Acylcarnitine Metabolomic Profiles Inform Clinically-Defined Major Depressive Phenotypes

Abstract

Edward Craighead, PhD provided funding to treat non-remitters to the first treatment with combination medication and psychotherapy, to allow follow-up of patients for up to two years to identify predictors of recurrence, and to add patients to the sample to adequately power these studies. Additional support was received from PHS Grant UL1 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+))-following treatment with a selective serotonin reuptake inhibitor (SSRI). 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 eight weeks post-treatment were profiled for multiple-, short-, medium-and longchain acylcarnitine levels using AbsoluteIDQ®p180-Kit and LC-MS. Linear mixed effects models were used to examine whether acylcarnitine levels discriminate the clinical phenotypes at baseline or eight weeks post-treatment, and whether temporal changes in acylcarnitine profiles differ between groups. Results: At baseline, significantly lower concentrations of short-and long-chain acylcarnitines were found in CD+ and NVSM+ compared to ANX+, and the shortchain acylcarnitines remained lower after eight weeks. At eight weeks, the medium-and longchain acylcarnitines were significantly lower in NVSM+ compared to ANX+. Regarding changes baseline to week eight, short-chain acylcarnitine levels significantly increased in CD+ and ANX+, and medium-and long-chain acylcarnitines significantly decreased in NVSM+ and CD+. 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. 7

Integrative metabolomics‐genomics approach reveals key metabolic pathways and regulators of Alzheimer's disease

“…We may conclude TA B L E 1 Pearson correlation analysis of the top three modules (including acylcarnitines and amino acids) and the blood gene expression data in Alzheimer that CPT1A-dependent regulation of acylcarnitine transfer may control the levels of C12, C14.1, C14.2, and C16 as well as C18 in the plasma during disease progression. Acylcarnitine levels with mitochondrial fatty acid β-oxidation significantly increases in patients with major depression because of the metabolic dysfunction, 49 and the association of medium/long-chain acylcarnitines with AD revealed by this study shows the same notion. Anti-depressants that decrease acylcarnitine levels in major depression patients might be considered a potential treatment for AD patients.…”

“…Besides the opposite connection between obesity and type 2 diabetes, elevated medium/longchain acylcarnitines in plasma are associated with the disruption of βoxidation in depression. 48,49…”

“…Because previous studies showed increased use of branched amino acids is associated with type 2 diabetes and mitochondrial dysfunction is common in diabetes, 46,47 the association of BCAAs with AD revealed by this study opposite to this notion. Besides the opposite connection between obesity and type 2 diabetes, elevated medium/long‐chain acylcarnitines in plasma are associated with the disruption of β‐oxidation in depression 48,49 …”

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

“…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.…”

Genomics-based identification of a potential causal role for acylcarnitine metabolism in depression

“…A recent metabolomics study (13) on >1,000 subjects identified lower levels of the medium-chain acylcarnitines decanoylcarnitine (C10) and dodecanoylcarnitine/laurylcarnitine (C12) in participants with elevated depressive symptoms as compared to controls. Furthermore, ACs profiles have been shown to correlate with depression severity and variation in response to treatment with SSRIs and Ketamine (14)(15)(16).…”