Acylcarnitine metabolomic profiles inform clinically-defined major depressive phenotypes

Ahmed, Ahmed T.; MahmoudianDehkordi, Siamak; Bhattacharyya, Sudeepa; Arnold, Matthias; Liu, Duan; Neavin, Drew; Moseley, M. Arthur; Thompson, J. Will; Williams, Lisa St. John; Louie, Gregory; Skime, Michelle; Wang, Liewei; Riva‐Posse, Patricio; McDonald, William M.; Bobo, William V.; Craighead, W. Edward; Krishnan, Ranga; Weinshilboum, Richard M.; Dunlop, Boadie W.; Millington, David S.; Rush, A. John; Frye, Mark A.; Kaddurah‐Daouk, Rima

doi:10.1016/j.jad.2019.11.122

Cited by 36 publications

(26 citation statements)

References 41 publications

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“…Acyl-carnitines were increased in both males and females with antidepressant-free rrMDD, and the major vitamins needed for fatty acid oxidation (riboflavin and FAD) were decreased. Disturbances in mitochondrial function leading to acyl-carnitine abnormalities have been observed in several other independent studies of MDD 66 . These findings support the hypothesis that even in remitted rMDD a shift in mitochondrial function exists and persists.…”

Section: Discussionsupporting

confidence: 55%

Metabolic features of recurrent major depressive disorder in remission, and the risk of future recurrence

Mocking

Naviaux

et al. 2021

Transl Psychiatry

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Recurrent major depressive disorder (rMDD) is a relapsing-remitting disease with high morbidity and a 5-year risk of recurrence of up to 80%. This was a prospective pilot study to examine the potential diagnostic and prognostic value of targeted plasma metabolomics in the care of patients with rMDD in remission. We used an established LC-MS/MS platform to measure 399 metabolites in 68 subjects with rMDD (n = 45 females and 23 males) in antidepressant-free remission and 59 age- and sex-matched controls (n = 40 females and 19 males). Patients were then followed prospectively for 2.5 years. Metabolomics explained up to 43% of the phenotypic variance. The strongest biomarkers were gender specific. 80% of the metabolic predictors of recurrence in both males and females belonged to 6 pathways: (1) phospholipids, (2) sphingomyelins, (3) glycosphingolipids, (4) eicosanoids, (5) microbiome, and (6) purines. These changes traced to altered mitochondrial regulation of cellular redox, signaling, energy, and lipid metabolism. Metabolomics identified a chemical endophenotype that could be used to stratify rrMDD patients at greatest risk for recurrence with an accuracy over 0.90 (95%CI = 0.69–1.0). Power calculations suggest that a validation study of at least 198 females and 198 males (99 cases and 99 controls each) will be needed to confirm these results. Although a small study, these results are the first to show the potential utility of metabolomics in assisting with the important clinical challenge of prospectively identifying the patients at greatest risk of recurrence of a depressive episode and those who are at lower risk.

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Section: Discussionsupporting

confidence: 55%

Metabolic features of recurrent major depressive disorder in remission, and the risk of future recurrence

Mocking

Naviaux

et al. 2021

Transl Psychiatry

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“…These biochemical differences are likely to contribute to the biological processes that underlie the variability in clinical presentations of MDD. Taken together, this and others’ work (Ahmed, MahmoudianDehkordi et al 2020, Liu, Yieh et al 2016, Alshehri, Mook-Kanamori et al 2021, Kunugi, Hori et al 2015) demonstrates the utility of using biochemistry for dissecting the heterogeneity of MDD.…”

Section: Discussionsupporting

confidence: 59%

“…Besides the phospholipids and the FFAs, several medium and long chain acylcarnitines such as C10:2, C14:2OH, C16 and C14:2 were also higher in more severely anxious patients, likely indicating disrupted beta-oxidation in the mitochondrial energy metabolism in these patients. We have previously reported a decrease in several medium and long chain acylcarnitines after SSRI treatment within the clinical subtype of anxiety in a separate MDD cohort (Ahmed, MahmoudianDehkordi et al 2020, MahmoudianDehkordi, Ahmed et al 2021), suggesting that the SSRI, Citalopram/Escitalopram treatment may restore beta-oxidation related mitochondrial dysfunction in clinically anxious MDD patients.…”

Section: Discussionmentioning

confidence: 90%

“…Blood-based metabolomic analyses, which measure the presence of small molecules (e.g., amino acids, lipids, organic acids) in the systemic circulation, body fluids and tissues, is a powerful emerging tool for parsing heterogeneous complex disorders. Previous work by our group and others have identified correlations between serum/plasma metabolomic profiles and clinically defined features of MDD including response to treatment (Kaddurah-Daouk, Bogdanov et al 2013, Bhattacharyya, Ahmed et al 2019, Ahmed, MahmoudianDehkordi et al 2020, MahmoudianDehkordi, Ahmed et al 2021). Prior work has focused primarily on metabolomic analyses conducted on a single analytic platform (Brydges et al, in submission).…”

Section: Introductionmentioning

confidence: 89%

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Metabolomic and Inflammatory Signatures of Symptom Dimensions in Major Depression

Brydges¹,

Bhattacharyya

Dehkordi

et al. 2021

Preprint

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Background: Major depressive disorder (MDD) is a highly heterogenous disease, both in terms of clinical profiles and pathobiological alterations. Recently, immunometabolic dysregulations were shown to be correlated with atypical, energy-related symptoms but less so with the Melancholic or Anxious distress symptom dimensions of depression in The Netherlands Study of Depression and Anxiety (NESDA) study. In this study, we aimed to replicate these immunometabolic associations and to characterize the metabolomic correlates of each of the three MDD dimensions. Methods: Using three clinical rating scales, Melancholic, and Anxious distress, and Immunometabolic (IMD) dimensions were characterized in 158 patients who participated in the Predictors of Remission to Individual and Combined Treatments (PReDICT) study and from whom plasma and serum samples were available. The NESDA-defined inflammatory index, a composite measure of interleukin-6 and C-reactive protein, was measured from pre-treatment plasma samples and a metabolomic profile was defined using serum samples analyzed on three metabolomics platforms targeting fatty acids and complex lipids, amino acids, acylcarnitines, and gut microbiome-derived metabolites among other metabolites of central metabolism. Results: The IMD clinical dimension and the inflammatory index were positively correlated (r=0.19, p=.019) after controlling for age, sex, and body mass index, whereas the Melancholic and Anxious distress dimensions were not, replicating the previous NESDA findings. The three symptom dimensions had distinct metabolomic signatures using both univariate and set enrichment statistics. IMD severity correlated mainly with gut-derived metabolites and a few acylcarnitines and long chain saturated free fatty acids. Melancholia severity was significantly correlated with several phosphatidylcholines, primarily the ether-linked variety, lysophosphatidylcholines, as well as several amino acids. Anxious distress severity correlated with several medium and long chain free fatty acids, both saturated and polyunsaturated ones, sphingomyelins, as well as several amino acids and bile acids. Conclusion: The IMD dimension of depression is reliably associated with markers of inflammation. Metabolomics provides powerful tools to inform about depression heterogeneity and molecular mechanisms related to clinical dimensions in MDD, which include a link to gut microbiome and lipids implicated in membrane structure and function.

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“…For example, long-chain polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA) are enriched in the brain and are critical for neurologic development, but are also essential nutrients dependent on dietary intake in humans and rodents ( 1 , 2 , 3 , 4 , 5 ). Furthermore, neurologic dysfunctions such as depression ( 6 ) and autism spectrum disorders ( 7 , 8 , 9 , 10 , 11 ) have been associated with altered lipid metabolism. People with genetic disorders in lipid metabolism can also suffer from neurologic impairments including encephalopathies, seizures, and cortical atrophy ( 12 , 13 , 14 ).…”

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confidence: 99%

The role of ethanolamine phosphate phospholyase in regulation of astrocyte lipid homeostasis

White

Ellis

Wolfgang

2021

Journal of Biological Chemistry

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Dietary lipid composition has been shown to impact brain morphology, brain development, and neurologic function. However, how diet uniquely regulates brain lipid homeostasis compared with lipid homeostasis in peripheral tissues remains largely uncharacterized. To evaluate the lipid response to dietary changes in the brain, we assessed actively translating mRNAs in astrocytes and neurons across multiple diets. From this data, ethanolamine phosphate phospholyase ( Etnppl ) was identified as an astrocyte-specific fasting-induced gene. Etnppl catabolizes phosphoethanolamine (PEtN), a prominent headgroup precursor in phosphatidylethanolamine (PE) also found in other classes of neurologically relevant lipid species. Altered Etnppl expression has also previously been associated with humans with mood disorders. We evaluated the relevance of Etnppl in maintaining brain lipid homeostasis by characterizing Etnppl across development and in coregulation with PEtN-relevant genes, as well as determining the impact to the brain lipidome after Etnppl loss. We found that Etnppl expression dramatically increased during a critical window of early brain development in mice and was also induced by glucocorticoids. Using a constitutive knockout of Etnppl (Etnppl KO ), we did not observe robust changes in expression of PEtN-related genes. However, loss of Etnppl altered the phospholipid profile in the brain, resulting in increased total abundance of PE and in polyunsaturated fatty acids within PE and phosphatidylcholine species in the brain. Together, these data suggest that brain phospholipids are regulated by the phospholyase action of the enzyme Etnppl, which is induced by dietary fasting in astrocytes.

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Acylcarnitine metabolomic profiles inform clinically-defined major depressive phenotypes

Cited by 36 publications

References 41 publications

Metabolic features of recurrent major depressive disorder in remission, and the risk of future recurrence

Metabolic features of recurrent major depressive disorder in remission, and the risk of future recurrence

Metabolomic and Inflammatory Signatures of Symptom Dimensions in Major Depression

The role of ethanolamine phosphate phospholyase in regulation of astrocyte lipid homeostasis

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