Esketamine: NMDA Receptor Antagonist for Treatment-Resistant Depression
Esketamine (Spravato) is the S-enantiomer of ketamine, administered as a nasal spray for treatment-resistant depression (TRD) and MDD with acute suicidal ideation. It is the first truly novel antidepressant mechanism approved in over 30 years.
Rapid onset (hours rather than weeks) makes it uniquely valuable for acute suicidal crises. Must be administered in a certified healthcare setting with 2-hour post-dose monitoring.
Mechanism of Action
Non-competitive NMDA glutamate receptor antagonist. Rapid increase in synaptic glutamate triggers AMPA receptor activation and BDNF release, leading to rapid synaptogenesis and antidepressant effect. Different from all monoamine-based antidepressants.
Indications & Use
Treatment-resistant depression (failed ≥2 adequate antidepressant trials). MDD with acute suicidal ideation or behaviour (MDSI). Must be combined with an oral antidepressant. REMS programme required in the USA.
Dosage
56 mg or 84 mg intranasal. Acute phase: twice weekly for 4 weeks. Maintenance: once weekly (weeks 5–8), then once weekly or biweekly. Patient must not drive on day of administration.
Side Effects
Common: dissociation, dizziness, nausea, sedation (peak at 40 min, resolve within 90 min). Blood pressure increase (peak at 40 min). Abuse potential — controlled substance (Schedule III in USA). Nasal discomfort.
Drug Interactions
CNS depressants: additive sedation/dissociation. MAOIs: avoid (hypertensive crisis risk). Stimulants: may attenuate BP-lowering. Antihypertensives: monitor BP on dosing days.
Contraindications
Aneurysmal vascular disease, arteriovenous malformations, intracerebral haemorrhage, uncontrolled hypertension, hypersensitivity to ketamine or esketamine.
Frequently Asked Questions
How quickly does esketamine work?
Esketamine has a rapid onset — antidepressant and antisuicidal effects are often seen within hours to days, versus 2–6 weeks for standard antidepressants. This makes it particularly valuable in acute suicidal crises.
Why must esketamine be given in a clinic?
Dissociation, sedation, and blood pressure changes peak around 40 minutes post-dose and require supervised monitoring. Additionally, its abuse potential (related to ketamine's psychedelic effects) requires controlled dispensing.
Is esketamine addictive?
It has abuse potential — classified as a Schedule III controlled substance. However, with supervised bi-weekly administration in a clinical setting, addiction is considered low risk. It is not dispensed for home use.
References
- EMA Spravato SPC 2023
- FDA Approval esketamine (Spravato) 2019
- Daly EJ et al. NEJM 2018
Medical Disclaimer: This information is for educational purposes only and does not replace professional medical advice.