Novel targets for developing new treatments for treatment-resistant major depression are urgently needed. The glutamatergic system stands as an important to target to pursue in the developing improved treatments for mood disorders. In previous work, we found that the glutamate modulating agent riluzole (inhibitor of glutamate release, and enhancer of AMPA trafficking and glutamate reuptake) was effective in treatment-resistant unipolar and bipolar depression. These data suggest that the glutamatergic system might have a key role in the pathophysiology and treatment of depression, and that agents which modulate this neurotransmitter system, may represent a novel class of antidepressants. a) The efficacy of riluzole in treatment-resistant bipolar depression is currently being tested in a double-blind placebo-controlled study. b) We are also testing the efficacy of riluzole in a 4-site study (Massachusetts General Hospital, Baylor College, Yale University and NIMH) as an add-on treatment in treatment-resistant depression. This study is still ongoing and will be reported under MH002927-03 Target validation of novel therapeutic agents in mood disorders. Acute efficacy will be determined by demonstrating a greater response rate in the Montgomery-Asberg Depression Rating scale. This controlled study is still ongoing and actively recruiting subjects. The study blind has not been broken. Results of the add-on riluzole study in treatment-resistant unipolar depression should be completed in 2-3 years. This study will be reported under MH002927-03 Target validation of novel therapeutic agents in mood disorders. c) Forty-two subjects (18-65) with TRD and a MADRS score of 22 received a single intravenous infusion of ketamine (0.5 mg/kg). Four to six hours post-infusion, subjects were randomized to double-blind treatment with either riluzole (100-200 mg/day; n=21) or placebo (n=21) for 4 weeks. Depressive symptoms were rated daily. A significant improvement (P<0.001) in MADRS scores from baseline was found. The effect size of improvement with ketamine was initially large and remained moderate throughout the 28-day trial. Overall, 27% of ketamine responders had not relapsed by 4 weeks following a single ketamine infusion. The average time to relapse was 13.2 days. However, the difference between the riluzole and placebo treatment groups was not significant, suggesting that the combination of riluzole with ketamine treatment did not significantly alter the course of antidepressant response to ketamine alone.