Ketamine vs. Esketamine: Which Depression Treatment Actually Works Better?

What question is this article answering? 

Is intranasal esketamine as good as intravenous ketamine for treatment-resistant depression?

Synopsis

For people suffering from treatment-resistant depression, finding a therapeutic solution can be a long and frustrating experience. Two drug cousins that have recently emerged as promising new treatments are esketamine and ketamine. While both have shown robust antidepressant actions, accumulating evidence suggests that intravenous (IV) ketamine may be better than its intranasal cousin, esketamine [1]. This article will contrast and compare these two treatments, look over the trials pitting their effectiveness against one another, and give insight into the ramifications for patients seeking to overcome crippling depression.

The Esketamine vs. Ketamine Smackdown: Which is the Better Gamble to Beat Depression?

Picture trying dozens, or even scores of different medications for your depression, without any of them providing permanent relief. This is the existence of millions of people with treatment-resistant depression (TRD). For each of these individuals, a quest for a good treatment can be a Sisyphean endeavor. Recently, however, there has been a new and unanticipated competitor in the race: ketamine. Originally developed as an anesthetic, ketamine was found to have rapid and powerful antidepressant effects. This spurred the development of two distinct, but related, treatments: intravenous (IV) ketamine and intranasal esketamine.

Ketamine is a racemic, that is, it consists of two mirror-image molecules, esketamine and arketamine. Esketamine is the "S" molecule and is more potent and has been isolated and developed into a nasal spray, Spravato, which was FDA-approved for use in TRD. IV ketamine consists of both molecules together, and they are injected directly into the blood. While both drugs have been shown to be effective in the treatment of patients with TRD, the query remains: is one better than the other?

Growing research suggests that IV ketamine may be the outright winner. A new examination of charts that were published in The Psychiatrist found that TRD patients who were treated with repeated ketamine infusions had a greater reduction in their depression symptoms compared to patients who were treated with intranasal esketamine [1]. This is not an isolated finding. A 2020 systematic review and meta-analysis published in the Journal of Affective Disorders concluded that IV ketamine appears to be more effective than intranasal esketamine for the treatment of depression [2]. This is a critical difference that could have a great impact on treatment decisions among both providers and patients.

So why should IV ketamine potentially be more effective? One of the reasons could be how it's administered. IV delivery has 100% bioavailability, i.e., the entire dose of drug actually reaches the bloodstream and thus the brain. Intranasal delivery has lower and less consistent bioavailability, i.e., the amount of drug that actually gets absorbed is different from person to person and sometimes even dose to dose. It can lead to less consistent and possibly even less effective treatment.

A 2023 retrospective chart review publication in The Journal of Clinical Psychiatry found that intravenous ketamine and intranasal esketamine contained the same response and remission rates in TRD patients, but noted considerable differences in the number of treatments required to achieve response [3]. Another thing that needs to be considered is the composition of the medication itself. While esketamine is stronger of the two molecules, some researchers believe that the "R" molecule, arketamine, shares antidepressant properties. Since it's using the entire racemic mixture, IV ketamine may be providing a more synergistic and overall effect.

A 2024 systematic review and meta-analysis of the effectiveness of ketamine and esketamine at a series of dosages for depression went on to further illustrate their therapeutic potential but highlighted a call for more head-to-head comparisons [4]. Interestingly, it is also noted that esketamine was trialed in clinical trials with a standard oral antidepressant, while some of the IV ketamine studies have been conducted as monotherapy. This makes it difficult to compare the two treatments side by side.

Although evidence suggests that IV ketamine may be more potent, esketamine has one overriding benefit: it is FDA-approved and therefore likely to be covered by insurance. IV ketamine, on the other hand, is given off-label for depression, so it frequently isn't covered by insurance and can be an enormous out-of-pocket expense for patients. This has created a muddled and often frustrating scenario for patients seeking treatment. While esketamine may be more convenient, it is not always optimal for everyone.

A comprehensive 2021 review in the American Journal of Psychiatry stated that no one knows whether intravenous ketamine or intranasal esketamine is best in terms of effectiveness, safety, tolerability, and/or cost-effectiveness, and recommends head-to-head comparative trials [5]. Ultimately, the decision of whether or not to undergo treatment with IV ketamine or intranasal esketamine is a personal one that should be made only after consulting a qualified healthcare professional. Both treatments have the potential to provide significant relief to those suffering from TRD, but both also possess a unique set of benefits and risks. As with any area of research, it is constantly evolving, and one day we may know exactly which treatment is most ideal for which patient. In the meantime, in accordance with the evidence, for those patients that have not had a response to other modes of treatment, IV ketamine may be an even more effective and powerful option.

References

1. Psychiatrist.com. (2024). Repeated Ketamine Infusion vs Intranasal Esketamine in Patients With Treatment-Resistant Depression: A Chart Review. https://www.psychiatrist.com/jcp/repeated-ketamine-infusion-vs-intranasal-esketamine-patients-treatment-resistant-depression-chart-review/

2. Bahji, A., Vazquez, G. H., & Zarate, C. A. (2020). Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. Journal of Affective Disorders, 278, 542-550. https://pmc.ncbi.nlm.nih.gov/articles/PMC7704936/

3.Singh, B., Brawer, A., & McIntyre, R. S. (2023). Comparative Effectiveness of Intravenous Ketamine and Intranasal Esketamine in Clinical Practice Among Patients With Treatment-Refractory Depression: A Retrospective Chart Review. The Journal of Clinical Psychiatry, 84(2), 22r14545. https://pubmed.ncbi.nlm.nih.gov/36724113/

4. Seshadri, A., Wilkinson, S. T., & McCloud, T. (2024). A systematic review and meta-analysis of the efficacy of ketamine and esketamine at various dosages for depression. Journal of Affective Disorders, 351, 1039-1048. https://pubmed.ncbi.nlm.nih.gov/38537759/

5. McIntyre, R. S., Rosenblat, J. D., & Nemeroff, C. B. (2021). Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression. American Journal of Psychiatry, 178(5), 383-399. https://psychiatryonline.org/doi/full/10.1176/appi.ajp.2020.20081251

Disclaimer: Psychedelic Assisted Psychotherapy has not been approved by any regulatory agencies in the United States, and the safety and efficacy are still not formally established at the time of this writing.