Depression is projected to become the second greatest cause of disability worldwide by 2020. It can be a chronic disorder with 5-9 episodes per lifetime. The first six months following successful antidepressant treatment represents the highest risk period for relapse, with a relapse rate of 40-60% in patients with resistant depression. Continuation antidepressant treatment and psychotherapies have established roles in relapse prevention. However, many people still experience recurrent episodes and the optimal duration of treatment is unknown. Thus, there is a need for better relapse prevention strategies in recurrent depressive disorder. A recent paradigm shift in treating depression and understanding its biology has been the finding that the competitive glutamate NMDA receptor antagonist ketamine has a robust rapid-onset (i.e. hours rather than weeks), though relatively short-lived, antidepressant effect. Ketamine mediates these effects through rapid activation of neuroplasticity pathways involving mammalian target of rapamycin (mTOR) and brain derived neurotrophic factor (BDNF) signalling, amongst others. The novel hypothesis underlying this proposal is that ketamine-mediated neurotrophic support can be used to prevent relapse in high-risk patients. The main objective of this study, therefore, is to conduct a patient- and rater-blinded randomised controlled pilot trial (n=40) of an eight-week course of fortnightly ketamine infusions for relapse prevention following successful antidepressant treatment in people with recurrent depressive disorder. Midazolam will be used as an active comparator. The main aim is to assess trial procedures that will inform a future definitive trial. Safety and tolerability of repeated doses of ketamine have not been reported in this particular population and cognitive, psychotomimetic, and haemodynamic safety outcomes will be compared between groups. Developing a novel method for relapse prevention would represent a major improvement in the overall management of recurrent depression.
