Drug Database
TR

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

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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PubMedAmerican journal of ophthalmology2026-07-11

Epidemiology, Safety of Dilation, and Medication-Associated Risk of Acute Angle-Closure Crisis in the United States.

Shah Jainam J, Pathuri Sachin S, Adamovich-Zeitlin Richard R, Oseni Jessinta J et al.

To evaluate the epidemiology of acute angle-closure crisis (AACC), the safety of pharmacologic dilation, and medication-associated AACC risk in the United States. Retrospective clinical cohort study. Adults (≥18 years) in a multicenter federated electronic health record network. Using deidentified electronic medical record data from 2010 to 2025, AACC cases were identified using ICD-10-CM codes followed by definitive therapeutic intervention within 14 days. Incidence, prevalence, and diagnostic trends were evaluated with Mann-Kendall tests. Dilation-associated AACC risk was assessed among patients undergoing dilation-associated ophthalmic examinations, with incident AACC identified within 14 days (with 24-hour sensitivity analysis). Medication-associated AACC risk was evaluated using active-comparator cohorts with 1:1 propensity score matching and Cox proportional hazards models over a 30-day window. AACC incidence (per 100,000 dilation-associated examinations) and hazard ratios (HRs) with 95% confidence intervals (CIs) for medication-associated AACC risk. From 2010 to 2025, the cumulative incidence of AACC was 0.014%, and the prevalence of primary angle closure glaucoma (PACG) among patients with AACC was 16.7%. Both AACC incidence and the prevalence of PACG among patients with AACC increased over time (all P < 0.001). Gonioscopy utilization declined, whereas anterior segment imaging increased (all P < 0.001). Across 3,400,372 dilation-associated examinations among 2,444,570 patients, post-dilation AACC was rare (3.1 per 100,000; 95% CI: 2.3-3.4), with similar findings in a 24-hour sensitivity analysis; events concentrated among patients with anatomical risk factors. Increased AACC risk was observed for medications with established associations: pilocarpine (HR: 1.77), topiramate (2.07), hydrochlorothiazide (2.13), albuterol (1.57), enoxaparin (2.17), and trihexyphenidyl (2.12) (all P < 0.05). Commonly prescribed medications without established associations were also associated with increased risk: lactulose (1.67), metoclopramide (1.38), sumatriptan (1.64), prazosin (1.32), and terazosin (1.77) (all P < 0.05). Previously unreported associations were observed for calcitonin gene-related peptide (CGRP) antibodies (erenumab [HR: 1.33]), calcium channel blockers (verapamil [1.89], diltiazem [1.74]), and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (alirocumab [1.54], evolocumab [1.46]) (all P < 0.05). AACC following pharmacologic dilation was rare and occurred predominantly among patients with anatomical risk factors, supporting the safety of dilation in routine clinical care. Medication-associated risk signals were observed across commonly prescribed drugs at the population level, including previously unreported associations, highlighting the importance of proactive ocular risk assessment and medication reconciliation in anatomically predisposed patients. Novel medication associations with calcium channel blockers, CGRP monoclonal antibodies, and PCSK9 inhibitors warrant further investigation.

PMID 42431436
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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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PubMedDevelopmental medicine and child neurology2026-06-22

Intervention outcomes of children with non-degenerative dystonia and associated hyperkinetic movement disorders: A scoping review.

Gimeno Hortensia H, Scott Hannah H, Sanchez Rocio Muñoz RM, Doohan Alice A et al.

To identify the outcomes reported in published studies of intervention approaches used with non-degenerative childhood hyperkinetic movement disorders, including dystonia, dyskinesia, hypertonia, athetosis, chorea, cerebral palsy, involuntary movement, and kernicterus, and map them to the International Classification of Functioning, Disability and Health (ICF) framework. This was a scoping review that used the Arksey and O'Malley's framework. Medline, CINAHL plus, and EMBASE were searched from 2001 (when the ICF was approved for use by the World Health Assembly) to February 2025. Data were extracted and mapped to the ICF framework. A total of 294 studies included 159 surgical (e.g. deep brain stimulation, intrathecal baclofen pump), 81 pharmacological (e.g. levodopa, trihexyphenidyl, toxin injections), 51 non-pharmacological and non-surgical studies, and three studies reporting outcomes longitudinally. Neuromodulation, particularly deep brain stimulation, was reported in 122 studies. Over half of the non-pharmacological/non-surgical studies described the management of the underlying impairments. Outcomes were reported as measured objectively 650 times with 209 unique tools. The most evaluated ICF domain was body functions and structures (375 of 635, 59%), followed by activity (165 of 635, 26%), and participation (37 of 635, 5.8%). The least assessed domains were quality of life (28 of 635, 0.04%), goals (25 of 635, 0.04%), and environment (5 of 635, 0.007%). The major focus of assessment of interventions for children with non-degenerative hyperkinetic movement disorders is on body structure and function. The voices of children remain unheard across all studies, with a lack of individualized measurement. Partnering with children to understand what meaningful outcomes mean to them will go a long way to address this gap.

PMID 42324642
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