Major depressive disorder (MDD) is the leading cause of disability worldwide and thus a major public health problem. The recent approval by the US Food and Drug Administration of esketamine as the first rapid-acting therapy for treatment-resistant depression (TRD) was welcome news to many suffering patients. But many doctors have questions, and some have legitimate concerns. What is so special about esketamine? And what type of patient should we consider for this treatment? Where do we send patients for treatment? What are the risks? Here, I try and answer some of these questions to better inform psychiatrists.
Why ‘S’ ketamine?
Esketamine is the S-enantiomer of ketamine, which is more potent at the N-methyl-D-aspartate receptor (a glutamate receptor) than its mirror image, R-ketamine. The traditional theory of how ketamine produces antidepressant effects is that it works through the NMDA receptor to lead to a growth of new nerve connection (synapses). This is one of the reasons the S-enantiomer was chosen over the R-enantiomer by the company that developed esketamine.
How does esketamine compare with (racemic) ketamine?
Many clinicians wonder how esketamine compares with racemic ketamine (comprised of a 50/50 mix of S- and R-ketamine) with respect to clinical effectiveness. The short answer: there is a lot we don’t know.
One comparative effectiveness study by Correia-Melo and colleagues1 showed that intravenous esketamine is not inferior to intravenous ketamine in patients with TRD. However, this study was fairly small for a non-inferiority study (N=63) and only evaluated patients at 24 hours after a single dose. At least in this context, it does not seem like there is a large difference between the two drugs when given intravenously based on the results of this study.
Part of the excitement about ketamine and esketamine is that this approach has the potential to improve mood and other depressive symptoms on a much shorter time scale than classic antidepressants, such as selective serotonin-reuptake inhibitors. In the early studies of ketamine, a substantial portion of patients would experience dramatic improvement just 4 hours after dosing.
While some patients may need several treatments before effects are noticeable, the possibility of helping patients experience significant improvement after just one treatment—as seen in the following clinical vignette—is an important advancement over traditional antidepressants. Some experts question whether the effects of esketamine are as rapid as those of ketamine; nonetheless, these treatments provide a distinct mechanism of action and are an improvement upon existing therapies.
Mr Jones is a 34-year-old, single man with major depressive disorder who was referred to our depression clinic by his nurse practitioner for refractory symptoms. He reported a 5-year history of depressive symptoms that had only minimally abated with medication trials—which included fluoxetine, bupropion, duloxetine, lithium augmentation, and brexpiprazole—in recent years.
His work as an engineer was beginning to suffer due to his worsening depression. After a thorough consultation as well as physical examination and laboratory assessment, a treatment protocol commenced with intranasal esketamine at 56 mg, twice weekly. His depression symptoms decreased significantly after the first treatment, and he is now in remission and receiving esketamine every other week as part of the maintenance phase of treatment.
Dr Wilkinson is Assistant Professor of Psychiatry; Assistant Director, Yale Depression Research Program, New Haven, CT. The author reports he has received contract funding to conduct research from Janssen (manufacturer of esketamine), Sage Therapeutics, LivaNova, and Oui Therapeutics. He has received consulting fees from Janssen, Oui, and Biohaven, which has been subject to the consulting policies of Yale University. Yale University has a share of the patent of ketamine/esketamine for depression; this patent does not include Dr. Wilkinson.
1. Correia-Melo GS, Leal GC, Vieira F, et al. Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: A randomized, double-blind, non-inferiority study. J Affect Disord. 2019 Nov 14 [Epub ahead of print].
2. 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. Am J Geriatr Psychiatry. 2020;28:121-141.
3. Fedgchin M, Trivedi M, Daly EJ, 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).
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5. 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;176:428-438.
6. 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 (in press).