Imipramine
| Evidence Level: L3 | Predicted Indications: 7 |
Table of Contents
Imipramine: From Anxiety Disorder to Attention Deficit-Hyperactivity Disorder
One-Sentence Summary
Imipramine is a tricyclic antidepressant, originally used for anxiety disorder, neurotic disorder, dysthymic disorder and nocturnal enuresis. The TxGNN model predicts it may be effective for attention deficit-hyperactivity disorder (ADHD), but there are no registered clinical trials and only 20 publications, mostly older reviews and small studies, supporting this direction.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Anxiety disorder, neurotic disorder, dysthymic disorder, nocturnal enuresis (from the knowledge graph; no approved indication text is available for the New Zealand licences) |
| Predicted New Indication | Attention deficit-hyperactivity disorder |
| TxGNN Prediction Score | 99.90% |
| Evidence Level | L3 |
| New Zealand Market Status | ✗ Cancelled only |
| Number of Authorizations | 4 (all cancelled) |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on the known pharmacology of tricyclic antidepressants, imipramine inhibits reuptake of norepinephrine and, to a lesser extent, serotonin. The pharmacology data compiled for this report show activity at the norepinephrine transporter (NET) and the serotonin transporter (SERT). It also shows activity at the M2 muscarinic receptor, Kv10.1 and Kir3 channels (the Kir3 data are from mouse).
ADHD is thought to involve reduced noradrenergic signalling in prefrontal circuits. Other noradrenergic agents, such as desipramine and atomoxetine, are used in ADHD. This gives a plausible mechanistic basis for imipramine, although the link is inferred rather than demonstrated in the data. Imipramine's existing use in anxiety, dysthymia and nocturnal enuresis (which often co-occurs with ADHD) also places it in a neighbouring clinical space.
The evidence is mostly old, small-scale or review-level. Newer ADHD agents with better safety profiles are available, and cardiac safety is a concern with tricyclics in children.
Clinical Trial Evidence
Currently no related clinical trials registered.
Literature Evidence
The most relevant publications for ADHD are listed below.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 6849467 | 1983 | Clinical report | Am J Psychiatry | Report specifically on imipramine for attention deficit disorder (no abstract available) |
| 18304665 | 2008 | Clinical study | Int J Psychophysiol | Effects of imipramine on EEG in children with ADHD who did not respond to stimulants |
| 9465283 | 1996 | Clinical study | Clin EEG | Prolonged P300 latency predicted poor response to imipramine in 17 children with ADHD who responded poorly to pemoline |
| 8705955 | 1996 | Cohort | Can J Psychiatry | ECG changes in paediatric patients on desipramine and imipramine, with possible sudden-death risk |
| 15794722 | 2005 | Review | Expert Opin Drug Saf | Safety of non-stimulant ADHD agents; imipramine and desipramine may be effective but atomoxetine is preferred second-line |
| 17078784 | 2006 | Review | Expert Rev Neurother | Non-selective norepinephrine reuptake inhibitors (desipramine, imipramine) can be effective in ADHD |
| 10790990 | 1999 | Review | Evid Rep Technol Assess | Evidence report on pharmacological and non-pharmacological ADHD interventions |
| 31776871 | 2019 | Review | CNS Drugs | Overview of drug-drug interactions for ADHD agents |
| 1351794 | 1992 | Review | Clin Ther | ADHD in adults |
| 14501767 | 2003 | Study | J Urol | Management of urinary incontinence and nocturnal enuresis in ADHD |
New Zealand Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| 2015250 | Tofranil | Tab 25 mg | Not available (cancelled) |
| 2015269 | Tofranil | Tab 10 mg | Not available (cancelled) |
| 2452804 | Tofranil | Tab 10 mg | Not available (cancelled) |
| 2669692 | Imipramine Crescent | Tab 25 mg | Not available (cancelled) |
Safety Considerations
- Contraindications and conditions of concern (from the knowledge graph, not label text): The knowledge graph links imipramine to the following conditions as contraindications:
- Cardiovascular: coronary artery disease, heart disease, cardiovascular disease, heart conduction disease, sudden cardiac arrest, stroke, cerebrovascular disorder, cerebral infarction
- Neurological and psychiatric: epilepsy, bipolar disorder, major affective disorder, substance abuse/dependence
- Eye and gastrointestinal: angle-closure glaucoma, closed-angle glaucoma, ocular hypertension, ileus, paralytic ileus, intestinal obstruction
- Urinary and prostate: benign prostatic hyperplasia, pyoureter
- Haematological: neutropenia, agranulocytosis, thrombocytopenia
- Organ disease: kidney disease, liver disease, gallbladder disease
- Endocrine: hyperthyroidism, Graves disease, thyrotoxicosis
- Paediatric cardiac safety: ECG changes have been documented in children on tricyclic antidepressants including imipramine, which is directly relevant to an ADHD population.
- Pharmacological interactions: Imipramine acts on NET, SERT, the M2 muscarinic receptor, Kv10.1 and Kir3 channels. These are pharmacological targets rather than listed drug-drug interactions, but they indicate potential for additive noradrenergic, serotonergic, anticholinergic and cardiac effects with other agents.
Conclusion and Next Steps
Decision: Hold
Rationale: The mechanistic rationale is plausible and older literature includes imipramine use in ADHD, but there are no registered trials and the evidence is mostly old, small or review-level. Cardiac safety concerns in children, newer alternatives with better safety profiles, and the cancelled status of all four New Zealand licences all argue against moving forward now.
To proceed, the following is needed:
- Package insert warnings and contraindications from Medsafe (currently missing, which blocks safety screening)
- Mechanism of action data from DrugBank
- Controlled trial evidence comparing imipramine against current ADHD standards (stimulants, atomoxetine)
- A cardiac safety and ECG monitoring plan, especially for paediatric use
- Confirmation of whether any imipramine product could be re-registered in New Zealand
Other predicted indications (for reference):
- Obsessive-compulsive disorder (score 99.01%, L3, Research Question): imipramine is not an established OCD therapy. A 1985 comparison found clomipramine generally superior, and the standard of care is SSRIs, clomipramine and CBT.
- ADHD inattentive type, faciodigitogenital syndrome, specific developmental disorder, chondromyxoid fibroma and benign paroxysmal torticollis of infancy: Hold, with no direct supporting evidence or only indirect literature.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.