Efficacy and Safety of Intranasal Esketamine in Treatment-Resistant Depression in Adults: A Systematic Review

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.