Does Enhanced Glutamate Transporter Function Produce Antidepressant Effects in People With Major Depression?

Overview

Background: \- At least one third of individuals with major depressive disorder (MDD) remain treatment-refractory after receiving currently available antidepressants underscoring the urgent need for new antidepressant therapies. Of the novel pharmacotherapeutic strategies seeking to rapidly alleviate depressive symptoms, glutamatergic modulators have emerged as promising potential targets. The present study sought to examine the potassium (KATP) channel activator diazoxide as a possible treatment for MDD. Diazoxide increases glutamate uptake from the synaptic cleft by activating the KATP channel to chronically increase expression of the excitatory amino acid transporter (EAAT)-2 system in glial cells. Diazoxide is FDA-approved for the treatment of sulfonylurea-induced hypoglycemia, hypoglycemia due to hyperinsulinemia, and hypertension. Objectives: \- To assess the ability of diazoxide, potassium channel activator, to improve overall depressive symptomatology in patients with treatment-resistant MDD currently experiencing a major depressive episode. The efficacy of a three-week course of diazoxide will be compared to three weeks of placebo. The MADRS will serve as the main outcome measure Eligibility: \- Adults 18 to 65 years old with MDD who are currently depressed without psychotic features. Design: * Study Phase I (Day -28 to 0): \-- Screen and taper off medications (Days -28 to -14): Prior to consenting to this study, subjects will have undergone a screening consisting of laboratory tests, psychiatric and medical history, and psychiatric and physical examinations under protocol 01-M-0254, "The Evaluation of Patients with Mood and Anxiety Disorders and Healthy Volunteers". After consenting to this study, patients will be tapered off medications. Medications allowed and not allowed are listed in Appendix 1. Patients will be reminded to report all drugs, OTC products, and other agents to the investigators so that they can screen to avoid interactions that might make participation unsafe or might confound the research results. Patients are expected to meet all inclusion and exclusion criteria before medications are tapered (which is usually 1-2 weeks long). Subjects who are not taking medications will enter the drug-free period directly. All participants must have a score of ≥20 on the MADRS at screening and baseline of Study Phase I. Subjects who do not have a score of ≥20 on the MADRS by the end of Study Phase I will be excluded and will receive standard treatment. * Drug-free period (Day -14 to day 0): \-- Subjects will begin a 2-week drug-free period prior to the administration of diazoxide or placebo. * Study Phase II (Day 0 to 56): * In this study phase, subjects will be blindly randomized to receive either diazoxide 200-400 mg/day (given BID) or a placebo administered daily by mouth for three weeks. All patients except those who have a 50% or greater decrease in MADRS from baseline at the end of the first cross over point will cross over. To avoid carry-over effects between the different test sessions, there will be an interval of 14-21 days, pending response to test session 1. Subjects will then be blindly crossed over to the second experimental condition (either diazoxide or placebo) for another three weeks. All subjects who discontinue the study or who complete study phase II will then receive either clinical treatment or the opportunity to participate in another research protocol. Patients maintaining response to treatment condition 1 after two weeks will receive an additional one week washout before being crossed over to condition 2.The total duration of the study is approximately 11-13 weeks. The duration of Study Phase I including the 14-day drug-free period is approximately 4 weeks. Study phase II is 8-9 weeks long. Thus, the total duration of the study is approximately 11-13 weeks, except for those patients who were unmedicated at time of entry into the study and therefore do not need to undergo the initial tapering off medications. Subjects will be required to be hospitalized during the entire study. Passes will be permitted if the subject is clinically stable and the pass does not interfere with the study or unit procedures.