Depression is the leading cause of disability worldwide. Current pharmacotherapies are limited by delayed onset of antidepressant effects and significant relapse rate. Even more alarming, over one-third of individuals with major depressive disorder will experience treatment-resistant depressive episodes. The recent discovery that low doses of ketamine, a medication long used as an anaesthetic, can result in rapid antidepressant effects and reduce suicidal thoughts has been hailed as a paradigm shift in the treatment of depression. Health Canada recently approved esketamine, an intranasal form of ketamine that can be administered under medical supervision. Further research is needed to optimize translation of this medication from clinical trials to clinical practice, and to add to the body of evidence needed to advocate for equal access to this treatment. This was the impetus behind the development of The Royal’s Esketamine Service, where innovative, measurement-based, evidence-informed care is fully integrated with research.

Based on randomized clinical trials, Health Canada approved the use of intranasal esketamine for treatment-resistant depression in 2020. How clinical trial findings translate into clinical practice, however, is not clear. While there has been rapid commercialization of ketamine, real-world efficacy studies are lacking. The goal of this project was to establish a clinical service in which reliable methodology was integrated into clinical care to allow for rigorous real-world monitoring to generate scientific knowledge that may lead to improved outcomes. All patients receiving treatment in our hospital-based esketamine service undergo standardized clinical and self-report assessment of symptoms at designated time points to allow tracking of response and remission rates with treatment. Our focus is on capturing changes in depressive symptoms, suicidal ideation, anxiety, anhedonia, hopelessness, quality of life, and individualized patient-identified goals. Embedded research projects focus on three key areas. Firstly, a key limitation of ketamine treatment is the transient nature of the antidepressant and anti-suicidal effects. Following our pilot study showing the potential benefits of sequential treatment with intravenous ketamine and behavioral activation, a component of cognitive behavioural therapy and a stand alone treatment for depression, we will conduct a prospective randomized trial examining concurrent treatment with esketamine and behavioral activation versus esketamine alone. A growing literature showing increased neuroplasticity with ketamine suggests that concurrent treatment with a psychological intervention may improve clinical outcome. A second area of research examines whether changes in inflammatory and metabolic biomarkers can be useful in predicting clinical outcome during esketamine treatment. Emerging evidence implicates metabolic alterations in depression treatment-nonresponse and suggests this link is mediated through low-grade inflammation. A third area of research under development focuses on the anti-suicidal effects of esketamine. Specifically, this work aims to harness the rapid effects of esketamine to explore neuroimaging changes linked to decreased suicidal ideation to shed light on mechanisms underlying alleviation of suicidal thoughts through treatment. A key accomplishment for our project is integrating the esketamine service into the research and clinical infrastructure of the Royal.

Papers supporting development of our project:

Phillips JL, Blier P, Talbot J (2023). Sustaining the benefits of intravenous ketamine with behavioural activation therapy for depression: A case series. Journal of Affective Disorders Reports, 14:100613. doi: 10.1016/j.jadr.2023.100613.

Phillips JL, Norris S, Talbot J, et al. (2020). Single and repeated ketamine infusions for reduction of suicidal ideation in treatment-resistant depression. Neuropsychopharmacology, 45(4):606-612. doi: 10.1038/s41386-019-0570-x.

Phillips JL, Norris S, Talbot J, et al. (2019). Single, repeated, and maintenance ketamine infusions for treatment-resistant depression: A randomized controlled trial. American Journal of Psychiatry, 176(5):401-409. doi: 10.1176/appi.ajp.2018.18070834