Chlorpromazine Therapy Research Articles

Chlorpromazine as Treatment for Refractory Agitation Associated with Pediatric Delirium.

Delirium and agitation can be devastating and prolong the length of hospitalization. As part of our continuous improvement efforts, we implemented the use of intermittent chlorpromazine therapy to target refractory agitation associated with hyperactive or mixed delirium (RAA-D). The purpose of this study was to evaluate the effectiveness of chlorpromazine on RAA-D and delirium symptoms as well as any adverse effects in critically ill children. Retrospective chart review was conducted for children admitted to the pediatric intensive care unit who were treated with chlorpromazine for RAA-D from March 2017 to January 2019. The primary end point was to determine differences in Cornell Assessment for Pediatric Delirium (CAPD) and State Behavioral Scale (SBS) scores 24 hours before and after chlorpromazine administration. The secondary end points were the 24-hour cumulative dosing of narcotic and sedative agents before and after chlorpromazine administration and adverse events associated with chlorpromazine use. Twenty-six patients were treated with chlorpromazine for RAA-D; 16 (61.5%) were male with a median age of 14.5 months (IQR, 6-48). The mean CAPD (n = 24) and median SBS (n = 23) scores were significantly lower 24 hours after chlorpromazine use when compared to baseline scores, 12 vs 8.9 (p = 0.0021) and 1 vs -1, (p = 0.0005) respectively. No significant adverse effects were observed. Chlorpromazine use in critically ill children with RAA-D was helpful for managing symptoms without adverse events. Further investigation is needed to evaluate the use of chlorpromazine to treat RAA-D to avoid long-term use of an antipsychotic.

Agmatine reduces chlorpromazine prooxidant effects in rat hippocampus and striatum

The use of the antidepressant drug chlorpromazine (CPZ) is linked to the occurrence of oxidative stress in some brain structures. Thus, overcoming the side effects of CPZ is of great importance. Because agmatine (AGM) can act as a free radical scavenger, it is an interesting compound as an adjunct to CPZ therapy. The aim of our study was to investigate the enzymatic parameters of oxidative stress in the hippocampus and striatum of rats after CPZ treatment, and the potential protective effects of AGM. Rats were injected as follows with (i) 1 mL/kg b.w. saline; (ii) a single intraperitoneal (i.p.) dose of CPZ (38.7 mg/kg); (iii) CPZ (38.7 mg/kg) and AGM (75 mg/kg); (iv) AGM (75 mg/kg). CPZ induced an increase in superoxide anion radical (O2 ?-) concentration, while the activities of the antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR), were lowered in both the hippocampus and striatum. Cotreatment with CPZ and AGM protected the examined brain structures by reversing the antioxidant enzyme activities to the control values. Following CPZ treatment, the effects were more pronounced for SOD and GPx in the hippocampus, and for SOD, CAT and GPx in the striatum. The full effect of restored superoxide production was achieved in the striatum, which points to the role of CAT. The obtained results suggest that CPZ in combination with AGM may be considered as a new treatment strategy.

Taurine and coenzyme Q10 synergisticallyprevent and reverse chlorpromazine-induced psycho-neuroendocrine changes and cataleptic behavior in rats.

Over the years, mounting evidences have suggested a strong association between chronic chlorpromazine therapy, a popular first-generation antipsychotic drug, and psycho-neuroendocrine changes. In this study, we aim to examine whether treatment with taurine and coenzyme Q10 (COQ-10), compounds with steroidogenic-gonadotropin hormone-enhancing properties, can attenuate the negative impacts of chlorpromazine on steroidogenic, gonadotropin, thyroid and HPA-axis hormones, dopamine levels, catalepsy behavior and neuronal cells of the hypothalamus and pituitary gland in the preventive and reversal treatments in male Wister rats. In the drug treatment alone or preventive protocol, rats received oral administration of saline (10mL/kg), taurine (150mg/kg/day), COQ-10 (10mg/kg/day), or both (taurine + COQ-10/day) alone for 56 consecutive days, or in combination with oral chlorpromazine (30mg/kg/day) treatment from days 29 to 56. In the reversal protocol, the animals received chlorpromazine or saline for 56days prior to taurine, COQ-10, or the combination from days 29 to 56. Thereafter, serum prolactin, steroidogenic (testosterone, estrogen, progesterone), gonadotropin (luteinizing hormone, LH, follicle-stimulating hormone, FSH), thyroid (thyrotropin-stimulating hormone, tetraiodothyronine, triiodothyronine) hormones, corticosterone, brain dopamine levels and cataleptic behavior were investigated. The histopathological features of the hypothalamus and pituitary gland were also evaluated. Taurine, COQ-10, or their combination prevented and reversed chlorpromazine-induced hyperprolactinemia, decrease in FSH, LH, testosterone, progesterone and dopamineconcentrations, as well as the increase in estrogen levels. Taurine and COQ-10 reduced the changes in thyroid hormones, corticosterone release, histological distortions of the hypothalamus and the pituitary gland of chlorpromazine-treated rats. Taurine and COQ-10 attenuated chlorpromazine-induced catalepsy. The study showed that taurine and COQ-10 prevented and reversed chlorpromazine-induced changes in reproductive, thyroid hormones, dopamine level, corticosterone release, neurodegenerations, and cataleptic behavior in rats.

Melanogenesis and antioxidant defense system in normal human melanocytes cultured in the presence of chlorpromazine

Chlorpromazine is used in the treatment of schizophrenia and psychotic disorders and belongs to phenothiazine class of neuroleptic drugs. It shows severe side effects such as extrapyramidal symptoms as well as ocular and skin disorders, but the mechanism is still not fully established. The aim of this study was to examine the effect of chlorpromazine on cell viability, melanogenesis and antioxidant defense system in normal human melanocytes. It has been demonstrated that chlorpromazine induces concentration-dependent loss in cell viability. The value of EC50 was calculated to be 2.53μM. Chlorpromazine in lower concentrations (0.0001, 0.001 and 0.01μM) increased the melanin and microphthalmia-associated transcription factor (MITF) content and tyrosinase activity, while changes of antioxidant enzymes activity were not observed. It suggests that long-term chlorpromazine therapy, even with low drug doses, may lead to hyperpigmentation disorders in skin and/or eye. The use of the analyzed drug in higher concentrations (0.1 and 1.0μM) caused significant alterations of antioxidant enzymes activity in normal melanocytes, what may explain a potential role of chlorpromazine in the depletion of cellular antioxidant status leading to other adverse effects associated with the high-dose and/or long-term therapy.

Salivary flow rate and decayed, missing, and filled teeth (DMFT) in female patients with schizophrenia on chlorpromazine therapy

Background/purposeThe purpose of the study was to investigate relationship between saliva flow rates, estrogen levels, and caries prevalence in female psychiatric patients under antipsychotic therapy. Materials and methodsSixty-one institutionalized psychiatric females (31 patients treated with chlorpromazine only and 30 patients treated with chlorpromazine and biperiden) were compared with 36 unmedicated healthy females. The unstimulated whole saliva (UWS) flow rate and serum estrogen were measured. Caries prevalence was recorded in terms of decayed, missing, and filled teeth (DMFT). ResultsThe UWS flow rate in the control group was 0.35 ± 0.18 mL/min and the DMFT 18.8 ± 5.7. In comparison, UWS flow rates were 0.25 ± 0.15 mL/min (P = 0.003) and 0.07 ± 0.05 mL/min (P = 0.000) in patients on chlorpromazine and patients on chlorpromazine as well as biperiden, respectively, and DMFT values were 22.7 ± 4.6 (P = 0.003) and 26.5 ± 5.3 (P = 0.000), respectively. Patients on chlorpromazine with amenorrhea had reduced UWS flow rate and estrogen levels with respect to controls (P = 0.036; P = 0.000, respectively). Correlation analysis revealed significant correlations between UWS flow rate and DT, DMFT, number of used drugs and estrogen level. ConclusionIt seems that chlorpromazine-induced hyposalivation included (apart from its antimuscarinic effect) a neuroendocrine effect which affected the estrogen levels.

Chlorpromazine-induced status epilepticus: A case report

It is largely known that some antipsychotic agents could have proconvulsive and proepileptogenic effects in some patients and could induce EEG abnormalities as well. However, the association of status epilepticus with certain antipsychotic drugs has been very rarely reported. A case of an 18-year-old adolescent girl, with chlorpromazine therapy started for anxiety-phobic disorder was reported. Her personal history disclosed delayed psychomotor development. Shortly after the introduction of the neuroleptic chlorpromazine therapy in minimal daily dose (37.5 mg), she developed myoclonic status epilepticus, confirmed by the EEG records. Frequent, symmetrical bilateral myoclonic jerks and altered behavior were associated with bilateral epileptiform discharges of polyspikes and spike-wave complexes. This epileptic event lasted 3.5 hours and it was stopped by the parenteral administration ofvalproate and lorazepam; she was EEG monitored until stable remission. Status epilepticus as initial epileptic event induced by neuroleptic agent was not previously reported in our national literature. Introduction of chlorpromazine to a patient without history of seizures is associated with the evolution of an epileptic activity, including the occurrence of status epilepticus. Clinical evaluation of the risk factors possibly related to chlorpromazine-induced seizure is recommended in individual patients before administering this drug.

Angioedema Occurring in Patient Prescribed Iloperidone and Haloperidol: A Cross-Sensitivity Reaction to Antipsychotics From Different Chemical Classes

Angioedema Occurring in Patient Prescribed Iloperidone and Haloperidol: A Cross-Sensitivity Reaction to Antipsychotics From Different Chemical Classes

Tardive Tourette-Like Syndrome in a Patient Treated With Paliperidone

Tardive Tourette-Like Syndrome in a Patient Treated With Paliperidone

Expression of Bcl2l1, Clcf1, IL-28ra and Pias1 in the mouse heart after single and repeated administration of chlorpromazine

Several chlorpromazine (CPZ)-related deaths have been suspected in forensic autopsies but these are difficult to identify precisely because only low concentrations of CPZ can usually be detected. Patients on CPZ therapy exhibit various cardiovascular diseases, such as arrhythmia and cardiomyopathy. As our previous study revealed that CPZ administration affects the expression of immediate early genes that are induced before any other genes, we expected that CPZ probably affects the heart and, in particular, the gene expression in heart. CPZ changes tumor necrosis factor (TNF) production. After stimulation of TNF, the Janus kinase signal transducer and activator of transcription (JAK-STAT) signaling pathway is activated via TNF receptor (TNF-R), and the pathway participates in the regulation of cellular responses such as apoptosis [1]. We used semi-arrays to determine the JAK-STAT signaling pathway in a mouse cardiomyocyte cell line, HL-1, and real-time quantitative-PCR to determine whether the semi-array data applied in vivo in mouse heart after single and once-daily repeated (1–4 weeks) low-dose (0.75 mg/kg) or high-dose (7.5 mg/kg) CPZ treatment. We found that expression of B cell lymphoma 2 like 1 ( Bcl2l1), Cardiotrophin-like cytokine factor 1 (Clcf1), Interleukin-28 receptor alpha ( IL-28ra) and Protein inhibitor of activated STAT-1 ( Pias1) were significantly changed in vivo. All these genes are associated with apoptosis. The expression level of Bcl2l1 was elevated after a single high-dose CPZ treatment and after 1 week of repeated high doses, but returned to baseline from week 2 to week 4. Clcf1 and IL-28ra expression increased from week 2 or 3 after low-dose CPZ treatment. Pias1 also increased from week 2 after low-dose CPZ treatment. Our results indicate that different doses of CPZ can induce distinct patterns of gene expression for preventing the apoptotic progression in mouse cardiomyocytes, suggesting that CPZ can affect cardiomyocytes via the JAK-STAT signaling pathway and that this might lead to cardiomyopathy. In addition, our data may help to clarify the pathophysiology of cardiomyopathy induced by CPZ and to diagnose cardiac sudden death following CPZ treatment.

In vivo observations of chlorpromazine ocular deposits in a patient on long‐term chlorpromazine therapy

Chlorpromazine is known to deposit in ocular tissues when taken at high doses for prolonged periods. Chlorpromazine therapy in a 59-year-old schizophrenic man with a cumulative dosage exceeding 2500 g resulted in multiple white deposits in both corneas especially in the endothelium. Confocal microscopy revealed significant pleomorphism and polymegethism of endothelial cells. The anterior lens capsules opacities were star-shaped and concentrated in the centre. Because of cataract and chronic angle closure glaucoma our high-myopic patient underwent surgery, and light microscopic evaluation of the obtained anterior lens capsule during cataract surgery showed golden brown cytoplasmic deposits in the central epithelial cells and capsule. The peripheral epithelial cells of the removed capsule had no deposit. There were no sign of retinal deposits in the fundoscopy, optical coherence tomography and fluorescein angiography. In this patient chlorpromazine deposited mainly in the corneal endothelium, central anterior lens capsule and epithelial cells.

In Vivo Observations of a Case of Chlorpromazine Deposits in the Cornea Using an HRT II Rostock Corneal Module

In vivo study of corneal deposits in a patient receiving chlorpromazine therapy was done by using a confocal microscope, the HRT II Rostock corneal module (RCM). A 23-year-old woman who had been on chlorpromazine therapy for 5 years complained of bilateral photophobia and was referred to our clinic. She had suffered from light sensitivity for 4 years. Slit-lamp microscopy revealed white deposits, particularly in the layers of the endothelium and Descemet membrane, which were concentrated in the center of both corneas. Deposition of many white granules was observed in the superficial subepithelial stroma of the cornea by HRT II RCM. Granular deposits were observed at the center of most cells in the corneal endothelium. The HRT II RCM could clearly detect deposits in the corneal endothelium, as well as in other regions such as the corneal epithelium and stroma.

Factors related to antipsychotic oversupply among central Texas Veterans

There have been many studies of underadherence to antipsychotics, but antipsychotic overadherence, or medication oversupply, in which patients receive more prescription medications than are needed, has been overlooked. Both underadherence and oversupply can have an important impact on clinical outcomes. This study examined adherence (based on the medication possession ratio [MPR]) among patients treated with antipsychotics in the Central Texas Veterans Health Care System (CTVHCS) and investigated factors associated with their adherence status. Data from September 1995 to October 2002 were extracted from the computerized patient record system of the CTVHCS for continuously enrolled adult outpatients receiving antipsychotic monotherapy and filling at least 2 prescriptions within a year of the index date. Patients' prescription records were tracked for up to 12 months. Underadherence was defined as an MPR <0.8, good adherence as an MPR from 0.8 to 1.2, and oversupply as an MPR >1.2. Of 3268 eligible patients, 49.9% had good adherence, 42.6% were underadherent, and 7.6% had medication oversupply. The overall mean (SD) MPR was 0.83 (0.33). Multinomial logistic regression analysis revealed that compared with patients with good adherence, underadherent patients were significantly more likely to be nonwhite (P < 0.001), younger (P < 0.01), and receiving chlorpromazine therapy (P < 0.05), and were less likely to be receiving fluphenazine (P < 0.01), olanzapine (P < 0.05), or risperidone (P < 0.05). Patients with medication oversupply were significantly more likely to be receiving olanzapine (P < 0.001), quetiapine (P < 0.01), or risperidone (P < 0.05) than those with good adherence. Although half of adult outpatients receiving antipsychotic monotherapy in the CTVHCS were adherent to their treatment regimens, a large proportion were underadherent, and a small proportion had medication oversupply. Patients receiving second-generation antipsychotics were more likely to be adherent and were more likely to have medication oversupply than patients receiving first-generation antipsychotics.

In vivo confocal microstructural analysis of corneal endothelial changes in a patient on long-term chlorpromazine therapy

Deposits in the cornea and lens are a known complication of long-term chlorpromazine therapy. A 59-year-old woman had previously taken chlorpromazine for 20 years with doses up to 1,200 mg/day, with a mean dose of 400 mg/day. She presented with gradual onset of blurred vision in her left eye. Slit-lamp biomicroscopy revealed multiple fine creamy-white deposits on her corneal endothelium and anterior crystalline lens capsule bilaterally. In vivo confocal microscopy of the cornea identified irregular hyper-reflective deposits on the posterior surface of the endothelium. The deposits varied from 1 microm to 70 microm in diameter and had well-defined edges. Endothelial morphology was otherwise normal bilaterally. This is the first report of in vivo confocal imaging of deposits resulting from long-term chlorpromazine use. Microstructural analysis of the corneal endothelium reveals that there were no abnormalities in cellular morphology resulting from these deposits.

Chlorpromazine-Induced Lupus with Cardiac Tamponade

Although the association of the phenothiazines with immunologic abnormalities is well known, reports of clinical lupus erythematosus are rare. We describe a 52-year old schizophrenic man on chronic chlorpromazine therapy who developed fever and pleuropericarditis with cardiac tamponade. Examination of the pleural and pericardial fluids showed anti-nuclear antibodies. The clinical syndrome responded to a short course of steroids and discontinuation of the chlorpromazine. Drug-induced lupus is a self-limited illness that resolves without long-term sequelae. However, patients should be observed carefully because cardiac tamponade may occur.

Chlorpromazine-induced vanishing bile duct syndrome leading to biliary cirrhosis

We describe a 33-yr-old pregnant woman in whom a primary biliary cirrhosis-like syndrome developed after 2 wk of chlorpromazine therapy. The clinical course was characterized by severe jaundice lasting 22 mo, intense pruritus, fever, steatorrhea, high alkaline phosphatase levels and hypercholesterolemia. Jaundice resolved with initiation of ursodeoxycholic acid therapy, but subclinical cholestasis and low-level inflammatory activity persisted and ultimately evolved into biliary cirrhosis. The pathological substrate of this severe and prolonged cholestatic reaction was found to be the vanishing bile duct syndrome with a marked transient pseudoxanthomatosis.

Cutaneous and ocular side effects with chlorpromazine therapy

Cutaneous and ocular side effects with chlorpromazine therapy

Mouse Strain Sensitivity to Chlorpromazine and Amantadine Interaction

Amantadine, a dopaminergic agonist, has been used in the management of neurolepticinduced dyskinesia and in Tourette’s syndrome. Genetic predisposition has been implicated in both of these movement disorders with a possible underlying abnormality in cerebral biogenic amine function. The effect of repeated administration of amantadine prior to chlorpromazine therapy on motor activity, whole brain dopamine, 5-hydroxytryptamine (5-HT, serotonin) and some major metabolites was studied as a function of mouse strain. Chlorpromazine-enhanced amantadine therapy produced increases in motor activity in outbred albino ICR mice but not in inbred BALB/c mice. Combined drug treatment prevented chlorpromazine-mediated reduction of brain dopamine, suggesting that amantadine antagonises this effect. Amantadine counteracted chlorpromazine-induced increases of BALB/c but not ICR mouse brain 5-hydroxyindoleacetic acid. This interaction may be useful in investigating the suggested imbalance between catecholamine and indoleamine systems implicated in drug-induced tremors and extrapyramidal disorders. The results suggest a genotypic-dependent amantadine-chlorpromazine interaction involving motor function and brain monoamines that may underlie individual susceptibility to the development of neuroleptic-induced dyskinesia and/or the variable responses to amantadine therapy in patients with tardive dyskinesia or Tourette’s syndrome.

Chlorpromazine-Induced Immunopathy: Progressive Increase in Serum IgM

Long-term chlorpromazine therapy has been associated with the asymptomatic development of a high incidence of antinuclear antibodies, coagulation inhibitors, and increased serum levels of IgM. The purpose of this study has been to characterize the natural history of this chlorpromazine-induced (CPZ) immunopathy. To this end we carried out a prospective study of schizophrenic patients with the immunopathy to compare the effect of continuing CPZ versus switching to haloperidol therapy. Although no marked differences were noted between the 2 groups at the end of 5 years, 6 of 29 patients who continued to receive CPZ, as compared to none of 14 patients on haloperidol, had progressive elevations of serum IgM. In spite of a high incidence of antinuclear antibodies, none of the patients developed a lupus-like syndrome. One patient, however, who had been maintained on CPZ for more than 15 years, developed Waldenström macroglobulinemia, as characterized by an IgM monoclonal gammopathy and a lymphocyte immunoglobulin heavy and kappa light chain gene rearrangement. Another CPZ-treated patient developed immune thrombocytopenia. Based on the potential serious sequelae of prolonged stimulation of the immune system by CPZ, we recommend that patients who develop an increase in serum IgM while on CPZ be switched to other types of anti-psychotic medications.

Microprobe analysis of inclusion bodies related to two benzofuran derivatives

Two benzofuran derivatives, chlorpromazine and amiodarone, are known to produce inclusion bodies in human tissues. Prolonged high dose chlorpromazine therapy causes hyperpigmentation of the skin with electron-dense inclusion bodies present in dermal histiocytes and endothelial cells ultrastructurally. The nature of the deposits is not known although a drug-melanin complex has been hypothesized. Amiodarone may also cause cutaneous hyperpigmentation and lamellar lysosomal inclusion bodies have been demonstrated within the cells of multiple organ systems. These lamellar bodies are believed to be the product of an amiodarone-induced phospholipid storage disorder. We performed transmission electron microscopy (TEM) and energy dispersive x-ray microanalysis (EDXA) on tissue samples from patients treated with these drugs, attempting to detect the sulfur atom of chlorpromazine and the iodine atom of amiodarone within their respective inclusion bodies.A skin biopsy from a patient with hyperpigmentation due to prolonged chlorpromazine therapy was fixed in 4% glutaraldehyde and processed without osmium tetroxide or en bloc uranyl acetate for Epon embedding.

The negative symptoms of schizophrenia and the monoamine oxidase inhibitors.

Thirty chronic ambulatory schizophrenic patients whose main psychopathology was characterized by the persistence of negative symptoms, such as emotional withdrawal, depressed mood, motor retardation and blunted affect were included in this project in order to evaluate the therapeutic efficacy of tranylcypromine plus chlorpromazine therapy. The results show that tranylcypromine when added to the usual dose of chlorpromazine, in many instances, induces a definite improvement in these patients' clinical condition, that such treatment is safe and it may be also useful in preventing the occurrence of extra-pyramidal symptoms.