Esketamine
| Evidence Level: L5 | Predicted Indications: 2 |
Table of Contents
Esketamine: Agoraphobia
One-Sentence Summary
The TxGNN model’s top-ranked prediction is Agoraphobia, but this prediction has no clinical trials and no publications behind it. The best-supported candidate in the data compiled for this report is Neurotic Depression (a relabelling of depression, for which esketamine is already used in treatment-resistant depression), with 20 publications including several RCTs.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not recorded in the local data |
| Predicted New Indication | Agoraphobia |
| TxGNN Prediction Score | 0.9957 |
| Evidence Level | L5 |
| Australia Market Status | Listed on the PBS Schedule (1 of 1 items) – TGA (ARTG) registration status is not included in this data |
| Number of PBS Items | 1 (valid: 1) |
| Recommended Decision | Hold |
Other predicted indications reviewed:
| Rank | Predicted Indication | Score | Evidence Level | Decision | |——|——|——|——|——|
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. From the literature, esketamine is an NMDA receptor antagonist that acts through glutamatergic modulation, AMPA receptor activation and downstream synaptic plasticity (BDNF/mTOR pathways), producing rapid antidepressant effects.
However, no trial or publication directly supports this use. The high score probably reflects network proximity to anxiety and depression nodes rather than specific evidence, so it should be treated as a hypothesis only.
Neurotic depression and melancholia (ranks 3-4): These sit within the depressive disorder spectrum, where esketamine nasal spray is already approved in other jurisdictions for treatment-resistant depression (TRD) and for major depression with acute suicidal ideation. This is largely a relabelling of an existing indication rather than true repurposing. Evidence is not specific to the melancholic subtype, so subtype efficacy is an inference.
Evidence so far is limited to reviews, case reports and small case series.
Insomnia (rank 8): Esketamine may improve sleep indirectly through antidepressant, analgesic and anxiolytic effects. The trials were in perioperative settings, not primary insomnia.
Ranks 2, 5, 7, 9 and 10: These are rare genetic or paediatric conditions (CACNA1A-related paroxysmal disorder, cobalamin metabolism disorder, KCNJ6-related syndrome, congenital endocrine deficiency, hereditary neuropathy phenotype) with no plausible link to NMDA antagonism. Use of an NMDA antagonist in infants would also raise safety concerns.
Clinical Trial Evidence
There are no registered trials for agoraphobia. The trials below relate to the other predicted indications.
| Trial Number | Phase | Status | Enrolment | Key Findings |
|---|---|---|---|---|
| NCT04480918 | N/A | Recruiting | 1000 | Observational patient registry of interventional psychiatry treatments (ECT, TMS, ketamine, intranasal esketamine) for TRD and OCD; not an OCD-specific efficacy trial |
Insomnia and sleep quality
| Trial Number | Phase | Status | Enrolment | Key Findings |
|---|---|---|---|---|
| NCT05718024 | Phase 4 | Completed | 174 | Night-time dexmedetomidine-esketamine infusion and sleep in ventilated ICU patients |
| NCT05950646 | Phase 4 | Completed | 154 | Mini-dose dexmedetomidine-esketamine on sleep in older patients having knee or hip replacement |
| NCT05732064 | Phase 4 | Completed | 180 | Nasal dexmedetomidine-esketamine at night for perioperative sleep in breast cancer patients |
| NCT05715671 | N/A | Completed | 138 | Subanaesthetic esketamine alone on sleep quality and gut recovery after laparoscopic uterine surgery |
| NCT06773143 | N/A | Recruiting | 184 | Subanaesthetic esketamine alone on sleep quality in breast cancer patients after chemotherapy |
| NCT06566482 | Phase 4 | Completed | 100 | Mini-dose dexmedetomidine-esketamine analgesia for postoperative sleep in patients at high risk of obstructive sleep apnoea |
| NCT06414941 | N/A | Unknown | 105 | Dexmedetomidine plus esketamine on sleep quality after mastectomy |
| NCT06300944 | N/A | Completed | 100 | Low-dose ketamine for postoperative pain and sleep after laparoscopic uterine surgery (indirect) |
| NCT07610343 | Phase 4 | Not yet recruiting | 60 | Intranasal dexmedetomidine-esketamine on sleep and cognition in older adults with cognitive impairment |
No ANZCTR trial identifiers were available in the data compiled for this report. No trials were registered for neurotic depression or melancholia in the data compiled.
Literature Evidence
Neurotic depression / melancholia (treatment-resistant depression evidence)
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 31109201 | 2019 | RCT | Am J Psychiatry | Flexibly dosed esketamine nasal spray plus a new oral antidepressant vs active comparator in TRD |
| 31166571 | 2019 | RCT | JAMA Psychiatry | Esketamine plus oral antidepressant for relapse prevention in TRD |
| 40601310 | 2025 | RCT | JAMA Psychiatry | Esketamine monotherapy in adults with TRD |
| 39876682 | 2025 | Systematic review/meta-analysis | Am J Psychiatry | Efficacy against depression and suicidality, and side effects |
| 33022440 | 2021 | Systematic review/meta-analysis | J Affect Disord | Comparative efficacy of racemic ketamine and esketamine |
| 33726522 | 2021 | Systematic review | Am J Psychiatry | International expert synthesis of evidence for ketamine and esketamine in TRD |
| 35416105 | 2022 | Review | Expert Opin Drug Saf | Long-term safety of ketamine and esketamine |
| 40319349 | 2025 | Long-term extension study | Int J Neuropsychopharmacol | Long-term safety and efficacy of esketamine in TRD |
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 37213965 | 2023 | Systematic review | Cureus | Clinical effectiveness of NMDA antagonists in adult OCD |
| 42075883 | 2026 | Scoping review | Pharmaceuticals | Clinical and mechanistic evidence for ketamine and esketamine in OCD |
| 42036648 | 2026 | Case series | BMC Psychiatry | Repeated intranasal esketamine in treatment-resistant OCD with comorbid MDD (8 cases) |
| 38194244 | 2024 | Retrospective chart review | Clin Neuropharmacol | Esketamine augmentation in treatment-resistant OCD |
Insomnia / sleep disturbance
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 36454569 | 2022 | RCT | JAMA Netw Open | Intraoperative esketamine and postoperative sleep disturbance after gynaecological laparoscopy |
| 40523523 | 2025 | RCT | Anaesth Crit Care Pain Med | Sub-anaesthetic esketamine on sleep disturbance and pain after lumbar fusion |
| 41285735 | 2025 | RCT | Transl Psychiatry | Esketamine prevents postoperative sleep disturbance in patients with preoperative sleep disorders |
| 40732353 | 2025 | Pilot cohort study | Pharmaceuticals | Insomnia outcomes with esketamine add-on in TRD |
No publications were found for agoraphobia.
Australia Market Information
| ARTG Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| ARTG 14786F | Spravato | Nasal spray device, 28 mg in 2 actuations | Not available in the data compiled; refer to the TGA Product Information |
Safety Considerations
- Contraindications (from the knowledge graph, not label text): vascular disease; arteriovenous haemangioma/malformation.
- Drug Interactions: 70 interactions were identified. Major interactions include diethylpropion, phentermine, fenfluramine, mazindol and caffeine (sympathomimetic/stimulant agents). Moderate interactions include opioids (morphine, opium, loperamide, diphenoxylate, difenoxin), cannabinoids (dronabinol, nabilone), metoclopramide, scopolamine, and several nasal corticosteroids and decongestants (beclomethasone, budesonide, triamcinolone, dexamethasone, ephedrine).
- Guardrails suggested for the depressive indications: supervised administration, monitoring for dissociation and blood pressure elevation, abuse potential assessment and long-term safety monitoring.
Please refer to the TGA-approved Product Information (PI) for formal warnings and contraindications.
Conclusion and Next Steps
Decision: Hold (for the top-ranked prediction, agoraphobia)
Rationale:
- Agoraphobia has no trials or literature, so the 0.9957 score rests on model prediction alone.
- Neurotic depression and melancholia merit Proceed with Guardrails, but they are largely relabellings of the TRD/MDD use rather than new repurposing. OCD and insomnia are research questions pending controlled trials.
To proceed, the following is needed:
- Full TGA Product Information (warnings, contraindications and the approved indication text for Spravato)
- Detailed mechanism of action data
- For agoraphobia: any direct preclinical or clinical evidence, ideally a controlled pilot trial
- For OCD: randomised controlled trials of esketamine
- For insomnia: a trial in primary insomnia, not perioperative settings
- A safety monitoring plan covering dissociation, blood pressure, abuse risk and the interactions above
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.