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.
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.
Papers cited by this study that are also in Blossom
Voineskos, D., Daskalakis, Z. J., Blumberger, D. M. · Neuropsychiatric Disease And Treatment (2020)
Gastaldon, C., Raschi, E., Kane, J. M. et al. · Psychotherapy and Psychosomatics (2020)
Chen, X., Hou, X., Bai, D. et al. · American Journal of Psychiatry (2023)
Major depressive disorder (MDD) is a common and disabling condition; around 264 million people are affected worldwide and in the United States 7.1% of adults experienced a major depressive episode in 2017. Standard biogenic amine antidepressants are effective for many patients but have a delayed onset of effect and about one-third of patients fail to respond, a situation commonly labelled treatment-resistant depression (TRD), often defined as non-response to at least two adequate antidepressant trials in the current episode. Management of TRD is complex and includes switching agents, augmentation strategies, ECT and psychotherapy, and there is growing interest in novel pharmacotherapies such as ketamine and its enantiomer esketamine. Sapkota and colleagues set out to synthesise the contemporary evidence on intranasal esketamine for adults with TRD, focusing on both efficacy and safety. The review targets phase-three clinical trials and related post hoc, observational and review literature published since 2016, in order to clarify the drug's clinical effects and adverse-event profile and to identify gaps that remain for real-world use and future research.
The investigators performed a systematic literature search in PubMed, MEDLINE (via PubMed) and Google Scholar using MeSH terms and keywords including “esketamine”, “intranasal esketamine” and “treatment resistant depression”. Searches were automated and filtered on 16 April 2021; the extraction reports 498 PubMed hits and a total of 2,208 records across databases prior to screening. After removal of duplicates and title/abstract screening, full-text eligibility assessment and independent quality appraisal by two reviewers (AS and HK) produced a final set of 10 articles. Inclusion criteria specified phase-three clinical trials, post hoc studies, observational studies and narrative/systematic reviews in English, enrolling adults (≥18 years) with TRD treated with intranasal esketamine given alongside an oral antidepressant (OAD). Excluded materials included phase I/II trials, animal studies, grey literature, case reports/series, letters, non-English papers and studies published before 2016. Quality appraisal tools were applied; the narrative review was assessed with SANRA. The review synthesised findings narratively and tabulated study characteristics; no pooled meta-analytic estimates or a formal risk-of-bias meta-analysis are reported in the extracted text.
The final sample comprised 10 studies: five phase-three clinical trials (three short-term induction trials—TRANSFORM-1, TRANSFORM-2, TRANSFORM-3—plus a withdrawal-design relapse prevention study SUSTAIN-1 and a long-term study SUSTAIN-2), three post hoc analyses, one case/non-case pharmacovigilance study and one narrative review. Efficacy: Among the three short-term induction trials (four-week designs), only TRANSFORM-2 demonstrated a statistically significant greater reduction in Montgomery–Åsberg Depression Rating Scale (MADRS) with esketamine plus OAD versus placebo plus OAD (least squares mean difference [LSMD] = -4.0, SE = 1.69, 95% CI -7.31 to -0.64, p = 0.020). TRANSFORM-1 (LSMD = -3.2, 95% CI -6.88 to 0.45, p = 0.088) and TRANSFORM-3 (LSMD = -3.6, 95% CI -7.20 to 0.07, p = 0.059) showed numerical effects of similar magnitude but did not reach statistical significance. The trials defined a clinically meaningful MADRS difference as 2 points or greater; however, the clinical relevance of the observed group differences has been debated. A post hoc re-analysis by Gastaldon and colleagues reported a mean MADRS difference of -4.08 (95% CI -6.20 to 1.97) but questioned its clinical meaningfulness. Relapse prevention and long-term data: In SUSTAIN-1 (withdrawal design), continued esketamine plus OAD reduced risk of relapse compared with placebo plus OAD: among stable remitters hazard ratio (HR) = 0.49 (95% CI 0.29–0.84, p = 0.003) and among stable responders HR = 0.30 (95% CI 0.16–0.55, p < 0.001). The authors note concerns raised by others that withdrawal effects could confound relapse measurement in a discontinuation design. SUSTAIN-2 (up to one year) reported induction-phase remission and response rates of 47.2% and 78.4%, respectively, and optimization/maintenance rates of 58.2% and 76.5%; responders who continued treatment showed sustained symptom improvement. A post hoc comparison (Ochs‑Ross et al.) found similar efficacy in younger (18–64 years) and older (≥65 years) subgroups (mean MADRS change -16.6 vs -15.4; remission rates ~46.5% vs 50% post-induction). Other efficacy metrics: Citrome and colleagues’ pooled post hoc analysis across four randomized trials yielded a Number Needed to Treat (NNT, the number of patients who need treatment for one additional favourable outcome) below 10 for esketamine versus placebo, indicating potential clinical effectiveness though interpretation is qualified by study designs and populations. Safety: Across short-term and longer trials the most frequent adverse events (AEs) were nausea, dizziness, dissociation, headache, vertigo, somnolence and dysgeusia; most were mild–moderate and transient, typically emerging shortly after dosing, peaking around 40 minutes and resolving within about 1.5 hours. Gastaldon’s re-analysis found dissociation to be approximately seven times more likely with esketamine plus OAD versus placebo plus OAD, with about 25% of patients experiencing dissociation. Mean blood pressure increases were greater in esketamine groups; for example, TRANSFORM-2 reported mean maximum systolic increases of +11.6 mmHg (esketamine) versus +5 mmHg (placebo) and diastolic increases of +8.1 mmHg versus +4.5 mmHg. Serious events and rare signals: SUSTAIN-1 recorded serious AEs considered related to esketamine including dysautonomia, hypothermia, disorientation, lacunar stroke and a simple partial seizure; no deaths were reported. SUSTAIN-2 reported two deaths (one respiratory and cardiac failure, one suicide) that study reports judged unrelated to esketamine. Withdrawal-type symptoms at endpoint in SUSTAIN-2 included insomnia (22.7%), anxiety/nervousness (19.3%), difficulty concentrating/remembering (19.3%) and dysphoric mood (18.2%). A case/non-case pharmacovigilance study detected rare AEs such as panic attacks, ataxia, mania, akathisia, self-harm ideation, autoscopy and increased loquacity, and signalled events including dissociation, sedation, feeling drunk, euphoric mood, depression, suicidal ideation and completed suicide; that analysis suggested serious AEs were dose-dependent and more likely in females and in patients receiving multiple psychotropic or somatic treatments. The FDA has required a Risk Evaluation and Mitigation Strategy (REMS) for esketamine administration in supervised healthcare settings with post-dose monitoring, reflecting concerns about dissociation, sedation and potential for misuse or abuse. Limitations reported in the included studies included exclusion of patients with significant medical/psychiatric comorbidities, substance-use disorders or imminent suicide risk, limited non-white participant representation, potential unblinding due to characteristic acute AEs, and the presence of several post hoc analyses which may introduce bias.
Sapkota and colleagues interpret the assembled evidence as showing that intranasal esketamine can reduce depressive symptoms in TRD within clinical trial settings, with several trials reporting statistically significant or clinically meaningful group differences and long-term/relapse-prevention studies suggesting sustained benefit for some patients. They caution, however, that the clinical meaningfulness of the observed treatment effects and the generalisability of trial safety findings to real-world populations remain uncertain. The authors place their findings in the context of earlier research and regulatory action: approval of intranasal esketamine was driven by phase-three data, but critics and post‑licensing surveillance reports have raised safety signals that merit attention. Key uncertainties highlighted include the interpretation of discontinuation/withdrawal effects in relapse-prevention designs, the limited inclusion of medically or psychiatrically complex patients in trials, and the potential for unrecognised harms when the drug is used outside tightly supervised research settings. Important limitations acknowledged by the review include narrow trial populations (excluding comorbidities and active substance use), methodological issues such as potential unblinding from transient acute effects, reliance on post hoc analyses in parts of the evidence base and the exclusion of grey literature and ongoing trials from the review. These factors constrain the ability to judge long-term efficacy, real-world safety and comparative effectiveness against existing TRD treatments. As implications, the authors recommend continued post-marketing surveillance and enforcement of REMS-type safeguards, and they call for more robust, long-term randomised controlled trials and comparative studies to better define clinical benefit, long-term safety and the place of intranasal esketamine in treatment algorithms for TRD.
Intranasal esketamine demonstrates efficacy in reducing depressive symptoms in clinical-trial populations with TRD and has a largely transient and manageable adverse-event profile in those settings. Nonetheless, uncertainty remains about the clinical magnitude of benefit and the occurrence of rare but potentially serious harms in broader, real-world populations. The authors conclude that long-term randomized trials, comparative effectiveness studies and rigorous post-marketing monitoring are needed to clarify esketamine’s safety and clinical value in TRD.
Major depressive disorder (MDD) is a common psychiatric condition affecting around 264 million people worldwide. In the United States alone, an estimated 7.1% of the adult population (equivalent to 17.3 million adults) were reported to have at least one major depressive episode in 2017. MDD can impair psychosocial functioning and is one of the common antecedents of suicide. Biogenic amine antidepressants are effective medications for treating MDD, albeit with limitations; one of which being the delayed onset of effect ranging from four to six weeks. During this time, patients can remain symptomatic and are at risk of developing suicidal tendencies, which pose a major challenge to the treatment. Furthermore, around one-third of patients with MDD do not respond to antidepressant therapy and eventually may develop treatment-resistant depression (TRD). Despite a lack of consensus definition, TRD has been commonly defined as the failure of patients to respond to at least two different antidepressants given at an adequate dose and duration, in the current depressive episode. The management of TRD can be complex and difficult. It involves the use of multiple strategies such as switching therapies to a different antidepressant class; augmentation therapy using lithium, second-generation antipsychotics, and triiodothyronine; electroconvulsive therapy (ECT); and psychotherapeutic approach. More recently, ketamine, psilocybin, and anti-inflammatories are being considered as novel therapeutics. Esketamine is the S-enantiomer of racemic ketamine and is found to have three to four times more affinity for N-methyl-D-aspartate (NMDA) receptors than R-enantiomer of ketamine (arketamine), thus making esketamine efficient even at a lower dose. Intranasal form of esketamine was approved by the FDA for the treatment of TRD in adults in 2019. Since there's always been a growing need for new effective treatments for TRD, the approval of intranasal esketamine has received quite a momentum. While many have praised and welcomed esketamine as a novel therapy for TRD, other experts have raised questions regarding the legitimacy of its efficacy and safety in the real-world population. In the light of these new concerns, our research aims to assess further and add to the existing knowledge about esketamine, regarding its efficacy and safety, by conducting a systematic review using the latest existing evidence.
The databases such as PubMed, MEDLINE (through PubMed), and Google Scholar were systematically searched for collecting data. We explored the PubMed database with the help of Medical Subject Heading (MeSH) terms and keywords: Esketamine, Intranasal Esketamine, Treatment Resistant Depression. We performed an automated search (with the application of filters) on April 16, 2021, and came across 498 articles in PubMed. The details regarding the search strategies are described in Table.
Inclusion criteria: (a) study type: phase-three clinical trials, post hoc studies, observational studies and reviews (systematic reviews and narrative reviews); (b) language: English; (c) patients who are 18 years and above, with TRD; (d) intervention: intranasal esketamine (given along with oral antidepressant (OAD)). Exclusion criteria: animal studies, phase one and two clinical trials, gray literature, articles in languages other than English, case reports and series, letters to the editor, and studies published before 2016.
We obtained a total of 2208 articles after searching through databases using automation tools. Records were then screened on the basis of title and abstract, duplicates were removed, and 43 articles were retrieved. After applying inclusion/exclusion criteria and quality appraisal, we had a total of 10 articles. Two reviewers (AS and HK) went through screening process, quality assessment, and data extraction independently. Quality assessments were performed using the following tools: Narrative review= Scale for the Assessment of Narrative Review Articles (SANRA) Figureshows the PRISMA flow diagramwhich demonstrates the steps taken during the conduction of the search and the final articles included.
PRISMA: Preferred reporting items for systematic review and meta-analysis Tables 2, 3 summarize the characteristics of the studies included. We included a total of 10 studies which consisted of five phase-three clinical trials, three post-hoc studies, one case/non-case study, and one narrative review. Post hoc study Four phase-three clinical trials were reviewed (TRANSFORM-1, TRANSFORM-2, TRANSFORM-3, SUSTAIN-1). Efficacy re-analysis, as well as re-analysis of the incidence of dissociation, was done on three short-term phase-three clinical trials (TRANSFORM-
The mechanism of action of ketamine as an anesthetic has been well researched. However, much remains unknown about the basis of antidepressant effects of esketamine. One of the proposed mechanisms includes improvement in brain plasticity (via increased neuronal dendritic growth and improved synaptogenesis) by stimulating the production of brain-derived neurotrophic factor (BDNF) and by activating the mammalian target of rapamycin (mTOR). Studies show that ketamine has a more direct stimulating action on BDNF and mTOR compared to oral antidepressants. The same may apply to esketamine, and could explain the reason for its rapid onset of action, and the continuation of its effects even after elimination of the drug from the body. The intranasal form of esketamine has multiple positive benefits as opposed to other modes of administration, as it is less painful and invasive, while also having a greater bioavailability than oral form. Figureshows the proposed mechanism of action of esketamine.
NMDA: N-methyl-D-aspartate; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BDNF: brainderived neurotrophic factor; mTOR: mammalian target of rapamycin
Out of the three short-term (four weeks) induction studies (TRANSFORM-1, TRANSFORM-2, TRANSFORM-3) included in this review, only TRANSFORM-2 showed a statistically significant reduction in Montgomery-Asberg Depression Rating Scale (MADRS) in esketamine plus OAD group compared to placebo plus OAD group, with least squared mean difference (LSMD) of -4.0 (standard errror (SE) = 1.69, 95% confidence interval (CI) = -7.31 to -0.64, p = 0.020). The mean difference in MADRS scoring between esketamine plus OAD vs placebo plus OAD in TRANSFORM 1 (LSMD = -3.2, 95% CI = -6.88 to 0.45; p = 0.088) AND TRANSFORM 3 (LMSD = -3.6, 95% CI = -7.20 to 0.07, p = 0.059) was similar to TRANSFORM-2 but failed to yield a statistical significance. Clinically significant treatment effect was reported to be present in all three short-term studies. These studies have taken a mean difference of 2 points or higher in the MADRS score between two treatment arms (esketamine plus OAD vs placebo plus OAD) as the acceptable cut-off to define clinically meaningful benefit. However, there seem to be variations when it comes to defining "clinically meaningful improvement" among other experts, and this is one of the reasons why clinical relevance of these results has been debated. On a post hoc analysis done by Gastaldon et al., re-analysis was performed on the above mentioned clinical trials which showed a mean difference in MADRS score between esketamine plus OAD vs placebo plus OAD to be -4.08 (95% CI = -6.20 to 1.97), but the clinical meaningfulness of the result was stated to be uncertain. All three studies were similar in terms of study design including inclusion/exclusion criteria, but differed in dose regimen and age criteria (TRANSFORM-1 and TRANSFORM-2: age 18-64; TRANFORM-3: age ≥ 65 years) (Table). SUSTAIN-1was a relapse prevention study based on withdrawal design where patients who achieved stable remission or stable response were randomized to either continue esketamine or discontinue it and switch to placebo nasal spray, and subsequent relapse was measured between the two groups. Among the stable remitters, risk of relapse decreased by 51% in those receiving esketamine plus OAD (hazard ratio [HR] = 0.49, 95% CI = 0.29-0.84, p = 0.003) compared to placebo plus OAD. Among the stable responders, risk of relapse decreased by 70% in those receiving esketamine plus OAD (HR = 0.30, 95% CI = 0.16-0.55, p<0.001) compared to placebo plus OAD. However, this study has received several feedbacks from other researchers, with one of their biggest concerns being the study design itself. Some experts argue that the effects experienced as a result of withdrawal from esketamine can be mistaken for relapse of depressive symptoms, thereby confounding the result on relapse rate. SUSTAIN-2was a phase-three long-term (up to a year) study used to assess long-term efficacy and safety of esketamine and included patients of age group ≥18 years. The percentage of remitters and responders at the end of induction phase was 47.2% and 78.4%, respectively. Similarly, at the end of optimization/maintenance phase was 58.2% and 76.5%, respectively. In terms of efficacy, sustained improvement in depressive symptoms was reported among responders and in those who continued the treatment for up to a year. A post hoc study was conducted by Ochs-Ross et al.which compared the safety and tolerability of esketamine between young TRD patients aged 18-64 and older TRD patients aged ≥65 years included in SUSTAIN-2. Following the induction phase, mean change in the MADRS score was reported to be -16.6 in the younger age group and -15.4 in the older age group, with the remission rate being 46.5% and 50.0%, respectively. Similarly, the remission rate at the end of optimization/maintenance phase was reported to be 56.6% and 64.3% in the younger and older age groups, respectively. Thus, the efficacy of esketamine between the two age groups was found to be comparable. Moreover, a post hoc study conducted by Citrome et al.using data from four randomized clinical trialsshowed that Number Needed to Treat ( NNT) for efficacy outcome for esketamine vs placebo was less than 10, which indicates esketamine to be a potentially effective treatment for TRD.
The most commonly reported adverse effects (AE) in short-term clinical trialswere 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 studiesshowed 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. The most common symptoms reported in relapse prevention study and long-term clinical studywere dysgeusia, dissociation, vertigo, dizziness, and somnolence. Similar to the results of short-term clinical trials, these symptoms were mild to moderate in severity and most resolved on the same day of dosing. No respiratory depression or interstitial cystitis were observed in these studies. During the induction phase in SUSTAIN-1, the serious side effects considered to be due to esketamine included dysautonomia, hypothermia, disorientation, lacunar stroke, simple partial seizure, and sedation. No death was reported in this study. On the contrary, in SUSTAIN-2, two deaths were reported. One of the deaths was due to respiratory and cardiac failure and the other death was due to suicide. Psychotic-like symptoms following dosing were found to be transient and resolved the same day. Dissociative symptoms pattern in both the studies was comparable to short-term studies, and were observed shortly after dosing, peaked at 40 minutes, and resolved by 1.5 hours. In SUSTAIN-1, no withdrawal symptoms were observed, whereas in SUSTAIN-2, the most common withdrawal symptoms following discontinuation of esketamine at the endpoint were insomnia (22.7%), anxiety/nervousness (19.3%), difficulty concentrating/remembering (19.3%), and dysphoric mood-depression (18.2%). 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 studydetected 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. 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.
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Sanacora, G., Schatzberg, A. F. · Neuropsychopharmacology (2021)
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