Esketamine Guide: Pharmacology, Indications, Dosing Guidelines and Adverse Effects

In a nutshell

Esketamine is an NMDA receptor antagonist delivered via intranasal administration for treatment-resistant depression and major depression with suicidal ideation. Its primary clinical advantage is a rapid onset of antidepressant effect (within 24 hours), faster than traditional antidepressants, although long-term efficacy remains unclear. Due to risks of dissociation, sedation, blood pressure elevation, and potential for misuse, esketamine requires specialized administration and monitoring through the REMS program.

• When to consider adding esketamine:
  • When rapid response is needed (24-hour onset vs. weeks for traditional antidepressants)
  • For treatment-resistant depression after failure of ≥2 adequate antidepressant trials
  • As a “response accelerator” in the acute phase, while waiting for oral antidepressants to take effect
  • When standard antidepressants haven’t been tolerated or have failed
• Esketamine may not be appropriate when:
  • Patient cannot attend required in-office treatment sessions with monitoring
  • Cardiovascular risk factors (especially uncontrolled hypertension)
  • History of psychosis or substance use disorders
  • Respiratory compromise
  • Cost or accessibility concerns (requires REMS-certified facility)
  • Long-term maintenance is the primary goal (limited long-term data)

Pharmacodynamics and mechanism of action

• Primary mechanism: Non-competitive, nonselective NMDA receptor antagonist ^[1,2]
  • Esketamine (S-enantiomer) has 2-3 fold higher NMDA receptor affinity than R-ketamine ^[2,3]
  • Binds to the phencyclidine (PCP) binding site within the NMDA receptor channel pore, blocking glutamate-induced calcium influx ^[4]
  • Preferentially inhibits NMDA receptors on GABAergic interneurons, leading to disinhibition and increased excitatory neuron firing ^[5]
• AMPA receptor modulation
  • Indirectly enhances AMPA receptor signaling by blocking NMDA receptors, with this glutamate signaling shift potentially critical for rapid antidepressant effects ^[5–7]
• Downstream effects on brain plasticity
  • Increases BDNF release, potentially explaining rapid synaptogenic and antidepressant effects ^[5,6]
  • Activates mTOR signaling pathway, leading to increased protein synthesis and dendritic spine formation in prefrontal cortex ^[8,9]
  • These neuroplasticity effects contrast with conventional antidepressants, which require weeks for similar adaptations ^[9]
• Secondary pharmacological targets: Opioid receptors
  • Binds to mu (μ, MOR: mu opioid receptors), kappa (κ), and delta (δ) opioid receptors with low affinity (10-20 fold weaker than to NMDA receptors) ^[5,6]
    • Affinity for kappa and delta receptors is generally even weaker
  • The role of opioid interactions in esketamine’s antidepressant effects remains debated, with conflicting evidence from naltrexone studies and genetic analyses ^[5,7,10]
• Additional receptor interactions
  • Weak inhibitory activity at monoamine transporters (SERT, NET, DAT) ^[5,11]
  • Weak agonist activity at dopamine D2 receptors and antagonist activity at serotonin 5-HT3 receptors ^[11]

Pharmacokinetics

Metabolism

• Esketamine is primarily metabolized through oxidation via CYP2B6 and CYP3A4 ^[1,12]
• Minor pathways involve CYP2C19 and CYP2C9
• Esketamine levels potentially increased by:
  • CYP3A4 inhibitors
    • Clarithromycin, ketoconazole, itraconazole
  • CYP2B6 inhibitors
    • Ticlopidine
• Esketamine levels potentially decreased by:
  • CYP3A4 inducers
    • Carbamazepine, rifampin, St. John’s Wort.
• However, dose adjustment of esketamine is not warranted in patients taking an inhibitor of CYP2B6 or CYP3A4, an inducer of CYP3A4 or CYP2B6 ^[13]
• Esketamine is not expected to significantly alter the metabolism of other drugs by inhibiting or inducing CYP enzymes in standard antidepressant doses ^[1,14]
• Drug interactions:
  • CNS depressants
    • Concomitant use may increase sedation
    • Close monitoring is recommended when used with CNS depressants (benzodiazepines, opioids, alcohol) ^[1]
  • Psychostimulants and MAOIs
    • May enhance hypertensive effects
    • Close blood pressure monitoring is required with concurrent psychostimulant or MAOI use ^[1]
  • Nasal corticosteroids or decongestants
    • May diminish therapeutic effect of intranasal esketamine
    • Administer at least 1 hour before esketamine on treatment days ^[1]
• Note: Esketamine can trigger false-positive methadone results in urine immunoassays. Confirmatory testing is recommended for positive screens ^[1]

Half-life

• Esketamine
  • Elimination half-life of approximately 7-12 hours, increased in moderate hepatic impairment ^[1]
  • Time to maximum concentration (Tmax): 20-40 minutes after administration ^[1]
• Noresketamine (active metabolite) half-life is approximately 8 hours ^[5]

Dosage forms

Dosage forms

• Intranasal spray device (Spravato)
  • 28 mg per device (delivers two sprays of 14 mg each)

Logistical aspects

• Requires REMS program certification for dispensing
• Must be administered under direct healthcare professional supervision
• Device practicalities:
  • Do not prime the device before use
  • Use 2 devices (for a 56 mg dose) or 3 devices (for an 84 mg dose), with a 5-minute rest between the use of each device
• Patient preparation ^[1]
  • Avoid food for at least 2 hours before administration
  • Avoid drinking liquids at least 30 minutes before administration
  • Administer nasal corticosteroids or decongestants (if needed) at least 1 hour before Esketamine
  • Patient must not drive on the day of administration
• Administration monitoring ^[1]
  • Assess blood pressure before dosing
  • Reassess blood pressure approximately 40 minutes post-dose
  • Monitor respiratory status (including pulse oximetry) for at least 2 hours
  • Patient may be discharged only if clinically stable for at least two hours post-dose

Indications

FDA-Approved Indications

Treatment-resistant depression (TRD)

• Esketamine is indicated for TRD in adults who have failed to respond to at least two different trials of antidepressants of adequate dose and duration in the current depressive episode ^[1,15]
• Approved for use both as monotherapy or in conjunction with an oral antidepressant ^[1]
• Second-line treatment option for adjunctive medication for Difficult to Treat Depression, according to latest CANMAT guidelines ^[16]
• Onset of action:
  • Rapid onset of action within 24 hours, with clinical improvement occurring faster than traditional antidepressants ^[17,18]
  • Significant but modest early effect (24 hours): Effect size 0.33 ^[19]
  • Some authors suggest esketamine may function as a response accelerator.
    • It could be used initially to achieve faster improvement and then discontinued once a response is achieved ^[19]
• Long-term efficacy:
  • Long-term efficacy remains inconclusive, with evidence of diminishing effects over time ^[17,19,20]
    • Short-to-medium term findings (Meta-analysis evidence)
      • Progressive decline in effect sizes: 0.33 at 24 hours → 0.25 at week 1 → 0.15 at week 2 → 0.23 at week 4 ^[19]
      • Most trials (5 of 6) were negative at week 4 for primary outcomes ^[19]
      • SUSTAIN-1 maintenance trial showed high relapse rates after discontinuation, with potential withdrawal effects contributing to relapse ^[19]
    • Long-term extension data (SUSTAIN-3 study):
      • 49-50% remission rates at 2 years (5+ years follow-up, 3,777 patient-years) ^[21]
    • Practical considerations:
      • Most patients (75% of visits) require frequent dosing (weekly or every 2 weeks)
      • Raises questions about long-term sustainability and feasibility
• Dosing:
  • Induction phase (weeks 1-4)
    • Starting dose: 56 mg twice weekly
    • May increase to 84 mg twice weekly based on efficacy and tolerability
  • Maintenance phase (weeks 5 and beyond)
    • Week 5-8: 56 mg or 84 mg once weekly
    • Week 9 and beyond: 56 mg or 84 mg once weekly or once every 2 weeks
    • Use the lowest effective frequency to maintain response or remission ^[1]
  • Assess therapeutic benefit periodically to determine the need for continued treatment

Major depressive disorder (MDD) with acute suicidal ideation or behavior

• Indicated for the rapid reduction of depressive symptoms in adults with MDD who have suicidal ideation with intent ^[1,22]
• Used in conjunction with an oral antidepressant
  • May provide acute symptom relief while conventional antidepressants take effect ^[17]
• Not a substitute for hospitalization when indicated ^[1]
• Conflicting evidence:
  • A recent systematic review and meta-analysis found no significant effect on suicidality at any time point (effect size 0.10 at days 2-5, 0.04 at week 4), calling into question this indication ^[19]
• Dosing:
  • Starting dose:
    • 84 mg twice weekly for 4 weeks
    • Dosage may be reduced to 56 mg twice weekly based on tolerability
  • Reassess to determine the need for continued esketamine treatment.
    • Its use beyond 4 weeks has not been systematically evaluated for this indication ^[1]

Off-label Uses

Bipolar depression

• Not recommended for routine use in bipolar depression
• Several systematic reviews report promising results for racemic ketamine, with response rates of 48–55% and remission rates of 30–50% ^[23,24]
• Esketamine-specific data remains sparse, as most systematic reviews do not separate outcomes by compound
• Caution due to theoretical risk of mood switching in bipolar patients ^[23,24]

Side Effects

Most common side effects

Neurological/Psychiatric

• Dissociation (28% TRD, 48% MDD with suicidal ideation)
  • Most common adverse effect and primary reason for treatment discontinuation in MDD-with suicidal ideation ^[1,15]
  • May involve transient perceptual changes, depersonalization, and derealization.
  • Typically begins shortly after administration and resolves within 2 hours; attenuated after repeated administrations ^[15,25]
  • Higher rates reported using structured scales in clinical assessments ^[1]
• Dizziness (22% TRD, 45% MDD with suicidal ideation) ^[1,26]
• Sedation/somnolence (6-29% incidence)) ^[1]
  • Monitoring for at least two hours post-administration is recommended, due to the risk of delayed or prolonged sedation
  • 0.3% to 0.4% of esketamine-treated patients may experience loss of consciousness
  • Patients should not drive or operate machinery until the next day after restful sleep ^[1]
  • Higher rates reported using structured scales in clinical assessments ^[1]
• Headache (19% incidence)
• Dysgeusia (altered taste) (4-20% incidence)
• Anxiety (10-15% incidence)
• Cognitive impairment (11-13% incidence) ^[26]
  • Temporary cognitive deficits can occur, typically observed within the first 40 minutes post-dose, returning to baseline within approximately 2 hours.
  • Long-term effects on cognitive function with repeated use are not fully characterized.
    • Cognitive functioning remained stable or slightly improved over extended treatment periods in 1-year and 3-year open-label clinical trials ^[25,27]

Cardiovascular

• Blood pressure increase (5%; including hypertension)
  • Characteristics
    • Transient, dose-dependent elevations peaking at 40 minutes post-dose, persisting ~4 hours.
    • Typical increases: 7-10 mmHg systolic, 4-6 mmHg diastolic ^[1]
    • 3-19% of patients experience substantial increases (≥40 mmHg systolic and/or ≥25 mmHg diastolic) within the first 1.5 hours ^[1]
    • Substantial increases may occur even if smaller effects observed with previous doses ^[1]
  • Blood pressure monitoring required
    • Assess BP prior to each administration
    • Monitor for at least 2 hours post-dose, with measurement around 40 minutes post-dose
    • Continue monitoring until values decline to acceptable levels ^[1]
  • Hypertensive crisis
    • Rare but potentially severe elevations in blood pressure may require emergency intervention
    • Contraindicated in patients for whom BP increases pose serious risks
    • Enhanced monitoring recommended for patients with a history of hypertensive encephalopathy
    • Requires special attention with concomitant psychostimulants or MAOIs ^[1]
    • Consider delaying treatment in patients with elevated BP (>140/90 mmHg)
    • Use with caution in patients with other cardiovascular or cerebrovascular conditions

Gastrointestinal

• Nausea (25-32% incidence) ^[1]
  • Most common gastrointestinal side effect
  • Generally transient, resolving the same day with a median duration of less than 1 hour
  • Can be minimized by fasting for at least 2 hours before administration ^[1]
• Vomiting (6-12% incidence) ^[1]
  • Also, it typically resolves the same day

Other common side effects

• Vertigo (3-23% incidence)
• Hypoesthesia: (4%-13% incidence)
• Fatigue (4-11% incidence)
• Feeling drunk (4-7% incidence)
• Urinary tract symptoms (pollakiuria, dysuria, micturition urgency, nocturia) (2-3% incidence) ^[1]

Severe side effects

• Respiratory depression
  • Rare but serious risk, including reports of respiratory arrest ^[1]
  • Monitoring required: Respiratory status and pulse oximetry for ≥2 hours post-dose; discharge only after confirming clinical stability ^[1]
  • Increased risk: Concomitant CNS depressants and compromised respiratory function ^[1]
• Ulcerative/intersticial cystitits
  • Cases reported with long-term off-label ketamine use, rare with therapeutic esketamine (1.1% of postmarketing AEs) ^[28–30]
  • Regular monitoring of urinary symptoms and periodic urinalysis recommended ^[16]
• Suicidal thoughts and behaviors
  • Recent meta-analysis raised concerns about deaths and emerging suicidality during esketamine trials ^[19]
  • SUSTAIN-3 long-term data: 9 deaths over 5 years (including 1 suicide), all deemed unrelated to esketamine by investigators ^[21]
  • Enhanced monitoring is recommended for all patients, especially during early treatment and dose adjustments ^[1]
• Abuse and dependence
  • Schedule III controlled substance due to abuse potential
  • Physical and psychological dependence may occur ^[1,31]
  • Despite concerns based on ketamine’s history ^[32], a recent literature review suggests minimal actual risk of misuse in therapeutic settings ^[33]
  • Careful patient selection and monitoring required, particularly in patients with a history of substance use disorders

Contraindications

• Aneurysmal vascular disease (including thoracic and abdominal aorta, intracranial, and peripheral arterial vessels)
• Arteriovenous malformation
• History of intracerebral hemorrhage
• Known hypersensitivity or allergic reaction to esketamine, ketamine, or formulation ingredients ^[1]

Use in special populations

Pregnancy

• Not recommended: Animal studies show potential fetal harm, with limited human data available for psychiatric use ^[1]
• Fetal brain development may be affected, particularly in the third trimester, based on published ketamine findings and NMDA receptor antagonist effects, with preclinical studies showing developmental delays and neurobehavioral impairments ^[1,34]
• Limited data from cesarean section analgesia studies provide insufficient conclusions about neonatal effects ^[35,36]

Breastfeeding

• Esketamine is present in human breast milk ^[1]
• The manufacturer does not recommend breastfeeding during treatment since NMDA receptor antagonism affects rapid brain development in infants ^[1]
  • The window of vulnerability to neurodevelopmental effects may extend to approximately 3 years of age ^[1]

Hepatic impairment

• Mild to moderate impairment (Child-Pugh Class A and B)
  • There are no dosage adjustments provided in the manufacturer’s labeling (esketamine has not been studied).
  • Patients with moderate impairment may need monitoring for adverse effects for a longer duration after administration ^[1]
• Severe impairment (Child-Pugh Class C)
  • Use not recommended; not studied in this population ^[1]

Renal impairment

• No dosage adjustments provided in the manufacturer’s labeling
• Limited study data available for patients with renal impairment ^[1]

Elderly

• Efficacy in geriatric treatment-resistant depression (TRD) not statistically superior to placebo at 4 weeks ^[1,37]
• Consider using lower initial doses (28 mg twice weekly for 4 weeks) ^[37,38]

Brand names

* US: Spravato – Canada: Spravato  – Other countries/regions: Spravato

References

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3. Liu, P., Zhang, S.-S., Liang, Y., Gao, Z.-J., Gao, W., & Dong, B.-H. (2022). Efficacy and Safety of Esketamine Combined with Antidepressants for Treatment-Resistant Depression: A Meta-Analysis. Neuropsychiatric Disease and Treatment, 18, 2855–2865. https://doi.org/10.2147/NDT.S388764
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