Ketamine and Esketamine in Psychiatry: A Comparative Review Emphasizing Neuroplasticity and Clinical Applications

Abstract

Ketamine and esketamine are two closely related compounds with fast-acting antidepressant properties that have reshaped the treatment landscape for individuals with treatment-resistant depression (TRD). Originally developed as anesthetic agents, both have since demonstrated rapid and robust antidepressant effects in patients who have not responded to conventional treatments such as selective serotonin reuptake inhibitors (SSRIs) or cognitive behavioral therapy. This narrative review synthesizes evidence on their pharmacology, mechanisms of action, clinical efficacy, safety profiles, and regulatory considerations, with a particular focus on their neuroplastic effects. While ketamine is a racemic mixture composed of equal parts R- and S-enantiomers, esketamine consists solely of the S-enantiomer and has been approved for intranasal use by the FDA and EMA for TRD. These agents have been shown to produce symptom relief within hours of administration—an unprecedented effect in psychiatric pharmacology. This rapid onset is particularly valuable in managing suicidal ideation, offering potential lifesaving benefits in acute settings. Furthermore, ketamine and esketamine’s influence on synaptic plasticity, brain-derived neurotrophic factor (BDNF), and glutamate transmission provides insights into novel therapeutic targets beyond monoaminergic systems. This review incorporates recent real-world findings and peer-reviewed literature to contextualize the clinical use of these agents in modern psychiatry, bridging experimental research with practical application.

1. Introduction

Treatment-resistant depression (TRD) affects up to one-third of patients diagnosed with major depressive disorder (MDD), posing a significant clinical challenge that contributes to increased morbidity, functional impairment, and healthcare burden [1]. These patients often endure years of persistent symptoms despite multiple trials of antidepressant medications, psychotherapy, and even augmentation strategies, highlighting the urgent need for more effective and faster-acting treatments. In contrast to conventional monoaminergic antidepressants, which typically require several weeks to exert clinical effects, ketamine and esketamine demonstrate a rapid onset of action—often within hours—and efficacy in otherwise unresponsive cases [2]. This swift therapeutic response can be particularly critical in situations involving acute suicidality, psychiatric emergencies, or severe functional decline, where traditional interventions may fall short and timely symptom resolution is essential for safety and stabilization.

This review is based on a narrative synthesis of peer-reviewed literature. Relevant publications were identified through PubMed, Scopus, and Google Scholar using keywords such as ‘ketamine’, ‘esketamine’, ‘neuroplasticity’, ‘treatment-resistant depression’, and ‘NMDA antagonists’. Studies were included if they were original research articles, meta-analyses, or systematic reviews published in English between 2000 and 2024. Priority was given to high-impact clinical trials and mechanistic studies. Editorials, non-peer-reviewed articles, and preprints were excluded.

The approval of esketamine for intranasal administration by major regulatory agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) marks a paradigm shift in the pharmacological management of TRD, offering a novel mechanism of action that diverges from the monoaminergic pathway. At the same time, the expanding off-label use of intravenous racemic ketamine in psychiatric clinics across the globe reflects a growing recognition of its therapeutic value, despite heterogeneity in clinical protocols, dosing strategies, and regulatory frameworks. These parallel developments have catalyzed renewed interest in understanding the pharmacokinetic and pharmacodynamic profiles of both agents, as well as their differential impact on glutamatergic signaling, synaptic remodeling, and neural circuit function.

Furthermore, recent advances in neuroimaging and biomarker research suggest that ketamine and esketamine may exert antidepressant effects by enhancing neuroplasticity in key brain regions, such as the prefrontal cortex, hippocampus, and anterior cingulate cortex. These neurobiological effects, coupled with their rapid symptom relief, have positioned ketamine-based treatments at the forefront of innovation in psychiatric therapeutics. However, ongoing questions about long-term safety, optimal treatment paradigms, patient selection criteria, and integration with psychotherapeutic approaches highlight the need for continued research and thoughtful clinical implementation.

2. Pharmacological Overview

2.1. Ketamine

Ketamine is a racemic mixture composed of two enantiomers: R-ketamine and S-ketamine (also known as esketamine). Although both enantiomers share structural similarities, they differ in their pharmacodynamic properties, receptor affinities, and potentially in their clinical effects. S-ketamine has a higher affinity for the N-methyl-D-aspartate (NMDA) receptor compared to R-ketamine and is primarily responsible for ketamine’s anesthetic potency. R-ketamine, while less potent at NMDA receptors, has shown promise in preclinical studies for its prolonged antidepressant effects and reduced psychotomimetic side effects. This distinction has generated significant interest in the development of R-ketamine as a future therapeutic agent with a more favorable side effect profile.

Ketamine acts primarily as a non-competitive antagonist at the NMDA receptor, a subtype of glutamate receptor involved in synaptic plasticity, learning, and memory. By blocking NMDA receptors on inhibitory GABAergic interneurons, ketamine disinhibits glutamate release, leading to enhanced excitatory neurotransmission. This increase in extracellular glutamate activates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, initiating a cascade of intracellular signaling pathways—including mTOR (mechanistic target of rapamycin) and BDNF (brain-derived neurotrophic factor)—that contribute to enhanced synaptogenesis and neuroplasticity [3]. These mechanisms are believed to underlie ketamine’s rapid and sustained antidepressant effects, offering a new framework for understanding and treating mood disorders.

2.2. Esketamine

Esketamine is the S-enantiomer of ketamine and exhibits approximately 2–3 times greater affinity for NMDA receptors than its R-enantiomer counterpart, contributing to its more potent anesthetic and dissociative effects [4]. This higher receptor affinity translates into greater pharmacodynamic activity at lower doses, which has informed its clinical formulation and dosing strategies. Unlike racemic ketamine, which is typically administered intravenously in off-label settings, esketamine has been developed as a standardized intranasal spray (marketed as Spravato^®), offering a more convenient and accessible route of administration. The intranasal delivery system allows for rapid absorption through the nasal mucosa, achieving therapeutic plasma levels within 20 to 40 min while bypassing first-pass hepatic metabolism.

Esketamine’s approval by the U.S. Food and Drug Administration (FDA) in 2019 represented a landmark moment in psychiatry—it was the first novel antidepressant mechanism approved in decades specifically for adults with treatment-resistant depression (TRD). Subsequently, its indications were expanded to include the treatment of depressive symptoms in adults with major depressive disorder (MDD) experiencing acute suicidal ideation or behavior, providing a critical option for clinicians managing psychiatric emergencies [5]. The regulatory approval was based on a series of randomized controlled trials demonstrating rapid reductions in depressive symptoms, particularly within the first 24 h, when used in conjunction with an oral antidepressant. Esketamine’s structured, clinic-based administration protocol also allows for close patient monitoring, which is especially important given its dissociative and hypertensive effects.

Comparative mechanisms of action and neuroplastic effects of ketamine and esketamine [6] are illustrated in Figure 1.

3. Mechanisms of Action and Neuroplasticity

Ketamine and esketamine promote rapid neuroplasticity by increasing synaptogenesis and restoring functional connectivity in brain regions critically involved in mood regulation, such as the prefrontal cortex, hippocampus, and anterior cingulate cortex [7]. These areas are commonly affected in patients with major depressive disorder (MDD), often exhibiting structural and functional deficits that correlate with symptoms such as anhedonia, cognitive impairment, and emotional dysregulation. By reversing synaptic loss and enhancing neural communication, ketamine-based treatments may directly address the core pathophysiological changes associated with chronic depression.

At the molecular level, ketamine and esketamine rapidly activate several intracellular signaling pathways that contribute to synaptic remodeling. Among the most studied are the brain-derived neurotrophic factor (BDNF), mammalian target of rapamycin (mTOR), and eukaryotic elongation factor 2 (eEF2) pathways [8]. Ketamine-induced disinhibition of glutamate release leads to downstream AMPA receptor activation, which in turn stimulates BDNF expression and mTOR signaling—key drivers of dendritic spine formation and synaptic protein synthesis. In parallel, inhibition of eEF2 kinase increases protein translation, further promoting the production of synaptic components. These neurobiological mechanisms support a fundamental paradigm shift away from the traditional monoamine hypothesis, which centers on neurotransmitter deficits, toward contemporary models emphasizing disrupted neurocircuitry, impaired synaptic plasticity, and maladaptive stress responses in the pathogenesis of depression.

Racemic ketamine includes both R- and S-enantiomers and is commonly administered intravenously or intramuscularly [6]. Esketamine, the S-enantiomer, has higher NMDA receptor affinity and is approved for intranasal use. These mechanisms underlie their rapid-acting antidepressant properties which are described in Figure 2.

4. Clinical Efficacy

Multiple randomized controlled trials have demonstrated the efficacy of both agents in TRD [5,9]. A 2022 retrospective naturalistic study by Mikellides et al. compared intramuscular ketamine to rTMS and found that both interventions significantly reduced depressive and anxiety symptoms without significant differences in response or remission rates [10]. Esketamine has demonstrated relapse prevention benefits in maintenance trials [11].

5. Safety and Tolerability

In controlled clinical settings, ketamine and esketamine are generally well tolerated when administered according to established protocols. Their side effect profiles are well characterized, with most adverse effects being transient and manageable. Commonly reported side effects include dissociation, dizziness, nausea, transient increases in blood pressure and heart rate, anxiety, and perceptual disturbances such as visual distortions or altered time perception. These effects typically peak within 30 to 60 min after administration and resolve within two hours, rarely requiring intervention. Dissociation is the most prominent acute side effect and, while often considered unpleasant by some patients, may also be associated with the antidepressant mechanism of action in certain theoretical frameworks.

Contrary to longstanding concerns stemming from recreational misuse of ketamine, therapeutic use under medical supervision has not been associated with significant long-term cognitive impairment or bladder toxicity—two complications frequently observed in chronic high-dose recreational users [12]. In clinical trials and real-world studies, patients receiving intermittent dosing under supervision have not shown persistent neurocognitive deficits or urological damage. Safety is further enhanced through the implementation of rigorous monitoring procedures. For esketamine, the U.S. FDA mandates a Risk Evaluation and Mitigation Strategy (REMS), which requires administration in certified healthcare settings under direct observation, with mandatory post-dose monitoring for at least two hours. These safeguards help mitigate risks and ensure patient safety in psychiatric practice.

6. Regulatory Status and Access

Esketamine is FDA- and EMA-approved for the treatment of treatment-resistant depression (TRD), with its use restricted to structured clinical settings certified under specific regulatory frameworks. In the United States, esketamine is administered exclusively where trained healthcare professionals supervise the dosing process, monitor for adverse effects, and ensure patients meet strict eligibility criteria. This controlled model ensures consistency in administration, enhances patient safety, and facilitates data collection for long-term outcomes. The standardization of dosing, monitoring protocols, and follow-up procedures enhances esketamine’s appeal from a regulatory and medico-legal standpoint, while also making it more acceptable to insurers in countries where reimbursement policies are in place.

In contrast, racemic ketamine—although not formally approved for depression—is widely used off-label in clinical practice, particularly in specialized psychiatric and anesthetic clinics that offer intravenous (IV) or intramuscular (IM) administration. This off-label use has grown significantly in recent years due to ketamine’s compelling evidence base and rapid antidepressant effects. Moreover, the lack of formal approval for depression limits insurance coverage in many jurisdictions, often resulting in high out-of-pocket costs that may hinder equitable access to care.

7. Psychotherapeutic Integration, Neuromodulation and Emerging Paradigms

Recent conceptual models propose that ketamine may do more than merely correct neurochemical imbalances—it may also facilitate emotional catharsis, inner exploration, and existential insight, particularly when administered in conjunction with psychotherapy. These models are part of a broader shift in understanding depression not only as a neurobiological disorder but also as a condition deeply rooted in unresolved trauma, maladaptive psychological patterns, and a disconnection from meaning or purpose. When used in a carefully prepared therapeutic setting, ketamine’s dissociative and consciousness-altering properties can open a unique window of opportunity for patients to access repressed emotions, revisit traumatic memories with greater detachment, and experience a renewed sense of clarity or perspective.

In 2024, Mikellides et al. published an article in Psychiatria Danubina on the phenomenon of catharsis by ketamine, proposing that some of ketamine’s therapeutic benefits may stem from a psychospiritual process that includes emotional purging, enhanced self-awareness, and shifts in existential worldview [13]. This view suggests that ketamine’s antidepressant action may involve a reorganization of meaning as much as neuroplasticity. These emerging perspectives align with the growing movement toward ketamine-assisted psychotherapy (KAP), a structured approach that combines ketamine administration with guided psychological support before, during, and after sessions. KAP aims to harness ketamine’s capacity to soften rigid cognitive frameworks and emotional defenses, thereby enhancing therapeutic engagement and long-term outcomes.

The integration of ketamine and esketamine into psychedelic-assisted psychotherapy (PAP) and neuromodulation paradigms represents a significant shift in contemporary psychiatric treatment frameworks. Unlike classical psychedelics, ketamine offers a dissociative rather than hallucinogenic experience, making it a unique pharmacological agent for inducing non-ordinary states of consciousness under guided psychotherapeutic settings. Ketamine-assisted psychotherapy (KAP) has shown promise in treating mood disorders, PTSD, and existential distress, often by enhancing emotional catharsis, memory reconsolidation, and shifts in self-perception [13]. These effects are believed to be synergistic with therapeutic guidance, enabling deeper processing of unresolved trauma and rigid thought patterns.

Esketamine, while less studied in formal PAP protocols due to its intranasal route and medicalized setting, still possesses dissociative properties that can open a brief therapeutic window. However, its fixed-dose administration and rapid pharmacokinetics make integration into psychotherapy more challenging without supportive frameworks. As the field evolves, the therapeutic set and setting—cornerstones of psychedelic treatment—are being adapted for esketamine administration, though further research is needed.

Parallel research has explored the synergistic use of ketamine with transcranial magnetic stimulation (TMS). Preliminary findings suggest that combining ketamine’s neuroplastic priming effects with TMS’s targeted neuromodulation may enhance response rates and shorten treatment timelines in treatment-resistant depression [10,13]. The underlying hypothesis is that ketamine enhances cortical receptivity via mTOR/BDNF signaling, while TMS provides circuit-specific activation that consolidates these neuroplastic changes.

Together, these approaches underscore a broader shift toward integrative, biopsychosocial models in psychiatry—where rapid-acting pharmacology, brain stimulation, and psychotherapy are not competing interventions, but coordinated tools aimed at unlocking neural flexibility and psychological healing.

8. Future Directions

Ongoing research continues to explore and refine the clinical applications of ketamine and its enantiomers, with particular focus on optimizing efficacy, safety, and personalization of treatment. One important avenue of investigation is the comparative analysis of R-ketamine versus S-ketamine (esketamine). Preclinical and early clinical studies suggest that R-ketamine may offer longer-lasting antidepressant effects with fewer dissociative and psychotomimetic side effects, potentially making it a superior alternative for long-term use. Understanding the differential pharmacodynamics, receptor profiles, and downstream molecular effects of these enantiomers may pave the way for more tailored therapeutic strategies based on individual patient characteristics.

Another promising area of study is the synergistic potential of ketamine when combined with other neuromodulation techniques, such as transcranial magnetic stimulation (TMS). Preliminary findings suggest that combining ketamine with TMS may enhance neuroplasticity and treatment response in patients with severe or refractory depression. These combined protocols could offer additive or even synergistic effects by targeting complementary neural pathways and optimizing the therapeutic window induced by ketamine.

Furthermore, efforts are underway to identify reliable biomarkers—such as EEG signatures, inflammatory markers, or neuroimaging correlates—that can predict individual response to ketamine-based treatments. Integrating real-world data from clinical settings and adopting structured therapeutic models, including standardized assessment tools and psychotherapeutic frameworks, will be crucial in refining protocols and maximizing the therapeutic benefit for diverse patient populations.

9. Broader Therapeutic Indications of Ketamine

Beyond its established role in treatment-resistant depression, ketamine has demonstrated therapeutic potential across a wide spectrum of psychiatric and pain-related conditions, underscoring its versatility as a neuromodulatory agent. In obsessive compulsive disorder (OCD), both open-label studies and randomized controlled trials have reported that intravenous ketamine can induce rapid and significant reductions in obsessive thoughts and compulsive behaviors. However, the duration of these effects tends to be short-lived, often necessitating repeated administration or adjunctive therapies to maintain benefits [14].

In the domain of anxiety disorders, ketamine has shown promising anxiolytic effects, particularly in generalized anxiety disorder (GAD) and social anxiety disorder (SAD). These effects are often observed within hours of administration, highlighting ketamine’s potential for acute symptom relief in populations with high distress or poor response to conventional treatments [15].

In post-traumatic stress disorder (PTSD), emerging evidence indicates that ketamine not only reduces core re-experiencing, avoidance, and hyperarousal symptoms, but may also attenuate dissociative distress. These benefits are thought to be mediated, in part, by ketamine’s effects on memory reconsolidation and synaptic plasticity, offering a novel mechanism distinct from traditional pharmacotherapy [16].

Ketamine has also gained traction in the management of chronic pain syndromes, including complex regional pain syndrome (CRPS) and neuropathic pain, where its action as a non-competitive NMDA receptor antagonist plays a key role in reducing central sensitization and hyperalgesia [17]. Its multimodal effects on both pain perception and mood may offer dual benefits in patients with comorbid pain and depression.

In the field of substance use disorders, ketamine has been associated with increased abstinence rates, reduced cravings, and enhanced psychological flexibility, particularly in individuals with alcohol and opioid dependence. These outcomes may be facilitated by ketamine’s ability to disrupt maladaptive reward circuitry and promote introspective insights during the acute phase of treatment [18].

Emerging evidence increasingly supports the notion that racemic ketamine may offer superior clinical benefits compared to esketamine, due not only to pharmacodynamic distinctions but also to differences in bioavailability, route of administration, and overall efficacy profiles. Racemic ketamine is typically administered intravenously or intramuscularly, offering high and consistent bioavailability in controlled settings. Intravenous ketamine achieves approximately 100% bioavailability, while intramuscular administration yields about 93%, ensuring stable plasma concentrations and facilitating reliable clinical responses, particularly in controlled treatment settings [19].

In contrast, esketamine (S-ketamine) is currently only approved in intranasal form for psychiatric use, a route that is associated with substantial interindividual variability in absorption. The bioavailability of intranasal esketamine is approximately 48%, with uptake significantly influenced by nasal mucosal integrity, delivery technique, and patient factors such as congestion or mucociliary clearance [20]. This variability may lead to inconsistent therapeutic outcomes and complicate dose optimization.

From a pharmacodynamic perspective, emerging preclinical studies suggest that the R-enantiomer (R-ketamine)—absent in esketamine formulations—may play a crucial role in mediating antidepressant effects. Notably, R-ketamine appears to exert potent and sustained antidepressant activity in animal models with a lower propensity for inducing dissociation, psychotomimetic symptoms, or cognitive disruption than S-ketamine. Mechanistic investigations have linked R-ketamine to greater synaptogenesis, enhanced AMPA receptor activation, and reduced oxidative stress and inflammation, potentially contributing to its prolonged efficacy and improved tolerability profile [21].

A systematic review and meta-analysis comparing intravenous racemic ketamine with intranasal esketamine in patients with treatment-resistant depression reinforced these observations. The analysis demonstrated that IV ketamine produced significantly greater reductions in depressive symptomatology, with more rapid onset of action, stronger response rates, and longer-lasting effects relative to intranasal esketamine [22]. These findings align with real-world clinical impressions and support the view that racemic ketamine, by delivering both R- and S-enantiomers through a highly bioavailable route, may offer a more comprehensive and durable therapeutic response.

10. Limitations and Controversies

Despite promising findings, the current evidence base for ketamine and esketamine contains several limitations. Many clinical trials have small sample sizes, short follow-up periods, and variations in dosing protocols, making comparisons difficult. Additionally, concerns persist regarding long-term safety, potential for misuse, and the interpretive challenges of dissociation as a therapeutic mechanism. These limitations underscore the need for cautious clinical implementation and ongoing research.

11. Conclusions

Ketamine and esketamine have introduced a significant shift in the treatment landscape of depression, particularly for patients with treatment-resistant depression (TRD). Their rapid antidepressant effects—mediated through NMDA receptor antagonism and downstream neuroplastic changes—offer a timely and potent alternative to conventional monoaminergic therapies. While both agents have demonstrated efficacy, racemic ketamine’s broader mechanism of action and greater bioavailability may provide enhanced clinical outcomes.

This review highlights key differences in pharmacology, administration routes, and regulatory status between ketamine and esketamine, as well as their expanding clinical roles beyond TRD. Emerging paradigms such as ketamine-assisted psychotherapy and combined neuromodulatory approaches underscore the versatility and depth of these treatments.

Future research should continue refining individualized protocols, examining long-term safety, and clarifying the therapeutic role of R-ketamine. Ultimately, ketamine-based therapies hold promise not only in addressing pharmacological gaps but also in reshaping modern psychiatric practice toward more integrative and responsive care.