Pilot Study of Metabolomic Clusters as State Markers of Major Depression and Outcomes to CBT Treatment.
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2019-01
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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.
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Bhattacharyya, Sudeepa, Boadie W Dunlop, Siamak Mahmoudiandehkordi, Ahmed T Ahmed, Gregory Louie, Mark A Frye, Richard M Weinshilboum, Ranga R Krishnan, et al. (2019). Pilot Study of Metabolomic Clusters as State Markers of Major Depression and Outcomes to CBT Treatment. Frontiers in neuroscience, 13. p. 926. 10.3389/fnins.2019.00926 Retrieved from https://hdl.handle.net/10161/24807.
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K. Ranga Rama Krishnan
I have validated in vivo methods of estimating volumes of subcortical structures utilizing MRI and sterology. These studies have suggested that depressed patients have smaller caudate, smaller putamen, altered water balance in the hippocampus, a smaller medulla and cerebellar vermis, and enlarged ventricles. Our group has demonstrated that late-life depression patients have increased MRI lesions in the fronto-parietal white matter and subcortical gray; and, have lesions in the caudate increase the risk of delirium with ECT and antidepressants. In the last year, we have developed high resolution MR proton spectroscopy methods to measure the concentration of a variety of physico-chemical moieties, including choline, lactic acid, water, glucose, N-acetylaspartate and glutamate in volumes of < one ml. We are utilizing this technique to study affective disorder, Alzheimer's disease and social phobia and the effect of psychotropic medications on these parameters. In an initial study, a state dependent increase in choline in depressed patients has been demonstrated; and, in Alzheimer's disease, a reduction in N-acetyl asparatate and an increase in Inositol which progresses as the disease advances. In addition, we are examining the relationship between fluoxetine concentrations in the brain using MRS and therapeutic efficacy. We currently use MR methods to assess drug efficacy in various disorders and in the development of new drugs. We have developed protocols to compare drugs developed for Alzheimer's disease based on their known effects on MRS parameters in dogs.
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