Ninewells Hospital & Medical School, Dundee, DD1 9SY

Esketamine for depression

We are often asked about whether we provide or recommend esketamine as a treatment for depression. Esketamine is a particular form of ketamine, which has been used to treat depression for many years, although the evidence for long-term benefit is lacking. This is not a complete summary of the evidence for ketamine/ esketamine, but it is a summary why we make particular recommendations.


What is esketamine?

Esketamine is a form of ketamine. All biological compounds typically come in two forms (or enantiomers) which are mirror images of each other. The 'R' form is typically much less active than the 'S' form, although the 'R' form may interact with the 'S' form when it comes to biological effects and it may contribute to side effects.

Esketamine is the isolated 'S' enantiomer of ketamine. Since ketamine was developed decades ago, it cannot be licensed as a new drug so drug companies often develop and then market the S enantiomer as a new drug, which allows it to be marketed as a new drug. For example, Escitalopram and Citalopram.

Mechanism of action

The exact mechanism of action of ketamine is unclear. However, ketamine (and esketamine) are NMDA-receptor antagonists. The NMDA receptor is a glutamate receptor and glutamate is the main excitatory neurotransmitter in the brain. Glutamate, therefore, will be involved in most mental processes. The NMDA receptor is thought to have a role in 'synaptic plasticity', or the ability of nerve connections (synapses) to strengthen or weaken over time. It is likely, therefore, that the NMDA receptor is involved in learning and memory.

Clinical trials of ketamine for depression

Trials of ketamine as a treatment for depression go back almost 20 years, with early studies (e.g. Zarate, 2006) pointing to rapid and definite effects on depressive symptoms. A number of systematic reviews have confirmed antidepressant effects for ketamine (Caddy, Amit, McCloud, et al, 2015; Coyle & Laws, 2015; Newport, Carpenter, McDonald, et al, 2015; Romeo, Choucha, Fossati, et al, 2015; Rosenblat, Carvalho, Li, et al, 2019; Schoevers, Chaves, Balukova, et al, 2016; Siegel, Di Vincenzo, Brietzke, et al, 2021; Walsh, Mollaahmetoglu, Rootman, et al, 2022).

However, most (if not all) reviews have found a similar outcome: that benefits appear to 'wear off' after 2-4 weeks, and maintaining any clinical benefit becomes difficult.

Approval of esketamine in the USA

Licensing of esketamine in the USA was contentious for several reasons:

  1. TRANSFORM-1 and TRANSFORM-3 were negative, and only TRANSFORM-2 demonstrated a statistically-significant difference from placebo (4 points on the MADRS)
  2. TRD is a chronic disorder, so short-term efficacy is uncompelling
  3. There’s limited evidence for relapse prevention (SUSTAIN-1) and such studies are affected by ‘functional unblinding’.

A detailed summary of approval for esketamine can be found in Turner (2019).

Approval in the UK

Esketamine was approved by the SMC for use in the Scottish NHS in 2020. It was approved for adults with TRD who have not responded to ≥ 2 antidepressants in the current episode (moderate to severe)…in combination with an SSRI or SNRI.

Esketamine was not approved by NICE in 2020. However, the decision was challenged by the by the Royal College of Psychiatrists (the main body representing psychiatrists in the UK) and Janssen (the manufacturer of the drug). NICE went back to review their approval in light of comments made by the RCPsych and Janssen.

In December 2022, NICE confirmed their lack of approval as it “…is unlikely to be an acceptable use of NHS resources…" They also said:

"The limitations in the clinical evidence and economic model mean it is not possible to determine a reliable cost-effectiveness estimate. Esketamine is unlikely to be an acceptable use of NHS resources, so it is not recommended. Further research is recommended to address some of the uncertainties."

General suggestions for the use of ketamine

  1. For the majority of people with chronic, treatment-refractory depression there is insufficient evidence that esketamine will be beneficial or cost-effective.
  2. There are almost always other treatments (with better evidence) that the patient will not have had. For example:
    • Tri-iodothyronine (T3) or Lithium.
    • Electroconvulsive Therapy (ECT). ECT is very likely to be more effective than ketamine (Rhee et al, 2022; Menon et al, 2023).
  3. The evidence that esketamine is better than ketamine is lacking, and intravenous ketamine has been shown to be superior to esketamine (Bahji et al, 2021).
  4. For most individuals, oral ketamine is easier to deliver than intravenous ketamine and probably has comparative efficacy (Andrade et al, 2019).
  5. For individuals with high levels of treatment resistance (i.e. they have tried lots of different therapies but failed to respond) who wish to explore the use of ketamine, a trial of oral racemic ketamine could be considered. A similar recommendation is usually made for individuals who have failed to respond to neurosurgical and/ or neuromodulatory treatment, since they will already have failed to respond to all reasonable treatments.
  6. The evidence for long-term efficacy with ketamine is, unfortunately, lacking. Benefits appear to be short-term and longer-term planning is required if such a trial is being undertaken.
  7. If a trial of oral ketamine is being considered, we would advice clinicians to get in touch with us since we may be able to help.


ANDRADE C. Oral Ketamine for Depression, 1: Pharmacologic Considerations and Clinical Evidence. Journal of Clinical Psychiatry. 2019; 80(2): 19f12820.

ANDRADE C. Oral Ketamine for Depression, 2: Practical Considerations. Journal of Clinical Psychiatry. 2019; 80(2): 19f12838.

BAHJI A, VAZQUEZ GH, ZARATE CA. Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis. Journal of Affective Disorders. 2021; 278: 542-555.

CADDY C, AMIT BH, MCCLOUD TL, RENDELL JM, FURUKAWA TA, MCSHANE R, HAWTON K, CIPRIANI A. Ketamine and other glutamate receptor modulators for depression in adults. Cochrane Database of Systematic Reviews 2015, Issue 9 Art No: CD011612 DOI: 101002/14651858CD011612pub2. Chichester, UK: John Wiley & Sons, Ltd; 2015.

COYLE CM, LAWS KR. The use of ketamine as an antidepressant: a systematic review and meta-analysis. Human Psychopharmacology: Clinical and Experimental. 2015; 30(3): 152-163.

DALY EJ, TRIVEDI MH, JANIK A, LI H, ZHANG Y, LI X, LANE R, LIM P, DUCA AR, HOUGH D, THASE ME, ZAJECKA J, WINOKUR A, DIVACKA I, FAGIOLINI A, CUBAŁA WJ, BITTER I, BLIER P, SHELTON RC, MOLERO P, MANJI H, DREVETS WC, SINGH JB. 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.

FEDGCHIN M, TRIVEDI M, DALY EJ, MELKOTE R, LANE R, LIM P, VITAGLIANO D, BLIER P, FAVA M, LIEBOWITZ M, RAVINDRAN A, GAILLARD R, AMEELE HVD, PRESKORN S, MANJI H, HOUGH D, DREVETS WC, SINGH JB. 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). International Journal of Neuropsychopharmacology. 2019; 22(10): 616-630.

MENON V, VARADHARAJAN N, FAHEEM A, ANDRADE C. Ketamine vs Electroconvulsive Therapy for Major Depressive Episode: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2023; 80(6): 639-642.

NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE. Esketamine nasal spray for treatment-resistant depression (TA854). London: National Collaborating Centre for Mental Health.

NEWPORT DJ, CARPENTER LL, MCDONALD WM, POTASH JB, TOHEN M, NEMEROFF CB. Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression. American Journal of Psychiatry. 2015; 172(10): 950-966.

OCHS-ROSS R, DALY EJ, ZHANG Y, LANE R, LIM P, MORRISON RL, HOUGH D, MANJI H, DREVETS WC, SANACORA G, STEFFENS DC, ADLER C, MCSHANE R, GAILLARD R, WILKINSON ST, SINGH JB. Efficacy and Safety of Esketamine Nasal Spray Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression - TRANSFORM-3. American Journal of Geriatric Psychiatry. 2020; 28(2): 121-141.

POPOVA V, DALY EJ, TRIVEDI M, COOPER K, LANE R, LIM P, MAZZUCCO C, HOUGH D, THASE ME, SHELTON RC, MOLERO P, VIETA E, BAJBOUJ M, MANJI H, DREVETS WC, SINGH JB. 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. American Journal of Psychiatry. 2019; 176(6): 428-438.

RHEE TG, SHIM SR, FORESTER BP, NIERENBERG AA, MCINTYRE RS, PAPAKOSTAS GI, KRYSTAL JH, SANACORA G, WILKINSON ST. Efficacy and Safety of Ketamine vs Electroconvulsive Therapy Among Patients With Major Depressive Episode: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2022; 79(12): 1162-1172.

ROMEO B, CHOUCHA W, FOSSATI P, ROTGE J-Y. Meta-analysis of short- and mid-term efficacy of ketamine in unipolar and bipolar depression. Psychiatry Research. 2015; 230(2): 682-688.

SCHOEVERS RA, CHAVES TV, BALUKOVA SM, ROT MAH, KORTEKAAS R. Oral ketamine for the treatment of pain and treatment-resistant depression. British Journal of Psychiatry. 2016; 208(2): 108-113.

SCOTTISH MEDICINES CONSORTIUM. SMC2258. Esketamine 28mg nasal spray, solution (Spravato®). Edinburgh: NHS Scotland.

TURNER EH. Esketamine for treatment-resistant depression: seven concerns about efficacy and FDA approval. Lancet Psychiatry. 2019; 6(12): 977-979.

ROSENBLAT JD, CARVALHO AF, LI M, LEE Y, SUBRAMANIEAPILLAI M, MCINTYRE RS. Oral Ketamine for Depression: A Systematic Review. Journal of Clinical Psychiatry. 2019; 80(3): 18r12475.

SIEGEL AN, DI VINCENZO JD, BRIETZKE E, GILL H, RODRIGUES NB, LUI LMW, TEOPIZ KM, NG J, HO R, MCINTYRE RS, ROSENBLAT JD. Antisuicidal and antidepressant effects of ketamine and esketamine in patients with baseline suicidality: A systematic review. Journal of Psychiatric Research. 2021; 137: 426-436.

WALSH Z, MOLLAAHMETOGLU OM, ROOTMAN J, GOLSOF S, KEELER J, MARSH B, NUTT DJ, MORGAN CJA. Ketamine for the treatment of mental health and substance use disorders: comprehensive systematic review. BJPsych Open. 2022; 8(1): e19.

ZARATE CA, JR., SINGH JB, CARLSON PJ, BRUTSCHE NE, AMELI R, LUCKENBAUGH DA, CHARNEY DS, MANJI HK. A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression. Archives of General Psychiatry. 2006; 63(8): 856-864.

Last Updated on 9 November 2023 by David Christmas
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