Vortioxetine
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Vortioxetine: From Depression to Melancholia
One-Sentence Summary
Vortioxetine is a multimodal serotonergic antidepressant, originally used for major depressive disorder and anxiety disorders. The TxGNN model predicts it may be effective for melancholia (a severe subtype of depression), supported by 6 clinical trials and 20 publications. However, this evidence comes mainly from the general major depressive disorder (MDD) population, so this is closer to an on-label or near-label use than a true repurposing opportunity.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Unipolar depression, endogenous depression, major depressive disorder, anxiety disorder (from the knowledge graph; the Singapore licences carry no indication text) |
| Predicted New Indication | Melancholia (the top-ranked prediction by TxGNN score is neurotic disorder, which is a legacy category; see the note below) |
| TxGNN Prediction Score | 99.08% (melancholia); the top-ranked prediction, neurotic disorder, scores 99.24% |
| Evidence Level | L1 (melancholia) |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 7 |
| Recommended Decision | Proceed with Guardrails |
Note on candidate selection: The highest-scoring prediction (neurotic disorder) is a broad, outdated category with only one narrative article and no vortioxetine-specific data (L4, Hold). This report focuses on melancholia, the prediction with the strongest supporting evidence. The other predictions are summarised in the final section.
Why is This Prediction Reasonable?
Detailed mechanism-of-action data is not available in the data compiled for this report. From the published literature, vortioxetine inhibits the serotonin transporter (SERT), agonises 5-HT1A receptors, partially agonises 5-HT1B receptors, and antagonises 5-HT3, 5-HT7 and 5-HT1D receptors. This increases serotonergic, noradrenergic, dopaminergic, cholinergic, histaminergic and glutamatergic neurotransmission in brain regions linked to mood and cognition.
Melancholia is a severe subtype of major depressive disorder, the condition for which vortioxetine is already established. The prediction is therefore mechanistically sensible. Note, however, that the supporting trials were run in general MDD populations, not specifically in patients with melancholic features. Subtype-specific efficacy has not been shown in the data compiled here.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT01163266 | Phase 3 | Completed | 462 | Randomised, double-blind, placebo-controlled study of 10 and 20 mg in acute MDD |
| NCT01153009 | Phase 3 | Completed | 614 | Placebo-controlled, duloxetine-referenced study of 15 and 20 mg in acute MDD |
| NCT00735709 | Phase 3 | Completed | 560 | Placebo-controlled, fixed-dose study of 3 doses in acute MDD |
| NCT01255787 | Phase 2/3 | Completed | 600 | Placebo-controlled dose-ranging study in MDD |
| NCT01152996 | Phase 3 | Completed | 1075 | Long-term open-label extension (15 and 20 mg); safety and tolerability |
| NCT00707980 | Phase 3 | Completed | 836 | Long-term open-label flexible-dose extension; safety and tolerability |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 29477251 | 2018 | Network meta-analysis | Lancet | Compared efficacy and acceptability of 21 antidepressants in acute adult MDD |
| 38957929 | 2024 | Meta-analysis of RCTs | Psychiatry Clin Neurosci | Dose-response relationship of vortioxetine in adult depression |
| 36253442 | 2023 | Network meta-analysis | Mol Psychiatry | Antidepressants in the maintenance phase of MDD |
| 34029378 | 2021 | Network meta-analysis | Cochrane Database Syst Rev | New-generation antidepressants in children and adolescents |
| 25016186 | 2015 | Review | Pharmacol Ther | Preclinical and clinical review of vortioxetine's multimodal activity |
| 29189941 | 2018 | Review | Clin Pharmacokinet | Pharmacokinetics (half-life about 66 h, bioavailability 75%) and drug interactions |
| 37032427 | 2023 | Clinical guideline | Clin Pharmacol Ther | CPIC pharmacogenetic guidance (CYP2D6 and others) for serotonin reuptake inhibitor antidepressants |
| 37424409 | 2023 | Review | Clin Psychopharmacol Neurosci | Anhedonia as a core symptom of depressive disorders |
| 28881483 | 2017 | Meta-analysis | Depress Anxiety | Hyperhidrosis risk with second-generation antidepressants |
| 33549697 | 2021 | Meta-analysis | Prog Neuropsychopharmacol Biol Psychiatry | Gastrointestinal side effects of antidepressants in MDD |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN14665P | BRINTELLIX Film-Coated Tablets 5 mg | Film-coated tablet | Not stated in the data |
| SIN14666P | BRINTELLIX Film-Coated Tablets 10 mg | Film-coated tablet | Not stated in the data |
| SIN14667P | BRINTELLIX Film-Coated Tablets 20 mg | Film-coated tablet | Not stated in the data |
| SIN16577P | BRINTELLIX Oral Drops, Solution 20 mg/ml | Solution | Not stated in the data |
| SIN16556P | VORTIOSON Film-Coated Tablet 10 mg | Film-coated tablet | Not stated in the data |
Two further VORTIOSON licences (5 mg, SIN16557P; 20 mg, SIN16555P) are also valid, for 7 valid single-ingredient registrations in total, all held by H. Lundbeck A/S.
Safety Considerations
Package-insert warnings and contraindications were not available for this report. Please refer to the package insert for safety information.
Drug interactions (100 interactions were found; examples of major-level ones):
- Bupropion
- Lorcaserin
- Diethylpropion
- Phentermine
- Dolasetron
- Palonosetron
Moderate-level examples include morphine, acetylsalicylic acid, dexamethasone, several insulins, and sulfonylureas such as glimepiride and chlorpropamide.
Published literature also points to pharmacogenetic dosing considerations for CYP2D6 poor metabolisers (CPIC guidance), and to class-wide adverse effects such as gastrointestinal symptoms, hyperhidrosis and sexual dysfunction. Antidepressants also carry a boxed warning for suicidality in young patients, which matters for any paediatric use.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Several completed Phase 3 placebo-controlled RCTs and multiple meta-analyses support vortioxetine in MDD, and melancholia is a severe subtype of MDD. The evidence is strong but indirect for melancholia specifically, and the safety data for this report are incomplete.
To proceed, the following is needed:
- Subtype-specific efficacy confirmation (post hoc or subgroup analyses in melancholic patients)
- Singapore package-insert warnings, contraindications and approved indication text (currently missing)
- Mechanism-of-action data from DrugBank
- CYP2D6 poor-metabolizer dosing guidance and a DDI management plan, especially for bupropion and other serotonergic agents
Other Predictions at a Glance
| Predicted Indication | Score | Evidence Level | Recommendation | Comment | |------|------|------|------|------| | Neurotic disorder | 99.24% | L4 | Hold | Legacy broad category; one narrative article, no vortioxetine-specific data | | Neurotic depression | 99.09% | L4 | Research Question | Maps to depressive disorders already covered by MDD evidence; no trials under this term | | Dysthymic disorder | 99.02% | L3 | Research Question | Only an MDD open-label extension is linked; dedicated controlled trials are needed | | Agoraphobia | 98.98% | L3 | Research Question | One open-label study in anxiety-spectrum subjects (panic disorder); controlled evidence needed | | Benign paroxysmal torticollis of infancy | 99.07% | L5 | Hold | No mechanistic rationale; paediatric safety concerns | | Ohdo syndrome and variants, Keppen-Lubinsky syndrome, congenital isolated ACTH deficiency | 97.9–98.7% | L5 | Hold | Rare genetic or endocrine disorders; computational prediction only, no supporting data |
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.