This collaborative R01 investigates the safety and efficacy of the glutamate-modulating and neuroprotective agent riluzole in a randomized double-blind placebo-controlled clinical trial (RCT) in patients with treatment- resistant depression (TRD). The recent findings of the STAR*D study highlight the fact that our current armamentarium of antidepressant medications, developed out of the monoamine hypothesis, has serious limitations. There is now emerging evidence that amino acid neurotransmitter (AANt) systems may also contribute to the pathophysiology of major depressive disorder (MDD), and that drugs targeting these systems may have potent antidepressant properties. Riluzole is currently approved by the US FDA for the treatment of amyotrophic lateral sclerosis (ALS). It has been shown to have a variety of neurobiological effects on glutamatergic function associated with the drug's neuroprotective and plasticity-enhancing properties. There have now been two recent open-label studies showing riluzole to be effective in TRD as well as several reports demonstrating riluzole's efficacy in bipolar depression, generalized anxiety disorder, and obsessive-compulsive disorder. However, no RCT has been performed in TRD. This randomized, double-blind, placebo-controlled trial, using a sequential parallel comparison design, evaluates the efficacy and safety of riluzole augmentation of the selective serotonin reuptake inhibitor citalopram in outpatients ages 18-65 with moderate TRD. Significance to Public Health: In this unique 5-year proposal, investigators from four institutions [Yale, MSSM, MGH and NIMH (MAP)] will conduct a RCT to examine the efficacy, safety and tolerability of adjunctive riluzole treatment in TRD. Demonstration of riluzole's benefit would represent a major advance for patients with difficult-to-treat depression, and may help elucidate our understanding of the pathophysiology of MDD and the mechanism of antidepressant action. Most immediately, since riluzole is already a FDA-approved medication that has been safely prescribed to thousands of patients with ALS, positive findings from this study could rapidly disseminate into clinical practice and would encourage further investigation of this strategy. Demonstrating riluzole's efficacy in TRD would open the door to the discovery of future medications targeting the glutamatergic system that could be used to fight this common and devastating disorder.

Public Health Relevance

Although there are now more than 20 different antidepressant medications available in the US, treatment resistant depression remains a common problem, with serious medical and economic consequences. The high rates of treatment resistant depression likely reflect the fact that existing antidepressant treatments were almost exclusively developed out of the monoaminergic hypothesis of depression pathophysiology and therefore largely share a common mechanism of action. The increasingly recognized limitations of this approach to antidepressant drug development provides a strong impetus for exploration of novel antidepressant treatments with unique targets of action such as that proposed in this study.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Study Section
Interventions Committee for Adult Disorders (ITVA)
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Hillefors, MI
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Yale University
Schools of Medicine
New Haven
United States
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Wilkinson, Samuel T; Kiselycznyk, Carly; Banasr, Mounira et al. (2018) Serum and plasma brain-derived neurotrophic factor and response in a randomized controlled trial of riluzole for treatment resistant depression. J Affect Disord 241:514-518
Mathew, Sanjay J; Gueorguieva, Ralitza; Brandt, Cynthia et al. (2017) A Randomized, Double-Blind, Placebo-Controlled, Sequential Parallel Comparison Design Trial of Adjunctive Riluzole for Treatment-Resistant Major Depressive Disorder. Neuropsychopharmacology 42:2567-2574
Cardoos, Amber; Inamori, Aya; Sanacora, Gerard et al. (2013) Delayed amnesic syndrome after riluzole use in major depressive disorder: a case report. Psychosomatics 54:488-92
Krystal, John H; Sanacora, Gerard; Duman, Ronald S (2013) Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond. Biol Psychiatry 73:1133-41
Sanacora, Gerard; Banasr, Mounira (2013) From pathophysiology to novel antidepressant drugs: glial contributions to the pathology and treatment of mood disorders. Biol Psychiatry 73:1172-9