ABSTRACT Depressive symptoms frequently accompany acute illness and are associated with delayed recovery and return to premorbid function, as well as increased healthcare costs. In illnesses such as acute ischemic stroke, depressive symptoms and major depression occur in at least 30-50% of patients, yet little is known about the evolution or mechanism of the symptoms. Our overall hypothesis is that early neurotransmitter and inflammatory changes are biomarkers of subsequent depressive symptom trajectory. Understanding the biomarkers and pathophysiology of depressive symptoms after acute stroke is crucial because it can guide treatment to prevent symptoms from developing into an independent illness. In this project, we will identify multimodal biomarkers of depressive symptom trajectory after acute ischemic stroke. Our biomarkers will include levels of neurometabolites (glutamate and GABA) and a cerebral antioxidant (glutathione) as well as inflammation (both transcriptional and peripheral). Acute ischemic stroke is a `high signal' environment as there are known changes in both neurometabolites and inflammation and a high incidence of depressive symptoms. Our approach includes a novel advance over previous work through the simultaneous measures of multiple neurometabolites/antioxidant and indices of the inflammation cascade. While previous work has demonstrated relations between neurometabolites and inflammation in MDD, none of these factors have been examined simultaneously as biomarkers of depressive symptom trajectory following acute stroke. We will enroll 40 participants with a range of depressive symptoms who have been admitted for an acute initial ischemic stroke at the UCLA Comprehensive Stroke Center. At study entry, our carefully phenotyped sample will receive: a magnetic resonance spectroscopy (MRS) scan, assays of peripheral and transcriptional measures of inflammation; and measures of depressive symptoms. Inflammation measures will be repeated after one month to explore early inflammatory change as a potential biomarker. For four months we will obtain bimonthly ratings of depressive symptoms ratings and, for exploratory purposes, anxiety, quality of life, and level of daily function. We hypothesize that initial levels of neurometabolites/antioxidant and inflammation will be related to early depressive symptoms. Further, we hypothesize that neurometabolite and cerebral antioxidant levels, as well as early changes in inflammation, will predict the depressive symptom trajectory. This information will provide valuable insight into the pathobiology and course of depressive symptoms and create the foundation for future larger-scale studies and potential interventions.