Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Mar 1:264:90-97.
doi: 10.1016/j.jad.2019.11.122. Epub 2019 Nov 30.

Acylcarnitine metabolomic profiles inform clinically-defined major depressive phenotypes

Ahmed T Ahmed  1 , Siamak MahmoudianDehkordi  2 , Sudeepa Bhattacharyya  3 , Matthias Arnold  4 , Duan Liu  5 , Drew Neavin  6 , M Arthur Moseley  7 , J Will Thompson  8 , Lisa St John Williams  9 , Gregory Louie  10 , Michelle K Skime  11 , Liewei Wang  12 , Patricio Riva-Posse  13 , William M McDonald  14 , William V Bobo  15 , W Edward Craighead  16 , Ranga Krishnan  17 , Richard M Weinshilboum  18 , Boadie W Dunlop  19 , David S Millington  20 , A John Rush  21 , Mark A Frye  22 , Rima Kaddurah-Daouk  23 ; Mood Disorders Precision Medicine Consortium (MDPMC)
Affiliations

Acylcarnitine metabolomic profiles inform clinically-defined major depressive phenotypes

Ahmed T Ahmed et al. J Affect Disord. .

Abstract

Background: Acylcarnitines have important functions in mitochondrial energetics and β-oxidation, and have been implicated to play a significant role in metabolic functions of the brain. This retrospective study examined whether plasma acylcarnitine profiles can help biochemically distinguish the three phenotypic subtypes of major depressive disorder (MDD): core depression (CD+), anxious depression (ANX+), and neurovegetative symptoms of melancholia (NVSM+).

Methods: Depressed outpatients (n = 240) from the Mayo Clinic Pharmacogenomics Research Network were treated with citalopram or escitalopram for eight weeks. Plasma samples collected at baseline and after eight weeks of treatment with citalopram or escitalopram were profiled for short-, medium- and long-chain acylcarnitine levels using AbsoluteIDQ®p180-Kit and LC-MS. Linear mixed effects models were used to examine whether acylcarnitine levels discriminated the clinical phenotypes at baseline or eight weeks post-treatment, and whether temporal changes in acylcarnitine profiles differed between groups.

Results: Compared to ANX+, CD+ and NVSM+ had significantly lower concentrations of short- and long-chain acylcarnitines at both baseline and week 8. In NVSM+, the medium- and long-chain acylcarnitines were also significantly lower in NVSM+ compared to ANX+. Short-chain acylcarnitine levels increased significantly from baseline to week 8 in CD+ and ANX+, whereas medium- and long-chain acylcarnitines significantly decreased in CD+ and NVSM+.

Conclusions: In depressed patients treated with SSRIs, β-oxidation and mitochondrial energetics as evaluated by levels and changes in acylcarnitines may provide the biochemical basis of the clinical heterogeneity of MDD, especially when combined with clinical characteristics.

Keywords: Acylcarnitines; Antidepressants; Depression; Metabolomics; P180; Phenotypes.

PubMed Disclaimer

Conflict of interest statement

Declaration of Competing Interest Richard Weinshilboum is a co-founder and stockholder in OneOme, LLC, a pharmacogenomic clinical decision support company. Dr. Kaddurah-Daouk is an inventor on patents related to metabolomics applications in the study of CNS diseases and holds equity in Metabolon, Inc., a biotechnology company that provides metabolic profiling capabilities. Dr. A. John Rush has received: consulting fees from Akili, Brain Resource Inc., Compass Inc., Curbstone Consultant LLC., Emmes Corp., Johnson and Johnson (Janssen), Liva-Nova, Mind Linc., Sunovion; speaking fees from Janssen and Liva-Nova; and royalties from Guilford Press and the University of Texas Southwestern Medical Center, Dallas, TX (for the Inventory of Depressive Symptoms and its derivatives). Dr. Rush is also named co-inventor on two patents: U.S. Patent No. 7795,033: Methods to Predict the Outcome of Treatment with Antidepressant Medication and U.S. Patent No. 7906,283: Methods to Identify Patients at Risk of Developing Adverse Events During Treatment with Antidepressant Medication. Drew Neavin's stipend has been supported in part by NIH T32 GM072474 and the Mayo Graduate School. Ahmed Ahmed's research was supported by National Institute of General Medical Sciences of the National Institutes of Health under award number T32 GM008685. Dr. Matthias Arnold was supported by National Institute on Aging [R01AG057452, RF1AG051550, R01AG046171], National Institute of Mental Health [R01MH108348], and Qatar National Research Fund [NPRP8-061–3–011]. The funders listed above had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. Dr. Dunlop has received research support from Acadia, Axsome, Janssen, Takeda and he serves as a consultant to Assurex Health and Aptinyx Inc. dr. Craighead is a board member of Hugarheill ehf, an Icelandic company dedicated to the prevention of depression, and he receives book royalties from John Wiley & Sons; his research is also supported by the Mary and John Brock Foundation and the Fuqua family foundations; he is a consultant to the George West Mental Health Foundation and is a member of the scientific advisory boards of the AIM for Mental Health Foundation and the Anxiety Disorders Association of America. dr. Bobo's research has been supported by the NIMH, AHRQ, Mayo Foundation for Medical Education and Research; he has contributed chapters to UpToDate on the treatment of bipolar disorders. Additional support was received from PHS Grant UL1 RR025008 from the Clinical and Translational Science Award program, National Institutes of Health, National Center for Research Resources, PHS Grant M01 RR0039 from the General Clinical Research Center program, and K23 MH086690 (BWD).

Figures

Figure 1.
Figure 1.. Venn Diagram of the Overlap between Positive MDD Phenotype [Core Depression (CD+), Neurovegetative Symptoms of Melancholia (NVSM+), and Anxiety (ANX+)].
Circles represent the group in each phenotype (CD+, NVSM+, and ANX+). The numbers inside overlapping circles represent participants who met criteria for two, or all three, of the phenotypes. The total number of participants with each pure phenotype was CD+ (n=31), NVSM+ (n=17) and ANX+ (n=44).
Figure 2:
Figure 2:. Short-, Medium- & Long-Chain Acylcarnitines ─ Baseline and 8 Weeks Stratified by Phenotype (+).
These plots show the baseline and week-eight acylcarnitine metabolite concentrations for each of the three phenotypes (CD+: Core Depression, ANX+: Anxiety, NVSM+: Neurovegetative Symptom of Melancholia). Asterisks indicate statistical significance of mean differences between the two groups (unadjusted p<0.05) at each visit. Error bars represent standard error of the means. P-values were obtained from linear mixed effect models corrected for age, sex, drug and 17-item Hamilton Rating Scale for Depression scores.
Figure 3.
Figure 3.. Metabolic Signature of Eight Weeks of Exposure to SSRI.
The heatmap depicts the log2 fold change of metabolite levels from baseline to week eight of SSRI treatment. CD+: Core Depression, ANX+: Anxiety, NVSM+: Neurovegetative Symptom of Melancholia. P-values were obtained using linear mixed effect models controlling for age, sex and baseline 17-item Hamilton Rating Scale for Depression scores. Red indicates an increase and blue indicates a decrease in metabolite levels over eight weeks of treatment; *:p-value<0.05, **:p-value<0.01 and ***:p-value<0.001.
See this image and copyright information in PMC

References

    1. John Rush A, Hicham M. Ibrahim, 2018. A Clinician’s Perspective on Biomarkers. FOCUS 16, 124–134. - PMC - PubMed
    1. Ahmed AT, Frye MA, Rush AJ, Biernacka JM, Craighead WE, McDonald WM, Bobo WV, Riva-Posse P, Tye SJ, Mayberg HS, Hall-Flavin DK, Skime MK, Jenkins GD, Wang L, Krishnan RR, Weinshilboum RM, Kaddurah-Daouk R, Dunlop BW, 2018. Mapping depression rating scale phenotypes onto research domain criteria (RDoC) to inform biological research in mood disorders. Journal of affective disorders 238, 1–7. - PMC - PubMed
    1. Baranyi A, Meinitzer A, Rothenhäusler H-B, Amouzadeh-Ghadikolai O, Lewinski DV, Breitenecker RJ, Herrmann M, 2018. Metabolomics approach in the investigation of depression biomarkers in pharmacologically induced immune-related depression. PloS one 13, e0208238–e0208238. - PMC - PubMed
    1. Beasley CL, Pennington K, Behan A, Wait R, Dunn MJ, Cotter D, 2006. Proteomic analysis of the anterior cingulate cortex in the major psychiatric disorders: Evidence for disease-associated changes. Proteomics 6, 3414–3425. - PubMed
    1. Bresolin N, Freddo L, Vergani L, Angelini C, 1982. Carnitine, carnitine acyltransferases, and rat brain function. Experimental Neurology 78, 285–292. - PubMed

Publication types