Ineffectiveness of Repeated Intravenous Ketamine Infusions in Treatment-Resistant Depression After a Post-Ketamine Relapse: Time for a Rethink?

Abstract

To the Editors: W orldwide, major depressive disorder (MDD) is a leading cause of disability and a major contributor to the overall global burden of disease. Up to 30%of patients with MDD have a lack of response to antidepressant therapies. These rates are even higher in bipolar depression, where treatment options are more limited than in MDD. Patients who do not achieve an adequate antidepressant response after several evidence-based treatment strategies are considered to have treatment-resistant depression (TRD). However, at present, there is a lack of a universally accepted operational definition of TRD, and its underlying pathophysiological mechanisms remain poorly understood. Several authors suggest that the failure of 2 adequate doseduration trials from different classes (either pharmacotherapy or psychotherapy, or their combination) in a current depressive episode represents an optimal cutoff point to identify patients with TRD. These individuals have an expected 1-year response rate of approximately 10% to all available standard treatments for depression. Nevertheless, in recent years, the development of novel antidepressant therapeutics targeted to the TRD population offers some grounds for optimism. In this vein, a growing body of research has provided evidence of the rapid and robust antidepressant effects of subanesthetic doses of ketamine—a noncompetitive glutamate N-methyl-D-aspartate receptor antagonist— as an off-label indication for nonpsychotic TRD. However, these properties are transient in both MDD and bipolar depression, lasting 3 to 14 days on average following a single ketamine infusion and up to 3 weeks after the last of a series of 6 intravenous infusions. Current efforts are focused toward the research of strategies to sustain