Antidepressant Efficacy of an Antiglutamatergic Agent in Bipolar Depression

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The treatments for acute unipolar depression have been extensively researched. However, despite the availability of a wide range of antidepressant drugs, clinical trials indicate that 30% to 40% of depressed patients fail to respond to first-line antidepressant treatment, despite adequate dosage, duration, and compliance. Very few studies have examined the efficacy of somatic treatments for the acute phase of bipolar depression. Thus, there is a clear need to develop novel and improved therapeutics for bipolar depression. Recent preclinical studies suggest that antidepressants may exert delayed indirect effects on the glutamatergic system. Clinical data suggests that lamotrigine an inhibitor of glutamate release and the NMDA antagonist ketamine may have antidepressant effects. Finally, our group recently found in two separate studies that the glutamate modulating agent riluzole was effective in treatment-resistant unipolar and bipolar depression (Zarate et al 2004; Zarate et al. 2005). Together, these data 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. In this study, we propose to extend our findings from open-label studies with riluzole in treatment-resistant depression by investigating its efficacy in a double-blind placebo-controlled study in bipolar depression. Patients, ages 18 to 70 years with a diagnosis of bipolar disorder I or II current episode depressed (without psychotic features), will be randomized to double-blind treated to receive either riluzole (50-200 mg/day) or placebo for a period of 8 weeks. Acute efficacy will be determined by demonstrating a greater response rate using specified criteria. Approximately 78 patients with acute bipolar depression will be enrolled in this study. This project is now highly integrated with project MH002857-04 Glutamatergic Modulators for Rapid & Sustained Antidepressant Effect where we found in our studies that a glutamatergic modulator led to rapid antidepressant effects in 4 hours what usually takes 6 weeks. The drug being tested in this project in bipolar depression (Riluzole) is also being used in the other project. During this past year, we have also conducted preclinical studies with riluzole and found that it increases expression of GluR1 and GluR2 subunits of the AMPA receptor involved in AMPA trafficking (Zarate and Manji 2008). Increasing AMPA trafficking we believe is involved in synaptic potentiation a process that we are studying and believe is involved in the rapid antidepressant effects of ketamine. We anticipate completing recruiting for the present project by next 1.5 years. At that time, we would then determine whether riluzole indeed offers a new treatment alternative (based on a new mechanism of action distinct from existing treatments) for patients with bipolar depression.