Esketamine is the only pharmacological agent with glutamatergic neuromodulatory properties approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2019 to enhance the effects of serotonin selective or serotonin and norepinephrine reuptake inhibitors (1). In the context of high rates of partial responsivity or non-response to currently available antidepressants, multiple mechanisms of action for novel pharmacological agents are being explored besides the stimulation of monoaminergic neurotransmission (2,3). However, although numerous molecules have been studied in phases II and III of clinical research, it is difficult to predict which will reach the market in the following decades. Until now, only esketamine and brexanolone, the latter being a γ-aminobutyric acid (GABA)-A receptor positive allosteric modulator, are antidepressants with non-monoaminergic activity, that have been approved by FDA for use under supervision in patients with treatment-resistant depression (TRD) and post-partum depression, respectively (4). Furthermore, tolerability issues associated with antidepressants already in clinical use indicate the need to find novel pharmacological agents for treating major depression (5).

Esketamine nasal spray is recommended for adults diagnosed with major depressive disorder (MDD) who did not respond to at least two antidepressants, and who currently have a major depressive episode of moderate or severe intensity (1,6). Intensive monitoring is mentioned in the EMA approval and specified in the summary of the characteristics of the product, with an algorithm of pre- and post-administration assessment (6). Similar recommendations have been formulated by the FDA (1,6).

The pharmacodynamic profile of esketamine is characterized by non-selective, non-competitive antagonism of N-methyl-D-aspartate (NMDA) receptors, which are ionotropic glutamatergic receptors (Table I) (6). Activation of NMDA receptors causes a transient increase in glutamate release, leading to stimulation of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (6). Furthermore, signaling via neurotrophic factors is enhanced and synaptogenesis is improved in brain regions involved in regulating mood and emotional behavior (6). Restoring dopaminergic neurotransmission from areas responsible for regulating motivation and reward contributes to a rapid clinical response (for example, reduction of anhedonia), but the release of dopamine in the striatum may explain the psychotomimetic effects of this agent (Fig. 1) (6,7). The fast onset of esketamine may be associated with direct stimulation of the mammalian target of rapamycin complex 1 (mTORC1), a signaling pathway involved in the regulation of protein synthesis, which stimulates synaptogenesis and brain-derived neurotrophic factor production (8).

Glutamatergic mechanisms of depression are currently the focus of attention after preclinical studies supported the importance of this neurotransmission system in the pathogenesis of mood disorders (9,10). Abnormal levels of glutamate are found in cerebrospinal fluid, plasma and brain tissue during autopsy studies in individuals with mood disorders (10). Magnetic resonance spectroscopy detects abnormal levels and ratios of glutamate/GABA in brain areas associated with MDD (10). Glial cell functionality may be decreased after exposure to prolonged stress, leading to synaptic loss and activation of the apoptotic pathway via glutamatergic mediation (10). Ketamine is associated with rapid-acting antidepressant effects and NMDA receptor-mediated signaling, inhibition of extrasynaptic NMDA receptors and blockade of NMDA receptors in the synapse (9,10). Ketamine blocks excitatory glutamate transmission and increases overall activity of the prefrontal cortex by inhibiting NMDA receptors expressed in GABA neurons preferentially (10,11). The disinhibition of cortical GABA interneurons by NMDA receptor inhibition explains the excitatory effect of ketamine on the firing of pyramidal neurons (10,11). Also, ketamine triggers an antidepressant effect through direct inhibition of extrasynaptic NMDA receptors by specific blocking of extrasynaptic GluN2B-NMDA receptors (via mTOR signaling), which leads to the excitation of pyramidal neurons (10). Furthermore, the blockade of NMDA receptors enhances synaptic plasticity based on mTORC1 signaling via Akt and ERK activation; this mechanism explains the increasing number and function of synapses in the prefrontal cortex (10). A less explored mechanism of action of ketamine assumes the existence of NMDA receptor inhibition-independent effects because other pharmacological agents, such as memantine or lanicemine, are not efficient in treating mood disorders (10,12,13).

Intravenous administration of esketamine has been reported to induce rapid-acting and sustained activity in refractory patients with MDD, but it is also associated with favorable results in treatment-resistant patients with imminent risk of suicide in phase II studies (14,15). Additionally, the effects of intranasal esketamine have been explored in patients with depression and suicidal intent because of the rapid onset of antidepressant effects reported after single-dose administration (16,17).

The anti-suicidal effect of esketamine represents a key reason to explore its properties since managing suicidal behavior in patients with MDD is difficult with the use of previous generations of antidepressants. The identification of risk markers for suicidal behaviors by combining genomic assessment and clinical evaluation has led to an increased interest in drugs that may modulate mechanisms such as neural connectivity and activity, immune and inflammatory response (18). Ketamine and esketamine have been explored in this type of pathology because the dysregulation of glutamate neurotransmission has been suggested to serve a central role in the onset of suicidal behavior (18-20). Besides its ability to non-selectively antagonize NMDA receptors, ketamine may modulate the activity of σ and µ opioid, serotonin 5HT3, muscarinic and α7 nicotinic receptors, as well as catecholamine transporters in the prefrontal cortex and hippocampus; these pharmacodynamical properties may be involved to a certain degree in anti-suicidal properties of ketamine (18-20).

However, one study has suggested that ‘the excitement over a new treatment for depressed patients with suicidal intentions should be re-evaluated after real-world experience’ (16). Therefore, a carefully structured assessment of suicide risk should be combined with an empathic approach focused on the subjective experiences of patients with MDD (16). Suicide is not ingrained in the experience of depression; therefore, suicidal risk should be regarded as a complex dimension that only partially overlaps with the depressive phenomenology (16). This is why suicide may be perceived as a way to escape extreme negative emotions or acute anguish, not simply as another MDD symptom (16,21).

The pharmacokinetic properties of esketamine are summarized in Table II. An active metabolite, (S)-norketamine, has been identified, which results from cytochrome P450 metabolization of its parent compound and possesses a notable affinity for NMDA receptors, higher than that of (R, S)-ketamine and (S)-ketamine [inhibitor constant (Ki)=1.7 µM vs. 0.53 µM and 0.3 µM, respectively] (7,8,22). This metabolite is associated with a rapid and potent antidepressant effect in rodent models of depression (22). While preclinical studies reported the abuse potential of esketamine, its metabolite was reported as being safer (i.e., lower risk of psychotomimetic and addictive potential) (7,8,22).

The primary objective of the present review was to evaluate the existing evidence in the literature on the efficacy and tolerability of esketamine in the management of TRD. Secondary objectives were: i) To explore other potential benefits and risks of esketamine in short- and long-term administration; ii) to formulate clinical recommendations based on the analysis of these data and iii) to establish future research directions that may enrich knowledge on the effects of esketamine.

The efficacy and safety profile of esketamine was analyzed by reviewing the results of studies found in electronic databases (PubMed-https://pubmed.ncbi.nlm.nih.gov/, Cochrane-https://www.cochrane.org/, EMBASE-https://www.embase.com and Clarivate Web of Science-https://www.webofscience.com/). All studies published between January 2010 and May 2022 were included in the primary analysis. Prospective clinical trials were included regardless of the methodology used (randomized/non-randomized, open/single-blind/double-blind and controlled/uncontrolled) and retrospective trials were also included. Studies including nasal or intravenous (i.v.) infusion of esketamine were allowed in the reviewing stage. Patients enrolled in the trials within the current review were diagnosed with TRD, MDD, psychotic depression or any other type of depressive disorder. Studies exploring esketamine effects in healthy volunteers were allowed if these effects were evaluated using validated instruments. There were no limitations related to the age or sex of the enrolled patients in the clinical trials. Exclusion criteria were as follows: Case reports, case series, systematic and narrative reviews, and meta-analyses; sources written in languages other than English; studies with unspecified outcomes, duration or outcome measures.

A total of nine randomized controlled trials exploring the efficacy and tolerability of esketamine nasal spray were included in the review. Additionally, one esketamine vs. ketamine i.v. study, one single dose of esketamine i.v. study, one retrospective analysis, one post-hoc analysis and one esketamine vs. ketamine and R-ketamine i.v. study were also reviewed (Table III).

TRANSFORM-1 was a phase III, double-blind, randomized, multicenter trial, which enrolled 346 patients with moderate/severe MDD that did not respond to ≥2 antidepressants (23). The effects of esketamine nasal spray (56 or 84 mg, twice weekly) were compared with placebo as an add-on to a newly initiated oral antidepressant (such as duloxetine, escitalopram, sertraline or venlafaxine extended release), which was administered in an open-label manner for 4 weeks (23). The primary objective of this trial was to observe the decrease in the Montgomery-Asberg Depression Rating Scale (MADRS) (24) from baseline to the end of the study. After 28 days, there were no significant differences between the active and placebo groups regarding the MADRS score (23).

Another phase III study, TRANSFORM-2, had a double-blind, randomized, multicenter, active comparator design, and 227 patients with moderate/severe MDD who did not respond to ≥2 antidepressants were enrolled (25,26). The intervention consisted of esketamine (56 or 84 mg, twice weekly) vs. placebo nasal spray as an add-on to antidepressants, and the study duration was 4 weeks. The change in MADRS score in patients receiving esketamine + antidepressant was significantly greater than in those treated with an antidepressant + placebo spray (25,26). Patient Health Questionnaire-9(27) scores also improved significantly in the active group vs. placebo and the improvement in depressive symptoms was observed earlier in patients who received the active intervention (25,26). The most improved items on MADRS in the esketamine vs. placebo group were ‘apparent sadness’ and ‘inability to feel’ (26).

In TRANSFORM-3, another phase III, double-blind trial, 138 patients ≥65 years of age with TRD were randomized on flexible doses of esketamine (28, 56 or 84 mg, administered twice weekly) or placebo nasal spray in addition to a newly initiated oral antidepressant (28). The duration of the study was 4 weeks, and the primary outcome was change in MADRS total score from baseline to endpoint (28). No significant difference was reported in the improvement of depressive symptoms in patients receiving esketamine + antidepressant vs. placebo + antidepressant, according to the MADRS score (28). However, there were more significant differences between groups that favored patients aged 65 to 74 years vs. those >75 years of age and patients with an earlier onset of depression (<55 years of age) (28).

A randomized, double-blind, non-inferiority clinical trial compared the effects of esketamine and ketamine, both administered as i.v. infusion, in a single dose of 0.25 and 0.5 mg/kg, respectively, in 63 patients with TRD (29). The results collected 24 h post-infusion showed that 24.1% of patients who received ketamine and 29.4% of those treated with esketamine obtained remission, according to MADRS scores (29). Therefore, the non-inferiority hypothesis was confirmed in this trial at 24 h post-treatment (29).

Another randomized, multicenter, double-blind, placebo-controlled study included 30 patients with TRD who received 0.2 or 0.4 mg/kg i.v. infusion of esketamine or placebo for 40 min (15). In the second phase, non-responsive patients who received a placebo in the first stage were randomized again to i.v. esketamine or placebo on day 4(15). Patients treated with esketamine (both dosing regimens) achieved clinical improvements (according to MADRS scores) vs. placebo on the second day after therapy (15). The effect of esketamine was fast, its onset being detected 2 h post-treatment administration (15).

A retrospective analysis of medical records included 15 patients with MDD with psychotic features and evaluated the effects of a single dose of 0.5 mg/kg esketamine (30). A significant difference was observed in MADRS scores 24 h after administration, but no differences were reported between patients with MDD who exhibited psychotic features vs. those who do not (30).

In a double-blind, multicenter, phase III study, ASPIRE I, 226 patients with MDD and active suicidal ideation who also presented suicidal intent were randomized to 84 mg esketamine or placebo nasal spray twice/week for 4 weeks as an add-on to standard-of-care therapy (hospitalization and newly initiated or enhanced oral antidepressant) (31). MADRS scores indicated a significantly greater improvement in patients treated with esketamine 24 h after the first dose (31). The favorable effect was observed earlier in the esketamine group vs. placebo (4 h after administration of the drug) (31). However, no differences were reported between groups in the severity of suicide risk during monitoring (31).

In ASPIRE II, a phase III, double-blind, randomized trial, 230 patients with MDD and active suicidal ideation with intent received treatment with 84 mg esketamine or placebo nasal spray twice/week with a monitoring period of 4 weeks, together with comprehensive standard care (antidepressant being included) (32). MADRS scores indicated a significantly greater improvement in patients treated with esketamine after 24 h from the first dose of treatment (32). The favorable effect was observed earlier in the active group vs. placebo, at 4 h after esketamine administration (32). The Clinical Global Impression-Severity (33) scores also improved in both groups, but without significant differences between groups (32).

A post hoc analysis of data collected from the ASPIRE I and II studies on 24 h post-treatment outcomes of patients at risk of suicide showed that the active group improved significantly (indicated by MADRS scores) vs. placebo + standard care (34). Patients who had ≥1 suicide attempt in their history showed a more significant reduction in suicidal behavior and/or ideation, based on the between-group difference in the Clinical Global Impression-Severity of Suicidality-Revised (35) scores 24 h post-treatment (34).

A placebo-controlled phase IIb study involved the enrollment of 202 patients with MDD who were non-responsive to ≥1 but <5 different antidepressants, randomized to esketamine (28, 56 or 84 mg) or placebo nasal spray as an add-on to a new antidepressant, with an active monitoring period of 4 weeks (36). In the double-blind phase, a similar improvement in depressive symptoms was observed in all groups, with no difference between the active substance and placebo, according to the primary outcome (MADRS score) (36).

A randomized, double-blind study that evaluated the comparative efficacy of esketamine and ketamine i.v. infusion on cognition in 54 patients with treatment-resistant MDD at 24 h and 7 days post-treatment found no significant differences between the two substances on cognitive function (37). Both drugs improved short-term visuospatial memory, executive functioning, processing speed and episodic verbal memory, evaluated via neuropsychological tests (37). These results were different from those of a previous study, which compared i.v. racemic ketamine (0.5 mg/kg) with esketamine (0.25 mg/kg) and R-ketamine (1 mg/kg), in a prospective, randomized, double-blind, crossover design on healthy subjects (38). Objective concentration capacity and retention in primary memory were less affected by esketamine compared with R-ketamine and racemic ketamine at 1 min post-administration (38). After 5 min, immediate recall, anterograde amnesia, retention in primary memory, short-term storage memory and intelligence quotient were less decreased after administration of isomers vs. racemic ketamine (38).

A single-blind, randomized, cross-titration study compared the effects of 84 mg intranasal esketamine vs. placebo on driving performance at 18±2 h post-administration (38). Another phase of the same study evaluated the impact of the same drug on driving ability at 6.0±0.5 h post-administration, in a regimen of esketamine delivered twice/week for three weeks (39). All patients had a diagnosis of mild-to-moderate MDD without psychotic features (n=27) (39). In both the first and second phase, esketamine did not significantly alter driving performance compared with placebo (39).

SUSTAIN-1 was a phase III study that monitored the effects of controlled withdrawal of active medication in patients (n=297) who achieved a stable level of remission/response under esketamine + antidepressant and who were randomized to continue this drug or discontinue it and switch to placebo nasal spray (40). The duration of monitoring was 16 weeks. The risk of relapse was lower by 51-70% under continued treatment with esketamine + antidepressant vs. placebo + antidepressant (40).

In another phase III trial, SUSTAIN-2, which had an open, multicenter design, 802 patients with treatment-resistant MDD were randomized to 28, 56 or 84 mg esketamine nasal spray added to a new oral antidepressant (41). Esketamine was administered twice/week during a 4-week induction phase, then weekly or every 2 weeks in patients who obtained a response in the first phase of the study. The duration of monitoring was 48 weeks; MADRS scores decreased during the induction phase (41). This improvement was maintained in the continuation, open-label phase, with decreased MADRS scores from baseline at the endpoint (41).

The overall tolerability of intranasally administered esketamine in clinical trials is good, with no mood switches or emergent psychotic manifestations being observed (23). Adverse effects, such as transient dissociative phenomena as well as a potential addictive risk (unconfirmed in short-term clinical trials and ≤2 weeks after completion of adjuvant therapy), require caution in the administration of esketamine (23,25,26,28). In the TRANSFORM-1 study, the most commonly reported side effects were nausea, dissociation, dizziness, and headache (23). In the TRANSFORM-2 study, patients primarily reported nausea, dizziness, dissociation, dysgeusia and dizziness (25,26). In the TRANSFORM-3 study, the incidence of the reported adverse effects in the esketamine + antidepressant therapy group was 70.8% vs. 60% in the esketamine + placebo group and were primarily dizziness, nausea, transient increase in blood pressure, fatigue, headache and dissociation (28).

Adverse events in the SUSTAIN-1 and -2 trials in patients receiving esketamine were dysgeusia, vertigo, dissociation, drowsiness, nausea, headache and dizziness (40,41). These side effects were of moderate or mild intensity, being detected especially following administration of the medication and typically remitted on the same day (40,41). Discontinuation due to side effects was reported in 7% of patients in the SUSTAIN-2 trial (41).

In the ASPIRE I and II trials, the most commonly reported side effects (>20%) were dizziness, dissociation, nausea, drowsiness and headache (31,32,34).

Based on results from four phase III studies, the number needed to treat (NNT) value (the number of patients that would need to be treated to obtain a favorable outcome) was 8 for patients treated with esketamine + antidepressant in the acute phase trials (38). Regarding the relapse prevention study, the NNT value was <10(42). These values suggest a potential benefit of combining esketamine with an antidepressant for both acute and maintenance phases.

Another NNT for esketamine was 6 in the short-term, based on the results of 297 adults treated with esketamine as an add-on to antidepressants in a double-blind study (40). In the long term, the NNT was 4 for preventing relapse during esketamine treatment (40).

Based on analysis of the results from the same four phase III studies, the number needed to harm (NNH) value (the number of patients that would need to receive treatment to report an adverse effect) was <10 for patients treated with esketamine and antidepressants (34). NNH reached 17 for discontinuation due to adverse effects in the acute phase studies and 178 (insignificant) in the maintenance study (38).

The present study is not a systematic review, and therefore, relevant studies on this topic may be missing. Also, several trials included in the present review are short-term, which limits the possibility of analyzing the efficacy and tolerability of esketamine in the long term.

Esketamine has been shown to be effective in decreasing the severity of short-term depressive symptoms, but questions about its medium- and long-term action, as well as its tolerability profile, remain to be elucidated as novel clinical studies explore its pharmaco-clinical properties. The advantages and disadvantages of esketamine treatment are presented in Table IV.

Regarding the secondary objectives, based on the reviewed data, esketamine nasal spray may be recommended in patients with TRD (defined by ≥2 periods of treatment with different antidepressants that did not result in remission of symptoms) as an adjunct to antidepressant treatment. No significant results have been shown in patients >75 years of age, but this conclusion is based on limited data (28). There are also studies exploring esketamine which reported a lack of significant efficacy on depressive severity symptoms in patients with TRD, but there is insufficient data about potential factors that may adversely influence the progression of these patients (23,28,36,37). Active suicidal ideation with intent was not significantly decreased by esketamine, but prior suicidal behavior may indicate a favorable response to this drug (31,34). Regarding suicidal risk in MDD and the potential benefits of esketamine, several models show the complexity of the suicide dimension and its partial overlap with MDD (16,17,21). This makes the interpretation of pharmacological trials difficult as these are based on limited descriptions of suicidal scenarios (43).

The presence of psychotic features in MDD was not apparently associated with a different progression compared with non-psychotic depression during esketamine treatment (30). The impact of esketamine on cognitive functioning may be positive or neutral (37-39).

As reported by previous reviews and expert opinions (44,45), the data about the effects of esketamine in TRD might position it above racemic ketamine in terms of safety (although it must be noted that no direct comparison between S-ketamine, R-ketamine and racemic ketamine exists). Several aspects in this domain require further investigation, including methodological variables, such as duration, frequency of administration and continuing with safety data (such as abuse potential), as well as logistical parameters, such as cost and availability (44,45). Unlike the aforementioned reviews, in the present paper, studies regarding the cognitive effects of esketamine were included in healthy individuals and patients with MDD (37-39). Also, studies comparing ketamine and esketamine were included, as well as trials exploring both nasal spray and i.v. infusion forms of administration. The present review supports conclusions similar to the meta-analysis of Papakostas et al (46), which found that esketamine is significantly more effective than placebo as an adjuvant to ongoing antidepressant treatment, based on MADRS scores. These results remained significant regardless of whether esketamine was added to newly initiated antidepressants or to already ongoing treatment (46). The safety of intranasal esketamine was also supported by a meta-analysis conducted by Jawad et al (47), which explored the tolerability of this agent in long-term studies (>4 weeks and ≤1 year).

Research directions for future studies are the efficacy of esketamine for bipolar and geriatric depression, depression with addictive comorbidities and MDD in adolescents, as well as the detection of favorable/unfavorable response factors of this treatment. The pharmacogenetics of adjuvant therapy with esketamine is another potential domain that should be explored from the perspective of individualized medicine.