Bottom line: No magic bullet.
In this post, I link to and excerpt frombEfficacy and Safety of Intranasal Esketamine in Treatment-Resistant Depression in Adults: A Systematic Review [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. Cureus. 2021 Aug 21;13(8):e17352.
All that follows is from the above resource.
Intranasal form of esketamine, the S-enantiomer of racemic ketamine, was approved by the US FDA in 2019 for treatment-resistant depression (TRD) in adults. Since intranasal esketamine is a newly approved drug with a novel mechanism of action, much still remains unknown in regard to its use in TRD. The objective of this study is to systematically review the latest existing evidence on intranasal esketamine, and provide a better insight into its safety and efficacy in TRD in adults. PubMed, MEDLINE (through PubMed), and Google Scholar were systematically searched from 2016 to 2021, using automation tools. After removal of duplicates and screening on the basis of title/abstract, eligibility criteria were applied and quality appraisal was done independently by two reviewers. A total of 10 studies were selected for the final review which included five clinical trials (three short-term trials, one withdrawal design relapse prevention study, and one long-term study), three post hoc studies, one case/non-case study, and one review article. Out of three short-term clinical trials, only one demonstrated a statistically significant difference between treatment with esketamine plus oral antidepressant (OAD) vs placebo plus OAD. The result of the relapse prevention study showed significantly delayed relapse of depressive symptoms in esketamine plus OAD arm when compared to placebo plus OAD arm. Similarly, the result of the long-term clinical trial showed that the improvement in depressive symptoms was found to be sustained in those using esketamine. The most common adverse effects of esketamine included nausea, dizziness, dissociation, headache, vertigo, somnolence, and dysgeusia (altered sense of taste); most were mild-moderate in severity. One case/non-case study reported rare adverse effects including panic attacks, mania, ataxia, akathisia, self-harm ideation, increased loquacity (talkativeness), and autoscopy. Intranasal esketamine has shown efficacy in reducing depressive symptoms in clinical trials, but the clinical meaningfulness of the treatment effect in the real-world population still needs to be explored. Although the safety profile of esketamine appears to be favorable in most clinical trials, some serious side effects are being reported to the FDA Adverse Event Reporting System, and therefore requires further investigation. More robust clinical trials, especially long-term randomized controlled trials are needed which can help provide a better assessment on the efficacy and safety of intranasal esketamine in the treatment of TRD.
Keywords: adverse event; esketamine; intranasal; ketamine; treatment-resistant depression.
Copyright © 2021, Sapkota et al.
Conflict of interest statement
The authors have declared that no competing interests exist.
Safety of Esketamine
The most commonly reported adverse effects (AE) in short-term clinical trials [17–19] were nausea, dizziness, dissociation, headache, vertigo, and dysgeusia. Most of the AE were mild to moderate in severity and resolved the same day following dosing. In all three studies, the dissociative symptoms were seen shortly after dosing, which peaked at 40 minutes, and resolved in 1.5 hours. In a re-analysis done by Gastaldon et al. , the occurrence of dissociation was found to be seven times higher in esketamine plus OAD group compared to placebo plus OAD group, and around 25% of patients receiving esketamine were reported to have experienced dissociation during treatment. No symptom of psychosis was reported.
All three short-term studies [17–19] showed a greater mean increase in systolic as well as diastolic blood pressure (BP) in esketamine plus OAD group compared to placebo plus OAD group. For instance, in TRANSFORM-2, the mean maximum increase in systolic BP was +11.6 mmHg and +5 mmHg in esketamine plus OAD group and placebo plus OAD group, respectively and mean increase in diastolic BP was +8.1 mmHg and +4.5 mmHg in the two treatment groups, respectively. Similarly, a greater percentage of patients from esketamine plus OAD group reported moderate to greater sedation when compared to placebo plus OAD group in all three studies. During two weeks of follow-up, no withdrawal symptoms were observed after the discontinuation of esketamine plus OAD. The safety concerns of esketamine as reported by the FDA, which require Risk Evaluation and Mitigation Strategies (REMS) not only include dissociation and sedation but also misuse and abuse. Although no misuse or abuse was seen in any of the short-term studies, it is important to note that these studies were conducted in highly specialized centers with strict supervision . Therefore, the possibility of such occurrences (misuse or abuse) in real-world setting shouldn’t be dismissed.
A post hoc study by Citrome et al.  reported that the use of esketamine plus OAD was three times more likely to result in acute remission rather than discontinuation as a result of side effects. Similarly, it was reported that the side effects with Number Needed to Harm (NNH) values of less than 10 included dissociation, nausea, vertigo, dizziness, and dysgeusia. Thus, these AEs were reported to be more common and can be expected to occur as frequently as the treatment response itself. Likewise, in a post hoc study , safety/tolerability profile of esketamine was found to be comparable between younger age group (18-64) and older age group (≥65 years) except for the treatment-emergent AE of acute hypertension which was observed more frequently in the older age group.
In addition to the above mentioned AE, a case/non-case study  detected some rare AEs, which have not been reported by most studies. These include panic attacks, ataxia, mania, akathisia, self-harm ideation, autoscopy, and increased loquacity. Signals were detected for several side effects including dissociation, sedation, feeling drunk, euphoric mood, depression, suicidal ideation, and completed suicide. This study also reported that most of the serious side effects were found to be dose-dependent, and were more likely to occur in females and those receiving multiple antidepressants, benzodiazepines, antipsychotics, mood stabilizers, and somatic treatments.
Due to concerns regarding some of the AEs of esketamine, after licensing of esketamine the FDA has recommended the REMS, which requires the drug to be given in a specialized healthcare setting under strict monitoring for two hours after drug administration . However, several researchers have placed some concerns regarding certain safety signals, which they felt were not sufficiently addressed by the FDA. In a review done by Horowitz and Moncrieff , several of the concerns regarding the clinical trials submitted to the FDA have been highlighted. For instance, there was one death due to motor vehicle accident in TRANSFORM-2 in a patient receiving esketamine, which was reported to be unrelated to esketamine. However, the reviewer argues that impaired hand-eye coordination and dissociation can increase the risk of road traffic accidents in ketamine users. Similarly, two deaths were reported in SUSTAIN-2, one was due to acute respiratory and cardiac failure and the other death was due to suicide; both were stated not to be due to esketamine. Again, based on previous studies of ketamine, increased BP has been shown to result in heart failure as well as myocardial infarction in those who are at risk [31–34]. Moreover, the death due to suicide, as reported in SUSTAIN-2, occurred in a patient with no previous history of suicidal behavior or intent, and the patient was also in clinical remission during this occurrence. Based on the review, there’s a possibility that these adverse outcomes could be linked to esketamine, and therefore requires careful attention and further studies .
Most of the clinical trials mentioned in this review excluded patients with several significant medical/psychiatric comorbidities, those with a history of substance use disorder, and MDD patients who are at imminent risk of suicide. There was also a limited number of non-White patient inclusion. This has led to limitation in the generalizability of the results. Similarly, AEs of esketamine such as dissociation and sedation can lead to potential unblinding, in many of the clinical trials, which is important to be noted. Furthermore, three of the studies included in this review are post hoc studies which can have inherent bias. Additionally, since our study excluded gray literature, ongoing clinical trials on esketamine were not included, which could have been potentially useful in reaching out additional conclusions.
Esketamine appears to be effective in reducing depressive symptoms in TRD patients and has a decent safety profile based on the results of the clinical trials. However, the clinical relevance of the treatment effect and the safety demonstrated by most clinical trials cannot be guaranteed in the real-world setting. First, there’s a paucity of long-term clinical trials on esketamine due to which its efficacy and safety on a long-term basis is still uncertain. Similarly, the superiority in the efficacy of esketamine over the pre-existing treatment modalities for TRD is also questionable due to the lack of comparative clinical trials so far. Although, most clinical trials have reported transient mild to moderate AEs of esketamine, new data are emerging which suggest the likelihood of its association with rare but potentially serious side effects. Therefore, in addition to strict post-marketing monitoring of esketamine, more robust and long-term randomized controlled clinical trials are needed to get a better insight into its safety and efficacy.