Pilot Study of Metabolomic Clusters as State Markers of Major Depression and Outcomes to CBT Treatment

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.

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

“…Recently, a targeted metabolomic study focusing on neurotransmitters and their metabolites in plasma, found a biochemical signature that could diagnose MDD-patients with up to 95% accuracy 13 , 14 . Moreover, metabolomics may predict MDD-recovery 15 , and response to therapy 16 , 17 . However, similar studies of biochemical signatures of remitted rMDD (rrMDD), with prospective follow-up to identify subjects at increased risk of future recurrence have not yet been conducted.…”

Metabolomic Biomarkers in Anxiety Disorders

“…There is also a lack of research on whether metabolomic biomarkers can predict or moderate treatment response to anxiolytic medication and psychotherapy. However, in major depressive disorders, for instance, studies indicate predictive potential of the pretreatment metabolomics profile of the response to antidepressant medication [135], and also one pilot psychotherapy study revealed that several plasma metabolites might serve as moderators of the outcome of psychotherapy [136]. Future studies should also explore metabolomics changes in anxiety due to psychotherapy treatment, which might also help to understand better the mechanistic underpinnings of the effect of psychotherapy on symptom change and whether these changes are associated with metabolomics alterations.…”

Multi-Omics Characterization of Early- and Adult-Onset Major Depressive Disorder

“…This assay is not exhaustive of all potential metabolite correlates of early onset depression, and it does not measure several metabolites which are well-studied in psychiatry (i.e., dopamine, GABA). However, these analytes have enhanced our understanding of the biology of MDD [ 20 , 50 , 51 , 52 ], schizophrenia [ 53 ], and psychosis [ 54 , 55 ], warranting their investigation in the context of early-onset MDD. Metabolomic profiling and quality control were conducted separately for the PGRN-AMPS and CO-MED cohorts, as described in previous publications [ 51 , 52 , 56 ].…”

“…However, these analytes have enhanced our understanding of the biology of MDD [ 20 , 50 , 51 , 52 ], schizophrenia [ 53 ], and psychosis [ 54 , 55 ], warranting their investigation in the context of early-onset MDD. Metabolomic profiling and quality control were conducted separately for the PGRN-AMPS and CO-MED cohorts, as described in previous publications [ 51 , 52 , 56 ]. Metabolites with ≥10% missingness were excluded from the current analysis, leaving 153 metabolites available for analysis ( Supplementary Table S1 ).…”