Amitriptyline
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
- Amitriptyline
- Amitriptyline: From Anxiety and Depressive Disorders to Benign Paroxysmal Torticollis of Infancy
Amitriptyline: From Anxiety and Depressive Disorders to Benign Paroxysmal Torticollis of Infancy
One-Sentence Summary
Amitriptyline is a tricyclic antidepressant, originally used for anxiety disorder, neurotic disorder, dysthymic disorder and mixed anxiety and depressive disorder. The TxGNN model's top-ranked prediction is benign paroxysmal torticollis of infancy, but no clinical trials and no publications support it; the prediction rests on model output alone. Of the ten predicted indications, the best-supported is major depressive disorder (6 registered trials and 20 publications), which largely overlaps with the drug's existing use rather than being a true repurposing.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Anxiety disorder, neurotic disorder, dysthymic disorder, mixed anxiety and depressive disorder (the Singapore licence records contain no indication text) |
| Predicted New Indication | Benign paroxysmal torticollis of infancy (top-ranked prediction) |
| TxGNN Prediction Score | 97.72% |
| Evidence Level | L5 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 4 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available in the data compiled for this report. Based on the literature, amitriptyline inhibits serotonin and norepinephrine reuptake and also acts on histamine, muscarinic and other receptors. This is the established basis of its antidepressant effect.
Benign paroxysmal torticollis of infancy is regarded as a paediatric migraine equivalent. Amitriptyline is used in migraine prophylaxis, so a link is plausible, but it has not been verified. No trials or publications were found for this condition. Paediatric safety (anticholinergic effects, cardiac effects, QT prolongation) would also need separate evaluation.
The other predictions fall into three groups:
- Overlap with existing use: Major depressive disorder, unipolar depression, endogenous depression, melancholia and neurotic depression are depressive conditions, close to amitriptyline's original indications. They reflect terminology overlap, not new repurposing.
- Indirect evidence: Agoraphobia and phobic disorder have a plausible monoaminergic rationale, but the retrieved literature is mostly about other drugs.
- Likely model artifacts: Ohdo syndrome and its variants are rare genetic syndromes with no pharmacological rationale for amitriptyline.
Clinical Trial Evidence
No clinical trials are registered for the top-ranked prediction (benign paroxysmal torticollis of infancy). Currently no related clinical trials registered.
For reference, the best-supported depressive-disorder entries (major depressive disorder and unipolar depression) share the following trials:
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT02014363 | Phase 2 | Completed | 164 | Double-blind non-inferiority study of ETS6103 versus amitriptyline in depression with unsatisfactory response to SSRIs; amitriptyline is the active comparator |
| NCT05952713 | N/A | Completed | 73,336 | Nationwide real-world comparison of 15 antidepressants in major depressive disorder (observational) |
| NCT01049347 | Phase 3 | Completed | 127 | Cortisol (HPA axis) monitoring during amitriptyline and paroxetine treatment; mechanistic focus |
| NCT00351910 | Phase 3 | Completed | 494 | Quetiapine SR added to an antidepressant versus antidepressant alone; class-level relevance only |
| NCT02237937 | Phase 4 | Unknown | 80 | Genotype-guided (ABCB1) dose escalation of antidepressants |
| NCT00325000 | N/A | Terminated | Not reported | Interpersonal psychotherapy plus pharmacotherapy in severely depressed inpatients |
Literature Evidence
No publications were retrieved for the top-ranked prediction. Currently no related literature available.
For reference, the most relevant publications for major depressive disorder:
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 23235671 | 2012 | Cochrane systematic review | Cochrane Database Syst Rev | Amitriptyline versus placebo for major depressive disorder |
| 29477251 | 2018 | Network meta-analysis | Lancet | Comparative efficacy and acceptability of 21 antidepressants |
| 36253442 | 2023 | Network meta-analysis | Mol Psychiatry | Antidepressants in the maintenance phase of major depressive disorder |
| 38902199 | 2025 | Network meta-analysis | Chin Med J | Efficacy and dose-response relationships of antidepressants |
| 41290573 | 2025 | Network meta-analysis | Transl Psychiatry | Comparative gastrointestinal effects of antidepressants |
| 38360024 | 2024 | Network meta-analysis | Lancet Psychiatry | Pharmacological treatments for psychotic depression |
| 3897204 | 1985 | Randomised double-blind trial | J Clin Psychiatry | Fluoxetine versus amitriptyline in 44 outpatients; both effective |
| 32565594 | 2020 | Randomised open-label study | Indian J Pharmacol | Vilazodone, escitalopram and amitriptyline compared in major depressive disorder |
| 33438398 | 2021 | Review | ACS Chem Neurosci | Pharmacology of amitriptyline, including its cardiotoxicity concerns |
| 38856993 | 2024 | Review | JAMA | Management of depression in adults |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN00089P | APO-AMITRIPTYLINE TABLET 10 mg | Tablet, film coated | Not stated in the licence record |
| SIN00090P | APO-AMITRIPTYLINE TABLET 25 mg | Tablet, film coated | Not stated in the licence record |
| SIN00415P | TRIPTA TABLET 10 mg | Tablet, sugar coated | Not stated in the licence record |
| SIN00414P | TRIPTA TABLET 25 mg | Tablet, sugar coated | Not stated in the licence record |
All four licences are valid single-ingredient oral products. None has been cancelled.
Safety Considerations
- Contraindication signals from the knowledge graph (not label text):
- Cardiac and blood pressure: long QT syndrome (including the familial form), torsades de pointes, orthostatic hypotension, postural orthostatic tachycardia syndrome, multiple system atrophy.
- Neurological and psychiatric: epilepsy, basal ganglia disease, manic bipolar affective disorder, psychotic and schizophrenia-spectrum disorders, substance abuse/dependence.
- Organ and metabolic: liver disease, kidney disease, gallbladder disease, porphyria, hyperglycaemia.
- Haematological: thrombocytopenia, neutropenia, agranulocytosis.
- Other: open-angle glaucoma, benign prostatic hyperplasia, female breast carcinoma.
- Drug interactions: The interaction screen returned 100 records. The first 20 shown include these Major interactions: epinephrine, bupropion, cisapride, dexfenfluramine, dolasetron and ephedrine. The Moderate ones include famotidine, cimetidine, atropine, clarithromycin and several anticholinergic agents (clidinium, dicyclomine).
- Specific cautions noted in the literature: cardiotoxicity, anticholinergic burden, overdose lethality, caution in older adults, and suicidality monitoring in young patients. For the top prediction in infants, the same cardiac and anticholinergic effects would need separate paediatric evaluation.
Package insert warnings and contraindications were not available for this report. Please refer to the package insert for authoritative safety information.
Conclusion and Next Steps
Decision: Hold
Rationale: The top-ranked prediction, benign paroxysmal torticollis of infancy, has only a model score (97.72%). There are no trials or publications, and the safety of amitriptyline in infants is unaddressed. The better-supported depressive-disorder predictions (L1 for major depressive disorder and unipolar depression) are essentially confirmations of existing use, not new repurposing.
To proceed, the following is needed:
- Literature and clinical evidence for amitriptyline in paediatric migraine equivalents, including benign paroxysmal torticollis of infancy
- A paediatric safety assessment covering QT prolongation, anticholinergic effects and overdose risk
- Package insert warnings and contraindications from the HSA, plus the approved indication text for the four Singapore licences
- Detailed mechanism of action data
- If depressive subtypes are pursued, confirmation that they add nothing beyond the existing indications, with guardrails on cardiac risk, anticholinergic burden, overdose lethality, use in older adults, and suicidality monitoring
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.