Abstract
Major depressive disorder (MDD) is a common and disabling syndrome with multiple etiologies that is defined by clinically elicited signs and symptoms. In hopes of developing a list of candidate biological measures that reflect and relate closely to the severity of depressive symptoms, so-called “state-dependent” biomarkers of depression, this pilot study explored the biochemical underpinnings of treatment response to cognitive behavior therapy (CBT) in medication-free MDD outpatients. Plasma samples were collected at baseline and week 12 from a subset of MDD patients (N = 26) who completed a course of CBT treatment as part of the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study. Targeted metabolomic profiling using the AbsoluteIDQ® p180 Kit and LC-MS identified eight “co-expressed” metabolomic modules. Of these eight, three were significantly associated with change in depressive symptoms over the course of the 12-weeks. Metabolites found to be most strongly correlated with change in depressive symptoms were branched chain amino acids, acylcarnitines, methionine sulfoxide, and α-aminoadipic acid (negative correlations with symptom change) as well as several lipids, particularly the phosphatidlylcholines (positive correlation). These results implicate disturbed bioenergetics as an important state marker in the pathobiology of MDD. Exploratory analyses contrasting remitters to CBT versus those who failed the treatment further suggest these metabolites may serve as mediators of recovery during CBT treatment. Larger studies examining metabolomic change patterns in patients treated with pharmacotherapy or psychotherapy will be necessary to elucidate the biological underpinnings of MDD and the -specific biologies of treatment response.
Highlights
Major depressive disorder (MDD) is a clinical syndrome that has multiple etiologies and responds to a diverse range of treatments that affect various biological pathways
One-hundred-fifteen patients were assigned to cognitive behavior therapy (CBT), of whom 26 had serum samples available for metabolomic analyses at baseline and week 12; these 26 patients are the subjects of the current analysis
Univariate analysis To define the association between changes in metabolite levels from baseline to week 12 of CBT treatment and the changes in depressive symptom of total HAM-D17 scores over that time, linear mixed effects models were fitted to each metabolite change, adjusting for age and gender and with subjects as a random variable
Summary
Major depressive disorder (MDD) is a clinical syndrome that has multiple etiologies and responds to a diverse range of treatments that affect various biological pathways. Plasma lipid and acylcarnitine profiles, which have been implicated in animal models of depression, suggest inflammatory conditions and incomplete mitochondrial β-oxidations as primary phenomena associated with the pathophysiology of MDD (Chen et al, 2014) This pilot study utilized a sample from the cognitive behavior therapy (CBT) arm of the Emory Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study, a randomized controlled trial of previously untreated patients with MDD (Dunlop et al, 2017a). This sample avoids the likely confounding effects of medications on endogenous metabolomic processes under study; i.e., the sample ensures that when patients improve symptomatically(or not), there is no confounding effect of concurrent antidepressant medication. We report observed metabolite alterations within a biomarker panel targeting 186 plasma metabolites from 5 distinct metabolite classes (amino acids, biogenic amines, acylcarnitines, glycerophospholipids, and sphingolipids) available in the Biocrates AbsoluteIDQ R p180 Kit
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