Maintaining Rapid Antidepressant Effects Following Ketamine Infusion: A Major Unmet Need

Objective: Several controlled trials have demonstrated the rapid effects of intravenous ketamine. As a result, the use of this off-label treatment has grown exponentially in recent years. This use is expected to continue to grow after the approval by the US Food and Drug Administration of intranasal esketamine for treatment-resistant depression—a decision that 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, although intravenous ketamine has proved 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 was searched from inception to March 1, 2019, using the following terms: ketamine, randomized, depression, and placebo. There were no language or date restrictions.

Study Selection: The search was limited to randomized, placebo-controlled trials to maintain initial treatment gains of intravenous ketamine for major depressive disorder. A total of 115 manuscripts were identified, and 110 were excluded because they did not describe randomized, double-blind clinical trials.

Data Extraction: The remaining 5 articles were reviewed.

Results: Three negative studies involving 2 oral agents (lithium and riluzole), a small negative study involving repeated ketamine infusions, and a positive yet insufficiently controlled larger study supporting infusions 2 or 3 times weekly were 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.