Esketamine

Indications

• FDA-approved for treatment-resistant depression in adults, defined as inadequate response to at least two adequate antidepressant trials.
• Approved in January 2025 as monotherapy for treatment-resistant depression, in addition to the original combination indication.
• FDA-approved with an oral antidepressant for depressive symptoms in adults with major depressive disorder and acute suicidal ideation or behavior.
• Effectiveness in preventing suicide or in reducing suicidal ideation itself has not been demonstrated, so it does not replace hospitalization.
• Not approved as an anesthetic and not approved for pediatric patients; safety and effectiveness under 18 years are not established.
• Off-label use outside a certified REMS treatment center is not permitted, and the drug is never dispensed for use at home.

Mechanism of action

• The S-enantiomer of ketamine, acting as a noncompetitive antagonist at the NMDA glutamate receptor with higher affinity than the R-enantiomer.
• NMDA blockade on GABAergic interneurons disinhibits pyramidal cells, producing a glutamate surge and AMPA receptor activation.
• Downstream AMPA signaling triggers BDNF release and mTORC1 activation, driving rapid synaptogenesis in prefrontal cortex.
• This synaptic mechanism explains an antidepressant onset within hours to days rather than the weeks required by monoamine agents.
• Dissociation and sedation arise from the same NMDA antagonism and are expected transient effects rather than idiosyncratic reactions.

Pharmacokinetics

• Intranasal bioavailability is approximately 48 percent, with peak plasma concentrations reached 20 to 40 minutes after the last spray.
• Terminal half-life is roughly 7 to 12 hours, and dissociative and sedative effects generally resolve within 1.5 hours of dosing.
• Metabolized primarily by CYP2B6 and CYP3A4 to noresketamine, an active metabolite with substantially lower NMDA affinity.
• Clearance is high and the drug is largely eliminated as metabolites in urine, with less than 1 percent excreted unchanged.
• Nasal corticosteroids or decongestants should be given at least 1 hour before dosing so that absorption is not altered.

Dosing

• Each device delivers 28 mg as two sprays, one per nostril; give devices 5 minutes apart with a 5-minute rest between them.
• For treatment-resistant depression, give 56 mg on day 1, then 56 or 84 mg twice weekly for weeks 1 through 4 of induction.
• Maintenance is 56 or 84 mg once weekly for weeks 5 through 8, then every 2 weeks or weekly thereafter based on response.
• For depression with acute suicidal ideation, give 84 mg twice weekly for 4 weeks, reducing to 56 mg only for tolerability.
• Start at 28 mg in adults 65 years and older, and self-administration is never permitted outside direct clinician observation.
• Patients must avoid food for 2 hours and liquids for 30 minutes before dosing to reduce the risk of nausea and vomiting.

Adverse effects

• Dissociation occurs in roughly 41 percent of patients, dizziness in about 29 percent, and nausea in about 28 percent.
• Sedation affects roughly 23 percent; vertigo, hypoesthesia, anxiety, and lethargy are also common during the observation period.
• Respiratory depression can occur, and sedation combined with a central nervous system depressant raises that risk during observation.
• Transient blood pressure elevation peaks about 40 minutes after dosing and can exceed 180 systolic or 110 diastolic in some patients.
• Abuse and misuse potential led to Schedule III control, and dependence has been reported with recreational ketamine use.
• Cognitive impairment and impaired driving persist for hours; patients must not drive until the next day after restful sleep.

Monitoring

• Measure blood pressure before dosing, again about 40 minutes after dosing, and thereafter until values are clinically acceptable.
• Observe every patient for at least 2 hours after each dose for sedation, dissociation, and hemodynamic changes before discharge.
• Do not dose if baseline blood pressure is elevated enough to make an acute rise unsafe, generally above 140 over 90 in most protocols.
• Assess depression severity and suicidality with a standardized scale before each session and reassess the need for continued treatment.
• Confirm the patient has arranged transportation home, since driving after a session is prohibited until the following day.

Interactions

• Central nervous system depressants including benzodiazepines, opioids, and alcohol increase sedation and prolong recovery time.
• Psychostimulants and monoamine oxidase inhibitors can compound the blood pressure rise and should generally be avoided.
• Strong CYP3A4 or CYP2B6 inducers such as rifampin may lower exposure, though dose adjustment is not formally recommended.
• Contraindicated in aneurysmal vascular disease, arteriovenous malformation, or any history of intracerebral hemorrhage.
• Contraindicated in patients with hypersensitivity to esketamine, ketamine, or any component of the nasal spray formulation.

Special populations

• Esketamine may cause fetal harm and is not recommended in pregnancy; there is a national pregnancy exposure registry for the drug.
• Breastfeeding is not recommended during treatment because esketamine is present in human milk and infant effects are unknown.
• Not approved under 18 years of age, and pediatric use carries the antidepressant class suicidality concern without efficacy data.
• In adults 65 and older start at 28 mg, since exposure is higher and sedation, falls, and confusion are more likely.
• Use caution in moderate hepatic impairment and avoid in severe impairment, since exposure and recovery time both increase.

Clinical pearls

• Never dispensed for home use; every dose is observed for 2 hours in a certified REMS site.
• Blood pressure peaks about 40 minutes after dosing, so check it then, not just at baseline.
• No driving until the next day after restful sleep, regardless of how well the patient feels.