Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation

Mcintyre and colleagues frame the paper by noting that a large proportion of people with major depressive disorder do not achieve full symptomatic or functional recovery with conventional monoamine-based antidepressants, and that remission rates in treatment-resistant depression (TRD) are reportedly less than 15% after two prior conventional treatment or augmentation failures. Intranasal esketamine received regulatory approval for TRD in 2019 (and an expanded U.S. indication in 2020 for major depression with suicidal ideation or behaviour), and growing clinical and public interest has accompanied expanding use of ketamine formulations. At the same time, uncertainties remain about long-term efficacy, safety, tolerability, patient selection, abuse liability, and appropriate clinical settings and personnel for safe implementation. This article presents an expert synthesis of the literature on ketamine and esketamine for adults with TRD, focusing on pharmacology, efficacy, safety, tolerability, and practical implementation at the point of care. The authors explicitly state this is not an exhaustive systematic review but rather an international expert opinion that summarises key findings from clinical trials, meta-analyses, regulatory documents, and preclinical work, and identifies areas of consensus and priorities for future research and implementation guidance.

The extracted text does not provide a conventional methods section describing a formal systematic search, selection criteria, or meta-analytic methods. Instead, the paper is presented as an international expert synthesis drawing on replicated randomized controlled trials, registration trial programmes (notably for intranasal esketamine), meta-analyses, preclinical studies, regulatory reports, and clinical experience from community and academic settings. Because the paper is an expert opinion rather than a formal systematic review, the authors note it is not meant to be exhaustive and that several recent systematic reviews and meta-analyses of ketamine and esketamine already exist. The synthesis integrates pharmacodynamic and pharmacokinetic data, randomized trial results and pooled estimates reported elsewhere (for example, an intranasal esketamine meta-analysis of five trials), safety and adverse-event data from development programmes, and practical considerations for patient selection, dosing, monitoring, and service delivery. The extracted text does not describe prespecified inclusion criteria, search dates, databases searched, or a formal risk-of-bias assessment.

Pharmacodynamics and pharmacokinetics: The authors summarise prevailing mechanistic hypotheses in which ketamine acts as an N-methyl-D-aspartate receptor (NMDAR) antagonist on GABAergic interneurons, producing a glutamate surge that activates AMPA receptors and downstream intracellular signalling (BDNF-TrkB-ERK, PI3-AKT-mTOR) that facilitate synaptogenesis. Other low-affinity targets, including mu-, kappa- and delta-opioid receptors, and ion channels, are described as potentially relevant. A small proof-of-concept human study (N=30) reported that pretreatment with naltrexone attenuated antidepressant and anti‑suicidal effects of an intravenous ketamine infusion, implicating opioidergic systems, but other small and post hoc data do not fully support a simple opioid-mediated mechanism. Pharmacokinetic points noted include route-dependent bioavailability (intravenous ~100% versus intranasal esketamine ~30%-50%), plasma protein binding ~10%-15%, elimination half-lives ~2–4 hours for racemic ketamine and ~5 hours for esketamine, and metabolic pathways involving CYP3A4 and CYP2B6 to norketamine and downstream metabolites. The text cautions that definitive dosing equivalence between intravenous racemic ketamine and intranasal esketamine is not established, although 0.5 mg/kg intravenous racemic ketamine has been estimated to approach the bioavailability of ~56 mg esketamine. Efficacy in TRD: Intranasal esketamine co-initiated with a conventional antidepressant and intravenous racemic ketamine (administered as monotherapy or adjunct) have the most compelling evidence base for short-term, rapid antidepressant efficacy in adults with TRD. The authors acknowledge concerns that functional unblinding (for example, dissociative effects) and expectancy might inflate apparent effect sizes. Dose-ranging data for intravenous ketamine suggest greater group-level efficacy at 0.5–1.0 mg/kg than at lower doses, but no clear evidence that 1.0 mg/kg is superior to 0.5 mg/kg. Intranasal esketamine registration trials used 56 mg and 84 mg doses, with an initial twice-weekly schedule for 4 weeks followed by weekly or biweekly maintenance. A cited meta-analysis of five intranasal esketamine trials (N=5,774) reported a standardized mean difference for Montgomery-Åsberg Depression Rating Scale change of 0.36 (95% CI 0.24 to 0.49, p<0.0001). The pooled risk ratios for response and remission were 1.4 and 1.45 (both p<0.0001), with numbers needed to treat of 6 for response and 7 for remission. Relapse-prevention analyses showed intranasal esketamine plus an antidepressant reduced relapse risk by 51% among those in stable remission and 70% among those with stable response, although the authors note site-specific anomalies influenced results and that elderly (≥65 years) efficacy is not clearly established. Comparative effectiveness and other formulations: No adequately powered head‑to‑head trials definitively comparing intravenous racemic ketamine and intranasal esketamine exist. Some analyses suggest similar efficacy across routes at early timepoints, while others report possible superiority of intravenous ketamine in some outcomes, but heterogeneity across studies limits firm conclusions. Preliminary and limited data exist for oral, intramuscular and subcutaneous ketamine, with oral bioavailability noted to be low (10%–20%) and sublingual higher (~30%); these formulations lack robust randomized controlled evidence for acute rapid-onset efficacy. Suicidality: Single‑dose and repeat‑dose studies report rapid reductions in suicidal ideation, often evident for up to 7 days after single dosing and in some repeat-dose studies for up to 6 weeks. The reduction in suicidal ideation may partly be independent of overall depression symptom change. However, phase 2 and 3 trials of intranasal esketamine in patients at imminent suicide risk did not demonstrate significant reductions in suicidal ideation versus placebo at 24 hours or at later prespecified timepoints, although these programmes contributed to the FDA approval for major depression with suicidal ideation or behaviour. No data were reported with suicidality as a primary outcome for maintenance treatment. Tolerability and safety: Adverse events are grouped as psychiatric (dissociation, psychotomimetic effects), neurologic/cognitive, hemodynamic, genitourinary, and abuse liability. Dissociation is common and more frequently reported in intravenous racemic ketamine studies (about 72% of trials report dissociation) than in non‑intravenous studies (36%); dissociation typically peaks within ~40 minutes and resolves within 1–2 hours, and rates decline with repeated administration. The Clinician‑Administered Dissociative States Scale (CADSS) has been widely used but is considered by the authors to undercapture the full range of psychotomimetic experiences. Psychosis induction remains a concern in vulnerable individuals; preliminary evidence suggests people with a history of psychosis are more prone to dissociation but not necessarily sustained psychosis when treated. Neurologic and cognitive effects reported in trials have not shown replicated persistent cognitive deficits with racemic ketamine in TRD; 1‑year intranasal esketamine exposure was not associated with cognitive impairment in the development programmes. Preclinical signals of neurotoxicity (for example, excitotoxic lesions) exist, but their relevance to clinical maintenance use is unknown. Hemodynamic effects include dose‑dependent increases in heart rate and blood pressure, reported in 10%–50% of patients and typically transient within 2–4 hours; esketamine trials reported antihypertensive treatment in 2.1% of patients versus 1.2% with placebo. Genitourinary toxicity (lower urinary tract symptoms) is well described in recreational users (20%–40%) with some persistent cases (~5%), but repeated‑dose intranasal esketamine trials have not identified a significant signal for genitourinary toxicity. Abuse liability: Ketamine is a scheduled, potentially abusable substance and increases subjective drug liking in healthy volunteers and recreational users at clinical doses. The authors report no clear evidence that clinical use of racemic ketamine or esketamine, when administered in trial or programme settings, has increased incidence of substance use disorder, but long‑term surveillance data are limited. An open‑label 1‑year esketamine safety study reported no new‑onset drug or alcohol misuse among completers, but post‑study status is unknown. Implementation, patient selection, dosing and monitoring: The authors recommend that ketamine and esketamine be used primarily for adults with TRD—commonly defined in trials as failure to respond to at least two antidepressants—and note preliminary, investigational evidence for bipolar depression, OCD and PTSD. Contraindications or relative exclusions include uncontrolled hypertension, significant cardiac disease, recent cardiovascular events, and prior hypersensitivity to ketamine. For intravenous ketamine, a commonly recommended starting infusion is 0.5 mg/kg over 40 minutes, with dosing based on ideal body weight for overweight/obese patients; clinicians are advised to reassess after four to six infusions and consider discontinuation if minimal response (#20% improvement). Intranasal esketamine dosing starts at 56 mg and may be titrated to 56–84 mg twice weekly for 4 weeks, then weekly or biweekly; therapeutic benefit should be judged after 4 weeks. Settings should have personnel trained in mood‑disorder assessment and cardiorespiratory monitoring; in the U.S., esketamine requires a Risk Evaluation and Mitigation Strategy (REMS) with at least 2 hours of post‑dose monitoring before discharge. The recommended monitoring includes vital signs, cardiorespiratory surveillance, assessment of dissociation and psychotomimetic effects, and patient transport arrangements. Maintenance and duration: Intranasal esketamine has trial evidence supporting safety and efficacy up to 1 year; long‑term data for intravenous ketamine are inadequate. Strategies tested to prolong ketamine benefit (for example, adjunctive lithium or riluzole) have not produced replicated positive results. Repeated dosing prolongs benefit relative to single dosing, but most patients relapse within about a month (median ~18 days) after a single administration.

The authors interpret the assembled evidence as indicating that ketamine and intranasal esketamine represent important, rapid‑onset, non‑monoaminergic treatment options for adults with TRD, with replicated short‑term antidepressant efficacy and, for esketamine, more rigorous short‑ and longer‑term data including relapse‑prevention findings. They emphasise that functional unblinding, heterogeneity across trials, and methodological differences complicate effect-size interpretation and comparisons across formulations and routes of administration. Safety and tolerability are highlighted as central uncertainties. The paper draws attention to psychiatric adverse events such as dissociation and psychotomimetic experiences, transient hemodynamic changes including dose‑dependent blood pressure elevations, genitourinary toxicity described in recreational users, and the theoretical and observed signals for abuse liability. The authors note specific concerns flagged in regulatory adverse‑event reporting, including reports linking esketamine with dissociation, sedation, “feeling drunk,” suicidal ideation and completed suicide in pharmacovigilance databases, and they call for fuller characterisation of rare but serious events through larger datasets. Key limitations are acknowledged: absence of a definitive head‑to‑head comparison between intravenous racemic ketamine and intranasal esketamine, insufficient long‑term controlled data for intravenous ketamine, heterogeneity of study populations and designs, and a lack of validated biomarkers or clinical predictors that reliably forecast individual response or safety. The authors also note limited evidence for some patient groups (older adults, people with comorbid substance use disorders, psychotic depression) and for alternative formulations (oral, subcutaneous, intramuscular). For clinical practice and research, the authors recommend restricting administration to settings with appropriate infrastructure and multidisciplinary personnel, applying recommended monitoring (including REMS where applicable), and using conservative patient‑selection criteria aligned with the TRD evidence base. They call for a data commons or access to large public/private databases to detect infrequent adverse events, studies of predictors of response and safety (including pharmacogenomics), trials combining ketamine with manual‑based psychotherapies, trials testing strategies to prolong benefit, and further empirical work on abuse risk, withdrawal phenomena, and comparative effectiveness versus other somatic interventions such as ECT and second‑generation antipsychotics.

Mcintyre and colleagues conclude that intravenous ketamine and intranasal esketamine offer important rapid‑onset therapeutic options for adults with TRD but that substantial gaps remain regarding long‑term efficacy and safety. They urge ongoing post‑treatment surveillance to characterise rare and delayed adverse events, caution that these agents should be delivered only in centres with appropriate infrastructure and multidisciplinary expertise, and prioritise research to identify response predictors, safer maintenance strategies, and the relative risk of substance‑use consequences. The authors list research priorities including data‑sharing initiatives, biomarker development, trials of maintenance and combination psychosocial approaches, evaluation of other formulations and derivatives, and further safety characterisation.