Selegiline
| 證據等級: L5 | 預測適應症: 4 個 |
目錄
Selegiline: From Parkinson’s Disease to Schizophrenia (Negative Symptoms)
One-Sentence Summary
Selegiline is a selective, irreversible monoamine oxidase type-B (MAO-B) inhibitor originally used for Parkinson’s disease (oral) and major depressive disorder (transdermal). The TxGNN model predicts it may be useful as an augmentation therapy for negative symptoms of schizophrenia, with 1 registered clinical trial and 20 publications — including several double-blind, placebo-controlled RCTs — supporting this direction. Three other TxGNN-predicted indications (a rare cerebral malformation syndrome, a congenital glycosylation disorder, and a retinal dystrophy syndrome) show no mechanistic plausibility or supporting evidence and are assessed as likely knowledge-graph artifacts — they are not carried forward in this report.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Parkinson’s Disease (oral); Major Depressive Disorder (transdermal) — per literature (PMID 37087864); no formal Taiwan license record available |
| Predicted New Indication | Schizophrenia (negative symptoms, adjunct to antipsychotics) |
| TxGNN Prediction Score | 99.14% |
| Evidence Level | L3 (multiple published RCTs and a systematic review/meta-analysis; no confirmed completed Phase 2/3 registry trial) |
| US Market Status | Not Marketed |
| Number of NDAs | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed structured mechanism-of-action data is not available for this drug in the evidence pack. Based on the literature evidence collected, selegiline is an irreversible, selective MAO-B inhibitor approved for Parkinson’s disease (oral formulation) and major depressive disorder (transdermal formulation); at oral doses ≥20 mg/day it loses MAO-B selectivity and behaves as a non-selective MAOI (PMID 37087864).
The dopaminergic hypothesis links selegiline’s mechanism to schizophrenia’s negative symptoms: negative symptoms have long been hypothesized to reflect regionally deficient CNS dopaminergic activity (PMID 8627275), and MAO-B inhibition increases synaptic dopamine availability. This provides a plausible pharmacological rationale for using low-dose selegiline as an adjunct to antipsychotic therapy specifically to target negative symptoms — a treatment gap that standard antipsychotics do not adequately address.
By contrast, the three other TxGNN top predictions (polymicrogyria with cerebellar hypoplasia, a congenital disorder of glycosylation, and a retinal dystrophy syndrome) are rare monogenic structural/metabolic disorders with no known relationship to monoaminergic or dopaminergic pathways. The retrieved “literature” for these diseases consists of unrelated ophthalmology/neuroanatomy papers matched only by disease-name keywords, not drug-disease evidence. These are assessed as likely false positives arising from sparse nodes in the knowledge graph and are excluded from further evaluation.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00456976 | Early Phase 1 | Completed | 70 | RCT evaluating selegiline augmentation of antipsychotic medication for negative symptoms in chronic inpatient schizophrenia; primary endpoint was reduction in negative symptoms vs placebo. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 15677608 | 2005 | RCT | Am J Psychiatry | Double-blind, placebo-controlled, multicenter trial of selegiline augmentation in outpatients with schizophrenia and moderate-or-greater negative symptoms. |
| 17972359 | 2008 | RCT | Hum Psychopharmacol | 8-week double-blind RCT of selegiline add-on to risperidone for negative symptoms of chronic schizophrenia. |
| 8102552 | 1993 | RCT | Biol Psychiatry | Placebo-controlled trial of selegiline (10 mg/day) for neuroleptic-induced tardive dyskinesia; also assessed parkinsonism, akathisia, and negative symptoms. |
| 37087864 | 2023 | Systematic Review/Meta-analysis | Eur Neuropsychopharmacol | Systematic review and meta-analysis of efficacy/safety of selegiline (oral and transdermal) across psychiatric disorders. |
| 17405823 | 2007 | Review | Ann Pharmacother | Reviews the role of selegiline specifically in treating negative symptoms of schizophrenia. |
| 16930948 | 2006 | Systematic Review | Schizophr Res | Systematic review of pharmacological treatments (including selegiline) for primary negative symptoms in schizophrenia. |
| 8627275 | 1996 | Open-label pilot study | J Nerv Ment Dis | Pilot study testing the dopamine-deficiency hypothesis of negative symptoms using low-dose selegiline augmentation. |
| 10080262 | 1999 | Case series | Compr Psychiatry | Case series of 3 schizophrenia patients showing improvement in negative symptoms and functioning after adding selegiline. |
| 7831475 | 1994 | Mechanism review | Prog Neurobiol | Reviews possible mechanisms of action of deprenyl (selegiline) and other MAO-B inhibitors in neurologic/psychiatric disorders. |
| 8988464 | 1996 | Review | J Neural Transm Suppl | Reviews clinical potential of deprenyl across neurologic and psychiatric disorders beyond Parkinson’s disease. |
Market Information (Taiwan)
No Taiwan marketing authorization records are available for selegiline in this evidence pack — market status is recorded as Not Marketed, with 0 licenses on file.
Safety Considerations
Please refer to the package insert for safety information. Key warnings, contraindications, and drug interaction data are not currently available in this evidence pack (a Blocking data gap — TFDA label/warning data is required before this candidate can proceed to safety pre-assessment, given selegiline’s known MAOI-related interaction risks, e.g., serotonergic drugs and dietary tyramine, which are not yet documented here).
Conclusion and Next Steps
Decision: Hold
Rationale:
- Mechanistic rationale and multiple published double-blind RCTs support selegiline augmentation for negative symptoms of schizophrenia, but no completed Phase 2/3 registry trial confirms efficacy, and results across existing small trials have been mixed.
- A Blocking data gap (missing TFDA label warnings/contraindications) prevents safety pre-assessment (S1), and the drug currently has zero market authorizations in this jurisdiction.
To proceed, the following is needed:
- TFDA label / package insert data (warnings, contraindications, DDI) — required to clear the Blocking gap (DG001)
- Structured mechanism-of-action data from DrugBank (DG002)
- A confirmatory Phase 2/3 RCT specifically powered for negative-symptom endpoints, given the existing trials are small, heterogeneous, and largely from the 1990s–2000s
- Formal review of the 2023 systematic review/meta-analysis (PMID 37087864) to consolidate pooled efficacy/safety estimates before further investment
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.