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Samuel T. Wilkinson, MD, discusses the risks and benefits, as well as the challenges of clinical implementation of esketamine, for treatment-resistant depression.
Major depressive disorder is the leading cause of disability worldwide. Esketamine’s approval by the US Food and Drug Administration as the first rapid-acting therapy for treatment-resistant depression (TRD) was welcome news to
patients. But many doctors have questions and legitimate concerns. What is so special about esketamine? What
type of patient should we consider for this treatment? Where do we send patients for treatment? What are the
risks? Here, I try to answer some of these questions.
Why ‘S’ ketamine?
Esketamine is the S-enantiomer of ketamine, which is more potent at the N-methyl-D-aspartate (NMDA) 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.
Esketamine v R-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 that included fluoxetine, bupropion, duloxetine, lithium augmentation, and brexpiprazole.
His work as a business manager was beginning to suffer because of the worsening depression. After a thorough consultation as well as physical examination and laboratory assessment, a treatment protocol commenced with 56-mg intranasal esketamine, 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.
Which patients benefit?
The patients who were enrolled in the esketamine trials for TRD had a specific profile. Generally, in clinical trials, patients with major medical problems or psychiatric comorbidities are excluded. In the clinical trials of esketamine that led to FDA approval for TRD, key exclusion criteria included active substance use disorder (or within 6 months), current or past psychosis, and bipolar disorder.2-5 These patients were moderately to severely depressed, and in generally had failed two or more adequate antidepressant courses in the current episode but generally no more than 8 (different upper limits were used in different trials; most trials used 5) and have not failed electroconvulsive therapy (ECT).
In selecting appropriate patients for esketamine treatment, the Interventional Psychiatry Service at Yale strives to align with the key inclusion/exclusion criteria of the trials, with some exceptions. For instance, in clinical practice, there is no legitimate reason to exclude patients if they have failed more than 8 adequate antidepressant trials or if they have failed ECT.
Of chief concern to us is to be cautious when the potential risk-benefit analysis is shifted by a clinical factor. For example, we generally do not treat TRD in patients who are actively using illicit substances or misusing habit-forming substances that are legal (ie, alcohol, cannabis). Other clinical and demographic factors (ie, presence of psychosis, older age) are also considered carefully.
Despite the excitement about esketamine, it has been a very difficult treatment for psychiatrists to implement. A lot of this has to do with a different route of administration as compared with most of our treatments, which are pills. Patients who receive esketamine must be treated on-site, at a doctor’s office, or other health care facility. Patients must be observed for 2 hours following esketamine administration, which includes measuring vital signs. Most psychiatrists’ offices do not have the
space or other resources needed for such. Furthermore, while it is easy to get insurance to pay for the cost of the drug, the reimbursement process and compensation for two hours of monitoring is unclear.
Exploring the risks
Despite the potential benefit of esketamine, there are several risks. The FDA label for esketamine includes a black box warning of the potential for misuse of esketamine. It is also important for clinicians to know that patients should not drive on the days they receive treatment. Cognition is impaired in the acute period following esketamine administration, but usually resolves within 60 to 90 minutes.
Long-term and persistent cognitive impairment is a theoretical risk and has been seen in those who misuse ketamine repeatedly; however, in a longer-term study, a negative effect on cognition was detected.6 These risks should be weighed carefully against the potential benefit for each patient. Moreover, esketamine should not be used in patients who have not had adequate trials of oral antidepressants.
The bottom line
Esketamine offers a novel treatment approach that can lead to rapid improvement in patients with depression. However, significant logistical barriers prevent the medicine from being implemented widely and questions remains about the long-term approach to treating depression with esketamine.
Esketamine offers a novel treatment approach that can lead to rapid improvement in patients with depression. However, significant logistical barriers prevent the medicine from being implemented widely, and questions remain about the long-term approach to treating depression with esketamine.
This article was originally posted on February 6, 2020, and has since been updated. -Ed
Dr Wilkinsonis 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).
Int J Neuropsychopharmacol. 2019;22:616-630.
4. 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 Jun 5 [Epub ahead of print].
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).