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 G?s 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 G?s ensconsed in lipid rafts and preliminary data suggest that this is also observed in blood cells, where the extent of G?s 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 G?s 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.
The burden of depression, both from a societal and economic standpoint, ranks second only to ischemic heart disease. By the year 2020, the World Health Organization projects that depression will be the leading cause of disability worldwide. Depression and suicide are particularly prevalent in military returning from deployment and the population of Veterans they become. As many as one third are resistant to antidepressants and they are at greatest risk for suicide. We will use cultured cells to screen new compounds with potential antidepressant activity and attempt to identify common molecular themes among antidepressants. We will also determine whether these molecular signatures are observed in blood cells from depressed and treated patients. Knowledge gained from this study should help to develop a rapid and inexpensive screen for antidepressant responsiveness, allowing changes in therapy long before the current 4-6 week lag time.
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