Esketamine (Spravato®): A Comprehensive Monograph on its Pharmacology, Clinical Efficacy, and Role in Modern Psychiatry

Section 1: Introduction and Molecular Profile

1.1. A Paradigm Shift in Antidepressant Therapy

Esketamine represents a landmark development in the pharmacological management of mood disorders and a significant paradigm shift in antidepressant therapy. As the first ketamine-derived medication to receive regulatory approval for a psychiatric indication, it offers a novel therapeutic avenue for some of the most challenging-to-treat patient populations.[1] Specifically, its approval addresses a profound unmet need for individuals with treatment-resistant depression (TRD) and for those with major depressive disorder (MDD) experiencing acute suicidal ideation or behavior (MDSI).[2] An estimated one-third of the more than 21 million adults in the United States with MDD do not respond adequately to at least two conventional antidepressant treatments, meeting the criteria for TRD.[6] For these individuals, cycling through multiple medications with similar mechanisms of action often leads to frustration and continued suffering.[7]

The therapeutic innovation of esketamine lies in its distinct mechanism of action, which diverges fundamentally from the monoaminergic pathways targeted by traditional antidepressants like selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). Esketamine acts on the brain's glutamate system, the primary excitatory neurotransmitter pathway involved in synaptic plasticity and neural communication.[5] This novel mechanism is believed to be responsible for its most notable clinical feature: a rapid onset of action. Unlike conventional therapies that may take several weeks or months to exert their full effect, esketamine has demonstrated the ability to produce improvements in depressive symptoms in as little as 24 hours post-administration.[3]

This rapid action is delivered via a unique intranasal spray formulation, which facilitates swift absorption but also contributes to a distinct and acute side-effect profile.[3] Consequently, its clinical use is defined by a set of stringent regulatory controls mandated by the U.S. Food and Drug Administration (FDA). These controls are formalized in a Risk Evaluation and Mitigation Strategy (REMS) program, which requires administration by the patient under the direct supervision of a healthcare provider in a certified healthcare setting, followed by a mandatory post-dose observation period.[4]

The development and approval of esketamine also reflect a significant strategic evolution in pharmaceutical development. Racemic ketamine, a generic mixture of two enantiomers, was first approved as an anesthetic in 1970 and has been used off-label for depression for over two decades.[1] However, the lack of patent protection for this generic compound created a significant financial disincentive for pharmaceutical companies to invest in the large, expensive Phase 3 clinical trials required for a formal psychiatric indication.[12] By isolating, studying, and developing the S-enantiomer, esketamine, the manufacturer was able to pursue a new drug application for a distinct molecular entity. This strategy allowed for patent protection and market exclusivity, justifying the substantial investment in a full clinical development program and ultimately bringing a ketamine-based therapy through the formal regulatory process for specific psychiatric indications.[13] This pathway, driven by both scientific and commercial logic, has successfully established a new class of antidepressant therapy.

1.2. Chemical Identity and Stereochemistry

Esketamine is a small molecule drug that is chemically classified as a cyclohexanone derivative.[2] Its definitive chemical and regulatory identifiers are as follows:

• DrugBank ID: DB11823 [2]
• CAS Number: 33643-46-8 (free base) [3]
• Type: Small Molecule [2]
• IUPAC Name: (2S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one [3]
• Chemical Formula: C13​H16​ClNO [16]
• InChI: InChI=1S/C13H16ClNO/c1-15-13(9-5-4-8-12(13)16)10-6-2-3-7-11(10)14/h2-3,6-7,15H,4-5,8-9H2,1H3/t13-/m0/s1 [3]
• InChIKey: YQEZLKZALYSWHR-ZDUSSCGKSA-N [3]
• SMILES: CN[C@@]1(CCCCC1=O)C2=CC=CC=C2Cl [3]
• Synonyms: Esketamine is also known by several other names, including (S)-Ketamine, S(+)-Ketamine, (-)-Ketamine, and its brand names Spravato (for depression) and Ketanest (for anesthesia).[3]

A critical aspect of esketamine's identity is its stereochemistry. Racemic ketamine is a chiral compound that exists as a mixture of two enantiomers—non-superimposable mirror-image molecules—known as (S)-ketamine and (R)-ketamine (arketamine).[3] Esketamine is the isolated S-(+)-enantiomer.[3] Enantiomers can have significantly different pharmacological properties, and this is the case with ketamine. Esketamine is the more pharmacologically active enantiomer with respect to antagonism of the N-methyl-D-aspartate (NMDA) receptor, exhibiting a three- to four-fold higher affinity for the receptor than arketamine.[4] This increased potency is clinically relevant; esketamine is approximately twice as potent as an anesthetic compared to the racemic mixture.[4]

While esketamine is the more potent NMDA receptor antagonist, the pharmacological profile of its counterpart, arketamine, is a subject of ongoing scientific interest. Some preclinical research in mice has suggested that arketamine may produce a greater and more sustained antidepressant effect than esketamine, and potentially with fewer psychotomimetic (dissociative or hallucinogenic) side effects.[4] This finding complicates the simple narrative that greater NMDA receptor potency directly translates to superior antidepressant efficacy and highlights the complex neurobiology underlying the therapeutic effects of these compounds. This distinction underscores that the selection of esketamine for clinical development was based on its higher affinity for the primary pharmacological target, a logical but not necessarily definitive, approach to optimizing the therapeutic profile of ketamine.

Section 2: Comprehensive Pharmacological Profile

2.1. Mechanism of Action (MOA)

The primary mechanism of action of esketamine is its function as a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, which is an ionotropic receptor for the excitatory neurotransmitter glutamate.[2] Despite this well-defined primary target, the precise downstream cascade of events that produces its rapid and robust antidepressant effect is not fully understood and remains an area of active investigation.[2]

The leading scientific explanation is often referred to as the "glutamate hypothesis" of antidepressant action. This model posits that in a depressed state, there may be deficits in glutamate signaling and synaptic function. Esketamine is thought to preferentially bind to and block NMDA receptors located on inhibitory GABAergic interneurons.[17] This blockade effectively "disinhibits" the pyramidal neurons that are normally suppressed by these interneurons. The result is a brief but powerful surge of glutamate release in cortical and limbic brain regions, such as the prefrontal cortex.[8] This glutamate surge then preferentially activates a different type of glutamate receptor, the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, on postsynaptic neurons. The activation of AMPA receptors is believed to trigger downstream signaling pathways that enhance neurotrophic factor expression (like Brain-Derived Neurotrophic Factor, BDNF), promote synaptogenesis, and restore synaptic plasticity—the cellular processes thought to underlie the rapid improvement in mood and depressive symptoms.[8]

However, the mechanism is likely more complex than this linear model suggests. Research indicates that esketamine's effects are not limited to the glutamate system. It also inhibits dopamine transporters eight times more effectively than its enantiomer, arketamine, leading to an increase in synaptic dopamine activity which may contribute to its antidepressant and rewarding properties.[4] Furthermore, recent findings challenge the simplicity of the "glutamatergic burst" hypothesis. Studies have shown that some of esketamine's effects, particularly on dopamine tone, are partially blocked by the opioid receptor antagonist naloxone.[17] This suggests a more intricate, circuit-dependent interaction between the glutamate, dopamine, and endogenous opioid systems, rather than a simple disinhibition mechanism.[17]

Adding another layer of complexity is the activity of esketamine's metabolites. The primary circulating metabolite, noresketamine, is formed through N-demethylation in the liver. This metabolite is also pharmacologically active and functions as an NMDA receptor antagonist, although its affinity for the receptor is weaker than that of the parent compound, esketamine.[18] The contribution of noresketamine and other metabolites to the overall therapeutic effect is not fully elucidated but remains an important consideration in its complete pharmacological profile.

2.2. Pharmacodynamics

The pharmacodynamic effects of esketamine are multifaceted, encompassing profound impacts on the central nervous system, cognition, and cardiovascular function.

Central Nervous System (CNS) Effects:

Esketamine is classified as a central nervous system depressant.2 Its administration is associated with a predictable set of CNS effects, including sedation, dizziness, and lethargy.2 The most characteristic pharmacodynamic effects are its dose-dependent dissociative and perceptual changes.2 Dissociation is a transient state described by patients as feeling disconnected from oneself (depersonalization), one's thoughts, feelings, or surroundings (derealization), and may include distortions of time and space.17 Clinical trial data indicate that between 61% and 75% of patients treated with Spravato® experience these dissociative symptoms shortly after administration.17

Cognitive Effects:

Acutely, esketamine administration leads to transient impairment of cognitive functions. These impairments affect attention, judgment, executive function, reaction speed, and motor skills.2 In a study of healthy volunteers, a single dose of esketamine resulted in a measurable decline in cognitive performance at 40 minutes post-administration, with subjects reporting a need for greater mental effort to complete cognitive tasks compared to placebo.2 These acute cognitive effects are temporary, with performance and effort levels returning to baseline levels comparable to placebo by 2 hours after administration.2 While chronic misuse or abuse of racemic ketamine has been associated with long-term cognitive and memory impairment, a one-year open-label safety study of intranasal esketamine did not identify any adverse effects on cognitive function.2 Nevertheless, it must be emphasized that the long-term cognitive effects of intermittent esketamine use beyond a one-year period have not been systematically evaluated, and this remains a knowledge gap.2

Hemodynamic Effects:

Esketamine consistently and predictably causes transient increases in both systolic and diastolic blood pressure at all approved therapeutic doses.2 This hypertensive effect is a direct pharmacodynamic consequence of the drug's action. The peak elevation in blood pressure typically occurs approximately 40 minutes after the final spray of a treatment session, which temporally aligns with the peak plasma concentration (Cmax) of the drug.2 This blood pressure increase is often significant, with reports of elevations greater than 40 mmHg in systolic pressure and 25 mmHg in diastolic pressure in up to 17% of patients.19 The effect generally lasts for approximately 4 hours before returning to baseline.2

Cardiac Electrophysiology:

The effect of esketamine on cardiac repolarization was specifically investigated in a thorough, randomized, placebo- and positive-controlled crossover study. Healthy volunteers received 84 mg of intranasal esketamine, as well as an intravenous dose for comparison. The study concluded that, despite causing a marked increase in heart rate (often greater than 10 bpm), esketamine does not cause clinically relevant prolongation of the QTc interval at therapeutic doses.2 This finding suggests a low risk of inducing Torsades de Pointes or other serious ventricular arrhythmias related to QTc prolongation.

2.3. Pharmacokinetics (Absorption, Distribution, Metabolism, and Excretion)

The clinical behavior of esketamine, including its rapid onset of action and the need for in-clinic monitoring, is dictated by its pharmacokinetic properties.

Absorption:

Following administration via nasal spray, esketamine is absorbed rapidly through the highly vascular nasal mucosa.2 This rapid absorption leads to a short time to reach maximum plasma concentration (Tmax), which is consistently observed to be between 20 and 40 minutes after the last nasal spray of a treatment session.2 The mean absolute bioavailability of the intranasal formulation is approximately 48%.2 The absorption process is complex; a portion of the administered dose is absorbed directly and quickly through the nasal passages, while the fraction of the dose that is inevitably swallowed is absorbed more slowly through the gastrointestinal tract and is subject to extensive first-pass hepatic metabolism, which reduces its contribution to systemic drug levels.17

Distribution:

Esketamine distributes extensively throughout the body, as indicated by its large volume of distribution at steady state (Vss), which is estimated to be approximately 752 L.23 This large value signifies that the drug is not confined to the bloodstream and penetrates extensively into peripheral tissues.

Metabolism:

Esketamine undergoes extensive hepatic metabolism, primarily mediated by the cytochrome P450 (CYP) enzyme system.18 The main enzymes responsible for its biotransformation are CYP2B6 and CYP3A4, with minor contributions from CYP2C9 and CYP2C19.18 The major metabolic pathway is N-demethylation, which converts esketamine into its primary active metabolite,

noresketamine. Noresketamine is subsequently metabolized further through CYP-dependent pathways, followed by glucuronidation to form water-soluble conjugates that can be easily excreted.[18]

Excretion:

The body eliminates esketamine primarily through renal excretion of its metabolites. Following a radiolabeled dose, approximately 78% or more of the dose is recovered in the urine, with a very small fraction (≤2%) found in the feces.18 Very little of the drug is eliminated in its original form; less than 1% of an administered dose is excreted as unchanged esketamine in the urine.17 The mean terminal elimination half-life (

t1/2​) of esketamine ranges from 7 to 12 hours.[18] Importantly, pharmacokinetic studies have shown that no accumulation of esketamine occurs in the plasma with the recommended twice-weekly dosing schedule during the induction phase.[23]

The direct and predictable relationship between esketamine's pharmacokinetics and pharmacodynamics is the cornerstone of its clinical management. The rapid intranasal absorption results in a Tmax of 20-40 minutes, which coincides precisely with the peak of its most intense and concerning pharmacodynamic effects: dissociation, sedation, and hypertension, which peak at approximately 40 minutes post-dose.[2] This rapid onset of profound physiological and psychological effects makes at-home use unsafe and is the direct reason for the FDA's mandate for in-clinic administration and a minimum 2-hour post-dose observation period.[5] This protocol is not an arbitrary safety measure but a necessary clinical procedure designed specifically to manage the patient through the window of peak drug effect, ensuring they are clinically stable before discharge. Thus, the choice of a rapid delivery route, while beneficial for achieving a fast antidepressant response, creates a significant safety and logistical framework that is the single most defining characteristic of esketamine therapy.

Parameter	Value	Source(s)
Bioavailability (Intranasal)	~48%	2
Time to Peak Plasma Concentration (Tmax​)	20-40 minutes	2
Terminal Half-Life (t1/2​)	7-12 hours	18
Volume of Distribution (Vss​)	~752L	23
Primary Metabolizing Enzymes	CYP2B6, CYP3A4	18
Primary Metabolite	Noresketamine (active)	18
Route of Excretion	Primarily renal (as metabolites)	18

Table 1: Key Pharmacokinetic Parameters of Intranasal Esketamine

Section 3: Clinical Efficacy and Therapeutic Application

3.1. Approved Indications and Place in Therapy

Esketamine, marketed as Spravato®, has received FDA approval for two specific and severe psychiatric conditions, positioning it as a critical therapeutic option for patients with limited alternatives.

Treatment-Resistant Depression (TRD):

The primary indication for esketamine is for the treatment of treatment-resistant depression in adults.2 TRD is clinically defined as major depressive disorder that has not responded adequately to at least two different oral antidepressant therapies, administered at a sufficient dose and for a sufficient duration, within the current depressive episode.3

Initially, in March 2019, esketamine was approved for TRD only when used in conjunction with a concurrently administered oral antidepressant.[3] This positioned it as an adjunctive therapy to augment the effects of conventional treatments. However, in a significant expansion of its label, the FDA approved esketamine in January 2025 as the first and only

monotherapy for TRD.[5] This landmark approval provides a new therapeutic pathway for patients who may not be able to tolerate oral antidepressants or who have failed to derive benefit from them, allowing esketamine to be used as a standalone treatment.[5]

Major Depressive Disorder with Acute Suicidal Ideation or Behavior (MDSI):

In August 2020, esketamine received a second crucial indication for the treatment of depressive symptoms in adults with MDD who are concurrently experiencing acute suicidal ideation or behavior.3 For this indication, esketamine is intended as an acute, short-term treatment for the rapid reduction of depressive symptoms in what is considered a psychiatric emergency.27 It is administered in conjunction with a comprehensive standard of care, which must include initiation or continuation of an oral antidepressant.7 It is critical to note that the product label explicitly states that esketamine has not been shown to prevent suicide or reduce suicidal actions, and it is not a substitute for hospitalization if a healthcare provider determines that it is clinically necessary, even if the patient experiences symptomatic improvement after the first dose.7

3.2. Critical Analysis of Pivotal Clinical Trials

The regulatory approval of esketamine was based on a comprehensive development program that included five pivotal Phase 3 studies: three short-term efficacy studies, one randomized withdrawal study to assess maintenance of effect, and one long-term safety study.[13] The evidence from these trials presents a complex but ultimately compelling case for its efficacy in its approved indications.

Trial ID / Name	Design	Population	Primary Endpoint	Result
TRANSFORM-1 (Fixed-Dose)	Short-term (4-week), randomized, double-blind, active-controlled (new oral AD + placebo)	Adults with TRD	Change in MADRS score at Day 28	Failed to meet statistical significance for either 56 mg or 84 mg dose vs. control 13
TRANSFORM-2 (Flexible-Dose)	Short-term (4-week), randomized, double-blind, active-controlled (new oral AD + placebo)	Adults with TRD	Change in MADRS score at Day 28	Statistically significant improvement for esketamine + oral AD vs. control 15
SUSTAIN-1 (Randomized Withdrawal)	Randomized withdrawal maintenance study. Patients who achieved remission/response after 16 weeks of esketamine were randomized to continue esketamine or switch to placebo.	Adults with TRD in stable remission or response	Time to relapse	Statistically significant delay in relapse. Esketamine reduced relapse risk by 51% in remitters and 70% in responders 14
ASPIRE I & II	Short-term (4-week), randomized, double-blind, placebo-controlled	Adults with MDD and acute suicidal ideation/behavior	Change in MADRS score at 24 hours	Met primary endpoint, showing rapid reduction in depressive symptoms 4
Monotherapy Trial	Short-term (4-week), randomized, double-blind, placebo-controlled	Adults with TRD	Change in MADRS score at Day 28	Statistically significant improvement for esketamine monotherapy vs. placebo. Led to 2025 monotherapy approval 5

Table 2: Summary of Pivotal Phase 3 Clinical Trial Outcomes for Esketamine

Narrative Analysis of Trials:

The results from the short-term efficacy studies in TRD were mixed. The TRANSFORM-2 study, which used a flexible-dosing schedule (56 mg or 84 mg), successfully met its primary endpoint, demonstrating a statistically significant and clinically meaningful reduction in depressive symptoms (as measured by the Montgomery-Åsberg Depression Rating Scale, MADRS) at four weeks compared to a control group receiving a newly initiated oral antidepressant plus a placebo nasal spray.15 In this study, the remission rate at day 28 was 52.5% for the esketamine group versus 31.0% for the placebo group.15 However, the TRANSFORM-1 study, which used fixed doses of 56 mg and 84 mg, failed to demonstrate a statistically significant superiority over the active comparator arm for its primary endpoint.13 This discrepancy highlights the potential importance of dose flexibility and underscores the statistical challenge of demonstrating superiority when the control group is also receiving an active, newly initiated antidepressant.

Given the mixed short-term results, the initial FDA approval in 2019 hinged heavily on the powerful and unambiguous results of the SUSTAIN-1 trial, a randomized withdrawal study designed to assess relapse prevention.[1] In this pivotal study, patients with TRD who had achieved stable remission or response after a 16-week course of esketamine plus an oral antidepressant were randomized to either continue their esketamine treatment or switch to a placebo nasal spray, while all patients continued their oral antidepressant. The results were compelling: among patients in stable remission, continuing esketamine reduced the risk of relapse by 51% compared to the placebo group. For patients who had achieved a stable response (but not full remission), the risk of relapse was reduced by 70%.[29] This demonstrated that for patients who are identified as "responders," continued esketamine treatment is highly effective at maintaining therapeutic benefit and preventing the return of depressive symptoms.[19] This finding established that esketamine's most robustly proven value at the time of initial approval was in the maintenance phase of treatment for those who had already benefited from it. The regulatory review of this study was not without scrutiny; the FDA noted that a single study site in Poland reported a 100% relapse rate in the placebo arm, raising concerns that this outlier site could have disproportionately driven the positive overall result.[1]

The subsequent approvals were supported by further robust data. The indication for MDSI was based on the ASPIRE I and II trials, which demonstrated a rapid reduction in depressive symptoms at 24 hours post-dose in patients with acute suicidality.[4] The landmark 2025 approval for monotherapy was supported by a dedicated randomized, placebo-controlled trial (NCT04599855) that showed esketamine alone was superior to placebo in improving depressive symptoms over four weeks, thereby broadening its utility for patients unable to take oral antidepressants.[5]

3.3. Dosing, Administration, and Treatment Protocol

The clinical use of esketamine is governed by a highly structured and rigorously controlled protocol for dosing and administration, designed to maximize efficacy while mitigating its significant safety risks.

Formulation and Dosage Forms:

Spravato® is supplied as a solution for nasal spray, packaged in a single-use device. Each device is designed to deliver a total of 28 mg of esketamine in two separate sprays (one 14 mg spray into each nostril).27 Therapeutic doses are achieved by using multiple devices in a single treatment session. A 56 mg dose requires the use of two devices, and an 84 mg dose requires three devices. To allow for adequate absorption of the medication from the nasal mucosa, there is a mandatory 5-minute rest period between the use of each device.27

Dosing Schedule for Treatment-Resistant Depression (TRD):

The treatment protocol for TRD is divided into distinct phases to establish and maintain a therapeutic response:

• Induction Phase (Weeks 1-4): Treatment begins with a starting dose of 56 mg on Day 1. For the remainder of the induction phase, the dose is either 56 mg or 84 mg, based on efficacy and tolerability, and is administered twice per week.[19]
• Maintenance Phase (Weeks 5-8): Patients who have responded to induction therapy transition to the maintenance phase. The dose remains 56 mg or 84 mg, but the frequency is reduced to once weekly.[19]
• Continued Maintenance (Week 9 and beyond): The dosing frequency is further individualized to the lowest frequency that effectively maintains the patient in remission or response. The dose of 56 mg or 84 mg is administered either once weekly or once every two weeks.[19] The need for continued treatment should be re-evaluated periodically.

Dosing Schedule for MDSI:

For adults with MDD and acute suicidal ideation or behavior, the recommended dosage is 84 mg administered twice per week for four weeks. The dose may be reduced to 56 mg based on individual patient tolerability. During this period, the patient must also be treated with an oral antidepressant.27

Special Populations:

For geriatric patients (age 65 and older), a more cautious dosing approach is recommended. The initial starting dose is 28 mg (one device). Subsequent doses can be titrated upwards in 28 mg increments to 56 mg or 84 mg, based on a careful assessment of efficacy and tolerability.27

Administration and Monitoring Protocol:

The administration of esketamine is a strict, medically supervised procedure.

1. Preparation: Patients are instructed to avoid eating for at least 2 hours and to avoid drinking liquids for at least 30 minutes prior to their scheduled treatment. This is to reduce the risk of nausea and vomiting and to ensure consistent absorption.[5]
2. In-Clinic Administration: The patient self-administers the nasal spray under the direct supervision of a healthcare professional in a certified healthcare setting. The patient must be instructed to recline their head back at approximately a 45-degree angle during administration and to sniff gently after each spray to keep the medication inside the nose.[5]
3. Post-Dose Observation: Following administration of the final device, the patient must be monitored by a healthcare provider for at least 2 hours. This observation period is critical for monitoring for adverse effects, particularly sedation, dissociation, and changes in blood pressure. The provider assesses when the patient is clinically stable and ready to leave the facility.[5]
4. Post-Treatment Restrictions: Patients are strictly prohibited from driving or operating heavy machinery until the following day, after a restful night's sleep, due to the potential for delayed sedation and cognitive impairment.[19] Patients must arrange for a caregiver or family member to drive them home from the treatment center.[5]

Section 4: Safety, Tolerability, and Risk Management

The unique benefits of esketamine are balanced by a significant and predictable adverse effect profile that necessitates a comprehensive risk management strategy. This strategy is built upon a thorough understanding of its adverse effects, contraindications, and a federally mandated REMS program.

4.1. Comprehensive Adverse Effect Profile

The adverse events associated with esketamine are common, transient, and directly related to its pharmacodynamic effects. They typically occur shortly after dosing and resolve within a few hours.

• Most Common Adverse Events: In clinical trials, the most frequently observed adverse reactions (defined as occurring at an incidence of ≥5% and at least twice the rate of placebo plus an oral antidepressant) were dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia (numbness or decreased sensitivity), anxiety, lethargy, increased blood pressure, vomiting, and feeling drunk.[21] The incidence of specific common side effects can be high; for example, dizziness, nausea, and vertigo may affect 20% to 30% of patients during treatment.[19]
• Neuropsychiatric Effects: The most characteristic side effects are neuropsychiatric. Dissociation, which includes perceptual changes, derealization, and depersonalization, is very common.[17] Other effects include anxiety, and in some cases, feelings of being very happy or excited, which may resemble hypomanic symptoms.[21] As with all antidepressants, there is a risk of worsening depression and the emergence of suicidal thoughts, which is addressed in the boxed warning.[7]
• Cardiovascular Effects: Transient but clinically significant increases in systolic and diastolic blood pressure are a consistent and expected effect of esketamine.[2] Blood pressure must be monitored before and after treatment. In rare cases, patients may experience symptoms of a hypertensive crisis (e.g., chest pain, shortness of breath, severe headache), which requires immediate emergency care.[19] Tachycardia (increased heart rate) is also a common cardiovascular effect.[22]
• Other Notable Effects: Although less common than with chronic, high-dose illicit ketamine use, there is a potential risk of bladder and urinary tract problems, such as ulcerative or interstitial cystitis. Patients should be advised to report symptoms like frequent or painful urination to their provider.[22] Transient problems with thinking clearly and memory are also listed as potential side effects.[37]

4.2. Contraindications, Warnings, and Precautions

To ensure patient safety, the use of esketamine is prohibited in certain populations and requires careful consideration in others.

Absolute Contraindications:

Spravato® is strictly contraindicated in patients with the following conditions, due to the significant risk posed by its transient hypertensive effects 22:

• Aneurysmal vascular disease: This includes known aneurysms in the thoracic and abdominal aorta, intracranial vessels, or peripheral arterial vessels, as well as arteriovenous malformations. The acute increase in blood pressure could lead to rupture.[10]
• History of intracerebral hemorrhage: Patients with a prior brain bleed are at an unacceptably high risk of a recurrent event.[10]
• Hypersensitivity: Known hypersensitivity or allergy to esketamine, racemic ketamine, or any of the excipients in the formulation.[10]

Warnings and Precautions:

• Embryo-fetal Toxicity: Esketamine may cause fetal harm. Its use is not recommended in pregnant women, and females of reproductive potential should be advised on pregnancy planning and prevention. It is also not recommended for use in breastfeeding mothers as it passes into human milk.[19]
• Hepatic Impairment: The use of esketamine has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and is therefore not recommended in this population.[19]
• History of Psychosis: Due to its potential to induce dissociative and perceptual changes, esketamine should be used with caution in patients with a current or prior psychotic disorder. Treatment should only be initiated if the potential benefit is judged to outweigh the risk of exacerbating psychotic symptoms.[22]
• History of Substance Use Disorder: As a Schedule III controlled substance, esketamine has a potential for abuse, misuse, and dependence. Careful consideration and monitoring are advised when treating individuals with a history of substance use disorder.[19]

4.3. The Spravato® REMS Program and Black Box Warnings

Due to its significant safety risks, the FDA mandated that esketamine be available only through a restricted distribution program known as the Spravato® Risk Evaluation and Mitigation Strategy (REMS).[1] This program is designed to ensure that the benefits of the drug outweigh its risks. The necessity of the REMS is underscored by the four distinct

FDA Boxed Warnings on the product's label [22]:

1. Sedation: Patients are at risk for significant sedation and, in some cases, loss of consciousness following administration.
2. Dissociation: Patients are at risk for transient but profound dissociative or perceptual changes.
3. Abuse and Misuse: As a derivative of ketamine and a Schedule III controlled substance, there is a risk of abuse, misuse, and psychological dependence.
4. Suicidal Thoughts and Behaviors: Consistent with other antidepressant medications, there is an increased risk of suicidal thoughts and behaviors, particularly in adolescents and young adults (age 24 and younger). Esketamine is not approved for use in children.

The Spravato® REMS program operationalizes the management of these risks through several key requirements [4]:

• Certified Centers and Providers: Healthcare settings (e.g., clinics, hospitals) where the drug is administered must be specially certified, and prescribers must be enrolled in the program.
• Patient Enrollment: Every patient receiving esketamine must be enrolled in the REMS patient registry.
• Supervised Administration: The drug must be dispensed and self-administered by the patient only within the certified healthcare setting and under the direct supervision of a healthcare professional.
• Post-Dose Monitoring: Patients must be monitored for at least two hours after each treatment session.
• No At-Home Use: The drug cannot be prescribed for or taken home by the patient.

The REMS program, while critical for ensuring patient safety, inherently creates substantial logistical and economic barriers to treatment. This framework is unprecedented for an antidepressant medication. For patients, it requires a significant time commitment for each visit (often several hours, twice weekly during induction), the need to arrange for transportation, and potential time away from work or other responsibilities.[5] For the healthcare system, it demands dedicated physical space for administration and observation, significant staff time for monitoring, and the administrative overhead associated with maintaining REMS certification and compliance. These factors, combined with the high cost of the medication itself [19], can limit access for many patients who might otherwise be candidates, particularly those without robust social support, flexible schedules, or comprehensive insurance coverage. This stands in stark contrast to the simple "take-home" prescription model of all other oral antidepressants.

4.4. Clinically Significant Drug Interactions

The potential for drug interactions with esketamine is primarily pharmacodynamic, related to additive effects on the CNS and blood pressure.

Pharmacodynamic Interactions:

• Central Nervous System (CNS) Depressants: Co-administration of esketamine with other CNS depressants can lead to synergistic effects. This includes opioids, benzodiazepines, and alcohol. Combining these substances with esketamine significantly increases the risk of excessive sedation, dizziness, and potentially life-threatening respiratory depression. Patients should be advised to avoid alcohol and to inform their provider of any use of opioids or benzodiazepines.[36] While some studies showed benzodiazepines did not reduce esketamine's efficacy, they were associated with increased sedation.[39]
• Agents that Increase Blood Pressure: Concomitant use of esketamine with other medications that can elevate blood pressure requires caution and close monitoring. This is particularly relevant for monoamine oxidase inhibitors (MAOIs) and psychostimulants (e.g., amphetamines, methylphenidate, modafinil). The combination may potentiate the transient hypertensive effect of esketamine.[19]

Pharmacokinetic Interactions:

Esketamine is metabolized by CYP2B6 and CYP3A4.18 Clinical pharmacology studies were conducted to assess the impact of potent inhibitors and inducers of these enzymes.

• The potent CYP3A4 inhibitor clarithromycin and the potent CYP2B6 inhibitor ticlopidine caused modest increases in esketamine exposure (e.g., ticlopidine increased AUC by ~30%).[40]
• The potent CYP inducer rifampin caused a modest decrease in esketamine exposure.[40]

However, these changes were not deemed to be clinically significant. Therefore, dose adjustments of esketamine are not considered necessary when it is co-administered with inhibitors or inducers of its primary metabolizing enzymes.40

Section 5: Regulatory and Comparative Context

5.1. Regulatory History and Post-Marketing Evolution

The journey of esketamine from an investigational compound to a key therapeutic agent has been marked by several key regulatory milestones, reflecting its novel status and the significant need for new depression treatments.

• September 4, 2018: Janssen submitted the New Drug Application (NDA) for esketamine nasal spray to the U.S. FDA for the indication of treatment-resistant depression.[26]
• February 12, 2019: An FDA Advisory Committee voted in favor of recommending approval for esketamine, signaling confidence in its benefit-risk profile.[26]
• March 5, 2019: The FDA granted its first approval for Spravato® (esketamine) for the treatment of TRD in adults, to be used in conjunction with an oral antidepressant. This marked the first approval of esketamine for any use and the first approval of a ketamine-related product for a psychiatric indication.[1]
• August 3, 2020: The FDA expanded Spravato's label, approving it for the treatment of depressive symptoms in adults with MDD with acute suicidal ideation or behavior, also in conjunction with an oral antidepressant.[1]
• January 21, 2025: In a major development, the FDA approved a supplemental NDA for Spravato® as a monotherapy for adults with TRD, making it the first and only standalone treatment in its class for this population.[5]

Following its initial launch, the uptake of esketamine was reportedly sluggish. However, its use has grown substantially since. Prescriptions in the United States nearly doubled from the beginning of 2023, with over 2,800 certified clinics offering the treatment. Annual sales were projected to surpass $1 billion in 2024.[1] As of early 2025, Spravato® has been approved for use in 77 countries and has been administered to more than 140,000 patients worldwide, solidifying its position in the global psychiatric treatment landscape.[5]

5.2. Comparative Analysis: Intranasal Esketamine vs. Off-Label Intravenous Ketamine

The approval of esketamine has created a complex clinical landscape where it coexists with the continued off-label use of intravenous (IV) racemic ketamine for mood disorders. A comparison of these two approaches reveals distinct differences in regulation, access, evidence, and administration.

• Regulatory Status and Accessibility: This is the most significant point of divergence. Intranasal esketamine (Spravato®) is an FDA-approved product with a specific label, a mandatory REMS program, and a standardized formulation and dosing schedule.[11] This regulatory status means it is often covered by major insurance plans, including Medicaid, making it financially accessible to a broader range of patients.[11] In contrast, IV ketamine use for depression is considered off-label. It is not FDA-approved for this indication, and its administration is not governed by a federal REMS program. As a result, treatment is typically paid for out-of-pocket by the patient, creating a significant financial barrier.[11]
• Administration and Dosing: Esketamine is administered as an intranasal spray with fixed-dose options (typically 56 mg or 84 mg) that the patient self-administers in a certified clinic.[27] IV ketamine is administered as a 40-minute intravenous infusion, with the dose typically calculated based on the patient's weight (most commonly 0.5 mg/kg).[12]
• Evidence Base: The evidence supporting esketamine is derived from a large, industry-sponsored Phase 3 clinical trial program involving thousands of patients, which provides robust data on efficacy and safety for its specific indications.[13] The evidence for IV ketamine, while promising, consists of numerous smaller, often academic-led clinical trials with varying methodologies and smaller sample sizes. There is a lack of large-scale, definitive Phase 3 trials for IV ketamine for depression, largely due to the lack of financial incentive for a generic drug.[12] Some comparative analyses suggest similar response and remission rates between the two, though one study noted that IV ketamine might require fewer treatment sessions to achieve a response.[11]
• Safety and Monitoring: The Spravato® REMS program ensures a highly standardized and regulated approach to safety monitoring for every patient.[1] While professional organizations have issued consensus statements recommending cardiac and respiratory monitoring for IV ketamine administration, the standards of care can vary significantly between independent clinics.[12]
• Patient Experience: Subjective reports on patient experience vary. Some research suggests that esketamine is generally considered more pleasant by patients, who may also recover mental function more quickly after treatment.[4] IV ketamine infusions can sometimes produce more prominent and intense psychoactive effects, such as derealization and depersonalization.[12]

The coexistence of esketamine and off-label IV ketamine represents two diverging models for the delivery of novel psychedelic-informed therapies. Esketamine embodies the traditional pharmaceutical path: a highly regulated, standardized, commercially developed product with a strong but narrowly defined evidence base. This approach ensures a consistent standard of safety but comes with high costs and the logistical burdens of the REMS program. Off-label IV ketamine represents a more grassroots, clinician-driven model, born from academic research and the repurposing of an older, generic drug. This path allows for greater flexibility and lower drug costs but suffers from a lack of standardization, variable quality of care, and an absence of definitive, large-scale safety and efficacy data. The choice between these two options for a patient is often dictated less by clear clinical superiority and more by practical factors like insurance coverage and out-of-pocket cost. The ongoing tension and comparison between these two models will undoubtedly shape the future regulatory and clinical landscape for this entire class of treatments.

5.3. Future Directions and Unanswered Questions

While esketamine has established its place in psychiatry, research continues to explore its full potential and address remaining knowledge gaps.

Emerging Research:

The field is actively investigating the application of esketamine beyond its current indications. A notable example is the pilot clinical trial (NCT06795659) exploring the feasibility of combining intranasal esketamine with Prolonged Exposure (PE) therapy for Post-Traumatic Stress Disorder (PTSD).38 This research seeks to determine if esketamine can augment the effects of a well-established psychotherapy by leveraging its neuroplastic effects to enhance fear extinction and the processing of traumatic memories. Success in this area could open up an entirely new therapeutic application for esketamine as a psychotherapy-enhancing agent.

Unanswered Questions:

Despite the extensive clinical trial program, several important questions about esketamine remain:

• Long-Term Cognitive Effects: The most pressing question is the nature of its long-term effects on cognitive function with sustained, intermittent use. While a one-year study was reassuring, data beyond this timeframe is lacking, and this remains a critical area for future surveillance and research.[2]
• Role of Metabolites: The precise contribution of the active metabolite noresketamine to the overall antidepressant effect is not fully understood.[18] Furthermore, research into other metabolites of ketamine, such as (2R,6R)-hydroxynorketamine, which may exert antidepressant effects without direct NMDA receptor inhibition, suggests that the complete mechanism of action is still being unraveled.[1]
• Predictive Biomarkers: A major goal for future research is the identification of biomarkers (e.g., genetic, neuroimaging, electrophysiological) that can predict which patients are most likely to respond to esketamine. Such tools would allow for more precise patient selection, improving overall efficacy rates and avoiding the burden of treatment for those unlikely to benefit.
• Long-Term Bladder Safety: While ulcerative or interstitial cystitis is a known risk of chronic ketamine abuse, the long-term risk associated with intermittent, clinically approved doses of esketamine needs continued monitoring and long-term safety data collection.[22]

Section 6: Expert Synthesis and Concluding Remarks

Esketamine (Spravato®) is undeniably a transformative therapeutic agent, representing the most significant innovation in antidepressant pharmacology in decades. Its introduction has provided a vital lifeline for a specific and profoundly difficult-to-treat patient population: adults with treatment-resistant depression and those experiencing major depressive episodes with acute suicidal ideation. For these individuals, many of whom have exhausted multiple conventional treatment options without success, esketamine offers the possibility of rapid and substantial symptom relief, fundamentally altering their clinical trajectory. Its novel glutamate-modulating mechanism has not only provided a new treatment but has also validated the glutamate system as a critical target for future antidepressant development, paving the way for a new era of rapidly acting psychiatric medications.

This profound clinical benefit, however, is inextricably linked to a significant and predictable profile of risks. The acute, transient effects of dissociation, sedation, and hypertension are not merely side effects but core pharmacodynamic properties of the drug. These effects, combined with its potential for abuse and misuse as a Schedule III controlled substance, necessitate a level of clinical oversight that is unprecedented for an antidepressant.

The resulting regulatory and logistical framework—the Spravato® REMS program—is therefore not an incidental feature of the therapy but a central and defining component. The requirements for certified centers, in-clinic administration, and extended post-dose monitoring are essential for mitigating the drug's risks. At the same time, this resource-intensive model creates substantial barriers to patient access related to time, cost, and logistics, which can limit its real-world application.

In conclusion, esketamine has successfully carved out a crucial niche in the psychiatric armamentarium. Its success in clinical practice hinges on a triad of factors: meticulous patient selection to identify those most likely to benefit, strict and unwavering adherence to the mandated safety protocols to manage its risks, and a healthcare system with the resources and infrastructure to support its unique administration model. While its long-term position in the therapeutic landscape continues to be defined, esketamine has firmly established a new pathway for treating severe depression and has irrevocably changed the conversation about what is possible in antidepressant therapy.

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