Metabolomics is a developing and promising tool for exploring molecular pathways underlying symptoms of depression and predicting depression recovery. The AbsoluteIDQ™ p180 kit was used to investigate whether plasma metabolites (sphingomyelins, lysophosphatidylcholines, phosphatidylcholines, and acylcarnitines) from a subset of participants in the Combining Medications to Enhance Depression Outcomes (CO-MED) trial could act as predictors or biologic correlates of depression recovery. Participants in this trial were assigned to one of three pharmacological treatment arms: escitalopram monotherapy, bupropion-escitalopram combination, or venlafaxine-mirtazapine combination. Plasma was collected at baseline in 159 participants and again 12 weeks later at study exit in 83 of these participants. Metabolite concentrations were measured and combined with clinical and sociodemographic variables using the hierarchical lasso to simultaneously model whether specific metabolites are particularly informative of depressive recovery. Increased baseline concentrations of phosphatidylcholine C38:1 showed poorer outcome based on change in the Quick Inventory of Depressive Symptoms (QIDS). In contrast, an increased ratio of hydroxylated sphingomyelins relative to non-hydroxylated sphingomyelins at baseline and a change from baseline to exit suggested a better reduction of symptoms as measured by QIDS score. All metabolite-based models performed superior to models only using clinical and sociodemographic variables, suggesting that metabolomics may be a valuable tool for predicting antidepressant outcomes.