Background: Depression is a common debilitating illness that, according to the WHO, is now the leading cause of disability worldwide and a major contributor to the global burden of disease. Unfortunately, 30% of patients don’t respond to adequate trials of antidepressants and/or psychotherapies. Moreover, when these treatments do work they can take many weeks to exert their effect. There is thus a need for better and rapid-acting treatments for depression. One possibility is to use the anaesthetic ketamine, a competitive NMDA glutamate-receptor antagonist. A recent paradigm shift in treating depression has been the finding that a single sub-anaesthetic infusion of ketamine has robust, rapid-onset, though short-lived, antidepressant effects. However, little has been reported about using ketamine as an adjunctive therapy in real-world practice or about repeated administration of ketamine and longer-term outcomes. Aim: To test the hypothesis that repeated ketamine infusions (once-weekly x4) as adjunctive therapy to routine care will improve outcome and accelerate recovery in patients hospitalized with depression, reduce health-care costs, and improve quality of life.
Objectives and methods: To conduct a pragmatic, patient- and rater-blinded, randomised, parallel-group, definitive trial of a four-week course of once-weekly ketamine infusions as adjunctive therapy for depression with a six-month follow-up. Consenting participants admitted to hospital with a major depressive episode (DSM-5; unipolar or bipolar) will be randomised (1:1) to a course of four once-weekly infusions of ketamine or an active comparator midazolam, which mimics some of the effects of ketamine. The primary outcome will be change in the Montgomery-Åsberg Rating Scale for Depression (MADRS) score after four-weeks. Recruiting 104 participants will allow 90% power to demonstrate, using a two-sided t-test at the 5% level, that mean reduction in MADRS score in the ketamine group will be ≥8 points that achieved in midazolam group. Secondary outcomes will include: response and remission rates; subjective mood; safety and tolerability; cognition; relapse status after six-months; quality-of-life and cost-effectiveness.
Discussion: This will be the first pragmatic trial of adjunctive ketamine for depression, an important possible use of ketamine. This trial has been informed by the KARMA-Dep pilot trial (NCT03256162).
