This review (2021, s=10) finds that only one of three short-term studies found favourable effects of esketamine over only antidepressants for depression, but other studies did find longer time to relapse or a longer sustained improvement in depressive symptoms.
Abstract
“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.”
Authors: Alisha Sapkota, Hajra Khurshid, Israa A. Qureshi, Nasrin Jahan, Terry R. Went, Waleed Sultan & Michael Alfonso
Summary
Abstract
Esketamine, the S-enantiomer of racemic ketamine, was approved by the US FDA in 2019 for treatment-resistant depression in adults. This study will provide a better insight into its use in TRD.
A total of 10 studies were included in the final review, including 5 clinical trials, 1 withdrawal design relapse prevention study, 1 long-term clinical trial, and 1 case/non-case study. The most common adverse effects of esketamine were nausea, dizziness, dissociation, headache, vertigo, somnolence, and dysgeusia.
Intranasal esketamine has shown efficacy in reducing depressive symptoms in clinical trials, but more robust clinical trials are needed to assess the efficacy and safety of esketamine in the treatment of TRD.
Introduction And Background
Major depressive disorder is a common psychiatric condition affecting around 264 million people worldwide. Biogenic amine antidepressants are effective medications for treating MDD, albeit with limitations, such as a delayed onset of effect and treatment-resistant depression.
TRD is a complex disorder involving multiple strategies such as switching therapies to a different antidepressant class, augmentation therapy using lithium, second-generation antipsychotics, and triiodothyronine, and psychotherapeutic approach.
Esketamine is the S-enantiomer of racemic ketamine and has been found to have three to four times more affinity for N-methyl-D-aspartate (NMDA) receptors than R-enantiomer of ketamine (arketamine). It was approved by the FDA for the treatment of TRD in adults in 2019.
Search Strategy
The databases PubMed, MEDLINE (through PubMed), and Google Scholar were systematically searched for collecting data. We came across 498 articles in PubMed.
Results
We searched 2208 articles in databases using automation tools, and retrieved 43 articles. Two reviewers went through screening process, quality assessment, and data extraction independently.
We included 10 studies, which consisted of 5 phase-three clinical trials, 3 post-hoc studies, 1 case/non-case study, and 1 narrative review.
Ketamine’s mechanism of action as an anesthetic has been well researched, but much remains unknown about the basis of esketamine’s antidepressant effects. It is proposed that esketamine improves brain plasticity by stimulating the production of brain-derived neurotrophic factor and by activating the mammalian target of rapamycin.
Efficacy of Esketamine
The short-term (four weeks) induction studies of esketamine plus OAD showed a statistically significant reduction in Montgomery-Asberg Depression Rating Scale (MADRS) scoring compared to placebo plus OAD in TRANSFORM-2, but not in TRANSFORM-1 or TRANSFORM 3.
In three short-term studies, clinically significant treatment effect was reported to be present. However, the clinical relevance of these results has been debated, and a re-analysis was performed, but the clinical meaningfulness of the result was stated to be uncertain.
SUSTAIN-1 was a relapse prevention study based on withdrawal design, but the study design itself has received several feedbacks. One of the biggest concerns is that the effects experienced as a result of withdrawal from esketamine can be mistaken for relapse of depressive symptoms.
SUSTAIN-2 was a phase-three long-term study of esketamine that included patients of age group 18 years. The study found that the efficacy of esketamine was comparable between young TRD patients aged 18-64 and older TRD patients aged 65 years.
Safety of Esketamine
In short-term clinical trials, nausea, dizziness, dissociation, headache, vertigo, and dysgeusia were the most commonly reported adverse effects (AE). Dissociative symptoms peaked at 40 minutes and resolved in 1.5 hours.
All three short-term studies showed that esketamine plus OAD group had greater mean increase in systolic as well as diastolic blood pressure (BP) and a greater percentage of patients reported moderate to greater sedation when compared to placebo plus OAD group. No withdrawal symptoms were observed after the discontinuation of esketamine plus OAD.
In relapse prevention study and long-term clinical study, the most common symptoms were dysgeusia, dissociation, vertigo, dizziness, and somnolence. No respiratory depression or interstitial cystitis were observed, and the most common withdrawal symptoms were insomnia, anxiety/nervousness, difficulty concentrating/remembering, and dysphoric mood-depression.
Esketamine plus OAD was three times more likely to result in acute remission rather than discontinuation as a result of side effects, and the frequency of these side effects was comparable between younger and older age groups.
Side effects include panic attacks, ataxia, mania, akathisia, self-harm ideation, autoscopy, and increased loquacity. Females and those receiving multiple antidepressants are more likely to experience serious side effects.
The FDA has recommended the REMS for esketamine due to concerns regarding some adverse effects. However, several researchers have placed concerns regarding certain safety signals. In a review done by Horowitz and Moncrieff , several concerns regarding the clinical trials submitted to the FDA were highlighted. It was argued that impaired hand-eye coordination and dissociation may increase the risk of road traffic accidents in ketamine users, and therefore requires careful attention and further studies.
Limitations
Most clinical trials included patients with several significant medical/psychiatric comorbidities, 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.
Conclusions
Esketamine appears to be effective in reducing depressive symptoms in TRD patients, but more robust and long-term randomized controlled clinical trials are needed to determine its safety and efficacy.
Disclosures
All authors declare that they have no conflicts of interest and that they have no financial relationships with any organizations that might have an interest in the submitted work.