Grant: Project Grant

Depression is now the leading cause of ill health and disability worldwide. There remain three important unmet needs in the treatment of depression. Specifically, there is urgency for medications with faster therapeutic action, a requirement for higher rates of recovery and effective strategies to maintain the antidepressant response for patients with major depressive disorder. With existing treatments, one third of patients remains ill even after several treatment trials and are designated as treatment-resistant. Among patients who do respond, all existing antidepressant treatments have a delayed action of several weeks and can stop working after few months. Strikingly, low doses of ketamine can produce a rapid antidepressant effect (within 24 hours) in a significant number of patients with treatment-resistant depression (TRD). This antidepressant effect however, dissipates within one week. The first goal of this project is to compare the mechanisms involved in the rapid and more delayed antidepressant effects induced, respectively, by ketamine and a treatment that combines two existing medications (combination of escitalopram and aripiprazole), also known to be efficacious in TRD. The second goal is to understand why the antidepressant effects of ketamine are not sustained and lead to patient relapse. The third goal is to determine the brain adaptations that occur with repeated ketamine administration that can maintain its antidepressant effects, as was shown in our clinical study. Understanding the mechanisms underlying the rapid antidepressant effects of ketamine, their transient nature, and how they can be maintained, will inform design of new treatment strategies aimed at inducing rapid and sustained antidepressant response.