Background: 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.
Objectives: Compare the acute effectiveness of IV ketamine with esketamine (IV or IN) in adults with TRD.
Design: 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.
Data sources and methods: 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.
Results: 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.
Conclusion: 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.
Trial registration: The study protocol was prospectively registered on the Open Science Framework (OSF) at https://osf.io/5jzev.
Keywords: depression; esketamine; intranasal; intravenous; ketamine; meta-analysis; rapid-acting antidepressants; systematic review.
Intravenous ketamine versus esketamine for adults with treatment-resistant depression Why this review matters About one in three people with depression still feel unwell after trying at least two antidepressants, a condition called treatment-resistant depression (TRD). Two recent treatment options include intravenous (IV) ketamine and esketamine, but it remains unclear which is more effective. What we set out to do We searched five large medical databases up to March 2025 and found eight studies comparing IV ketamine with esketamine for TRD. Seven studies, covering 915 participants, tested IV ketamine against intranasal (IN) esketamine; one smaller trial (n=63) compared both drugs by IV drip. Key findings When the seven similar studies were analyzed, IV ketamine and IN esketamine both helped people feel better at about the same rate, and neither proved clearly superior; the odds of improvement slightly favored IV ketamine, but the difference was not statistically significant. Three studies reported that mood lifted sooner with IV ketamine, sometimes after only two or three infusions, whereas the IN esketamine spray usually required more sessions. Both treatments caused short-lived side effects such as temporary rises in blood pressure or feelings of disconnection, and these effects were generally mild to moderate and rarely led to stopping treatment. Because most included studies were not randomized, the certainty of these comparisons is limited. What this means for patients and clinicians During the first four to eight sessions, IV ketamine and IN esketamine appear equally likely to ease depression symptoms. IV infusions may work faster, but the IN spray avoids needles and is FDA approved for TRD. The choice should consider how quickly relief is needed, comfort with IV access, clinic resources, and insurance coverage. Larger, randomized, high-quality studies that track patients for long-term are required to confirm these findings and to show how long the benefits last.
© The Author(s), 2025.