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.

Introduction

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.

References

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ANDRADE C. Oral Ketamine for Depression, 2: Practical Considerations. Journal of Clinical Psychiatry. 2019; 80(2): 19f12838. https://doi.org/10.4088/JCP.19f12838

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