Esketamine Nasal Spray: Mechanism of Action, Clinical, and Translational Science

ABSTRACT

Major depressive disorder (MDD) imposes a substantial burden worldwide, with treatment‐resistant depression (TRD) and major depressive disorder with acute suicidal ideation or behavior (MDSI) representing two of the most severe clinical challenges. Conventional antidepressants often require several weeks to exert benefit, leaving patients symptomatic and at risk during this delay. Esketamine nasal spray was the first glutamate‐modulating antidepressant to enter clinical practice and was recently approved as the first and only monotherapy for adults with TRD. Administered at 56 mg or 84 mg, esketamine offers a rapid onset of action. Intranasal delivery yields approximately 50% bioavailability and peak concentrations within 20–40 min, correlating with early clinical effects. N‐methyl‐D‐aspartate (NMDA) receptor antagonism on inhibitory interneurons disinhibits glutamate release and modulates downstream synaptic plasticity pathways, providing a mechanistic basis for the rapid antidepressant effects of esketamine. This review summarizes the regulatory approval, mechanism of action, and pharmacokinetic/pharmacodynamic characteristics, together with key clinical trial efficacy and safety data for esketamine nasal spray in TRD and MDSI.

Clinical and Translational Card for Esketamine Nasal Spray.

• Putative mechanism of action

  • ○
    Non‐competitive NMDA receptor antagonist; blocks NMDA receptors on inhibitory GABAergic interneurons, leading to disinhibition of glutamate release, and activation of AMPA receptors and downstream plasticity pathways (BDNF, mTORC1).
• Indication(s)

  • ○
    Treatment‐resistant depression (TRD), as monotherapy or in conjunction with an oral antidepressant, and depressive symptoms in major depressive disorder with acute suicidal ideation or behavior (MDSI) in conjunction with an oral antidepressant.
• Dosage and administration

  • ○
    56 or 84 mg, twice weekly during induction, followed by every 1 or 2 weeks during maintenance in TRD. 84 mg twice weekly in MDSI, with option to reduce to 56 mg based on tolerability. Administered as intranasal spray.
• Major Metabolic Pathway

  • ○
    Primarily hepatic metabolism via cytochrome P450 (CYP) 2B6 and CYP3A4.
• Key PK Characteristics

  • ○
    Intranasal bioavailability ~50%, short t _max of 20–40 min, large volume of distribution (~750 L), moderate protein binding (43–47%), initial rapid decline in plasma concentrations followed by a terminal elimination half‐life of 7–12 h, with negligible excretion of unchanged drug in urine.

1. Introduction

Major Depressive Disorder (MDD) is a prevalent and debilitating illness, affecting millions worldwide [1]. Up to one‐third of patients fail to respond to at least two adequate antidepressant trials within the index depressive episode and are considered to have treatment‐resistant depression (TRD) [2]. These individuals face ongoing severe depressive symptoms despite conventional treatments, and remain at heightened risk for suicidal ideation or behavior [3]. Traditional monoaminergic antidepressants often require weeks to achieve their therapeutic effect [4], leaving a critical gap in providing relief during which patients remain symptomatic. In this context, the discovery and regulatory approval of the rapid‐acting antidepressant esketamine nasal spray has been a major breakthrough. Esketamine, the S‐enantiomer of ketamine, is a non‐competitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist that modulates glutamatergic neurotransmission [5, 6], affording a mechanism distinct from that of conventional antidepressants. The intranasal formulation of esketamine (brand name SPRAVATO) offers a pragmatic route of administration in clinical settings. In 2019, esketamine nasal spray became the first glutamate‐based antidepressant approved for adults with TRD [7], introducing a new therapeutic paradigm for refractory depression. The scope of its use more recently was expanded to include adults with MDD and acute suicidal ideation or behavior (MDSI) [8], reflecting its ability to provide rapid symptom relief in psychiatric emergencies. Last year, the U.S. Food and Drug Administration (FDA) approved esketamine nasal spray as the first and only monotherapy in the treatment of TRD. This mini‐review summarizes the regulatory approvals, clinical pharmacology, efficacy, and safety profiles of esketamine, highlighting evidence from pivotal trials for both TRD and MDSI.

2. Regulatory Approval

Esketamine nasal spray was approved by the U.S. FDA in 2019 as an adjunctive therapy for adults with TRD, defined as MDD patients who have not responded to at least two antidepressants in the current episode [7]. Approval was based on a favorable benefit–risk in clinical trials when esketamine was combined with an oral antidepressant [7]. Under the FDA‐mandated Risk Evaluation and Mitigation Strategy (REMS) program, esketamine must be administered in certified healthcare settings with patients monitored for at least 2 h post‐dose to monitor for potentially serious sedation and dissociation [7]. The drug is classified as a Schedule III controlled substance, given its chemical relation to ketamine and potential for abuse. In December 2019 the European Medicines Agency (EMA) also approved esketamine for adults with TRD [9], aligning with the FDA and marking the first glutamatergic antidepressant in mainstream use. Subsequently, esketamine has been approved for use in TRD by health authorities in over 70 countries.

In 2020, the FDA‐approved label of esketamine was broadened with the approval of esketamine for the treatment of depressive symptoms in adults with MDSI as the first antidepressant specifically indicated for rapidly reducing depressive symptoms in actively suicidal patients [8]. Esketamine's MDSI indication is as an acute intervention aimed at “bridging the gap” in depressive symptom relief until traditional treatments take effect [8].

In 2025, the FDA additionally approved esketamine nasal spray as the first and only monotherapy for TRD. The new indication allows clinicians to prescribe esketamine without concurrent oral antidepressant therapy, which is particularly valuable for patients who cannot tolerate or who receive no benefit from oral antidepressants and thus seek to avoid their side effects.

3. Mechanism of Action

Esketamine's antidepressant effect putatively is attributable to the modulation of glutamatergic transmission rather than the inhibition of monoamine neurotransmitter reuptake. The (S)‐enantiomer of ketamine (esketamine) has about a 3‐ to 4‐fold higher affinity for the NMDA receptor than the R‐enantiomer (arketamine) [10]. Esketamine acts as a non‐selective, non‐competitive, open channel NMDA receptor antagonist, and at the exposures achieved at antidepressant doses is thought to preferentially act on NMDA receptors located on inhibitory γ‐aminobutyric acid (GABA)‐releasing interneurons because of the rapid opening and closing of these channels (Figure 1) [11]. By transiently blocking these NMDA receptors, esketamine is thought to briefly disinhibit glutamate release in key mood‐regulating circuits [12], resulting in the stimulation of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors post‐synaptically. This AMPA activation triggers intracellular signaling cascades that enhance synaptic plasticity. Notably, downstream effects reportedly include increased release of brain‐derived neurotrophic factor (BDNF) and activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway, which promote synaptogenesis in the medial prefrontal cortex and hippocampus [11, 13]. These changes can reverse stress‐induced neural atrophy and are believed to underlie the rapid alleviation of depressive symptoms [14]. Nevertheless, the precise antidepressant mechanism is still being established [15], as esketamine also engages other targets, including dopaminergic, serotonergic, adrenergic, cholinergic, opioid, and sigma receptors [16]. The rapid onset of esketamine's mood effects is attributed to neuroplastogenic mechanisms that result in synaptogenesis and potentiation of glutamatergic synapses [17, 18]. This represents a paradigm shift from traditional antidepressants and opens avenues for treating acute suicidality and TRD by targeting glutamate neurotransmission or other neuroplastogenic mechanisms [19].

FIGURE 1.

Intranasal dosing enables esketamine to cross the epithelial layers and enter the dense vascular plexus of the nasal cavity, bypassing first‐pass metabolism. Entry into the bloodstream allows fast systemic distribution and penetration into the brain. Upon crossing the blood–brain barrier, esketamine non‐competitively blocks NMDA receptors on inhibitory GABAergic interneurons in the cortex. By transiently reducing NMDA activity, esketamine disinhibits glutamate release, which activates postsynaptic AMPA receptors. This cascade is believed to enhance synaptic plasticity through BDNF release and mTORC1 activation, promoting synaptogenesis and connectivity in mood‐regulating circuits. AMPA, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid; BDNF, brain neurotrophic factor; F, bioavailability; GABA, γ‐aminobutyric acid; mTORC1, mammalian target of rapamycin complex 1; NMDA, N‐methyl‐D‐aspartate; TkrB, tropomyosin receptor kinase B.

4. Pharmacokinetic/Pharmacodynamic (PK/PD) Characteristics

Esketamine is administered as a metered intranasal spray, a route that ensures quick absorption while avoiding extensive first‐pass metabolism. The nasal spray delivers esketamine primarily to the respiratory epithelium (Figure 1) [20]. Intranasal bioavailability is approximately 50% at therapeutic doses [21], markedly higher than oral racemic ketamine (bioavailability 16%–29% [22]) due to bypassing gut and liver first‐pass effects. After intranasal dosing, esketamine reaches peak plasma concentrations (t _max) in about 20–40 min [21]. This rapid absorption correlates with the onset of transient side effects (e.g., dissociation, sedation, blood pressure elevation) within the first hour of administration [23, 24]. The drug is lipophilic with a large volume of distribution (~750 L) [21], indicating extensive tissue uptake, which occurs rapidly with an initial distribution (α phase) half‐life of approximately 7 min following intravenous administration [25]. The terminal elimination half‐life of intranasal esketamine is approximately 7–12 h [21, 26]. Despite extensive and rapid tissue distribution followed by a relatively short elimination half‐life, esketamine produces antidepressant effects that endure for several days, putatively reflecting neuroplastic adaptations that outlast any significant receptor occupancy of the drug [18]. Esketamine is moderately protein‐bound (43%–47%) in plasma [26, 27]. It undergoes hepatic metabolism primarily via CYP2B6 and CYP3A4 to form noresketamine [22]. While CYP enzymes are present in nasal mucosal tissues [28], their total concentration is approximately 5% of hepatic levels [29], indicating that metabolism within the local nasal mucosa is unlikely to meaningfully affect systemic esketamine exposure. The major metabolite noresketamine is less potent at the NMDA receptor [30] and has a 4–6 times lower brain‐to‐plasma ratio than the parent drug [26]. Furthermore, estimated brain concentrations and NMDA receptor occupancy of norketamine suggest this metabolite accounts for a relatively small proportion of the NMDA receptor antagonism [31]. Taken together, these findings suggest that noresketamine plays a limited role in the therapeutic effects observed with esketamine. Metabolites are excreted mainly in urine (around 78%), with minimal (< 1%) unchanged drug excreted [26]. No clinically significant pharmacokinetic drug–drug interactions have been identified; for instance, inducing metabolism with oral rifampin only modestly decreased the esketamine area under the plasma concentration‐time curve (AUC) by up to approximately 30% following intranasal and intravenous administration [26, 32].

Pharmacodynamically, esketamine's clinical effects are marked by rapid and sustained antidepressant action and a well‐characterized safety profile, including transient dissociative and hemodynamic effects. Patients often experience perceptual disturbances (dissociation), derealization, or dizziness shortly after dosing [33], reflecting its NMDA antagonist activity in the cortex [34, 35]. These symptoms typically peak within 40 min of the dose and resolve by about 1.5–2 h post‐dose [23, 24], presumably related to the aforementioned rapid clearance from plasma as the parent drug redistributes in body tissues. Esketamine can cause acute blood pressure elevations (increase in systolic and diastolic blood pressure) within the first hour after administration [23, 24]. Between the clinically used 56 mg and 84 mg doses, differences between the maximum mean changes in systolic and diastolic blood pressure are small and not suggestive of a dose‐dependent effect. Blood pressure is monitored at regular intervals following each dose; significant hypertension is rare and usually transient [36]. Due to these acute effects, patients administer esketamine under the direct supervision of a healthcare provider and remain under observation by a healthcare provider until the acute psychoactive and cardiovascular effects dissipate. Importantly, repeated dosing tends to attenuate the intensity of dissociative side effects over time [37, 38]. To illustrate, esketamine‐induced dissociation, as measured by the Clinician Administered Dissociative States Scale (CADSS), was most pronounced on Day 1, averaging 8.4 at 40 min post‐dose in the TRANSFORM‐2 study, and declined steadily across consecutive doses to 3.6, on average, by Day 25 (40 min post‐dose), a mean value that is below the threshold for significant dissociation [38]. Antidepressant effects appear to be sustained long‐term, with a manageable safety profile and no signs of physiological tolerance within approved dosing schedules [39, 40, 41].

In the treatment of TRD, esketamine is given as monotherapy or in conjunction with an oral antidepressant. Treatment is initiated at either 56 mg (two nasal spray devices) or 84 mg (three nasal spray devices) on the first treatment session and given twice weekly during an induction phase (Weeks 1–4). The 56‐ and 84‐mg intranasal doses attain plasma concentrations similar to those from a 0.2 mg/kg 40‐min intravenous infusion of esketamine [42], which showed robust antidepressant effects that were similar to those achieved using a higher dose (0.4 mg/kg) in a proof‐of‐concept study [43]. Regarding dosing frequency, an earlier study with intravenous ketamine showed no meaningful difference in the antidepressant response between twice and thrice weekly dosing, suggesting that a twice‐weekly schedule is sufficient for repeated administration [37]. After induction, patients with clinical benefit enter a maintenance phase where dosing is reduced to once weekly (Weeks 5–8) and then every 1–2 weeks thereafter depending on stability of remission [26]. The pharmacodynamic rationale is that repeated intermittent stimulation of glutamate pathways helps consolidate synaptic improvements and maintain antidepressant effects, as evidenced by significantly lower relapse rates with continued dosing [39]. In managing MDSI, esketamine is administered in combination with an oral antidepressant, where therapy is initiated at 84 mg twice weekly for 4 weeks. The 84‐mg starting dose was selected to offer the greatest potential for rapid onset of efficacy and longer durability of effect while maintaining acceptable tolerability in actively suicidal patients [44]. However, as indicated in the approved label, the dosage may be reduced to 56 mg twice weekly based on tolerability.

5. Key Clinical Trials

Esketamine nasal spray has been investigated in a broad clinical development program in TRD and MDSI, including early Phase 1 studies, key Phase 2 trials [42, 45], and large Phase 3 investigations, such as the long‐term SUSTAIN‐3 study [41] and the active‐controlled (quetiapine extended release) ESCAPE‐TRD trial [46]. Here, select pivotal adult Phase 3 trials and the pediatric development are highlighted.

TRANSFORM‐1 was a randomized, double‐blind, active‐controlled 4‐week Phase 3 trial in adults with TRD (N = 346 randomized), comparing fixed doses of esketamine (56 mg or 84 mg) together with a newly initiated oral antidepressant vs. an oral antidepressant with placebo nasal spray [23]. The primary endpoint was change in Montgomery‐Åsberg Depression Rating Scale (MADRS) score at Day 28, performed by blinded, remote raters. This trial did not meet its prespecified primary outcome. The high‐dose (84 mg) esketamine group showed a greater MADRS improvement than placebo, but the difference fell short of statistical significance (least‐squares [LS] mean difference [95% confidence interval (CI)] = −3.2 [−6.88 to 0.45]). Because of the hierarchical testing design, the 56 mg dose could not be formally tested; however, a nominal analysis suggested the 56 mg dose had about a 4‐point greater MADRS improvement vs. placebo (LS mean difference [95% CI] = −4.1 [−7.67 to −0.49]). For context, the minimum clinically important difference estimates between experimental treatment and control groups for the MADRS scale range between mean changes of 1.6 and 1.9 points [47]. Common adverse events in this study were dissociation, dizziness, nausea, and increased blood pressure, consistent with esketamine's known effects. In summary, TRANSFORM‐1 was a negative trial by primary analysis, but was considered suggestive of efficacy and confirmed the expected safety profile [7].

TRANSFORM‐2 was a randomized, double‐blind, active‐controlled 4‐week Phase 3 trial in adults with TRD (N = 227 randomized), using flexible esketamine dosing (twice weekly, initiated at 56 mg, with the possibility to increase the dose to 84 mg based on efficacy and tolerability thereafter) in combination with a newly initiated oral antidepressant vs. an antidepressant with placebo nasal spray [24]. This was one of the positive pivotal trials supporting FDA approval [7]. By Day 28, the esketamine group had a significantly larger reduction in MADRS scores compared to placebo. The treatment difference was in the order of 4 points on the MADRS in favor of esketamine (LS mean difference [95% CI] = −4.0 [−7.31 to −0.64]), a separation greater than that typically observed between oral antidepressants and placebo [48]. Clinically, more patients achieved response or remission with esketamine augmentation than with antidepressant alone [24]. TRANSFORM‐2's positive result was bolstered by secondary endpoints showing rapid onset of antidepressant effect, with clinically meaningful separation from placebo becoming evident at 24 h after the first dose. The safety findings mirrored TRANSFORM‐1. The most common side effects (dissociation, dizziness, vertigo, nausea, dysgeusia) were transient and more frequent in the esketamine group.

SUSTAIN‐1 was a Phase 3 longer‐term, double‐blind, randomized withdrawal study that evaluated esketamine's ability to prevent relapse of depression in TRD (N = 297 randomized) [39]. Patients who achieved stable remission or stable response after an induction and optimization phase with esketamine with an oral antidepressant were randomized to either continue esketamine (maintenance) or switch to placebo nasal spray, while continuing the oral antidepressant. Continued esketamine treatment significantly reduced the risk of depressive relapse compared to discontinuation. In patients who were in stable remission, the relapse rate was significantly lower in the esketamine group versus the placebo group. Specifically, esketamine together with an oral antidepressant decreased relapse risk by about 51% (hazard ratio [HR] [95% CI] = 0.49 [0.29 to 0.84]) relative to antidepressant alone. In those with stable response (but not full remission), the protective effect was larger still (HR [95% CI] = 0.30 [0.16 to 0.55]). Time‐to‐relapse was significantly longer with esketamine; for example, over the maintenance period, 26.7% of patients who achieved stable remission on esketamine relapsed vs. 45.3% on placebo (HR [95% CI] = 0.49 [0.29 to 0.84]). These findings demonstrate maintenance esketamine therapy sustains the initial clinical gains and prevents early recurrence of depression. SUSTAIN‐1 was pivotal in demonstrating the benefits for ongoing use of esketamine in TRD.

ASPIRE‐1 and ASPIRE‐2 were two identically designed double‐blind, randomized, placebo‐controlled Phase 3 trials in adults with MDSI (N = 226 and 230 randomized in ASPIRE‐1 and 2, respectively) [49, 50]. These trials evaluated esketamine (84 mg twice weekly for 4 weeks, with the possibility of a one‐time dose reduction to 56 mg after the first dose based on tolerability) given in addition to comprehensive standard of care (SOC; which included initial psychiatric hospitalization and a newly initiated oral antidepressant) vs. placebo nasal spray with SOC. The primary endpoint in each trial was the change in MADRS score 24 h after the first dose, aiming to capture rapid efficacy in a crisis setting. Esketamine produced a statistically significant and clinically meaningful greater reduction in MADRS scores at 24 h compared to placebo with SOC in each study. The results showed an improvement of approximately 4 points larger with esketamine than placebo at 24 h (LS mean difference [95% CI] = −3.8 [−6.56 to −1.09] and −3.9 [−6.60 to −1.11] for the ASPIRE‐1 and ‐2 studies, respectively). In both studies, esketamine's treatment difference compared to placebo in the context of comprehensive SOC was observed starting at 4 h post first dose. By the end of the 4‐week treatment period, group differences in MADRS scores remained and both arms improved substantially with ongoing treatment and support [49, 50]. Measures of suicidal ideation (using clinician‐rated scales like the Clinical Global Impression of Severity of Suicidality Revised version [CGI‐SS‐R]) improved in both the esketamine and control groups (who both received rigorous SOC treatment including hospitalization) but did not differ significantly between esketamine and placebo by 24 h in the Phase 3 trials. Consistent with that, the FDA's approval for MDSI was granted on the basis of depression symptom reduction, with a labeling note that no suicide prevention benefit has been established. The safety profile in ASPIRE trials matched previous studies, with transient dissociation, sedation, blood pressure rises, headache, and nausea being common, but no drug‐related deaths or suicides in the trials [49, 50]. All patients were observed in clinical settings, and adverse effects typically resolved the same day. Taken together, ASPIRE‐1 and ‐2 demonstrated that esketamine can be a valuable acute intervention in patients at high risk, treating depressive symptoms within hours—a critical window when managing patients experiencing suicidal crises.

A Phase 4, double‐blind, placebo‐controlled trial provided the foundation for esketamine's approval as monotherapy for TRD [51]. In this pivotal study, adults with treatment‐resistant depression received esketamine nasal spray alone, without an added oral antidepressant, at fixed doses of 56 or 84 mg twice weekly for 4 weeks or intranasal placebo (N = 378 randomized in Efficacy Analysis Dataset). Results showed a statistically significant and clinically meaningful improvement in depressive symptoms (MADRS score) at both doses as early as 24 h after the first dose (LS mean difference [95% CI] = −3.8 [−6.29 to −1.22] and −3.4 [−5.89 to −1.00] for the 56 mg and 84 mg doses, respectively). By Week 4, the LS mean differences (95% CI) were −5.1 (−7.91 to −2.33) and −6.8 (−9.48 to −4.07) for the 56 mg and 84 mg doses, respectively, and remission rates were 2‐ to 3‐fold higher in the esketamine arm compared to placebo. These findings confirmed that esketamine's antidepressant effect does not rely solely on synergy with traditional monoaminergic agents and validated its role as a standalone, rapid‐acting intervention. The safety profile remained consistent with earlier studies, with no new adverse signals observed.

A Phase 2b trial published by Kosik‐Gonzalez et al. [52] evaluated esketamine nasal spray in adolescents aged 12 to < 18 years with MDSI (N = 147 randomized). In this randomized, double‐blind, double‐dummy study, patients received fixed doses of esketamine (28 mg, 56 mg, or 84 mg twice weekly) or oral midazolam with intranasal placebo, alongside SOC treatment. Population pharmacokinetic model‐based simulations indicated comparable esketamine exposure between adolescents and adults, which informed the dosing approach for the pediatric trial. When pooled (primary endpoint), the 56 mg and 84 mg esketamine groups demonstrated significantly greater improvement in depressive symptoms on the Children's Depression Rating Scale‐Revised (CDRS‐R) at 24 h post‐dose compared to midazolam (LS mean difference [95% CI] = −5.8 [−11.2 to −0.35]). The 28 mg dose did not show a statistically significant effect (LS mean difference [95% CI] = −2.4 [−9.08 to 4.19]). A significant dose–response relationship in CDRS‐R total score was observed 24 h after the first dose (multiple trend test, one‐sided p = 0.030). Improvements persisted through Day 25 for all esketamine doses. Suicidality scores, as measured by CGI‐SS‐R, improved across all groups, but between‐group differences were not statistically significant. The safety profile was similar to that in adults, characterized by transient dissociation (occurring shortly post‐dose, typically resolving in 1.5 h, and attenuating with repeated dose administration), along with dizziness, nausea, and temporary blood pressure elevations consistent with those observed in adults ASPIRE trials [52]. These results support ongoing pediatric development to confirm these findings in a Phase 3 trial.

6. Clinical Efficacy and Safety

In summary, esketamine nasal spray has demonstrated clinically meaningful antidepressant effects in patients with TRD and in those with MDSI. The totality of evidence supports its role as a treatment, either alone or in combination with oral antidepressants in TRD, and as an effective adjunctive therapy for patients with MDSI. Esketamine is rapidly absorbed through the nasal mucosa, with peak plasma concentrations reached within 20–40 min, and its pharmacodynamic effects on glutamatergic transmission translate into symptom relief that can begin within hours. For patients at high risk, such as those recently hospitalized with suicidality, this rapid onset provides stabilization when it is most urgently needed. Safety data manifest a consistent profile, with transient dissociation, dizziness, and short‐lived blood pressure elevations being the most frequent adverse events. These generally peak within the first hour post‐dose and typically resolve within 1.5–2 h post dose. Long‐term studies indicate antidepressant effects persist over time, accompanied by a consistent and manageable safety profile, supporting esketamine's sustained use under appropriate supervision.

Funding

The authors have nothing to report.

Conflicts of Interest

M.W.v.H. D.J.F, W.C.D, and P.N.Z. are employees of Johnson & Johnson and hold stock and/or stock options in the company.