Meta-Analysis of Intravenous vs Intranasal Ketamine

Does route of administration affect antidepressant efficacy of ketamine? Researchers performed a meta-analysis of trials comparing intravenous and intranasal administration.



“Mr King” is a 50-year-old African-American male with a history of severe, recurrent major depressive disorder (MDD) without psychotic features. He has had partial or non-response, or tolerability issues with multiple classes of medications, including selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, lithium, and second-generation antipsychotics. He presents to the outpatient clinic to discuss a trial of ketamine. He asks whether there are any differences in efficacy between intravenous and intranasal routes of administration. As his psychiatrist, how would you respond?

There is evidence for efficacy of the N-methyl-D-aspartate receptor antagonist ketamine in the treatment of depression. Ketamine produces rapid antidepressant effects, within minutes to hours, that are most pronounced 24 to 48 hours after administration.1 Ketamine has 2 primary routes of administration: intravenous (IV) and intranasal (IN). The bioavailability for IV ketamine is 100% and 45% to 50% for IN.2

In 2019, IN esketamine was approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for MDD as well as acute suicidality. By contrast, IV ketamine is considered an off-label treatment for MDD.

A recent meta-analysis found that IV ketamine was superior to IN esketamine with regards to efficacy and dropout rates.3 However, a US study found evidence for superior cost-effectiveness of IN esketamine compared to IV ketamine from the patient perspective.4 Whether there are significant differences in the adverse effect profiles between IN esketamine and IV ketamine remains unclear. No previous studies have statistically compared the antidepressant effectiveness of IN and IV ketamine.

The Current Study

Meiering and colleagues5 performed a meta-analysis of randomized controlled trials in adults with MDD regarding the efficacy of a single dose of IN and IV ketamine to induce antidepressant response 24 hours after administration. They included randomized double-blind controlled trials of IV ketamine 0.5 ± 0.05 mg/kg body weight or IN esketamine 50 to 84 mg in patients aged 18-65 years with MDD.

Studies were published in international peer-reviewed journals, included data on response rates, and assessed depression with either the Montgomery-Asberg Depression Rating Scale or the Hamilton Depression Rating Scale (HDRS). They excluded investigations of ketamine for disorders other than MDD, studies with non-saline placebos, studies without a control group, and case studies.

The authors searched PubMed, EBSCO, the Cochrane Central Register of Controlled Trials, and Antidepressant response was defined as a 50% reduction in depression severity. Response rates for ketamine versus placebo were calculated as odds ratios (ORs). Individual studies were assessed for risk of bias. Data were analyzed using random effects meta-analysis.

Potential publication bias was tested using rank correlation and regression tests for funnel plot asymmetry. Differences in efficacy between IV and IN ketamine were assessed by a z-test of the mean log ORs derived from the meta-analysis.

The authors screened 77 full-text articles for eligibility, and 11 studies met the study inclusion/exclusion criteria. The risk of bias was assessed as low for 7 and high for 1 of these studies. The 4 IN trials included 586 patients who received esketamine and 479 who received placebo. The 7 IV trials included 145 patients who received ketamine and 130 who received placebo.

In the IV trials, the response rate at 24 hours was 42% for ketamine and 4.6% for placebo (OR=9.4, 95% CI 3.9-22.8), with no evidence of funnel plot asymmetry. In the IN trials, the response rate at 24 hours was 25% for esketamine and 16.5% for placebo (OR=3.3, 95% CI 1.2-9.0). Analysis of funnel plot asymmetry was limited due to the small number of studies. Despite the magnitude of the difference in the ORs for response to IV versus IN ketamine, this difference was not statistically significant (p=0.13).

Study Conclusions

The authors concluded that the odds of antidepressant response at 24 hours was 6 times greater for a single dose of ketamine versus placebo. There was not a statistically significant difference in the ORs for response to IV (9.4) and IN (3.3) ketamine.

A strength of the meta-analysis was the stringent inclusion/exclusion criteria. A major limitation of the meta-analysis was the lack of statistical power to detect a difference between the routes of administration due to the small number of studies. Furthermore, the authors investigated the effect of a single dose of ketamine, so the present study does not inform on potential differential efficacy of multiple doses of ketamine.

The Bottom Line

A single dose of IN or IV ketamine is associated with a 6-fold increased odds of antidepressant response at 24 hours compared to placebo. Due to the small number of studies, data are inadequate to make definitive conclusions about the relative efficacy of IN versus IV routes of administration.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric TimesTM. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.


1. Han Y, Chen J, Zou D, et al. Efficacy of ketamine in the rapid treatment of major depressive disorder: a meta-analysis of randomized, double-blind, placebo-controlled studiesNeuropsychiatr Dis Treat. 2016;12:2859-2867.

2. Zanos P, Moaddel R, Morris PJ, et al. Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms [published correction appears in Pharmacol Rev. 2018 Oct;70(4):879]. Pharmacol Rev. 2018;70(3):621-660.

3. Bahji A, Vazquez GH, Zarate CA Jr. Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis [published correction appears in J Affect Disord. 2020 Nov 20;:]. J Affect Disord. 2021;278:542-555.

4. Brendle M, Robison R, Malone DC. Cost-effectiveness of esketamine nasal spray compared to intravenous ketamine for patients with treatment-resistant depression in the US utilizing clinical trial efficacy and real-world effectiveness estimatesJ Affect Disord. 2022;319:388-396.

5. Meiering MS, Weigner D, Gärtner M, et al. Does route of administration affect antidepressant efficacy of ketamine? a meta-analysis of double-blind randomized controlled trials comparing intravenous and intranasal administration [published online ahead of print, 2022 Nov 9]. J Psychiatr Res. 2022;156:639-646.

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