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NMDA Receptor Antagonist (Treatment-Resistant Depression / Acute Suicidality) Pregnancy: Contraindicated — ketamine causes neonatal depression. Effective contraception required during treatment.

Esketamine

Brand names: Spravato

Adult dose

Dose: TRD induction: 56 mg or 84 mg intranasally twice weekly for 4 weeks. Maintenance: weekly for 4 weeks, then every 1–2 weeks. Acute suicidality (MDSI): 84 mg twice weekly for 4 weeks
Route: Intranasal (self-administered under healthcare supervision)
Frequency: Twice weekly (induction); weekly or biweekly (maintenance)
Max: 84 mg per session
MUST be administered in a healthcare setting with 2-hour post-dose observation for dissociation and sedation (MHRA/REMS requirement). Patient must NOT drive or operate machinery for 24 hours. Not for self-administration at home. Two indications: (1) Treatment-Resistant Depression (TRD) — failed ≥2 adequate antidepressants; (2) Major Depressive Disorder with acute suicidal ideation (MDSI). Source: BNF 90; NICE TA854.

Paediatric dose

Dose: Not licensed under 18 years N/A/kg
Route: N/A
Frequency: N/A
Max: N/A
Not licensed for paediatric depression.

Dose adjustments

Renal

No dose adjustment required for mild-moderate renal impairment. Severe renal impairment: not studied — use with caution.

Hepatic

Severe hepatic impairment (Child-Pugh C): reduce frequency — weekly dosing maximum (not twice weekly). Monitor for prolonged sedation and dissociation.

Paediatric weight-based calculator

Not licensed for paediatric depression.

Clinical pearls

  • Rapid antidepressant onset — the landmark advantage: conventional antidepressants take 2–6 weeks for response. Esketamine shows antidepressant effect within 24 hours of first dose, maintained over 4 weeks in TRANSFORM trials. For acute suicidality (MDSI), rapid onset is clinically critical — can reduce suicidal ideation before oral antidepressant takes effect.
  • NICE TA854 (TRD): esketamine + standard antidepressant is recommended for adults with TRD (failed ≥2 adequate antidepressant trials). First-line systemic recommendation — first fundamentally novel antidepressant mechanism in 30 years (previous decades all monoaminergic). SUSTAIN-2 trial maintained remission with biweekly dosing over 1 year.
  • REMS — mandatory healthcare setting: dissociation and hypertension require clinical monitoring for 2 hours post-dose. Patient uses the nasal device themselves under supervision — 2 actuations per nostril. After 2-hour observation, patient must be escorted home (cannot drive themselves). This limits access vs oral antidepressants but reflects genuine acute safety risks.
  • Mechanism: NMDA (N-methyl-D-aspartate) glutamate receptor antagonism → blocks tonic glutamatergic inhibition → burst glutamate release → AMPA receptor activation → BDNF release → rapid synaptogenesis. Fundamentally different from monoamine reuptake inhibitors. The S-enantiomer of ketamine has 4× greater NMDA affinity than R-ketamine.
  • Misuse potential: ketamine is a Schedule 3 controlled drug and Class B drug (UK). Esketamine (Spravato) is administered and dispensed only in certified healthcare facilities — not dispensed for home use — specifically to prevent misuse. Any signs of misuse should prompt review and possible discontinuation. Source: BNF 90; NICE TA854; MHRA SPC Spravato; Daly et al. NEJM 2018 (TRANSFORM trials).

Contraindications

  • Aneurysmal vascular disease or arteriovenous malformations (hypertension risk — NMDA antagonist increases BP)
  • History of intracerebral haemorrhage
  • Uncontrolled hypertension at time of administration (BP >180/110 — defer session)
  • History of psychosis or schizophrenia (may exacerbate psychotic symptoms)
  • Active substance use disorder (misuse potential — S-ketamine is a dissociative anaesthetic analogue)
  • Pregnancy and breastfeeding

Side effects

  • Dissociation (most common — derealization, depersonalization, perceptual disturbances — typically 40–50% at peak, resolves within 1–2 hours)
  • Dizziness, nausea, vomiting (during session)
  • Hypertension (transient — peaks 40 min post-dose; monitor BP before and after each session)
  • Sedation (2-hour observation mandatory)
  • Nasal discomfort, dysgeusia (intranasal administration)
  • Dissociative symptoms and psychomimetic effects (suicidal ideation paradoxically — monitor per REMS)
  • Cystitis (rare — at anaesthetic doses with chronic use; monitor urinary symptoms)

Interactions

  • Central nervous system depressants (benzodiazepines, opioids, alcohol): additive sedation — caution
  • MAO inhibitors: risk of cardiovascular instability and potentiation — avoid
  • Stimulants (methylphenidate, amphetamine): additive cardiovascular effects — caution
  • Antihypertensives: esketamine raises BP — monitor
  • Psychostimulants and anaesthetics: additive dissociation

Monitoring

  • Blood pressure before and after each session (at 40 minutes post-dose — peak effect)
  • Dissociation severity (CADSS scale) at each session
  • Suicidal ideation (especially in MDSI indication — paradoxical risk in acute phase)
  • Sedation level (MOAA/S scale during observation period)
  • Urinary symptoms (with prolonged use — esketamine-associated cystitis, analogous to ketamine bladder syndrome)
  • Depression rating scales (PHQ-9, MADRS) at 4, 8 weeks, then monthly

Reference: BNFc; BNF 90; NICE TA854 (esketamine for TRD); Daly et al. NEJM 2018 (TRANSFORM-2); MHRA SPC Spravato; REMS programme documentation. Verify against your local formulary and the latest BNF before prescribing.

Related

Curated clinical cross-links plus same-class fallbacks.

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