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trifluoperazine + trihexyphenidyl (Fluhex forte / Fluhex / Fluhexette)

✓ Approved

A. N. Pharmacia Laboratories · CHRM1 · Small Molecule

What is trifluoperazine + trihexyphenidyl?

trifluoperazine + trihexyphenidyl is a small molecule developed by A. N. Pharmacia Laboratories. It is approved for therapeutic indications via oral (po).

Drug Profile

Brand NamesFluhex forte, Fluhex, Fluhexette
CompanyA. N. Pharmacia Laboratories
Drug ClassSmall Molecule
Molecular TargetCHRM1
RouteOral (PO)
StatusApproved
Sources: ClinicalTrials.gov, A. N. Pharmacia Laboratories

Mechanism of Action

Molecular Targets

trifluoperazine + trihexyphenidyl acts on 1 molecular target:

CHRM1cholinergic receptor muscarinic 1 (M1, HM1)
Want deeper analysis?Noah AI can explain complex mechanisms and compare to similar drugs.

Therapeutic Indications

trifluoperazine + trihexyphenidyl is developed for 1 unique indication across 1 therapeutic area.

Therapeutic AreaConditionPhase
Psychiatric disordersSubstance-induced psychotic disorder✓ Approved

Related Research Articles

PubMedBiochimica et biophysica acta. Biomembranes2026-07-24

Molecular dynamics perspectives on annexin-mediated plasma membrane repair: From recruitment to membrane mechanics.

Hakami Zanjani Ali Asghar AA

This mini-review examines how molecular dynamics simulations reshape the view of annexin-mediated plasma membrane repair from simple recruitment to coupled protein-membrane states. Molecular dynamics simulations show that annexin-induced curvature is shaped by oligomerization, cholesterol, and anionic lipid chemistry, while engineering normally non-trimerizing annexin A3 into a trimer-forming state demonstrates that curvature generation alone does not ensure repair competence. Membrane-active perturbants such as trifluoperazine further suppress repair by altering bilayer thickness, lipid packing, phosphatidylserine mobility, and annexin binding. These findings shift the question from whether annexins arrive to how protein-membrane states generate repair-relevant remodeling.

PMID 42492800
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PubMedAntimicrobial agents and chemotherapy2026-07-23

Trifluoperazine exhibits broad-spectrum antiviral activity against arboviruses.

Mishra Laxmi L, Kalia Manjula M

The recurrent outbreaks and geographical expansion of mosquito-borne arboviruses pose a significant challenge to public health worldwide. The disease outcome for arboviral infections ranges from acute febrile illness to severe conditions such as encephalitis, hemorrhagic shock, and mortality. Current treatment options for these viruses are limited to supportive care, necessitating an urgent need for a safe and effective broad-spectrum antiviral. In this study, we have identified trifluoperazine (TFP), an FDA-approved antipsychotic, as a potent broad-spectrum antiviral against Japanese encephalitis virus (JEV), Dengue virus (DENV), and Chikungunya virus (CHIKV) infections. The antiviral effect of TFP was also seen in the animal models of JEV and CHIKV with significantly reduced disease severity. Mechanistically, TFP treatment increased the phosphorylation of eIF2a and induced an adaptive ER stress response in diverse cell types. Alleviation of TFP-induced ER stress by chemical chaperone 4PBA abolished the antiviral activity of the drug and rescued virus replication in cells and CHIKV mice model. The robust in vitro and in vivo efficacy of the drug against arboviruses highlights the potential for repurposing TFP as a broad-spectrum antiviral candidate and underscores the importance of ER stress as a therapeutic target.

PMID 42489647
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PubMedCureus2026-07-17

Multi-ancestry Transcriptome-Wide Association Study (TWAS)-Informed Prioritization of Antipsychotic Metabolic Risk: Evaluation of GLP1R as a Shared Mechanistic Link.

Cheung Ngo N

Antipsychotic-associated metabolic toxicity remains one of the most persistent clinical problems in psychopharmacology. Clozapine and olanzapine are especially effective for psychosis but carry high liability for weight gain, dyslipidemia, insulin resistance, and type 2 diabetes. Current monitoring recommendations recognize this risk, yet they remain largely uniform across patients and do not incorporate ancestry-specific genetic risk or mechanistic drug-gene information. We performed a transcriptome-wide association study-informed drug-gene prioritization analysis to examine whether approved antipsychotic target genes overlap with genes whose genetically predicted expression is associated with type 2 diabetes. The analysis used ancestry-specific type 2 diabetes transcriptome-wide association study (TWAS) results derived from a multi-ancestry genome-wide association study (GWAS) and approved antipsychotic drug-gene interactions from the Drug-Gene Interaction Database (DGIdb). For each drug, target genes were matched to TWAS genes across six metabolic tissues, and a weighted risk score was calculated as the sum of the absolute TWAS z-score multiplied by the drug-gene interaction score for significant targets. Follow-up analyses decomposed signals into targets with positive and negative TWAS directions, operationally interpreted as aggravating and compensatory, while also examining curated metabolic axis genes including GLP1R, GIPR, PPARG, and SLC2A4. The analysis identified recurrent exploratory target-overlap signals for clozapine and olanzapine. Clozapine showed the most consistent cross-ancestry aggravating profile, with recurrent target overlap involving GLP1R and immune-related genes. Olanzapine showed strong mechanistic-axis overlap involving GLP1R, GIPR, and PPARG, although its simple TWAS directionality was often classified as compensatory. Trifluoperazine emerged as a notable candidate, with significant target enrichment in the European ancestry analysis and top ranking in the Hispanic analysis. Fluspirilene also met the combined enrichment false discovery rate threshold in the European ancestry analysis, although its clinical metabolic interpretation was less direct. Haloperidol decanoate showed a high burden driven partly by SLC2A4, but its directionality was frequently mixed or compensatory. These findings nominate the incretin axis as a plausible translational bridge between antipsychotic metabolic liability and existing interventions such as GLP-1 receptor agonists. They also identify a key methodological gap. Future models must incorporate the pharmacologic mode of action to distinguish receptor blockade from activation. Except for the enrichment-positive European ancestry findings for trifluoperazine and fluspirilene, the results are exploratory prioritization signals and do not establish drug-specific metabolic effects, causal mechanisms, or ancestry-specific treatment effects. Overall, this TWAS-informed analysis provides a hypothesis-generating framework for ancestry-aware metabolic monitoring and targeted validation studies.

PMID 42465707
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PubMedJournal of medical case reports2026-07-12

Medicolegal autopsy reconstruction of a medication-related adverse event trajectory in a psychiatric inpatient with diabetes: a case report.

Tsutsumi Hiroshi H, Sasao Ako A, Hirata Kyoko K, Hiraiwa Ryota R et al.

Adverse drug events are common in psychiatric inpatient care because polypharmacy is frequent and metabolic comorbidities such as diabetes mellitus are prevalent. When nonspecific symptoms and reduced food intake are not promptly managed, clinically significant metabolic deterioration may be missed. We report a medicolegal autopsy case in which a review of nursing records, a postmortem investigation, and toxicology helped reconstruct a medication-related adverse event trajectory in a psychiatric inpatient with diabetes. A 47-year-old Japanese woman of Asian ethnicity with bipolar disorder, insomnia, and a 12-year history of type 2 diabetes mellitus was hospitalized in a psychiatric ward where medications were centrally managed. No blood tests were performed during hospitalization. From 8 days before death, nursing records documented frequent nonspecific symptoms and recurrent hypoglycemia. Her oral intake decreased from the evening of 2 days before death and became minimal after breakfast 1 day before death. She was found unresponsive and was pronounced dead, and the cause of death could not be determined clinically, including after postmortem computed tomography at another hospital. A medicolegal autopsy showed food material in the airway and bronchioles, with congested and edematous lungs, suggesting aspiration-related asphyxia. A femoral venous blood sample showed a metformin concentration of 46 mg/L and trihexyphenidyl concentration of 0.45 mg/L. The vitreous glucose concentration was markedly low at 0.33 mmol/L (6 mg/dL) in the left eye and 0.39 mmol/L (7 mg/dL) in the right eye. These findings suggested a complex medication-related adverse event trajectory involving reduced food intake, recurrent hypoglycemia, ongoing antidiabetic therapy, and possible contribution of metformin exposure before terminal aspiration-related death. This case illustrates that clinically important metabolic deterioration may be overlooked in psychiatric inpatients when nonspecific symptoms and reduced food intake are not promptly managed. Our findings suggest that a medicolegal autopsy and postmortem toxicology can help reconstruct clinically relevant adverse event pathways when an inpatient death remains unexplained.

PMID 42436565
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PubMedFrontiers in immunology2026-07-08

Astrocyte-derived HMGB1 compromises the integrity of the blood-brain barrier through the CaM/CaMKII/AQP4 pathway and the protective function of trifluoperazine.

Zou Song-Song SS, Chen Li-Li LL, Cui Min M

The integrity of the blood-brain barrier (BBB) is crucial for maintaining the function and homeostasis of the central nervous system (CNS), with astrocytes playing a key role in this process. Our study found that infection with the Japanese encephalitis virus (JEV) promoted the translocation of high-mobility group box 1 (HMGB1) from the nucleus to the extracellular space of astrocytes, a process directly associated with BBB disruption. Through bioinformatics analysis, we identified potential targets of encephalitis and constructed a protein-protein interaction (PPI) network. Subsequent functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, highlighted the calcium signaling pathway as an important regulatory mechanism. Evidence from our in vitro and in vivo model experiments showed that HMGB1 can induce the increase of calcium ions (Ca²+) in astrocytes, thereby activating the calcium signaling pathway and promoting the translocation of aquaporin-4 (AQP4) to the plasma membrane, ultimately leading to BBB disruption. We also performed molecular docking and molecular dynamics simulations to determine the binding affinity between trifluoperazine (TFP) and calmodulin (CaM). TFP binds to CaM and blocks the translocation of AQP4 to the plasma membrane, thereby alleviating HMGB1-mediated BBB disruption. Overall, our data indicate that TFP protects BBB integrity through the CaM-CaMKII-AQP4 axis and identifies this pathway as a promising therapeutic target for the clinical treatment of Japanese encephalitis and other central nervous system diseases.

PMID 42416052
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PubMedJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism2026-06-24

Trifluoperazine reduces infarct size, restores neurovascular coupling, and improves early outcomes in experimental acute ischemic stroke.

Tóth Réka R, Törteli Anna A, Szabó Melinda M, Kovács Noémi N et al.

Cerebral edema and neurovascular dysfunction are reliable predictors of outcome after acute ischemic stroke (AIS), yet effective targeted therapies remain limited. We investigated the therapeutic potential of trifluoperazine (TFP), an FDA-approved antipsychotic and calmodulin inhibitor that modulates astrocytic aquaporin-4 expression. TFP administered after recanalization in a mouse model of AIS reduced infarct volume and improved early neurological recovery. Importantly, TFP restored neurovascular coupling and enhanced cerebral blood flow responses to spreading depolarizations, indicating improved cerebrovascular function. Mechanistic studies in acute brain slice preparations demonstrated that TFP attenuates cytotoxic tissue swelling, suppresses spreading depolarizations, reduces aquaporin-4 expression and preserves neuronal integrity under osmotic stress. These findings suggest that transient modulation of astrocytic cytotoxic edema and vascular reactivity represents a viable strategy to improve early stroke outcomes. Given its established clinical use, TFP emerges as a promising candidate for therapeutic repurposing in AIS.

PMID 42339851
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