Intravenous ketamine versus esketamine for depression: a systematic review and meta-analysis

Depression affects approximately 5.7% of adults worldwide, and around one-third of these individuals develop treatment-resistant depression (TRD). Intravenous (IV) ketamine and esketamine (administered IV or intranasally (IN)) are novel treatment options for TRD; however, only IN esketamine currently holds FDA approval.

Compare the acute effectiveness of IV ketamine with esketamine (IV or IN) in adults with TRD.

Mantel-Haenszel random-effects meta-analysis of head-to-head studies. Response and remission at study end point were co-primary outcomes, expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Subgroup and sensitivity analyses explored the impact of diagnosis, study type, and publication format; heterogeneity was quantified with I ².

MEDLINE, Embase, Cochrane, APA Psycinfo, and Scopus were searched from inception through 19 March 2025. Eligible studies enrolled adults with unipolar or bipolar depression directly comparing IV ketamine with esketamine and reporting response or remission.

Screening 1089 records identified eight studies (n = 978). Seven observational studies (n = 915) comparing IV ketamine with IN esketamine were included in the meta-analysis, while one randomized controlled trial (RCT) comparing IV formulations was summarized qualitatively. Pooled response from six studies gave OR = 1.26 (95% CI, 0.92-1.71; p = 0.15) and remission from seven studies gave OR = 1.31 (95% CI, 0.93-1.86; p = 0.12), both nonsignificantly favoring IV ketamine with negligible heterogeneity (I ² = 0%). Sensitivity analyses excluding bipolar depression or abstract-only reports yielded similar effect estimates, reinforcing the robustness of the findings. Evidence across three studies for faster onset with IV ketamine ranged from significant in one study to modest trends in two.

Based on the currently available comparative evidence, which is almost entirely observational, IV ketamine and IN esketamine show comparable acute response and remission rates, though IV ketamine may act faster. Large head-to-head RCTs are needed to confirm these findings.

The study protocol was prospectively registered on the Open Science Framework (OSF) at https://osf.io/5jzev.