Esketamine (Spravato) is an approved nasal spray for treatment-resistant depression, with a strict protocol that makes funding decisions straightforward to test. Subcutaneous ketamine is a different, off-label treatment with a much weaker evidence base. This lesson teaches learners to tell them apart and to check a request against the protocol.
1. Treatment overview
- Esketamine is a form of ketamine given as a nasal spray in a clinic, under supervision. It acts on glutamate rather than serotonin, so it works differently from standard antidepressants.
- It is always given with a newly started oral antidepressant, never on its own.
- Ketamine by subcutaneous injection or infusion is a separate, off-label treatment, usually in private clinics.
2. Current literature and evidence
- In the pivotal TRANSFORM-2 trial, about 63% of people on esketamine plus a new oral antidepressant had responded by week 4, compared with about 50% on a new oral antidepressant plus placebo. Response means a 50% or greater drop in the MADRS depression score. That is a real but moderate advantage, and many people do not respond.
- Subcutaneous ketamine has limited evidence from small studies, with variable monitoring and no standard protocol.
- For PTSD, ketamine-based treatments remain experimental. Trauma-focused psychological therapy is the recommended first-line treatment.
3. Prescribing guidelines and regulation
- Esketamine is approved for adults with treatment-resistant major depression who have not responded to two or more adequate antidepressant trials. It has been PBS listed since 01/05/2025.
- PBS authority criteria (as summarised in IMM's funding framework): at least two prior antidepressant failures, started with a newly commenced oral antidepressant, given in a supervised healthcare setting, monitored after each dose, and evidence of response documented.
- Psychiatric supervision is required.
- Subcutaneous ketamine is not approved for depression and is privately funded.
4. Indications and contraindications
- Indication: treatment-resistant major depression in adults. An adequate antidepressant trial means an approved antidepressant, at a therapeutic dose, for at least 4 to 6 continuous weeks, with adherence confirmed. Treatment-resistant means at least two different antidepressants, each at an adequate dose and duration. Some psychiatrists prefer the two to come from different classes, but that is not a requirement.
- Absolute contraindications: aneurysmal vascular disease, history of bleeding in the brain, and hypersensitivity to ketamine or esketamine.
- Precautions: uncontrolled high blood pressure, recent heart attack or stroke, history of substance misuse, psychosis or severe psychiatric instability.
- Common effects: dissociation (feeling detached), sedation and a rise in blood pressure after each dose.
5. Processes
| Phase | Weeks | Dose | Frequency |
|---|---|---|---|
| Induction | 1 to 4 | Day 1: 56 mg (28 mg if 65 or over). Then 56 or 84 mg (28, 56 or 84 mg if 65 or over) | Twice weekly |
| Optimisation | 5 to 8 | 56 or 84 mg (28, 56 or 84 mg if 65 or over) | Weekly |
| Maintenance | 9 onward | 56 or 84 mg (28, 56 or 84 mg if 65 or over) | Weekly or every 2 weeks, at the lowest frequency that maintains response |
- Each session: blood pressure before and after dosing, observation for sedation and dissociation, and about 2 hours of supervision until stable.
- No driving or operating machinery until the next day, after a full night's sleep. The patient needs transport home.
- Review points: baseline (confirm TRD and severity, for example MADRS 20 or more), week 4, weeks 8 to 12, every 3 months, and a full reassessment at 12 months.
- Once improved, treatment usually continues for at least 6 months, with periodic reassessment.
- Signs it isn't working: less than 25 to 30% improvement after induction, no meaningful improvement by 8 to 12 weeks, no functional gain, intolerable side effects, or relapse despite treatment.
6. What it means for you
| Role | What to do |
|---|---|
| Case manager or IMA | Check the request against the protocol: confirmed TRD (two adequate trials), a new oral antidepressant started, a supervised clinic, a baseline score, and response measured at week 4 and weeks 8 to 12. Fund in phases tied to the review points. Treat subcutaneous ketamine as a separate, experimental request. |
| Rehab provider | Induction means two clinic sessions a week, each with about 2 hours of observation and no driving afterwards. Build that into RTW hours and transport. Track function and work capacity, not just mood scores. |
| WHS officer | No driving or safety-critical work on treatment days, until after a full night's sleep. During induction that is two days a week. |
Red flags
- Fewer than two adequate antidepressant trials, or no psychiatrist confirmation of TRD
- No baseline depression score, or no objective reassessment after induction
- Minimal improvement after induction, but treatment continues
- Uncontrolled high blood pressure or active substance misuse
- Treatment not given in a supervised setting, or no monitoring records