Donepezil
| Evidence Level: L5 | Predicted Indications: 8 |
Table of Contents
Donepezil: From Alzheimer Disease to Chronic Tic Disorder
One-Sentence Summary
Donepezil is an acetylcholinesterase inhibitor originally used to treat Alzheimer disease. The TxGNN model predicts it may be effective for chronic tic disorder (the top-ranked prediction, psychogenic movement disorders, has no supporting evidence, so this report focuses on the best-supported candidate), with 0 registered clinical trials and 5 publications currently supporting this direction, mostly small, uncontrolled or preclinical studies.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Alzheimer disease (from the knowledge graph; no approved indication text is available from the New Zealand licences) |
| Predicted New Indication | Top-ranked prediction: psychogenic movement disorders. Best-supported candidate: chronic tic disorder |
| TxGNN Prediction Score | 99.23% (psychogenic movement disorders); 99.19% (chronic tic disorder) |
| Evidence Level | L5 for the top-ranked prediction; L3 for chronic tic disorder |
| New Zealand Market Status | Cancelled only |
| Number of Authorizations | 2 (both cancelled) |
| Recommended Decision | Hold (top-ranked prediction); Proceed with Guardrails as a research question for chronic tic disorder |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on known information, donepezil is a selective acetylcholinesterase inhibitor (the pharmacology data show it acts on the ACHE target and is about 188-fold more selective for acetylcholinesterase than butyrylcholinesterase). By blocking the breakdown of acetylcholine, it raises central cholinergic tone. Its efficacy in Alzheimer disease is established, and mechanistically it may be applicable to movement disorders.
Top-ranked prediction (psychogenic movement disorders): No trials or literature were found. A cholinergic link to functional movement disorders is speculative and not supported by the data, so this prediction rests on the model score alone.
Chronic tic disorder (best-supported candidate): Striatal cholinergic dysfunction has been proposed in tics and ADHD. Mouse studies (PMIDs 14643839, 16045972) suggest donepezil modulates serotonergic and cholinergic circuits in a head-twitch model used to mimic tics. Small clinical reports and an 18-week open-label study in children and adolescents with tics and ADHD point the same way. The evidence is limited and mostly uncontrolled.
Other predictions in the list:
- Extrapyramidal and movement disease (L3) and lingual-facial-buccal dyskinesia (L4): cholinergic augmentation may correct the striatal dopamine-acetylcholine imbalance, and one report describes benefit in tardive movement disorders. However, a 2025 systematic review and several case reports and pharmacovigilance studies describe donepezil-associated movement disorders (such as Pisa syndrome and jaw tremor), so the direction of effect is uncertain.
- Primary orthostatic tremor, benign shuddering attacks, tremor-nystagmus-duodenal ulcer syndrome and benign paroxysmal tonic upgaze of childhood with ataxia: prediction only, with no direct supporting evidence.
Clinical Trial Evidence
Currently no related clinical trials registered for any of the predicted indications.
Literature Evidence
Chronic tic disorder
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 18343255 | 2008 | Clinical study (likely open-label, 18 weeks) | Clinical Therapeutics | Donepezil in children and adolescents with tics and ADHD; premise is striatal cholinergic dysfunction |
| 10440471 | 1999 | Case report/series | Journal of Clinical Psychopharmacology | Donepezil for Tourette's disorder and ADHD |
| 16986157 | 2006 | Commentary/case report | Movement Disorders | Asks whether donepezil is also effective in Tourette's syndrome |
| 16045972 | 2005 | Preclinical (mouse) | Pharmacology, Biochemistry, and Behavior | Donepezil, nicotine and haloperidol effects on the central serotonergic system; implications for Tourette's |
| 14643839 | 2003 | Preclinical (mouse) | Pharmacology, Biochemistry, and Behavior | Donepezil reduced DOI-induced head twitch response, a proposed tic model |
Extrapyramidal and movement disease
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 40224553 | 2025 | Systematic review | Brain Circulation | Movement disorders associated with acetylcholinesterase inhibitors in Alzheimer's dementia (safety signal) |
| 15669896 | 2005 | Clinical study | Journal of Clinical Psychiatry | Reported benefit of donepezil in elderly patients with tardive movement disorders |
Lingual-facial-buccal dyskinesia
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 29553158 | 2018 | Systematic review (Cochrane) | Cochrane Database of Systematic Reviews | Cholinergic medication for antipsychotic-induced tardive dyskinesia; donepezil-specific effect not clear from the title |
| 15610922 | 2004 | Meta-analysis of RCTs | Progress in Neuro-Psychopharmacology & Biological Psychiatry | Cholinergic drugs, including donepezil, for neuroleptic-induced tardive dyskinesia |
| 24127392 | 2014 | Pharmacovigilance study | Pharmacotherapy | Cholinesterase inhibitors and Pisa syndrome (a safety signal) |
No literature was found for psychogenic movement disorders, primary orthostatic tremor, benign shuddering attacks, or benign paroxysmal tonic upgaze of childhood with ataxia. The only paper retrieved for tremor-nystagmus-duodenal ulcer syndrome concerns Behçet disease and is indirect.
New Zealand Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| 2666898 | Ipca-Donepezil | Tab 10 mg | Not available (cancelled) |
| 2666871 | Ipca-Donepezil | Tab 5 mg | Not available (cancelled) |
Safety Considerations
- Contraindications and cautions flagged in the knowledge graph (not taken from package insert text): epilepsy, asthma (including intrinsic and allergic asthma), bladder neck obstruction, active peptic ulcer disease, sick sinus syndrome (including the familial form), and atrioventricular block.
- Pharmacological target: donepezil acts on acetylcholinesterase (ACHE), and this is the only interaction entry recorded.
- Predicted-indication concerns: increased cholinergic activity may aggravate duodenal ulcer, and donepezil has been associated with drug-induced movement disorders (Pisa syndrome, jaw tremor). Paediatric safety would need evaluation for chronic tic disorder.
Please refer to the package insert for full safety information.
Conclusion and Next Steps
Decision: Hold (top-ranked prediction, psychogenic movement disorders); Proceed with Guardrails as a research question for chronic tic disorder
Rationale:
- The top-ranked prediction has a high model score but no trials or literature, so it cannot be advanced. Chronic tic disorder has the most consistent supporting signal (an open-label paediatric study, case reports, and mouse models), but it is small, uncontrolled and has no registered trials. Movement-disorder predictions also carry a conflicting safety signal.
- Both New Zealand licences are cancelled, so there is currently no marketed product in the country.
To proceed, the following is needed:
- Package insert warnings and contraindications from Medsafe (currently missing and blocking safety screening)
- Detailed mechanism of action data from DrugBank
- Confirmation of the design and outcomes of the tic and ADHD studies (PMIDs 18343255, 10440471, 16986157)
- A controlled trial design for chronic tic disorder, with a paediatric safety plan covering gastrointestinal, cardiac (bradycardia, conduction block) and extrapyramidal effects
- Clarification of the regulatory pathway, since the existing licences are cancelled
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.