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Comparison of SPRAVATO and Ketamine  

Last Updated: 11/15/2022


  • Currently, there are no prospective, randomized, head-to-head trials comparing the efficacy and safety of SPRAVATOnasal spray and ketamine for treatment-resistant depression (TRD) or for the treatment of depressive symptoms with acute suicidal ideation or behavior (MDSI).
  • The efficacy and safety of SPRAVATO for TRD is supported by 3 short-term studies evaluating efficacy and safety, and 2 long-term studies evaluating maintenance of effect and safety up to 1 year, respectively.1-5
    • In clinical trials, TRD was defined as a DSM-5 diagnosis of major depressive disorder (MDD) in patients who have not responded adequately to at least two different antidepressants of adequate dose and duration in the current depressive episode.1-5
  • The efficacy and safety of SPRAVATO for MDSI is supported by 2 identically designed phase 3 studies.6, 7
  • Ketamine is not approved by regulatory authorities for depression-related conditions in any formulation, such as intravenous (IV), intramuscular (IM), subcutaneous (SC), or compounded intranasal (IN), oral, or sublingual (SL).8
    • A consensus statement from the American Psychiatric Association highlighted that the available data for ketamine in MDD and TRD is lacking, with trials that have relatively small sample sizes and limited data on longer-term efficacy and safety.9
  • An FDA alert to healthcare professionals in February 2022 about compounded intranasal ketamine emphasizes that the drug is not the same as FDA-approved SPRAVATO nasal spray.10
    • Compounded intranasal ketamine is not FDA approved and there is no data to support dosing conversion between this drug and SPRAVATO. The benefit-risk profile for SPRAVATO has been established while the benefit-risk profile for compounded ketamine nasal spray has not. Compounded drugs should only be used in patients whose medical needs cannot be met by an FDA-approved drug.
  • In a meta-analysis of 36 randomized controlled trials in adults with unipolar or bipolar depression and using various routes of administration for both ketamine and esketamine, ketamine was found to have a significant improvement in overall response and remission rates and depression severity compared to esketamine for short-term use.11 However, a subgroup analysis focused on the IV and IN route of administration found no significant differences between ketamine and esketamine with respect to these endpoints.
  • A retrospective analysis comparing the trajectory of depression severity, based on Montgomery-Asberg Depression Rating Scale (MADRS) score, between patients treated with up to 8 weeks of IV ketamine and SPRAVATO showed no significant difference between groups.12
  • Both esketamine and ketamine are DEA Schedule III controlled substances (CIII) and may be subject to abuse and diversion.8, 13
    • A phase I study compared the abuse potential of esketamine to IV ketamine in recreational polydrug users who had experience with perception-altering drugs and found both of them to have similar subjective “drug liking at the moment” and “take drug again” scores.14
    • SPRAVATO nasal spray is available only through a restricted program under a REMS (Risk Evaluation and Mitigation Strategy) called the SPRAVATO REMS because of the risks of serious adverse outcomes from sedation, dissociation, and abuse and misuse.15
  • Esketamine, the S-enantiomer of racemic ketamine, is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA).16-19 However, the precise mechanism of action of esketamine in MDD is unknown. The antidepressant pharmacologic action of esketamine is thought to be similar to ketamine.16-18, 20
  • Preclinical studies showed, when compared to racemic ketamine, esketamine had an up to two to three-fold higher affinity for the NMDA receptor, facilitating a lower dose volume via the intranasal route of administration.21-23

Clinical data

Bahji et al (2022)12 conducted a meta-analysis of 36 randomized controlled trials (RCTs, parallel and crossover designs), spanning from 2000 through 2021, in adults with unipolar or bipolar depression with the primary objective of analyzing the efficacy and safety of racemic ketamine and esketamine. The 36 RCTs included different routes of administration for both ketamine and esketamine, of which nine involved esketamine while the rest involved racemic ketamine. All studies used DSM criteria and most involved patients with MDD (n=33); 3 studies involved patients with bipolar depression. Most of these studies were focused on TRD (n=28). Subgroup analyses were also performed, which included an analysis by route of administration (IV vs. IN).


Overall, the pooled data for ketamine and esketamine was associated with an improved end-of-treatment response (RR=2.14; 95% CI, 1.72-2.66), remission (RR=1.64; 95% CI, 1.33-2.02), and depression severity (d = -0.63; 95% CI, -0.80 to -0.45) against placebo. An overall analysis using random-effects models showed ketamine as having a significant improvement over esketamine in treatment response rates (RR=3.01 vs 1.20); however, all other subgroup analyses, including route of administration (IV vs. IN), were not significant due to a lack of sufficient number of studies per subgroup. Similar trends were observed for the overall analyses and subgroup analyses for remission and depression severity, with no significant differences seen when comparing IV vs IN routes. Regarding safety, the odds of experiencing an adverse event with either ketamine or esketamine was twice that of placebo (OR=2.14; 95% CI, 0.82-5.60). There was no association between treatment with any form of ketamine/esketamine and retention in treatment (RR=1.00; 95% CI, 0.99-1.01) or dropouts due to adverse events (RR=1.56; 95% CI, 1.00-2.45).

The authors acknowledged important limitations to the meta-analysis, one of which was the high heterogeneity among studies, including differences in study design, sample sizes, population and demographics, and study implementation. In addition, negative studies may not have been identified and included as part of the meta-analysis, which may have inflated the effect sizes for response and remission.  

Nikayin et al (2022)12 conducted a comparative retrospective study for all Yale Interventional Psychiatric Service (IPS) patients (n=210) receiving 0.5 mg/kg IV ketamine over 40 min (n=129, 61.4%) or 56 mg or 84 mg SPRAVATO (n=81, 38.6%) between September 2016 and April 2021. Baseline demographics were balanced between groups. Adults with a major depressive episode receiving acute treatment (multiple treatments each ≤7 days apart for up to 8 total treatments) were included in the study.


With respect to the primary endpoint, no significant difference was found between the treatment groups with an estimated group difference in MADRS by treatment end of 2.15 (95% CI, -0.06 to 4.37; P=0.06). However, differences in secondary endpoints for Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) scores after 8 treatment sessions, and MADRS and QIDS-SR scores after the first 6 treatments were 1.59 (95% CI, 0.24-2.94; P=0.02), 2.49 (95% CI, 0.01-4.98; P<0.05) and 1.64 (95% CI, 0.08-3.19; P=0.04), respectively, and were all in favor of IV ketamine. There were no differences in response (ketamine, 37.8% vs. SPRAVATO, 36.0%) or remission (29.6% vs. 24.0%, respectively) rates. A subgroup analysis showed no differences between IV ketamine and SPRAVATO based on mean suicidal ideation scores from the MADRS item 10 and QIDS-SR item 12.

The authors stated that these findings should be interpreted with caution given the study limitations, which included patient demographics perhaps not being representative of the general population given the accessibility issues with these treatments and the nonrandomized, unblinded retrospective nature of the analysis.

Literature Search

A literature search of MEDLINE®, EMBASE®, BIOSIS Previews®, DERWENT® (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 9 June 2022. An independent abstract was also published on the subject and is referenced below.24


1 Daly EJ,  Trivedi MH,  Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2019;76(9):893-903.
2 Fedgchin M,  Trivedi M,  Daly E, et al. Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019;22(10):616-630.
3 Ochs-Ross R,  Daly EJ,  Zhang Y, et al. Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression - TRANSFORM-3. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry. 2020;28(2):121-141.
4 Popova V,  Daly EJ,  Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study. Am J Psychiatry. 2019;176(6):428-438.
5 Wajs E,  Aluisio L,  Holder R, et al. Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of long-term safety in a phase 3, open-label study (SUSTAIN-2). J Clin Psychiatry. 2020;81(3):19m12891.
6 Fu DJ,  Ionescu DF,  Li X, et al. Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent: double-blind, randomized study (ASPIRE I). J Clin Psychiatry. 2020;81(3):19m13191.
7 Ionescu DF,  Fu DJ,  Qiu X, et al. Esketamine nasal spray for rapid reduction of depressive symptoms in patients with major depressive disorder who have active suicide ideation with intent: results of a phase 3, double-blind, randomized study (ASPIRE II). Int J Neuropsychopharmacol. 2021;24(1):22-31.
8 U.S. Food and Drug Administration. Center for Drug Evaluation and Research. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed August 08, 2022.
9 Sanacora G,  Frye MA,  McDonald W, et al. A consensus statement on the use of ketamine in the treatment of mood disorders [published online March 1, 2017]. JAMA Psychiatry. 2017;74(4):399-405. doi:10.1001/jamapsychiatry.2017.0080.
10 Food and Drug Administration. FDA alerts health care professionals of potential risks associated with compounded ketamine nasal spray. https://www.fda.gov/drugs/human-drug-compounding/fda-alerts-health-care-professionals-potential-risks-associated-compounded-ketamine-nasal-spray. Accessed 24 February 2022.
11 Bahji A,  Zarate CA, Vazques GH. Efficacy and safety of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. [pubished online ahead of print March 9, 2022]. Expert Opin Drug Saf. doi:10.1080/14740338.2022.2047928.
12 Nikayin S,  Rhee TG,  Cunninham ME, et al. Evaluation of the trajectory of depression severity with ketamine and esketamine treatment in a clinical setting. JAMA Psychiatry. 2022;79(7):736-738.
13 Drug Enforcement Administration Diversion Control Division. Available at: https://www.deadiversion.usdoj.gov/fed_regs/rules/1999/fr0713.htm. Accessed March 4, 2020.
14 Center for Drug Evaluation and Research. Other Review. NDA 211243 - SPRAVATO (esketamine) - Reference ID: 4398871. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/211243Orig1s000OtherR.pdf. Published July 5, 2019. Accessed March 22, 2022.
15 SPRAVATO® REMS (Risk Evaluation and Mitigation Strategy) Website. Available at: https://www.spravatorems.com/.
16 Sanacora G,  Zarate CA,  Krystal JH, et al. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov. 2008;7(5):426-437.
17 Duman RS,  Lin N,  Liu RJ, et al. Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology. 2012;62(1):35-41.
18 Duman RS,  Aghajanian GK,  Sanacora G, et al. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22(3):238-249.
19 Kim J,  Farchione T,  Potter A, et al. Esketamine for treatment-resistant depression - first FDA-approved antidepressant in a new class. N Eng J Med. 2019;381(1):1-4.
20 Zanos P Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry. 2018;23:801-811.
21 Kapur S, Seeman P. NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D2 and serotonin 5-HT2 receptors - implications for models of schizophrenia. Mol Psychiatry. 2002;7:837-844.
22 Moaddel R,  Abdrakhmanova G,  Kozak J, et al. Sub-anesthetic concentrations of (R, S)-ketamine metabolites inhibit acetylcholine-evoked currents in alpha-7 nicotinic acetylcholine receptors. Eur J Pharmacol. 2013;698(1-3):228-234.
23 Ebert B,  Mikkelsen S,  Thorkildsen C, et al. Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord. Eur J Pharmacol. 1997;333:99-104.
24 Singh B,  Kung S,  Schak KM, et al. Comparative effectiveness of intravenous ketamine and intranasal esketamine in real-world setting among patients with treatment refractory depression. CNS Spectr. 2022;27(2, Abstract):232.