Spravato (Esketamine Nasal Spray)
esketamine hydrochloride
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Treatment-resistant depression (TRD) | Adults (≥18 years) | Monotherapy or adjunctive to oral antidepressant | FDA Approved |
| MDD with acute suicidal ideation or behavior (MDD-SI) | Adults (≥18 years) | Adjunctive to oral antidepressant | FDA Approved |
Esketamine nasal spray was first approved by the FDA in March 2019 for treatment-resistant depression in conjunction with an oral antidepressant. The indication for depressive symptoms in adults with MDD and acute suicidal ideation or behavior was added in July 2020. In January 2025, the FDA approved a supplemental application allowing esketamine to be used as monotherapy for TRD, without the requirement for a concomitant oral antidepressant. TRD is defined as an inadequate response to at least two oral antidepressants of adequate dose and duration in the current episode. Esketamine is available only through a restricted REMS program requiring administration in a certified healthcare setting with post-dose monitoring.
Acute pain management (emergency settings): Emerging evidence supports sub-anesthetic esketamine for procedural and trauma-related pain in emergency departments. Evidence quality: Low (case series and small RCTs).
Bipolar depression: Limited data from small open-label studies suggest potential benefit; however, risk of mood switching has not been adequately characterised. Evidence quality: Very low.
Dosing
Treatment-Resistant Depression — Adults
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| TRD induction (Weeks 1–4) | 56 mg or 84 mg twice weekly | 56 or 84 mg twice weekly | 84 mg twice weekly | Either dose may be used from Day 1; adjust based on efficacy and tolerability; evaluate at end of Week 4 for continuation Each 28 mg device = 2 sprays (1 per nostril); 56 mg = 2 devices, 84 mg = 3 devices |
| TRD early maintenance (Weeks 5–8) | 56 or 84 mg once weekly | 56 or 84 mg once weekly | 84 mg once weekly | Reduce frequency from induction; dose adjustments guided by response |
| TRD extended maintenance (Week 9+) | 56 or 84 mg every 1–2 weeks | 56 or 84 mg every 1–2 weeks | 84 mg once weekly | Individualize to least frequent dosing that maintains remission/response |
MDD with Acute Suicidal Ideation or Behavior — Adults
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| MDD-SI acute phase (4 weeks) | 84 mg twice weekly | 84 mg twice weekly | 84 mg twice weekly | Must be given with an oral antidepressant; one-time dose reduction to 56 mg permitted for tolerability Treatment beyond 4 weeks has not been systematically evaluated for this indication |
Special Populations
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Moderate hepatic impairment (Child-Pugh B) | 56 mg | 56 or 84 mg | 84 mg | Esketamine AUC ~103% higher; monitor for adverse reactions for a longer period No dose adjustment recommended, but extended post-dose monitoring warranted |
| Severe hepatic impairment (Child-Pugh C) | Not studied | Avoid use; no clinical data available | ||
| Renal impairment (any severity) | Standard dosing | Standard dosing | 84 mg | <1% excreted unchanged in urine; no adjustment needed. No data in patients on dialysis |
| Elderly (≥65 years) | 56 or 84 mg twice weekly | 56 or 84 mg | 84 mg | Same dosing as younger adults per FDA PI. TRANSFORM-3 trial used a 28 mg starting dose on Day 1 before uptitrating. Clinical judgement may favour conservative initiation. Hepatic blood flow declines with age, potentially prolonging exposure |
A 56 mg dose requires 2 devices and an 84 mg dose requires 3 devices, each with a 5-minute rest between devices. Patients should avoid food for at least 2 hours and liquids for at least 30 minutes before dosing. Nasal corticosteroids or decongestants used on a dosing day should be given at least 1 hour beforehand. Do not prime the device before use to prevent medication loss.
Pharmacology
Mechanism of Action
Esketamine is the S-enantiomer of racemic ketamine and functions as a non-competitive antagonist at the N-methyl-D-aspartate (NMDA) receptor. It possesses approximately four-fold higher affinity for the NMDA receptor compared to the R-enantiomer (arketamine). By blocking NMDA receptors on inhibitory GABAergic interneurons in cortical circuits, esketamine transiently disinhibits glutamate release. The resulting surge of glutamate activates postsynaptic AMPA receptors, triggering downstream signalling cascades involving brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), and mammalian target of rapamycin complex 1 (mTORC1). These pathways promote rapid synaptogenesis and restoration of synaptic connectivity in prefrontal and limbic mood-regulating circuits. This mechanism is fundamentally distinct from conventional monoaminergic antidepressants and is believed to underlie the rapid onset of antidepressant effect observed within 24 hours of administration. The precise mechanism by which NMDA antagonism translates into sustained mood improvement remains an area of active investigation.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Tmax 20–40 min after last nasal spray; bioavailability ~48% (intranasal); ~54% of dose absorbed via nasal mucosa, remainder swallowed | Rapid absorption enables onset of dissociative and antidepressant effects within minutes; nasal congestion may alter absorption |
| Distribution | Vss ~752 L; protein binding 43–45% (albumin and alpha-1 acid glycoprotein) | Large volume of distribution indicates extensive tissue penetration including CNS; low protein binding means minimal displacement interactions |
| Metabolism | Hepatic N-demethylation to noresketamine (active) primarily via CYP2B6 and CYP3A4; further metabolism to hydroxynorketamines and dehydronorketamine | Noresketamine has lower NMDA affinity than parent drug; hepatic impairment doubles esketamine AUC; CYP inducers/inhibitors have modest clinical impact due to high hepatic extraction |
| Elimination | t½ 7–12 h; <1% excreted unchanged in urine; metabolites primarily renal (≥78%) | No accumulation with twice-weekly dosing; renal impairment does not significantly affect parent drug clearance |
Side Effects
The adverse reaction profile of esketamine is dominated by acute, transient effects related to its NMDA receptor antagonism. Most events peak within 40 minutes of dosing and resolve within 1.5 hours. Data below are from pooled short-term Phase 3 TRD trials (esketamine + oral AD vs placebo nasal spray + oral AD, N=346 vs N=222) per the FDA prescribing information.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Dissociation | 41% | Includes depersonalisation, derealisation, perceptual changes, visual disturbances; typically resolves within 1.5 h; 61–84% of patients experience dissociative symptoms on CADSS scale |
| Dizziness | 29% | Includes postural dizziness; advise patients to remain seated/reclined during observation period |
| Nausea | 28% | Dose-related; fasting 2 h pre-dose reduces incidence; anti-emetics may be given if recurrent |
| Sedation | 23% | Includes somnolence and hypersomnia; 48–61% show sedation on MOAA/S scale; 0.3–0.4% experience loss of consciousness |
| Vertigo | 23% | Includes positional vertigo; patients should not stand unassisted until stable |
| Headache | 20% | Including sinus headache; similar in severity to placebo group (17%) |
| Dysgeusia | 19% | Metallic or unpleasant taste; transient; related to post-nasal drainage of medication |
| Hypoesthesia | 18% | Oral and pharyngeal numbness from local NMDA receptor blockade in nasal/oral mucosa |
| Anxiety | 13% | Includes agitation, panic attacks, nervousness, irritability; may require clinical reassurance during observation |
| Lethargy | 11% | Includes fatigue; dose-related; generally resolves within 2 h of dosing |
| Blood pressure increased | 10% | BP peaks at ~40 min (Tmax); resolves by ~4 h; 3–19% have ≥40 mmHg SBP or ≥25 mmHg DBP rise |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Vomiting | 9% | Usually accompanies nausea; pre-treatment with ondansetron may help in susceptible patients |
| Insomnia | 8% | May persist beyond acute dosing session; monitor sleep quality |
| Nasal discomfort | 7% | Includes nasal dryness, crusting, and pruritus; generally mild |
| Throat irritation | 7% | Related to post-nasal drainage of the drug solution |
| Diarrhoea | 7% | Similar incidence to placebo (6%); usually mild |
| Feeling drunk | 5% | Patients often describe a sensation of intoxication; part of the dissociative spectrum |
| Dry mouth | 5% | Anticholinergic-type effect; may compound if patient is on tricyclics |
| Euphoric mood | 4% | Contributes to abuse potential; important to document and monitor |
| Dysarthria | 4% | Slurred or slowed speech; resolves during observation period |
| Hyperhidrosis | 4% | Autonomic effect; transient |
| Pollakiuria | 3% | Urinary frequency; monitor for persistent bladder symptoms over long-term treatment |
| Tremor | 3% | Transient; distinguish from lithium or valproate co-medication effects |
| Tachycardia | 2% | Sympathomimetic effect; monitor with BP assessment |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Respiratory depression / arrest | Rare (postmarketing) | Minutes to 1 h post-dose | Continuous pulse oximetry for 2 h post-dose; airway management equipment must be available; discontinue if respiratory arrest occurs |
| Loss of consciousness | 0.3–0.4% | Within 40 min of dosing | MOAA/S score of 0; ensure patent airway; do not discharge until fully alert; consider dose reduction at next session |
| Hypertensive crisis | Rare | ~40 min post-dose (at Tmax) | Emergency referral if SBP >180 or DBP >120 with end-organ symptoms (chest pain, visual changes, seizure); IV antihypertensives as indicated |
| Suicidal ideation (worsening) | 0.5% (led to discontinuation) | Any time during treatment | Assess suicidality at each visit; consider discontinuation and hospitalisation if clinically warranted; class-effect with antidepressants in patients <25 years |
| Ulcerative / interstitial cystitis | Rare (reported with ketamine misuse; no confirmed cases in clinical trials up to 1 year) | Months of repeated exposure | Monitor for dysuria, urgency, haematuria; refer to urology if symptoms develop; consider discontinuation |
| Severe dissociative reaction / psychosis-like symptoms | Rare | Within 1 h post-dose | Observe in a calm environment; benzodiazepine if severe agitation; carefully reassess risk-benefit before further dosing in patients with psychosis history |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Anxiety | 1.2% | Most common reason across TRD Phase 3 trials |
| Depression (worsening) | 0.9% | May represent non-response rather than drug-induced worsening |
| Blood pressure increased | 0.6% | More common in patients with pre-existing hypertension |
| Dizziness | 0.6% | Severe or prolonged dizziness prompting treatment cessation |
| Suicidal ideation | 0.5% | Requires careful assessment to distinguish from underlying illness |
| Dissociation | 0.4% | Despite being the most common adverse event, rarely leads to discontinuation in TRD; higher discontinuation rate (2.6%) in MDD-SI trials |
Blood pressure peaks approximately 40 minutes post-dose, coinciding with esketamine Tmax, and generally returns toward pre-dose levels over approximately 4 hours. In clinical trials, 3–19% of esketamine-treated patients experienced a clinically significant rise (≥40 mmHg SBP or ≥25 mmHg DBP). Pre-dose BP should be checked at every session, and dosing should be deferred if baseline values exceed 140/90 mmHg unless the benefit clearly outweighs the risk. BP is reassessed at ~40 minutes and as clinically needed until stable. Patients with a history of hypertensive encephalopathy require more frequent and intensive monitoring.
Drug Interactions
Esketamine is metabolised primarily by CYP2B6 and CYP3A4. Despite this, dose adjustment is not routinely required with CYP inhibitors or inducers because esketamine undergoes high hepatic extraction and has a short pharmacodynamic window. The most clinically relevant interactions are pharmacodynamic, involving additive CNS depression or sympathomimetic blood pressure effects.
Esketamine can produce false-positive results for methadone and phencyclidine (PCP) on urine immunoassay drug screens. If a positive result is obtained, confirmatory testing with gas chromatography-mass spectrometry (GC-MS) is recommended before clinical decisions are made.
Monitoring
-
Blood Pressure
Pre-dose, ~40 min post-dose, then PRN
Routine Measure before every session to assess safety of dosing. Reassess at approximately 40 minutes (peak BP effect) and continue until values are declining and clinically stable. Do not discharge until BP is trending toward baseline. -
Sedation Level
Continuously for ≥2 h post-dose
Routine Use MOAA/S or equivalent sedation scale. Patient must not leave the healthcare setting until clinically stable and alert. Assess readiness to leave before discharge at each session. -
Respiratory Status
Pulse oximetry for ≥2 h post-dose
Routine Monitor oxygen saturation continuously during and after each treatment session. Airway management equipment should be readily accessible. Particular vigilance when patient is also on CNS depressants. -
Dissociative Symptoms
Each session during observation
Routine Assess using CADSS or clinical observation. Symptoms typically peak within 40 minutes and resolve by 1.5 hours. Patients with psychosis history require particularly careful monitoring. -
Suicidality
At initiation, each session, and dose changes
Routine Monitor for emergence or worsening of suicidal thoughts and behaviours, especially in patients <25 years. Consider discontinuation and hospitalisation if clinically indicated. Document at every visit per REMS requirements. -
Urinary Symptoms
Periodic inquiry
Trigger-based Ask about dysuria, urgency, frequency, nocturia, or haematuria at each visit. Ketamine-related cystitis is associated with chronic use; esketamine-related cystitis has not been confirmed in trials up to 1 year but theoretical risk remains with long-term use. Refer to urology if symptoms develop. -
Substance Use
Baseline and ongoing
Routine Assess risk of abuse and misuse prior to initiation. Monitor for drug-seeking behaviour, dose requests, and signs of ketamine diversion throughout treatment. Schedule III controlled substance with documented abuse potential. -
Cognitive Function
Annually or PRN
Trigger-based Long-term cognitive effects were stable in 1- and 3-year open-label clinical trials. However, cognitive impairment is reported with repeated ketamine misuse. Assess if subjective complaints arise.
Contraindications & Cautions
Absolute Contraindications
- Aneurysmal vascular disease — including thoracic aorta, abdominal aorta, intracranial, and peripheral arterial aneurysms
- Arteriovenous malformation — risk of catastrophic haemorrhage from acute BP elevation
- History of intracerebral haemorrhage — BP spikes may precipitate re-bleeding
- Hypersensitivity — to esketamine, ketamine, or any excipient in the formulation
Relative Contraindications (Specialist Input Recommended)
- Active psychotic disorder — esketamine can induce or exacerbate psychosis-like dissociative symptoms; initiate only if benefit outweighs risk following specialist assessment
- Unstable cardiovascular disease — uncontrolled hypertension, recent MI, unstable angina, or decompensated heart failure; transient BP elevations are expected
- Active substance use disorder — high risk of misuse given Schedule III classification; requires documented risk-benefit discussion and enhanced monitoring
- Pregnancy — animal data with ketamine show neuronal apoptosis and skeletal malformations; discontinue if patient becomes pregnant
Use with Caution
- Moderate hepatic impairment (Child-Pugh B) — esketamine AUC approximately doubles; extend post-dose monitoring duration
- Elderly patients (≥65 years) — reduced hepatic blood flow may prolong exposure; consider conservative dose selection and extended monitoring
- Concurrent CNS depressant use — additive sedation and respiratory depression risk
- History of hypertensive encephalopathy — even small BP increases may trigger encephalopathy; more intensive BP and symptom monitoring warranted
- History of traumatic brain injury or raised intracranial pressure — ketamine has historically been considered a concern in this setting, although evidence is evolving
Patients are at risk for sedation (including loss of consciousness), dissociative or perceptual changes, and respiratory depression following esketamine administration. Patients must be monitored for at least 2 hours after each dose in a certified healthcare setting. Esketamine has the potential for abuse and misuse; assess each patient’s risk before prescribing. Because of these risks, esketamine is available only through a restricted REMS program. Antidepressants, including esketamine, increase the risk of suicidal thoughts and behaviours in patients under 25 years of age.
Patient Counselling
Purpose of Therapy
Esketamine nasal spray is prescribed for depression that has not responded adequately to other antidepressant medications. It works differently from standard antidepressants by acting on the glutamate system in the brain, which may help restore connections between nerve cells involved in mood regulation. Some patients notice improvement within hours to days, though full response may take several weeks of treatment. For the suicidal ideation indication, it is used alongside an oral antidepressant to provide rapid relief of depressive symptoms during a crisis period.
How to Take
Esketamine is administered as a nasal spray at a certified clinic or healthcare setting — it cannot be taken home. Each treatment session involves spraying the medication into both nostrils using one, two, or three devices depending on the prescribed dose. You will need to stay at the clinic for at least 2 hours after each dose so the healthcare team can monitor your blood pressure, alertness, and overall state. Do not eat for at least 2 hours before your appointment and avoid drinking liquids for 30 minutes beforehand. If you use a nasal steroid spray or decongestant, take it at least 1 hour before your esketamine treatment.
Sources
- SPRAVATO (esketamine) nasal spray, CIII. Full Prescribing Information. Janssen Pharmaceuticals, Inc. Revised 03/2026. Janssen Labels Primary source for all dosing, contraindications, adverse reaction incidence rates, and pharmacokinetic parameters.
- FDA Approval Letter — Supplemental NDA for Spravato Monotherapy (January 21, 2025). FDA Access Data Documents the 2025 approval of esketamine as monotherapy for TRD without mandatory oral antidepressant.
- SPRAVATO REMS Program. SPRAVATOrems.com Outlines the Risk Evaluation and Mitigation Strategy requirements for healthcare settings and pharmacies.
- Fedgchin M, Trivedi M, Daly EJ, et al. Efficacy and safety of fixed-dose esketamine nasal spray combined with a new oral antidepressant in treatment-resistant depression: results of a randomized, double-blind, active-controlled study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019;22(10):616–630. DOI Phase 3 fixed-dose TRD trial demonstrating efficacy of 56 mg and 84 mg esketamine.
- Popova V, Daly EJ, Trivedi M, et al. Efficacy and safety of flexibly dosed esketamine nasal spray combined with a newly initiated oral antidepressant in treatment-resistant depression: a randomized double-blind active-controlled study (TRANSFORM-2). Int J Neuropsychopharmacol. 2019;22(10):631–640. DOI Pivotal flexible-dose TRD study showing statistically significant improvement versus active comparator.
- Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial (SUSTAIN-1). JAMA Psychiatry. 2019;76(9):893–903. DOI Withdrawal-design maintenance trial demonstrating relapse prevention with continued esketamine treatment.
- Wajs E, Aluisio L, Holder R, et al. Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of long-term safety in a phase 3, open-label study (SUSTAIN-2). J Clin Psychiatry. 2020;81(3):19m12891. DOI Long-term (up to 1 year) open-label safety study; 9.5% discontinuation due to adverse events.
- Fu DJ, Ionescu DF, Li X, et al. Esketamine nasal spray for rapid reduction of major depressive disorder symptoms in patients who have active suicidal ideation with intent: double-blind, randomized study (ASPIRE I). J Clin Psychiatry. 2020;81(3):19m13191. DOI Phase 3 trial in MDD with acute suicidal ideation; primary basis for the MDD-SI indication.
- McIntyre RS, Rosenblat JD, Nemeroff CB, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evidence and implementation. Am J Psychiatry. 2021;178(5):383–399. DOI International expert consensus on clinical positioning, patient selection, and practical implementation of esketamine in TRD.
- APA Practice Guidelines. Practice Guideline for the Treatment of Patients with Major Depressive Disorder, Third Edition. Am J Psychiatry. 2010. APA Online Foundational guideline on MDD management; esketamine is addressed in subsequent APA updates and position statements.
- Zanos P, Moaddel R, Morris PJ, et al. Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms. Pharmacol Rev. 2018;70(3):621–660. DOI Comprehensive review of ketamine/esketamine receptor pharmacology and the AMPA-BDNF-mTOR signalling hypothesis.
- Perez-Ruixo C, Rossenu S, Zannikos P, et al. Population pharmacokinetics of esketamine nasal spray and its metabolite noresketamine in healthy subjects and patients with treatment-resistant depression. Clin Pharmacokinet. 2021;60(4):501–516. DOI Population PK model quantifying nasal and oral bioavailability fractions, hepatic flow-limited clearance, and covariate effects.
- Ochs-Ross R, Daly EJ, Zhang Y, et al. Efficacy and safety of esketamine nasal spray plus an oral antidepressant in elderly patients with treatment-resistant depression — TRANSFORM-3. Am J Geriatr Psychiatry. 2020;28(2):121–141. DOI Phase 3 trial in patients ≥65 years; informs geriatric dosing recommendations and safety considerations.
- Fountoulakis KN, Saitis A, Schatzberg AF. Esketamine treatment for depression in adults: a PRISMA systematic review and meta-analysis. Am J Psychiatry. 2025;182(3):259–275. DOI Most recent comprehensive meta-analysis of esketamine efficacy across TRD and MDD-SI trials with pooled NNT estimates.