Every day, 22 veterans complete suicide, primarily due to the ramifications of untreated depression. Due to fear and stigma, many do not seek treatment. For those who do, about one third of the time, no drug offers relief and even those antidepressants that do work often require 6-8 weeks before therapeutic onset. Unfortunately, no unifying hypothesis for a molecular/cellular basis of action for antidepressant drugs (or depressive disorders) has emerged. Over the last several years, we have suggested that, in addition to pre- synaptic targets (uptake sites), a number of antidepressant drugs have a post-synaptic mechanism of action. Toward this end, we have observed that chronic treatment (3-5 days) of cultured neural or glial cells with a number of chemically diverse antidepressant compounds translocates the heterotrimeric G protein Gαs outof lipid rafts and into a closer association with adenylyl cyclase. Post-mortem tissue from depressed suicides shows just the opposite, with an increased proportion of Gαs ensconsed in lipid rafts and preliminary data suggest that this is also observed in blood cells, where the extent of Gαs in lipid rafts correlates with both depression and clinical response to antidepressants. Furthermore, several experimental compounds may have antidepressant effects as well as shorter therapeutic onset, and the proposed studies will search for a cellular “biosignature” for antidepressant action. Proposed studies will also attempt to establish a mechanistic understanding for the translocation of Gαs from lipid rafts as a hallmark of depression and as a conduit for antidepressant action. During the period covered by this proposal, we will pay particular attention to short- acting antidepressants like ketamine. One intent of the proposed studies is to develop a platform that can provide a cell- based screen for putative antidepressant compounds as well as a screening tool to indicate personalized antidepressant choice. Another intent of these studies is to provide a peripheral tissue biological marker for depression and an early (< 1 week) indicator of successful antidepressant treatment that can be developed into a clinically useful, inexpensive and simple biomarker for clinical use. The identification of a pathway for antidepressant action might lead to novel antidepressant drugs, while the assignation of a quantitative value for depression may help overcome stigma and encourage thousands of depressed veterans to seek treatment.