Nortriptyline
| Evidence Level: L2 | Predicted Indications: 2 |
Table of Contents
- Nortriptyline
- Pharmacist Assessment Report
- Nortriptyline: From Anxiety Disorder to Attention Deficit-Hyperactivity Disorder
- One-Sentence Summary
- Quick Overview
- Why is This Prediction Reasonable?
- Clinical Trial Evidence
- Literature Evidence
- Australia Market Information
- Safety Considerations
- Conclusion and Next Steps
- Disclaimer
Nortriptyline: From Anxiety Disorder to Attention Deficit-Hyperactivity Disorder
One-Sentence Summary
Nortriptyline is a tricyclic antidepressant, originally linked to anxiety disorder, neurotic disorder and dysthymic disorder. The TxGNN model predicts it may be effective for attention deficit hyperactivity disorder (ADHD), with no registered clinical trials but 15 publications (including a Cochrane review and a controlled paediatric trial) supporting this direction.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Anxiety disorder, neurotic disorder, dysthymic disorder (the Australian ARTG entry has no approved indication text recorded) |
| Predicted New Indication | Attention deficit-hyperactivity disorder |
| TxGNN Prediction Score | 0.9942 |
| Evidence Level | L2 |
| 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 | Proceed with Guardrails |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on known class pharmacology, nortriptyline is a tricyclic antidepressant that inhibits norepinephrine reuptake and, to a lesser degree, serotonin reuptake. A PET study in patients with depression (PMID 24345533) found that nortriptyline occupies the norepinephrine transporter, consistent with this mechanism.
Noradrenergic augmentation in prefrontal circuits is also the mechanism exploited by non-stimulant ADHD drugs such as atomoxetine. This gives a plausible pharmacological rationale for the prediction. Secondary-amine tricyclics, including nortriptyline, are described in the literature as established second-line alternatives for ADHD. Their use has been limited by a narrow therapeutic index and cardiovascular toxicity.
Note that this link rests on known class pharmacology rather than the supplied mechanism record.
Clinical Trial Evidence
Currently no related clinical trials registered for ADHD.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 11052409 | 2000 | RCT | J Child Adolesc Psychopharmacol | Controlled study of nortriptyline efficacy and tolerability in children and adolescents with ADHD |
| 25238582 | 2014 | Systematic review | Cochrane Database Syst Rev | Review of tricyclic antidepressants as second-line treatment for ADHD in children and adolescents |
| 22700161 | 2012 | RCT | Pediatr Nephrol | Randomised double-blind trial of nortriptyline for enuresis in children with ADHD |
| 15064003 | 2004 | Review | Psychiatr Clin North Am | Nonstimulant treatments for adult ADHD; nortriptyline and desipramine named as established but cardiotoxicity-limited options |
| 12270803 | 2002 | Review | Adolesc Med | Adolescent ADHD pharmacology; lists nortriptyline among effective tricyclics |
| 22303520 | 2012 | Guideline | Ann Clin Psychiatry | CANMAT recommendations for mood disorders with comorbid ADHD |
| 8428873 | 1993 | Clinical study | J Am Acad Child Adolesc Psychiatry | Nortriptyline in children with ADHD and tic disorder or Tourette’s syndrome |
| 8444763 | 1993 | Chart review | J Am Acad Child Adolesc Psychiatry | Chart review of 58 children and adolescents with ADHD treated with nortriptyline |
| 8444754 | 1993 | Retrospective study | J Am Acad Child Adolesc Psychiatry | Serum levels and ECG effects of nortriptyline in young people |
| 8138513 | 1994 | Safety report | J Am Acad Child Adolesc Psychiatry | Safety of clonidine and nortriptyline |
Australia Market Information
| ARTG Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| ARTG 2522R | Allegron | Tablet 10 mg (as hydrochloride), oral | Not recorded in the data compiled for this report |
Safety Considerations
- Contraindications suggested by the knowledge graph (these are drug-disease links from the TxGNN knowledge graph, not product label text):
- Cardiac: long QT syndrome (including familial), torsades de pointes, sudden cardiac arrest, heart conduction disease, myocardial infarction and coronary thrombosis
- Cerebrovascular: stroke, cerebrovascular disorder, cerebral infarction
- Neurological and psychiatric: epilepsy, manic bipolar affective disorder, substance abuse/dependence
- Eye and urinary: open-angle glaucoma and glaucoma, benign prostatic hyperplasia
- Endocrine: hyperthyroidism, Graves disease, thyrotoxicosis
- Organ failure and blood: liver failure, kidney failure, uremia, hemoglobinopathy
- Drug Interactions: The interaction screen returned 100 interactions in total; the 20 records supplied are summarised here.
- Major: epinephrine, bupropion, lorcaserin, potassium citrate, dolasetron
- Moderate (examples): famotidine, cimetidine, clarithromycin, morphine, loperamide, and anticholinergics (atropine, hyoscyamine, glycopyrronium, dicyclomine)
- Paediatric cardiac considerations: The ADHD literature repeatedly flags narrow therapeutic index and cardiovascular toxicity, and includes ECG monitoring and serum level data in young people (PMID 8444754).
Product Information (PI) warnings and contraindications were not available in the data compiled for this report. Please refer to the TGA-approved Product Information (PI) for full safety information.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: At least one controlled paediatric trial and a Cochrane review support nortriptyline as a second-line option in ADHD, and the noradrenergic mechanism is plausible. However, no registered trials exist, the evidence is mostly small and dated, and the cardiovascular safety profile is a significant limitation.
To proceed, the following is needed:
- TGA-approved Product Information review (warnings, contraindications, approved indications), as the safety data are incomplete
- Confirmation of mechanism of action data from DrugBank
- A cardiac screening and ECG/serum level monitoring plan, especially for children and for patients with the contraindications listed above
- Review of the newer or adult ADHD evidence, and comparison against approved ADHD therapies available in Australia
- Interaction management guidance, particularly for the major interactions listed
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.