Perphenazine
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
- Perphenazine
- Perphenazine: From Schizophrenia to Retinal Dystrophy (with or without Extraocular Anomalies)
Perphenazine: From Schizophrenia to Retinal Dystrophy (with or without Extraocular Anomalies)
One-Sentence Summary
Perphenazine is a phenothiazine antipsychotic, originally used for schizophrenia and mixed anxiety and depressive disorder. The TxGNN model predicts it may be effective for retinal dystrophy with or without extraocular anomalies, but there are 0 clinical trials and only 1 publication (a 1964 case report of drug-induced retinal toxicity from a related drug), so the evidence does not support this prediction.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Schizophrenia; mixed anxiety and depressive disorder (the local licence records carry no indication text, so this comes from the knowledge graph) |
| Predicted New Indication | Retinal dystrophy with or without extraocular anomalies |
| TxGNN Prediction Score | 99.96% |
| Evidence Level | L5 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 2 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available. Perphenazine is a phenothiazine antipsychotic that is generally understood to act mainly as a dopamine D2 receptor antagonist. Its efficacy in schizophrenia is established.
No credible mechanistic link to retinal dystrophy was identified. The only literature item is a 1964 case report of pigmentary retinopathy caused by thioridazine, a related phenothiazine. That report describes drug-induced retinal toxicity, not therapeutic benefit. If anything, it is a safety signal against using this drug class in retinal disease. The very high TxGNN score is most likely an artifact of the knowledge graph rather than a true biological signal.
A more plausible lower-ranked prediction: Among the other predictions, anxiety disorder (score 99.53%, evidence level L3) is biologically plausible. Perphenazine combined with amitriptyline has historically been used for mixed anxiety and depression, and reviews note some efficacy of typical antipsychotics on anxiety symptoms. However, benefit is confounded by the antidepressant combination, and sedation and extrapyramidal effects limit use. Because it overlaps with the existing mixed anxiety/depression indication, it is closer to a label extension than a true repurposing.
Clinical Trial Evidence
Currently no related clinical trials registered.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 14129300 | 1964 | Case report | The American Journal of Psychiatry | Pigmentary retinopathy associated with thioridazine (a related phenothiazine) at a maximum daily dose of 1400 mg. This is a toxicity report, not evidence of benefit. |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form |
|---|---|---|
| SIN00437P | APO-PERPHENAZINE TABLET 8 mg (Apotex Inc) | Film-coated tablet |
| SIN00444P | APO-PERPHENAZINE TABLET 4 mg (Apotex Inc) | Film-coated tablet |
Both licences are valid single-ingredient oral products. Approved indication text is not recorded for either.
Safety Considerations
- Contraindications suggested by the knowledge graph (not from label text):
- Cardiovascular and QT: long QT syndrome (including familial), torsades de pointes, sudden cardiac arrest, myocardial infarction, coronary thrombosis, orthostatic hypotension, postural orthostatic tachycardia syndrome, multiple system atrophy.
- Neurological: epilepsy, basal ganglia disease, focal hand dystonia, blepharospasm.
- Psychiatric: manic bipolar affective disorder, substance abuse/dependence.
- Haematological: neutropenia, agranulocytosis, thrombocytopenia, anaemia (including macrocytic), hemoglobinopathy.
- Metabolic and other: hyperglycaemia, obesity disorders, liver disease, gallbladder disease, open-angle glaucoma, benign prostatic hyperplasia, female breast carcinoma.
- Drug Interactions: 100 interaction records were identified. The Major ones in the listed subset are bupropion, morphine and potassium citrate. Many Moderate interactions were also listed, including:
- Antidiabetic agents: acarbose, metformin, pioglitazone, alogliptin, canagliflozin, chlorpropamide, albiglutide.
- Anticholinergic agents: atropine, hyoscyamine, glycopyrronium.
- Others: epinephrine, famotidine, clarithromycin, loperamide, lorcaserin, bisacodyl, picosulfuric acid.
- Retinal safety: The only retrieved publication on this indication reports retinal toxicity from a related phenothiazine, which is directly relevant to the proposed use.
Please also refer to the package insert for full safety information, as label warnings and contraindications were not available for this report.
Conclusion and Next Steps
Decision: Hold
Rationale: The prediction rests only on a model score. There are no clinical trials, and the sole publication describes retinal toxicity from a related drug rather than benefit. No plausible mechanism supports use in retinal dystrophy, and the available data point toward a safety concern.
To proceed, the following is needed:
- Detailed mechanism of action data, and any preclinical rationale linking perphenazine to retinal pathology
- Package insert warnings and contraindications from the Singapore regulator (HSA)
- Review of phenothiazine-associated retinopathy risk before any ocular indication is considered
- Consideration of redirecting effort to the lower-ranked anxiety disorder prediction, which has more supporting literature and overlaps with the existing label
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.