Chlorpromazine

證據等級: L5

預測適應症: 10 個

Chlorpromazine: From Schizophrenia to Retinal Dystrophy with or without Extraocular Anomalies

One-Sentence Summary

Chlorpromazine is a first-generation phenothiazine antipsychotic—the world’s first clinically used antipsychotic drug (1952)—originally developed to treat schizophrenia and other psychotic disorders through dopamine D2 receptor antagonism. The TxGNN model ranks Retinal Dystrophy with or without Extraocular Anomalies as its top predicted new indication (score: 99.95%); however, established pharmacovigilance evidence identifies this as a contraindicated direction—Chlorpromazine is itself a known cause of phenothiazine pigmentary retinopathy. Across all 10 predicted indications, only Early-Onset Schizophrenia (rank #10) carries biologically coherent mechanistic support, backed by 1 clinical trial and 8 publications.

Quick Overview

Item	Content
Original Indication	Schizophrenia and psychotic disorders (first-generation typical antipsychotic)
Predicted New Indication	Retinal Dystrophy with or without Extraocular Anomalies
TxGNN Prediction Score	99.95%
Evidence Level	L5
India Market Status	✗ Not Marketed
Number of Registrations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Detailed mechanism of action data is not available in this Evidence Pack (data gap DG002). Based on established pharmacology, Chlorpromazine exerts its primary effects through antagonism of dopamine D2 receptors in the mesolimbic and mesocortical pathways. It also has broad receptor-binding activity including α-adrenergic, histaminic H1, and muscarinic receptors, which underlies its many off-target effects.

The top predicted indication—retinal dystrophy with or without extraocular anomalies—is not only mechanistically unsupported, it is pharmacologically contradictory. Chlorpromazine is a well-documented cause of phenothiazine pigmentary retinopathy: prolonged high-dose exposure leads to melanin-binding pigment deposits in the retina, cornea, and lens, and may result in irreversible visual loss. One of the 15 retrieved literature items (PMID 5647013, Ophthalmologica, 1968) specifically documents this retinal toxicity. This represents a contraindicated direction—the drug is a pathogenic agent for this disease category, not a therapeutic one.

Among all 10 predicted indications, Early-Onset Schizophrenia (rank #10) is the only entry with a strong direct mechanistic link: Chlorpromazine’s D2 antagonism is the founding pharmacological basis for treating schizophrenia. The pediatric extension involves independent safety considerations—neurodevelopmental effects, higher extrapyramidal syndrome (EPS) susceptibility, and tardive dyskinesia risk in developing brains—but the biological rationale is fundamentally sound and evidence-supported.

Clinical Trial Evidence

Primary predicted indication (Rank #1 — Retinal Dystrophy with or without Extraocular Anomalies):

Currently no related clinical trials registered. ⚠️ Safety warning: This indication is contraindicated (see Safety Considerations).

Most Promising Repurposing Target — Early-Onset Schizophrenia (Rank #10):

Trial Number	Phase	Status	Enrollment	Key Findings
NCT06128408	N/A	Unknown	300	Longitudinal characterization of treatment-resistant schizophrenia (TRS) from illness onset; up to 30% of antipsychotic-naïve first-episode patients show poor treatment response; TRS-from-onset accounts for ~80% of all TRS patients. (Observational study; not a treatment efficacy trial.)

Literature Evidence

Primary predicted indication (Rank #1 — Retinal Dystrophy with or without Extraocular Anomalies):

PMID	Year	Type	Journal	Key Findings
5647013	1968	—	Ophthalmologica	⚠️ Inverse safety signal: Documents phenothiazine-retinopathy—retinal pigmentary damage caused by phenothiazine drugs including Chlorpromazine. Directly contradicts repurposing rationale.
38321238	2024	Review	Pediatric Radiology	Pediatric orbital lesions: congenital and developmental ocular pathologies (microphthalmos, coloboma, Coats disease); no mention of Chlorpromazine therapy.
38249493	2023	Review	Taiwan Journal of Ophthalmology	Congenital lens shape anomalies and associated anterior segment dysgenesis; structural disease focus, no pharmacological intervention discussed.
33806565	2021	—	Int J Mol Sci	Optic nerve and retinal abnormalities in congenital fibrosis of extraocular muscles (CFEOM); genetic basis (KIF21A, TUBB3).
24932988	2014	—	Am J Ophthalmology	Maculopathy pathogenesis associated with cavitary optic disc anomalies; structural treatment approach.
24413161	2014	Case Report	J Neuro-Ophthalmology	Congenital trochlear-oculomotor synkinesis in a 6-year-old; rare cranial dysinnervation disorder.
22241537	2012	Review	Klin Monatsbl Augenheilkd	Congenital ptosis from levator muscle fatty dystrophy and fibrosis; surgical management.
20127583	2010	Clinical Pearl	Seminars in Neurology	Systematic evaluation of diplopia from ocular, neurologic, and extraocular muscle etiologies.
7035111	1981	Review	Documenta Ophthalmologica	Wagner–Stickler syndrome: vitreoretinal degeneration with systemic extraocular manifestations including deafness and skeletal dysplasia.
9416661	1997	Review	Seminars in Ultrasound, CT, and MR	Orbital infections with sinusitis as primary etiology; systemic predisposing conditions including diabetes and malignancy.

Summary: None of the 15 retrieved publications support Chlorpromazine as a treatment for retinal dystrophy. The single most directly relevant paper (PMID 5647013) documents this drug class as a cause of retinal pathology.

Early-Onset Schizophrenia Literature (Rank #10 — the only viable repurposing target):

PMID	Year	Type	Journal	Key Findings
18408624	2008	Pharmacogenomic	Pharmacogenetics and Genomics	BDNF gene as schizophrenia risk factor and predictor of Chlorpromazine-induced extrapyramidal syndrome (EPS) in Chinese population; confirms direct chlorpromazine–schizophrenia pharmacological link.
17915974	2007	Pharmacogenomic	J Clinical Psychiatry	AKT1 gene polymorphisms associated with schizophrenia etiology and antipsychotic treatment response; AKT-dopamine signaling intersection.
10703271	1999	Retrospective	Social Psychiatry & Psychiatric Epidemiology	Earlier age at schizophrenia onset correlates with different neuroleptic dosage requirements; relevant to pediatric dosing calibration.
28976410	2017	Cross-sectional	Clinical Neuropharmacology	Early-onset schizophrenia with OCD comorbidity: clinical features and treatment correlates in pediatric population.
26916502	2016	Observational	Acta Neuropsychiatrica	Theory of mind deficits in adolescents with early-onset schizophrenia correlated with executive function and clinical severity.
24854724	2015	Observational	L’Encéphale	Neurological soft signs in early-onset schizophrenia as neurodevelopmental markers; relevant to monitoring antipsychotic side effects.
24289465	2013	Comparative	Psychogeriatrics	Clinical characteristics of late-onset vs. early-onset schizophrenia; supports distinct subtype characterization.
22802957	2012	Neuroimaging	PLoS ONE	Gray matter volume loss in temporal gyrus in first-episode early-onset schizophrenia; neuroanatomical baseline for treatment monitoring.

India Market Information

Chlorpromazine is currently not marketed in India. No drug licenses or registrations found in the regulatory database.

Safety Considerations

Drug Interactions: Chlorpromazine has 315 documented drug interactions (source: DDInter). Key interactions are summarized below:

Severity	Interacting Drug	Clinical Concern
Major	Bupropion	Significantly lowers seizure threshold
Major	Morphine	Additive CNS and respiratory depression
Moderate	Epinephrine	Risk of paradoxical hypotension (α-blockade reversal)
Moderate	Atropine, Hyoscyamine, Glycopyrronium	Additive anticholinergic toxicity
Moderate	Metformin, Acarbose, Alogliptin, Pioglitazone, Canagliflozin, Chlorpropamide, Albiglutide	Chlorpromazine may impair glycemic control and mask hypoglycemia; caution in diabetic patients on multiple agents
Moderate	Amphotericin B, Amphotericin B (lipid complex)	QT prolongation and electrolyte disturbance risk
Moderate	Loperamide, Bisacodyl, Famotidine, Hydrocortisone, Lorcaserin	Varied pharmacodynamic interactions

⚠️ Critical Ocular Safety Warning: Chlorpromazine is a known causative agent of phenothiazine pigmentary retinopathy with long-term or high-dose use. Pigment deposits in the retina, cornea, and lens can cause irreversible visual impairment. Any repurposing evaluation targeting ocular or retinal diseases must treat this as a fundamental biological contraindication.

Please refer to the package insert for complete warnings and contraindications (full TFDA labeling data currently unavailable — data gap DG001).

Conclusion and Next Steps

Decision: Hold

Rationale: The #1 TxGNN prediction (retinal dystrophy) is biologically contraindicated—Chlorpromazine causes retinal pigmentary degeneration, not treats it, and the retrieved literature confirms this inverse safety signal. Indications ranked #2 through #9 are all L5 evidence with no clinical trials, no relevant literature, and low mechanistic plausibility. The only viable candidate across all 10 predictions is Early-Onset Schizophrenia (rank #10), which is essentially a pediatric label extension of the drug’s established mechanism—but this requires independent pediatric safety, dosing, and neurodevelopmental evaluation before it can be advanced.

To proceed (specifically for Early-Onset Schizophrenia), the following is needed:

Retrieve complete MOA and pharmacology profile from DrugBank API (data gap DG002)
Download and parse the TFDA/India package insert for current warnings, contraindications, and approved pediatric dosing guidance (data gap DG001)
Conduct a systematic review comparing Chlorpromazine vs. atypical antipsychotics (e.g., risperidone, aripiprazole) in pediatric schizophrenia for efficacy and EPS/tardive dyskinesia risk
Evaluate neurodevelopmental long-term safety data in adolescent populations, particularly dopamine system interference during brain maturation
Assess the regulatory pathway in India for a pediatric schizophrenia indication, including whether new clinical data would be required given the drug’s off-patent status
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.