Project Summary

Carlos A. Zarate, M.D. (Independent Investigator 2005) of National Institute of Mental Health, point out that major depression is a common, severe, chronic and often life-threatening illness and is now recognized as a systemic disease with deleterious effects on multiple organ systems. One of the major problems with existing treatments is the lag of onset of action of several weeks, resulting in considerable morbidity and potentially even mortality by suicide. Thus, there is a clear need to develop novel and improved therapeutics for treatment-resistant major depression that have a rapid onset of action. Recent studies suggest that antidepressants may exert delayed indirect effects on the glutamatergic system. Clinical data suggests that glutamatergic modulators may have antidepressant effects in humans. Dr. Zarate’s prior studies suggest that the glutamatergic system may play a role in the pathophysiology and treatment of depression, and that agents which more directly reduce glutamatergic neurotransmission, may represent a novel class of antidepressants. He proposes to expand on findings on the efficacy of glutamatergic modulators in patients with severe recurring major depression by testing a specific, new mechanism in which riluzole is used to chronically decrease NMDA throughput in an effort to maintain the acute antidepressant effects brought about by acute NMDA antagonist administration. The specific aim of this study is to assess the efficacy and safety of riluzole 100 mg/day compared with placebo in maintaining the rapid antidepressant response achieved with a single intravenous dose of an NMDA antagonist (ketamine 0.5 mg/kg over 40 minutes) in patients with treatment-resistant major depression. Our primary hypothesis is that subjects with treatment-resistant major depression who respond to a single dose of an NMDA antagonist when randomized to riluzole 100 mg/day, will have a superior response rate at day 14 (maintain the initial antidepressant response) compared to subjects randomized to placebo. The model presented here is a clinical testable one, and one that if successful, hold the potential to develop rapidly acting pharmacological treatments that have sustained antidepressant effects.

Program Area: MOOD DISORDERS\Unipolar

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