Selegiline
| Evidence Level: L3 | Predicted Indications: 10 |
Table of Contents
Selegiline: From Parkinson's Disease to Schizophrenia
One-Sentence Summary
Selegiline is an MAO-B inhibitor originally used for Parkinson's disease and also associated with depression and anxiety disorders in the knowledge graph. The TxGNN model predicts it may be effective for schizophrenia (the highest-ranked prediction with actual supporting studies; the top-scored prediction, a rare brain malformation, has no supporting evidence), with 1 clinical trial and 20 publications currently supporting this direction.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Parkinson's disease (the Singapore licence has no indication text recorded; original indications come from the knowledge graph) |
| Predicted New Indication | Schizophrenia (selected over the rank-1 prediction, polymicrogyria with cerebellar hypoplasia and arthrogryposis, which has no trials or literature) |
| TxGNN Prediction Score | 99.14% |
| Evidence Level | L3 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 1 |
| Recommended Decision | Hold (research question; see Conclusion) |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the compiled data. Based on known information, selegiline is an irreversible, selective MAO-B inhibitor. At oral doses of 20 mg/day or more it also inhibits MAO-A. By slowing the breakdown of dopamine, it raises dopaminergic tone, which explains its use in Parkinson's disease.
Negative and cognitive symptoms of schizophrenia are linked to low dopamine activity in the prefrontal cortex. Antipsychotics treat positive symptoms well but have limited effect on negative symptoms. Adding a dopamine-enhancing drug alongside the antipsychotic is therefore mechanistically plausible. Selegiline may also have antioxidant effects, which relate to the oxidative-stress hypothesis of schizophrenia.
This remains a hypothesis. The only registered trial is small and early-phase, and the published studies are small with mixed results. It is worth noting that the other top-ranked predictions (rare developmental, metabolic, retinal and myopia conditions) have no plausible MAO-B-related mechanism.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00456976 | Early Phase 1 | Completed | 70 | Randomized, placebo-controlled trial of selegiline added to antipsychotics for negative symptoms in inpatients with chronic schizophrenia (2007). No results were provided, so the outcome cannot be assessed. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 37087864 | 2023 | Systematic review/Meta-analysis | Eur Neuropsychopharmacol | Appraises oral and transdermal selegiline across psychiatric disorders; the abstract provided does not include the findings |
| 17405823 | 2007 | Review | Ann Pharmacother | Reviews the role of selegiline in negative symptoms of schizophrenia |
| 15677608 | 2005 | Double-blind RCT | Am J Psychiatry | Multicenter placebo-controlled test of selegiline added to antipsychotics in outpatients with moderate or worse negative symptoms |
| 17972359 | 2008 | Double-blind RCT | Hum Psychopharmacol | 8-week trial of selegiline added to risperidone for negative symptoms; the abstract notes earlier results were contradictory |
| 10587287 | 1999 | Double-blind controlled study | J Clin Psychopharmacol | Deprenyl (selegiline) augmentation in 16 patients with predominantly negative symptoms |
| 8627275 | 1996 | Open-label pilot | J Nerv Ment Dis | Low-dose selegiline (5 mg twice daily) added to antipsychotics in 21 patients with schizophrenia or schizoaffective disorder |
| 8102552 | 1993 | Placebo-controlled RCT | Biol Psychiatry | Selegiline 10 mg/day vs placebo for tardive dyskinesia in 33 patients |
| 26848926 | 2016 | Systematic review | Cochrane Database Syst Rev | Antioxidant treatments for schizophrenia, in the context of oxidative stress |
| 29552749 | 2018 | Systematic review | Cochrane Database Syst Rev | Miscellaneous treatments for antipsychotic-induced tardive dyskinesia |
| 16930948 | 2006 | Systematic review | Schizophr Res | Pharmacological treatment of primary negative symptoms in schizophrenia |
Several other retrieved papers concern antipsychotic-induced sexual dysfunction and other side topics and are not listed here.
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN08681P | SELEGOS TABLET 5 mg (Medochemie Ltd) | Tablet | Not recorded in the compiled data |
Safety Considerations
- Contraindications flagged in the knowledge graph (these come from drug–disease links, not label text): multiple system atrophy, orthostatic hypotension, postural orthostatic tachycardia syndrome, kidney disease, liver disease, gallbladder disease, bipolar disorder, major affective disorder, psychotic disorders (including schizophreniform and schizoaffective disorder, and mental disorder in general), melanoma, sudden cardiac arrest, heart conduction disease, pheochromocytoma and paraganglioma, several cancers (duodenum, small intestine, heart, adrenal gland), and tardive dyskinesia.
- Of particular note for this prediction, psychotic and schizoaffective disorders appear on this list, which needs careful reconciliation with the proposed use.
- Drug Interactions: 100 interactions were identified, so the full list needs review. Examples of major-level interactions include bupropion, isometheptene, diethylpropion, phentermine and dexfenfluramine. Moderate-level interactions include epinephrine, metoclopramide, and many antidiabetic agents (various insulins, glimepiride, repaglinide, nateglinide, chlorpropamide, acetohexamide). Serotonergic agents and sympathomimetics deserve particular attention, as does the patient's own antipsychotic and any antidepressants.
Please refer to the package insert for label warnings; they were not available in the compiled data.
Conclusion and Next Steps
Decision: Hold
Rationale: Schizophrenia is the only predicted indication with a plausible mechanism and real studies, but the evidence is L3: one small early-phase trial without reported results, and older small studies with mixed findings. The knowledge graph also lists psychotic disorders as a contraindication, and the interaction burden is large. The other nine predictions, including the top-scored one, have no supporting trials or literature, so they remain at Hold with only model-prediction support.
To proceed, the following is needed:
- Read and appraise the full results of the randomized trials and the 2023 meta-analysis for negative-symptom outcomes
- Obtain the HSA package insert to confirm warnings, contraindications and the approved indication
- Obtain detailed mechanism of action data
- Resolve the psychotic-disorder contraindication flag and define an interaction-management plan for patients on antipsychotics and antidepressants
- If the evidence supports it, design a confirmatory Phase 2/3 trial of low-dose adjunctive selegiline for negative symptoms
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.