Maintaining Rapid Antidepressant Effects Following Ketamine Infusion

Abstract

Objective: Several controlled trials have demonstrated intravenous ketamine's rapid effects. As a result, the use of this off-label treatment has grown exponentially in recent years. This number is expected to continue to grow after the approval by the U.S. Food and Drug Administration of intranasal esketamine for treatment-resistant depression- a decision which firmly establishes N-methyl-D-aspartate (NMDA)-receptor antagonism as a valid antidepressant mechanism of action in the public view. The limitation, however, of intravenous ketamine administration is that much less is known about how to maintain initial treatment gains. Thus, while intravenous ketamine has proven to be a rapid-acting antidepressant, maintaining its early therapeutic gains in an efficient manner has emerged as a major unmet need in the field. Data sources: Pubmed/medline were searched from inception to March 1st, 2019 using the following terms: "ketamine", "randomized", "depression", and "placebo". There were no language or date restrictions. Study Selection: We selected for randomized, placebo-controlled trials to maintain initial treatment gains of intravenous ketamine for MDD. 115 manuscripts were identified and 110 were excluded because they did not describe randomized, double-blind clinical trials.Five trials were identified. Data Extraction: The remaining fivese articles were reviewed. Results: Three negative studies involving two oral agents (lithium, riluzole), a small negative study involving repeated ketamine infusions, as well as a positive yet insufficiently controlled larger study supporting 2-3 times weekly infusions have been published. Conclusions: This evidence-base is insufficient to inform clinical practice. Fortunately, a wide variety of molecular targets exist for this indication. Psychotherapy and exercise may also play a beneficial role. More studies are urgently needed to establish how best to maintain rapid symptom improvement seen with ketamine infusions.