Selegiline
| Evidence Level: L3 | Predicted Indications: 4 |
Table of Contents
Selegiline: From Parkinson Disease to Schizophrenia
One-Sentence Summary
Selegiline is a monoamine oxidase type B (MAO-B) inhibitor, originally used for Parkinson disease and depression. The TxGNN model predicts it may be effective for Schizophrenia (the second-ranked prediction, but the only one with meaningful supporting evidence), with 1 clinical trial and 20 publications currently supporting this direction.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Parkinson disease (also depression and anxiety disorder, per the knowledge graph) |
| Predicted New Indication | Schizophrenia (the top-ranked prediction, polymicrogyria with cerebellar hypoplasia and arthrogryposis, has no supporting evidence, so the best-supported candidate is evaluated here) |
| TxGNN Prediction Score | 99.14% |
| Evidence Level | L3 |
| US Market Status | Cancelled only (all licences cancelled) |
| Number of NDAs | 8 |
| Recommended Decision | Hold (treat as a research question) |
Why is This Prediction Reasonable?
Selegiline is an irreversible, selective MAO-B inhibitor. At higher oral doses (20 mg/day or more) it also inhibits MAO-A. By blocking dopamine breakdown, it increases dopaminergic tone. Detailed mechanism-of-action data were not available in the data compiled for this report, so the description above is based on the published literature.
Negative and cognitive symptoms of schizophrenia are thought to be linked to low dopaminergic activity in the prefrontal cortex, and they respond poorly to antipsychotics. Boosting dopamine with selegiline as an add-on to an antipsychotic is therefore a plausible approach. Selegiline also has antioxidant and neuroprotective properties, which fit the oxidative-stress hypotheses of schizophrenia.
The mechanistic rationale is reasonable, but clinical support is limited. The only registered trial is early-phase, and its results are not included in the data compiled for this report. Efficacy therefore cannot be asserted from these data. Several published trials of selegiline augmentation exist (see below), but their outcomes are not summarised in the available abstracts.
The other predictions have little support. The top-ranked prediction (polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis) and the third (congenital disorder of glycosylation with defective fucosylation) have no trials, no literature and no plausible mechanistic link to MAO-B inhibition. The fourth (retinal dystrophy) has a single tangential preclinical-type review.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00456976 | Early Phase 1 | Completed | 70 | Randomised, placebo-controlled test of selegiline added to antipsychotics for negative symptoms in inpatients with chronic schizophrenia (2007). Results not available in the compiled data. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 37087864 | 2023 | Systematic review/Meta-analysis | Eur Neuropsychopharmacol | Appraises oral and transdermal selegiline across psychiatric disorders |
| 15677608 | 2005 | Double-blind RCT | Am J Psychiatry | Selegiline augmentation of antipsychotics for negative symptoms in outpatients (multicentre, placebo-controlled) |
| 17972359 | 2008 | Double-blind RCT | Hum Psychopharmacol | Selegiline added to risperidone for negative symptoms in chronic schizophrenia (8 weeks) |
| 10587287 | 1999 | Double-blind controlled study | J Clin Psychopharmacol | Deprenyl (selegiline) augmentation for negative symptoms; 16 patients |
| 8102552 | 1993 | Placebo-controlled RCT | Biol Psychiatry | Selegiline 10 mg/day vs placebo for tardive dyskinesia in 33 patients |
| 8627275 | 1996 | Open-label pilot | J Nerv Ment Dis | Low-dose selegiline (5 mg twice daily) added to antipsychotics in 21 patients with negative symptoms |
| 17405823 | 2007 | Review | Ann Pharmacother | Role of selegiline in treating negative symptoms of schizophrenia |
| 26848926 | 2016 | Cochrane review | Cochrane Database Syst Rev | Antioxidant treatments for schizophrenia |
| 16930948 | 2006 | Systematic review | Schizophr Res | Pharmacological treatment of primary negative symptoms |
| 29552749 | 2018 | Cochrane review | Cochrane Database Syst Rev | Miscellaneous treatments for antipsychotic-induced tardive dyskinesia |
The abstracts available for this report do not state the outcomes of the randomised trials, so their results are not summarised here.
US Market Information
All eight US authorisations are cancelled; none are currently valid. The data compiled for this report contain no approved-indication text.
| Authorization Number | Product Name | Dosage Form | Status |
|---|---|---|---|
| NDA021336 | EMSAM | Patch | Cancelled |
| NDA021479 | ZELAPAR | Orally disintegrating tablet | Cancelled |
| ANDA074672 | Selegiline Hydrochloride | Tablet | Cancelled |
| ANDA206803 | Selegiline Hydrochloride | Capsule | Cancelled |
| ANDA074871 | Selegiline Hydrochloride | Tablet | Cancelled |
Three further abbreviated applications (ANDA075352, ANDA075321, ANDA074565; capsules and tablets) are also cancelled.
Safety Considerations
Contraindications flagged in the knowledge graph (these come from drug-disease relationships, not package-insert text):
- Psychiatric: psychotic disorder, schizoaffective disorder, schizophreniform disorder, mental disorder, bipolar disorder, major affective disorder. These are directly relevant to the proposed schizophrenia use and need careful review.
- Cardiovascular and autonomic: orthostatic hypotension, postural orthostatic tachycardia syndrome, multiple system atrophy, sudden cardiac arrest, heart conduction disease
- Organ disease: kidney disease, liver disease, gallbladder disease
- Tumours: phaeochromocytoma, sympathetic paraganglioma, melanoma, and several other cancers
- Movement disorders: tardive dyskinesia, lingual-facial-buccal dyskinesia
Drug interactions (100 interactions recorded; examples):
- Major: bupropion, phentermine, diethylpropion, dexfenfluramine, isometheptene
- Moderate: epinephrine, metoclopramide, and a range of antidiabetic agents (insulins, glimepiride, repaglinide, nateglinide, chlorpropamide, acetohexamide)
Metoclopramide and similar agents deserve attention in patients on antipsychotics. Please refer to the package insert for full warnings, as label text was not available in the data compiled for this report.
Conclusion and Next Steps
Decision: Hold (treat as a research question)
Rationale: Schizophrenia is the only prediction with plausible mechanistic and clinical support. Even so, the single registered trial is early-phase with no available results, and the evidence is placed at L3. The knowledge graph also lists psychotic and schizophrenia-spectrum disorders as contraindications, and all US licences are cancelled. The other three predictions (L5, or tangential literature only) have no actionable evidence.
To proceed, the following is needed:
- Extraction of efficacy results from the published randomised trials (e.g. PMIDs 15677608, 17972359, 10587287) and NCT00456976, ideally in a quantitative meta-analysis
- Reconciliation of the knowledge-graph contraindications (psychotic disorders) with the proposed indication
- The FDA package insert for warnings and contraindications (a blocking data gap), and mechanism-of-action data from DrugBank
- A review of interactions with antipsychotics and other co-medications, plus the regulatory pathway given that all US 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.