Esketamine
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Esketamine: From Anxiety Disorder to Agoraphobia
One-Sentence Summary
Esketamine is the S-enantiomer of ketamine, delivered as a nasal spray, and its original indications in the knowledge graph are anxiety disorder, neurotic disorder and dysthymic disorder. The TxGNN model's top-ranked prediction is agoraphobia, but this prediction has 0 clinical trials and 0 publications behind it. Better-supported alternatives among the other predictions are neurotic depression and melancholia (both L1), insomnia (L2) and obsessive-compulsive disorder (L3), described below.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Anxiety disorder, neurotic disorder, dysthymic disorder (knowledge-graph indications; the Singapore licence has no approved indication text) |
| Predicted New Indication | Agoraphobia |
| TxGNN Prediction Score | 99.57% |
| Evidence Level | L5 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 1 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available in the data compiled for this report. Esketamine is generally known as an NMDA receptor antagonist. Agoraphobia is an anxiety-related condition and is conceptually close to the anxiety disorders listed as esketamine's original indications. However, this link is indirect, and no trials or publications were retrieved to support it.
The top prediction should therefore be treated as a model output only. The data show that other predictions have much stronger support:
| Predicted Indication | TxGNN Score | Evidence Level | Decision |
|---|---|---|---|
| Agoraphobia | 99.57% | L5 | Hold |
| Neurotic depression | 97.83% | L1 | Proceed with Guardrails |
| Melancholia | 97.74% | L1 | Proceed with Guardrails |
| Obsessive-compulsive disorder | 97.31% | L3 | Research Question |
| Insomnia | 96.39% | L2 | Research Question |
Neurotic depression and melancholia. Esketamine's NMDA antagonism and downstream glutamatergic and synaptic plasticity effects underlie its rapid antidepressant action in treatment-resistant depression (TRD). These two predictions largely overlap with depressive disorders for which esketamine is already approved elsewhere, so they are closer to on-label use than true repurposing. Evidence is not specific to the melancholic subtype.
Obsessive-compulsive disorder (OCD). Glutamatergic dysfunction in cortico-striato-thalamo-cortical circuits provides a rationale, but the evidence is limited to a retrospective chart review, case reports and reviews.
Insomnia. The evidence comes from perioperative settings, often combined with dexmedetomidine, not from primary insomnia disorder.
Several other predictions (benign paroxysmal torticollis of infancy, vitamin B12-responsive methylmalonic acidemia, Keppen-Lubinsky syndrome, congenital isolated ACTH deficiency, autosomal dominant slowed nerve conduction velocity) have no evidence and no identifiable mechanistic basis. They are likely graph-model artifacts.
Clinical Trial Evidence
No clinical trials are registered for agoraphobia, the top-ranked prediction. Currently no related clinical trials registered.
For reference, the trials found for the next-best-supported predictions are:
Insomnia (L2)
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT05715671 | N/A | Completed | 138 | Subanesthetic esketamine alone on sleep quality after laparoscopic uterine surgery |
| NCT06773143 | N/A | Recruiting | 184 | Subanesthetic esketamine alone on sleep quality in breast cancer patients after chemotherapy-related surgery |
| NCT05718024 | Phase 4 | Completed | 174 | Night-time dexmedetomidine-esketamine on sleep in ICU patients on ventilation or high-flow oxygen |
| NCT05732064 | Phase 4 | Completed | 180 | Nasal dexmedetomidine-esketamine at night, perioperative sleep in breast cancer patients |
| NCT05950646 | Phase 4 | Completed | 154 | Mini-dose dexmedetomidine-esketamine on sleep in older patients after knee or hip replacement |
| NCT06414941 | N/A | Unknown | 105 | Dexmedetomidine plus esketamine on sleep quality after mastectomy |
| NCT06566482 | Phase 4 | Completed | 100 | Mini-dose dexmedetomidine-esketamine for postoperative sleep in patients at high risk of obstructive sleep apnea |
| NCT06300944 | N/A | Completed | 100 | Low-dose ketamine on postoperative pain and sleep quality (related compound) |
| NCT07610343 | Phase 4 | Not yet recruiting | 60 | Intranasal dexmedetomidine-esketamine in older adults with mild-to-moderate cognitive impairment |
Obsessive-compulsive disorder (L3)
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT04480918 | N/A | Recruiting | 1000 | Interventional psychiatry patient registry (ECT, TMS, ketamine, esketamine) for TRD and OCD. Observational, so it gives only indirect data |
Literature Evidence
No publications were retrieved for agoraphobia. Currently no related literature available.
For reference, key publications for the better-supported predictions:
Neurotic depression / melancholia (TRD 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 |
| 40601310 | 2025 | RCT | JAMA Psychiatry | Esketamine monotherapy in adults with TRD |
| 31166571 | 2019 | RCT | JAMA Psychiatry | Esketamine plus oral antidepressant for relapse prevention in TRD |
| 39876682 | 2025 | Meta-analysis | Am J Psychiatry | PRISMA systematic review of esketamine for depression and suicidality, including side effects |
| 33726522 | 2021 | Systematic review | Am J Psychiatry | International expert synthesis of ketamine and esketamine evidence in TRD |
| 40319349 | 2025 | Long-term extension | Int J Neuropsychopharmacol | Long-term safety and efficacy of esketamine in TRD |
Obsessive-compulsive disorder
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 38194244 | 2024 | Retrospective chart review | Clin Neuropharmacol | Esketamine augmentation in treatment-resistant OCD |
| 42075883 | 2026 | Scoping review | Pharmaceuticals | Clinical and mechanistic evidence for ketamine and esketamine in OCD |
| 34530843 | 2021 | Case report | Ann Gen Psychiatry | Esketamine in comorbid TRD and OCD |
Insomnia
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 36454569 | 2022 | RCT | JAMA Netw Open | Intraoperative esketamine infusion on postoperative sleep disturbance after gynecological laparoscopy |
| 40523523 | 2025 | RCT | Anaesth Crit Care Pain Med | Sub-anesthetic esketamine on postoperative 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 | Cohort / post hoc | Pharmaceuticals | Insomnia and esketamine add-on therapy in TRD (pilot study) |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN16033P | SPRAVATO NASAL SPRAY 28MG/VIAL | Spray | Not specified in the data compiled for this report |
Safety Considerations
- Knowledge-graph contraindications (from drug-disease graph edges, not label text): vascular disease; arteriovenous hemangioma/malformation.
- Drug Interactions: 70 known interactions were identified. Examples:
- Major: diethylpropion, phentermine, fenfluramine, mazindol, caffeine
- Moderate: opioids (morphine, liposomal morphine, opium, loperamide, difenoxin, diphenoxylate), cannabinoids (dronabinol, nabilone), metoclopramide, scopolamine, and nasal corticosteroids and decongestants (beclomethasone, budesonide, triamcinolone, dexamethasone, ephedrine)
- Class-level monitoring raised in the literature: dissociation, blood pressure changes, abuse potential, and DDI management.
Package insert warnings and contraindications were not available. Please refer to the package insert for full safety information.
Conclusion and Next Steps
Decision: Hold (for the top-ranked prediction, agoraphobia)
Rationale: Agoraphobia has a high model score but no trials or literature, so it is supported by prediction only. Within the same prediction list, neurotic depression and melancholia (both Proceed with Guardrails) are better-supported directions, though they largely overlap with depression indications esketamine already has elsewhere. OCD and insomnia are research questions.
To proceed, the following is needed:
- Mechanism of action data and package insert warnings and contraindications (both currently missing)
- For agoraphobia: any clinical or literature evidence in anxiety or phobic disorders, ideally controlled trials
- For OCD: controlled trials, since current evidence is only a registry, a chart review and case reports
- For insomnia: trials in primary insomnia using esketamine alone, since current trials are perioperative and mostly combined with dexmedetomidine
- A safety monitoring plan covering blood pressure, dissociation, abuse potential and interaction management, plus a check of the Singapore licence's approved indication wording
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.