascular disease. Luc F. Van Gaal, Ilse L. Mertens and Christophe E. De Block. Nature 444, (14 December 2006) doi: /nature05487

15 METABOLOMICS: SUMMARY The metabolomic profiles of bipolar subjects on atypical antipsychotics are different compared to bipolar subjects only on lithium A metabolite associated with insulin resistance pathway identified Future directions Verify putative metabolites of interest Use untargeted metabolomic findings to conduct a targeted metabolomic studies looking at metabolites or pathways of interest Combine metabolomics findings with pharmacogenomic and pharmcoepigenetic findings, as well as with diet and metabolic measures on subjects. Expand work with schizophrenia patients

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