Clinical applications of esketamine: Current status and future perspectives

Abstract

Ketamine, a dissociative anesthetic, has been extensively used in clinical anesthesia and sedation. However, its use in general anesthesia is gradually declining because of numerous adverse effects. In 2019, esketamine was introduced to the Chinese market. This narrative review aimed to summarize the current status of clinical applications and research progress of esketamine and to explore its future prospects in clinical practice. The scope of this review covered the pharmacological properties of esketamine; its clinical applications in surgical anesthesia, perioperative analgesia, painless diagnosis and treatment, intensive care, emergency care, and special populations (pediatric and obstetric patients); and its organ-protective effects and application value in the treatment of mental disorders. In addition, the adverse effects of esketamine have been summarized to provide a comprehensive reference for its rational clinical use. This study searched core databases, including PubMed, Embase, the Cochrane Library, and Web of Science. The search terms included esketamine, S-ketamine, anesthesia, analgesia, and depression, using a combined logical search of subject terms and free terms. The search period spanned from the establishment of each database through June 2025. Esketamine has since gained increasing popularity for surgical anesthesia, analgesia, and pain management because of its potent analgesic and anesthetic properties. Esketamine is important not only for anesthesia and analgesia in surgical patients during the perioperative period but also for broader applications in intensive care and emergency care, particularly in the treatment of mental illness. Therefore, Esketamine offers a broader and safer application prospect in surgical anesthesia, perioperative pain management, medication for special populations, and psychiatric disorders.

Introduction

Ketamine has been used as an intravenous anesthetic in clinical settings; however, adverse reactions associated with its use have posed challenges for medical staff. Recently, esketamine, the pure dextrorotatory isomer of ketamine, has been isolated. It retains the therapeutic benefits of ketamine and potentially reduces its adverse effects. This narrative review systematically collates and analyzes the latest research progress on esketamine, summarizes its pharmacological characteristics and clinical application in diverse fields, clarifies the current limitations of its clinical application, and discusses its future research and application directions to provide a comprehensive and evidence-based reference for the rational clinical use of esketamine.

Pharmacological characteristics of esketamine

Mechanism of action of esketamine

Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist developed in the early 1960s that contains S(+) and R(−) enantiomers. Its primary mechanism of action is the noncompetitive antagonism of NMDA glutamatergic receptors in the brain and spinal cord, thereby producing anesthetic and analgesic effects. Common adverse effects include dissociative anesthesia, increased secretion, and addiction. ¹ Esketamine is a pure dextrorotatory isomer isolated from ketamine, with a mechanism of action similar to that of ketamine. Its principal anesthetic and analgesic mechanism is the noncompetitive antagonism of NMDA receptors. In addition, esketamine can act on opioid, cholinergic, and sigma receptors. The affinity of esketamine for opioid receptors is 2–3 times higher than that of ketamine, and its affinity for NMDA receptors is 3–4 times higher than that of ketamine.^2–4

Pharmacokinetics of esketamine

There is small difference between the pharmacokinetics of esketamine and ketamine. Esketamine is both water-soluble and fat-soluble and can rapidly cross the blood–brain barrier. It is metabolized in the liver, and its primary metabolite is S-norketamine. The affinity of S-norketamine for NMDA receptors is approximately one-third that of esketamine, with an elimination half-life of 6–10 h. ⁵ In addition to intravenous administration, esketamine can be administered via multiple routes. Intranasal administration demonstrates a peak drug concentration time of 20–40 min, an elimination half-life of 7–12 h, and a bioavailability of 48%–54%. Oral administration has a peak drug concentration time of 18–22 min, an elimination half-life of 5–6 h, and a bioavailability of 8%–27%.^6,7 Compared with ketamine, esketamine exhibits better anesthetic and analgesic effects, can rapidly reduce pain intensity and opioid requirements, causes a lower degree of respiratory depression, and can slightly stimulate the sympathetic nervous system, thereby providing more stable hemodynamics. ⁸

Clinical application of esketamine

Application of esketamine in general anesthesia

Application of esketamine in anesthesia induction

The process of general anesthesia induction and tracheal intubation is often accompanied by noticeable hemodynamic changes, which may cause catastrophic consequences in certain groups, including older patients. Esketamine demonstrates sympathomimetic and potent analgesic effects, and its addition during general anesthesia induction can provide more stable hemodynamics. ⁹ Li et al. ¹⁰ conducted a study involving 80 older patients undergoing unilateral knee replacement surgery under general anesthesia and demonstrated that administration of 0.2 mg/kg esketamine during anesthesia induction achieved the same depth of sedation, with patients demonstrating more stable blood pressure and heart rate as well as a significantly lower incidence of cough. Another study ¹¹ showed that in pediatric patients, esketamine significantly enhanced cooperation with mask placement, increased the success rate of anesthesia induction, and reduced the frequency and intensity of agitation during this phase. These findings indicate that esketamine has clear advantages for anesthesia induction in older and pediatric patients.

Application of esketamine in surgery

Perioperative intravenous administration of esketamine can reduce the incidence of adverse events, including postoperative opioid-induced hyperalgesia (OIH), respiratory depression, and postoperative delirium. The mechanisms underlying OIH are complex. Central sensitization of the nociceptive pathway results in a decrease in the pain threshold, characteristic of OIH. Glutamate release and NMDA receptor activation may be critical factors in OIH and are associated with the clinical use of opioids. ¹² Animal experiments have shown that enhanced function and an increased number of NMDA receptors may be the primary mechanism by which remifentanil causes OIH. ¹³ Some researchers have treated OIH with low-dose ketamine infusion and confirmed its effectiveness. ¹⁴ Furthermore, there are few studies investigating the mechanism by which esketamine reduces OIH. Compared with ketamine, esketamine demonstrates a stronger affinity for NMDA receptors and would theoretically exhibit a better effect. The use of opioids during the perioperative period may cause life-threatening respiratory depression. In a clinical trial using a human model, ¹⁵ esketamine was effective against remifentanil-induced respiratory depression, which may be attributable to the ability of ketamine to enhance ventilatory CO₂ sensitivity. A clinical study of 80 patients undergoing thoracoscopic pneumonectomy showed that esketamine can reduce postoperative low minute ventilation and the incidence of hypoxemia. ¹⁶ Notably, the sample sizes of these two clinical studies were relatively small; therefore, multicenter studies with larger sample sizes are warranted to confirm the efficacy of esketamine. Postoperative delirium (POD) is an acute cerebral dysfunction that typically occurs within 1 week following surgery and is commonly observed in older surgical patients, with a prevalence of up to 12.0%–23.8%. ¹⁷ POD is strongly associated with prolonged hospital stay, increased mortality, and long-term postoperative cognitive dysfunction. ¹⁸ The pathogenesis of POD is complex, and neuroinflammatory response is considered an essential mechanism underlying POD. ¹⁹ Tu et al. ²⁰ demonstrated that esketamine can improve surgical stress and inflammatory responses as well as promote recovery of postoperative cognitive function. In a clinical study by Ma et al. ²¹ involving patients with gastrointestinal tumors undergoing general anesthesia, anesthesia was induced with 0.25 mg/kg esketamine and maintained with 0.125 mg/kg/h esketamine. The results showed that esketamine significantly reduced the incidence of delayed neurological recovery in older patients after general anesthesia but did not affect POD. Zhu et al. ¹⁹ suggested that the inconclusive findings on the effect of esketamine on POD may be attributable to differences in delirium assessment methods, variations in sample sizes, inconsistencies in outcome settings, and differences in the methods of esketamine administration. Their clinical study, which included patients undergoing total hip or knee replacement under spinal anesthesia, indicated that esketamine can reduce the incidence of POD in older patients. Chen et al. ²² reported that a near-anesthetic single dose of esketamine used for anesthesia induction increased the incidence of emergence delirium in preschool children after minor surgery.

Esketamine appears to reduce postoperative delirium in older patients; however, the incidence of delirium is increased after minor surgery in preschool children. This discrepancy may be attributable to the fundamental differences between the two groups in terms of brain development/decline, NMDA receptor characteristics, and baseline neuroinflammation. In addition, factors such as clinical dosing (low doses for older patients and near-anesthetic doses for children) and the types of delirium onset (chronic cognitive impairment in older patients and acute disturbance of consciousness in children) may contribute to this phenomenon. Consequently, the drug mainly exerts anti-inflammatory, neuroprotective, and antistress effects in older patients. In contrast, in pediatric patients, it triggers dissociative effects because of excessive blockade of NMDA receptors, disrupts neural balance, and synergizes with pain/anxiety to induce delirium. Therefore, further studies are necessary to confirm the efficacy of esketamine in the management of POD.

Application of esketamine in postoperative analgesia

Postoperative pain is one of the most common symptoms following surgery. Improper management of postoperative pain can not only lead to dysfunction of various organ systems, including insufficient lung ventilation, coronary ischemia, and decreased gastrointestinal motility, but also contribute to chronic pain, poor physical recovery, and impaired quality of life. ²³ Therefore, adequate postoperative analgesia is essential. Currently, opioids are commonly used for postoperative analgesia. Although their clinical demand is high, they are prone to overuse and abuse. Opioids can cause adverse reactions such as nausea, vomiting, respiratory depression, and addiction. The current concept of enhanced postoperative recovery proposes the use of multimodal analgesia to reduce postoperative pain maximally and advocates an opioid-free strategy to reduce the incidence of postoperative adverse reactions. ²⁴ Perioperative intravenous administration of ketamine has shown to reduce opioid dosage by approximately 19% and postoperative pain by 14%–22%. ²⁵ A meta-analysis evaluating the effectiveness of esketamine in patient-controlled intravenous analgesia (PCIA) showed that the combination of esketamine and sufentanil significantly improved postoperative pain control compared with sufentanil alone. The visual analog scale (VAS) score was significantly reduced, and the incidences of sufentanil-associated side effects such as nausea, vomiting, and skin itching also decreased significantly. ²⁶ In another clinical trial on cesarean section, Han et al. ²⁷ enrolled 375 women from a single center who were scheduled to undergo cesarean section followed by PCIA. They reported that PCIA with 0.01 mg/kg/h esketamine can significantly reduce VAS scores without increasing the incidence of adverse events. It has been reported that approximately 75% of pediatric surgeries are associated with insufficient postoperative analgesia. ²⁸ Inadequate management of postoperative pain in pediatric patients can directly affect the development of emotional and cognitive abilities. ²⁹ Timely and appropriate postoperative sedation and analgesia can stabilize hemodynamics in pediatric patients, reduce inflammatory responses, and improve prognosis. ³⁰ Xu et al. ³¹ assessed the safety and efficacy of esketamine for postoperative analgesia in pediatric patients undergoing hypospadias surgery. Compared with hydromorphone, esketamine was reported to reduce the incidence of hypotension and respiratory depression, with no significant differences in postoperative pain scores or incidences of nausea and vomiting, suggesting that esketamine provides analgesic effectiveness comparable to opioids without increasing adverse event rates. Li et al. ³² administered 0.25 mg/kg esketamine for analgesia after pediatric tonsillectomy and found that esketamine reduced the incidence of postoperative agitation in pediatric patients without delaying extubation or increasing postoperative adverse events. These findings confirm the potent efficacy of esketamine in postoperative analgesia. However, the extent to which esketamine can reduce opioid dosage has not been thoroughly investigated and warrants further investigation.

Application of esketamine in painless diagnosis and treatment

In painless diagnostic and therapeutic procedures, the most commonly used drug is propofol. However, it often causes adverse effects such as respiratory depression, injection pain, and hemodynamic fluctuations. Opioids are frequently used in combination with propofol to provide analgesia during procedures or examinations; however, this combination may further increase the risk of circulatory and respiratory depression. ³³ Therefore, the primary aim in painless diagnosis and treatment is to minimize the effects of sedative and analgesic drugs on circulation and respiration. Eberl et al. ³⁴ found that the use of esketamine during endoscopic retrograde cholangiopancreatography can reduce the required dosage of propofol without affecting recovery time or patient and endoscopist satisfaction and without increasing respiratory or cardiovascular adverse events. A meta-analysis ³⁵ involving 18 studies examined the efficacy and safety of esketamine for sedation in patients undergoing gastrointestinal endoscopy and reported that the combination of esketamine and propofol reduces the total dosage of propofol, shortens recovery time, and decreases the incidence of adverse events.

Application of esketamine in intensive care unit (ICU)

Patients in the ICU often receive sedatives and analgesics during mechanical ventilation to facilitate synchronization with the ventilator and to maintain stable hemodynamics and adequate gas exchange. There is growing interest in nontraditional sedative medications in the ICU as part of a multimodal analgesic strategy to maintain an appropriate depth of sedation, as recommended by clinical guidelines. ³⁶ Compared with propofol or dexmedetomidine, the use of ketamine as a sedative in intensive care may have beneficial hemodynamic effects, with a significantly lower incidence of hypotension and bradycardia. ³⁷ Peters et al. ³⁸ evaluated the use of ketamine for primary anesthesia and sedation in trauma patients undergoing critical surgery and requiring mechanical ventilation and reported that only 12% (n = 20) of 164 patients required a concomitant infusion of opioids. This finding indicates that the majority of patients were able to achieve adequate pain management with ketamine infusion alone. Notably, 7% of patients discontinued ketamine because of its side effects. Esketamine, which has more potent analgesic effects than ketamine, may theoretically be more suitable for use in the ICU setting.

Application of esketamine in emergency care

In an observational study of 2964 patients undergoing endotracheal intubation from 197 sites worldwide, ³⁹ 45.2% of patients experienced at least one major clinical event following intubation. These events primarily included cardiovascular instability (42.6%), severe hypoxemia (9.3%), and cardiac arrest (3.1%). It has been reported ⁴⁰ that emergency physicians prefer to use ketamine in patients with a shock index >0.9. The positive hemodynamic effects of esketamine and its ability to preserve respiratory function suggest that it may become a commonly used drug in emergency care.

Application of esketamine in special populations

Application of esketamine in pediatric patients

Esketamine has been used in pediatric patients for a long time and can be used safely and effectively as a premedical as well as an adjuvant drug for various diagnostic procedures. Currently, Propofol is the most commonly used intravenous anesthetic worldwide, and injection pain is one of its most common side effects. A study has shown ⁴¹ that the incidence of injection pain in children is 28%–85%, with a mean of 70%. Administration of 0.15 mg/kg esketamine 30 s prior to injection of propofol can significantly reduce the incidence of injection pain and provide more stable hemodynamics within 5 min following anesthesia induction. In pediatric patients who have difficulty with inhalation or intravenous anesthesia induction, esketamine can be administered transnasally. It has been shown ¹¹ that pediatric patients who receive 0.5 mg/kg esketamine combined with 1 μg/kg dexmedetomidine intranasally prior to surgery demonstrate better cooperation with anesthesia induction and a higher sedation success rate. In some therapeutic procedures in which artificial airway is not established, adult patients can cooperate with the doctor to complete diagnostic or therapeutic procedures, whereas pediatric patients require sufficient sedation and analgesia for the successful completion of the procedures. In pediatric patients undergoing magnetic resonance imaging in an outpatient setting, the combination of esketamine and propofol results in a lower dosage, faster anesthesia induction, and rapid recovery. ⁴² During dressing changes for burn wounds in children, the combination of ketamine and midazolam provides effective sedation and analgesia without the need for additional drugs. ⁴³ The use of 0.5 mg/kg esketamine combined with 2 mg/kg propofol during upper gastrointestinal endoscopy in pediatric patients can provide a higher first-time insertion success rate of endoscope and more stable hemodynamics. ⁴⁴

Application of esketamine in obstetric surgery

Esketamine demonstrates a rapid onset of action, strong analgesic effects, and minimal effects on neonates, making it particularly suitable for obstetric surgery. Liang et al. ⁴⁵ evaluated the effects of intravenous administration of 25 mg esketamine on neonates during cesarean section. Compared with the control group, umbilical arterial pH, base excess, and lactic acid levels were comparable between the two groups. Furthermore, there were no differences in Apgar scores at 1, 5, and 10 min after birth, indicating that intravenous administration of 25 mg esketamine is safe for neonates. For patients undergoing cesarean delivery with intrathecal anesthesia, a single intravenous dose of 0.15 mg/kg esketamine could reduce the intrathecal dosage of ropivacaine by 19.7%. In addition, the incidences of hypotension, bradycardia, nausea, and vomiting decreased, suggesting that esketamine reduces the incidence of hypotension and related adverse effects following intrathecal anesthesia. ⁴⁶ Several clinical trials have shown that esketamine can reduce the incidence of postpartum depression.^27,47 A recently published meta-analysis ⁴⁸ reported that high-dose ketamine/esketamine can significantly reduce the hazard ratio for postpartum depression (PPD) and the Edinburgh Postpartum Depression Scale (EPDS) scores at 1 and 4 weeks after surgery. PCIA administration was more advantageous than a single intravenous injection for the prevention of PPD, and esketamine was superior to ketamine in preventing PPD. However, clinicians should remain vigilant to adverse events such as dizziness, diplopia, hallucination, and headache associated with high doses of ketamine/esketamine.

Organ-protective effects of esketamine

Neuroprotective effects

Esketamine possesses significant neuroprotective effects. Spreading depolarization (SD) may occur in patients with severe brain trauma as well as after spontaneous subarachnoid hemorrhage, cerebral hemorrhage, and space-occupying middle cerebral artery infarction. SD results in a loss of neuronal activity and is an independent predictor of adverse outcomes. ⁴⁹ A retrospective cohort study ⁵⁰ reported that the incidence of SD was significantly reduced following the introduction of esketamine in patients with subarachnoid hemorrhage. Esketamine was more effective at higher doses (2.1–7.0 mg/kg/h) than at lower doses (0.1–2.0 mg/kg/h); however, its use is not recommended in patients with increased intracranial pressure.

Cardioprotective effects of esketamine

Bi et al. ⁵¹ investigated the effects of low-dose esketamine on markers of myocardial injury, including brain natriuretic peptide (BNP), high-sensitivity cardiac troponin T (hs-cTnT), and heart-type fatty acid-binding protein (H-FABP), following thoracoscopic lobectomy in 100 patients aged 70–85 years undergoing elective lobectomy. Compared with the control group, plasma concentrations of BNP, hs-cTnT, and H-FABP were found to be significantly decreased at 24 and 48 h after surgery. In addition, postoperative VAS pain scores were significantly decreased, and both the length of hospital stay and the incidence of postoperative myocardial ischemia were reduced in the esketamine group. In myocardial injury, BNP may increase before troponin and can therefore be used as a sensitive indicator for the early diagnosis of myocardial injury caused by various factors. ⁵² The marker hs-cTnT is highly sensitive to myocardial injury and can appear in the early stages of myocardial injury. It can be detected even at very low concentrations, thereby improving the early diagnosis of myocardial injury. ⁵³ H-FABP is widely present in human cardiomyocytes and is rapidly released into the bloodstream during myocardial ischemia and hypoxia. It has very high sensitivity and specificity for diagnosing early myocardial microinjury. ⁵⁴ Esketamine may have a beneficial effect in preventing postoperative myocardial injury, and its application in older patients and other populations warrants further investigation.

Application of esketamine in the field of mental diseases

Depressive disorders are common mental illnesses, affecting more than 300 million people worldwide. Approximately 15% of patients with major depressive disorder exhibit suicidal behaviors, and 3.4% die by suicide, imposing a substantial familial and societal burden.^55–57 The US Food and Drug Administration approved esketamine nasal spray for the treatment of adults with refractory major depressive disorder in March 2019. In August 2020, its use was extended to include the treatment of major depressive disorder with acute suicidal ideation or behavior. ⁵⁸ However, vigilance is required regarding the adverse reactions associated with esketamine nasal spray. Data from the FAERS database indicate that older patients (≥65 years) may be more prone to suicidal ideation than young adults, and suicidal ideation in female patients represents a high-risk signal. Some studies suggest that most of these events are associated with underlying diseases (major depressive disorder) rather than the direct effects of the drug.

Antidepressant effects

Both ketamine and esketamine exert rapid antidepressant effects in patients with treatment-resistant depression. However, ketamine is typically administered intravenously and is therefore limited by its dosage form, whereas esketamine has been approved as a nasal spray, making it more convenient for clinical use. The antidepressant mechanism of esketamine may involve binding to NMDA receptors, inhibiting the phosphorylation of elongation factor 2 in eukaryotic cells, and promoting the release of brain-derived neurotrophic factor. These actions enhance neuroplasticity and synapse formation. ⁵⁹ A randomized, double-blind, controlled study evaluated the efficacy and safety of esketamine nasal spray at doses of 28, 56, and 84 mg for the treatment of patients with refractory depression. ⁶⁰ The results indicated that esketamine produced a significant and clinically meaningful therapeutic effect compared with placebo. A clear correlation was observed between therapeutic dosage and antidepressant response, and improvements in depressive symptoms persisted after discontinuation of esketamine. The study also reported no new or unexpected safety concerns, suggesting a potent and sustained antidepressant effect. In a phase 3, multicenter, double-blind, randomized clinical trial conducted by Daly et al., ⁶¹ 455 adult patients with refractory depression were treated with esketamine nasal spray combined with oral antidepressants. After 16 weeks, 297 patients achieved stable remission or entered a randomized discontinuation phase. Treatment with esketamine combined with an antidepressant significantly reduced the risk of relapse by 51% compared with treatment with an antidepressant alone or placebo. Among patients who achieved stable remission, the risk of relapse was further reduced by 70%. These findings underscore the significant efficacy of esketamine in preventing recurrence of depressive symptoms.

Antisuicidal effects

In a double-blind, multicenter, proof-of-concept study, Canuso et al. ⁶² compared the efficacy of standard-of-care treatment supplemented with either esketamine nasal spray or placebo for the rapid reduction of suicidal risk in patients with major depressive disorder. The results demonstrated a significant improvement in scores for suicidal thoughts on the Montgomery–Åsberg Depression Rating Scale (MADRS) within 4 h following the first dose in the esketamine group compared with the placebo group. Furthermore, two clinical trials have been conducted to validate the benefits of esketamine in patients with major depressive disorder at risk of suicide.^63,64 One trial involved 226 hospitalized patients with major depressive disorder. The severity of depressive symptoms was assessed using the MADRS, and efficacy related to suicidal ideation and behavior was evaluated using the Suicide Ideation and Behavior Assessment Tool (SIBAT). The findings indicated that the improvement in total MADRS scores was greater in the esketamine group than in the placebo group from 4 h after the initial dose to the end of the double-blind phase. A rapid reduction in the severity of suicidality was observed in both groups, alongside a clear benefit of esketamine in improving depressive symptoms. These studies confirm that esketamine can rapidly and robustly reduce depressive symptoms in patients with major depressive disorder who exhibit active suicidal ideation.

Adverse effects of esketamine

The most common adverse events associated with esketamine in antidepressant treatment are dissociation, anxiety, nausea, elevated blood pressure, and headache. Most side effects are mild, transient, and dose-dependent, and they tend to diminish with subsequent treatments. ⁶⁵ Severe adverse reactions, such as loss of consciousness and serotonin syndrome, typically occur in patients with long-term use of esketamine, with those receiving higher oral doses being more susceptible to severe neurotoxicity. ⁶⁶ When used as an anesthetic adjuvant, esketamine may increase upper respiratory secretions; however, no severe respiratory adverse events have been reported. As a sedative and analgesic, esketamine demonstrates a lower incidence of side effects compared with ketamine, with most reactions being mild and tolerable. In addition, no cases of addiction have been reported with short-term use. ⁶⁷

Discussion

As a new generation of NMDA receptor antagonists, esketamine has been studied by 978 different institutions across 48 countries/regions over the past two decades.^68,69

Comparison with previous studies

The findings of this narrative review are consistent with the core conclusions of existing studies on esketamine. Faísco et al. ¹ and Zanos et al. ² confirmed the limitations of racemic ketamine and the superior pharmacological affinity of esketamine for NMDA receptors, laying the foundation for optimization of its clinical applications. Wang et al. ⁸ and Yao et al. ²⁶ verified the significant analgesic effects and safety of esketamine in perioperative care through meta-analyses, supporting our summary of its application in postoperative analgesia. For postoperative delirium, inconsistent results reported by Zhu et al. ¹⁹ and Ma et al. ²¹ were also analyzed in this review. The divergence may be attributed to differences in administration regimens, study populations, and assessment criteria, which is consistent with the existing research consensus. In psychiatry, Daly et al.^60,61 and Canuso et al. ⁶² validated the rapid antidepressant and antisuicidal effects of esketamine, which constitute key evidence supporting the psychiatric applications summarized in this review. This review also incorporates the latest clinical evidence available up to June 2025, thereby enriching the existing evidence base regarding the clinical applications of esketamine.

Relevance and novelty

This review systematically collates the pharmacological characteristics of esketamine and its clinical applications across multiple fields, including anesthesia, analgesia, critical care, psychiatry, and organ protection. It addresses the fragmentation of existing research and provides a comprehensive reference for rational clinical use. The novelty of this review lies in three aspects: (a) integration of the latest clinical evidence up to 2025, including recent research on myocardial protection and prevention of postpartum depression; (b) in-depth analysis of controversial issues (e.g. the efficacy of esketamine in postoperative delirium) and their influencing factors; and (c) a unified summary of the application characteristics of esketamine in special populations (pediatric patients, obstetric patients, and older patients), which has important implications for personalized clinical medication strategies.

Limitations of the review

As a narrative review, this study has several limitations: (a) potential literature selection bias due to the lack of strict systematic screening procedures, despite the use of Joanna Briggs Institute (JBI) tools for quality assessment of the included literature; (b) inconsistent conclusions on some topics (e.g., the effect of esketamine on postoperative delirium) due to the lack of high-quality, multicenter, large-sample randomized controlled trials; (c) insufficient long-term follow-up data in the included studies, which limits the evaluation of the long-term safety and efficacy of esketamine; and (d) limited studies on the use of esketamine in special populations (e.g. patients with severe hepatorenal insufficiency), resulting in insufficient evidence to support its application in these groups.

Conclusion and prospect

Compared with ketamine, esketamine offers broader and potentially safer application prospects in surgical anesthesia, perioperative pain management, treatment of patients in special populations, and psychiatric disorders. However, it should be noted that the current evidence base regarding monitoring of anesthesia depth, effects on cognitive function, and organ-protective roles remains limited, highlighting the need for further clinical research.