Major affective disorders are common, severe, chronic and often life-threatening illnesses. Major depression contributes to significant morbidity and mortality. Impairment in physical and social functioning resulting from depression can be just as severe as other chronic medical illnesses. Suicide is the cause of death in 10-20% of individuals with either bipolar or recurrent depressive disorders.
Despite the availability of a wide range of antidepressant drugs, clinical trials indicate that 30% to 40% of patients with major depression fail to respond to first-line antidepressant treatment, despite adequate dosage, duration, and compliance. Thus, there is a clear need to develop novel and improved therapeutics for unipolar and bipolar depression. Recent preclinical studies suggest that antidepressants may exert delayed indirect effects on the glutamatergic system. Furthermore, a growing body of data suggests that mood disorders are associated with regional volumetric reductions, and cell loss and atrophy. It is thus noteworthy that lamotrigine, which, among other effects reduces glutamate release, has antidepressant effects, and a pilot study has suggested that NMDA antagonists may have antidepressant effects. Together, this data suggests 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.
Riluzole, an agent that is Food and Drug Administration-approved for Amyotrophic Lateral Sclerosis has significant antiglutamatergic and neuroprotective properties, may prove to have antidepressant properties in depressed patients. In this study, we propose to investigate the potential antidepressant efficacy of riluzole, an agent which reduces glutamatergic throughput via inhibition of its release, which also exerts robus neurotrophic effects.
This is a 6-week single-arm, single-blind study that will examine the efficacy and safety of riluzole in patients with major depression without psychotic features.
The study has two Study Periods. Study Period I is the washout phase that will last 7 days. Study Period II is a monotherapy 6-week acute treatment phase in which the efficacy and tolerability of riluzole is compared to baseline.
Patients, ages 18 to 60 with a diagnosis of major depression without psychotic features, will in this pilot study (single arm, single-blind) receive riluzole (50-200 mg/day) for a period of 6 weeks. Acute efficacy will be determined by demonstrating a greater response rate using specified criteria.
Approximately 25 patients will enter the study to obtain 22 subjects who complete the 6 weeks of acute riluzole treatment. Therefore if 7/22 patients or greater have greater than 50% improvement on the primary efficacy measure, then based on statistically guidelines from the Optimal Two Stage Design for Clinical Trials, a controlled trial would be indicated to scientifically confirm the signal observed in the single arm trial.
