Haloperidol Levels Research Articles

Antipsychotic prescribing practices in real-life (APPREAL study): Findings from the French National Healthcare System Database (2007-2017).

Antipsychotics are used in a large variety of psychiatric and neurological disorders; investigating their use in real life is important to understand national prescribing practices, as well as to determine the levels of patient adherence. Using a 1/97e random sample (General Sample of Beneficiaries, EGB) of the French health insurance reimbursement database, we conducted a historical cohort study on the 2007-2017 period. The aim was to describe the sociodemographic characteristics of patients, the types of antipsychotics dispensed, the types of prescribers, the mean doses and average durations of treatment, the co-dispensed medications, and the levels of adherence to treatment. To exclude punctual uses of antipsychotics, we selected only patients with a continuous dispensing of the same antipsychotic over at least 3 months. In total, 13,799 subjects (1.66% of the EGB sample) were included (56.0% females; mean age 55.8 ± 19.4 years). Risperidone (19.3%), cyamemazine (18.7%), olanzapine (11.9%), tiapride (8.8%), and haloperidol (7.5%) were the five most prescribed antipsychotics. 44.9% of prescriptions were written by general practitioners, 34.1% by hospital practitioners, and 18.4% by private-practice psychiatrists. On average, the mean dispensed doses were relatively low, but the variation range was large. Long-acting forms were used in 5.4% of the sample, and clozapine in 1.3%. 34.2% of patients received more than one antipsychotic, and almost 15% were prescribed at least three concomitant antipsychotics. Paliperidone and clozapine were associated with the highest levels of adherence, and risperidone and haloperidol with the lowest ones. An important heterogeneity of antipsychotic prescribing practices was observed in France. The rate of use of long-acting antipsychotics was low, whereas multiple antipsychotic prescriptions were frequent.

Region-specific effects of acute haloperidol in the human midbrain, striatum and cortex

D2 autoreceptors provide an important regulatory mechanism of dopaminergic neurotransmission. However, D2 receptors are also expressed as heteroreceptors at postsynaptic membranes. The expression and the functional characteristics of both, D2 auto- and heteroreceptors, differ between brain regions. Therefore, one would expect that also the net response to a D2 antagonist, i.e. whether and to what degree overall neural activity increases or decreases, varies across brain areas. In the current study we systematically tested this hypothesis by parametrically increasing haloperidol levels (placebo, 2 and 3 mg) in healthy volunteers and measuring brain activity in the three major dopaminergic pathways. In particular, activity was assessed using fMRI while participants performed a working memory and a reinforcement learning task. Consistent with the hypothesis, across brain regions activity parametrically in- and decreased. Moreover, even within the same area there were function-specific concurrent de- and increases of activity, likely caused by input from upstream dopaminergic regions. In the ventral striatum, for instance, activity during reinforcement learning decreased for outcome processing while prediction error related activity increased. In conclusion, the current study highlights the intricacy of D2 neurotransmission which makes it difficult to predict the function-specific net response of a given area to pharmacological manipulations.

Human CYP2D6 Is Functional in Brain In Vivo: Evidence from Humanized CYP2D6 Transgenic Mice.

CYP2D metabolizes many drugs that act within the brain, and variable expression of CYP2D in the brain may alter local drug and metabolite levels sufficiently to affect behavioral responses. Transgenic mice that express human CYP2D6 (TG) were compared to wild type mice (WT). Following selective inhibition of human CYP2D6 in TG brain, we demonstrated in vivo that human CYP2D6 in the brain was sufficient to alter a drug-induced behavioral response. After a 4-h pre-treatment with intracerebroventricular (i.c.v.) propranolol, CYP2D activity in vivo and in vitro was reduced in TG brain, whereas CYP2D activity in vivo, but not in vitro, was reduced in WT brain. After a 24-h pre-treatment with i.c.v. propranolol, CYP2D activity in vivo and in vitro was reduced in TG brain, whereas CYP2D activity in vivo and in vitro was not changed in WT brain. These results indicate that i.c.v. propranolol irreversibly inhibited human CYP2D6 in TG brain but not mouse CYP2D in TG and WT brain. Pre-treatments with propranolol did not change liver CYP2D activity in vivo or in vitro. Furthermore, 24-h pre-treatment with i.c.v. propranolol resulted in a significant decrease of the haloperidol-induced catalepsy response in TG, but not in WT, without changing serum haloperidol levels in either mouse line. These studies reveal a new tool to selectively and irreversibly inhibit human CYP2D6 in TG brain and indicate that human CYP2D6 has a functional role within the brain sufficient to impact the central nervous system response from peripherally administered drugs.

Propranolol is a mechanism-based inhibitor of CYP2D and CYP2D6 in humanized CYP2D6-transgenic mice: Effects on activity and drug responses.

Genetics and drug interactions contribute to large interindividual variation in human CYP2D6 activity. Here, we have characterized propranolol inhibition of human and mouse CYP2D using transgenic (TG) mice, which express both mouse CYP2D and human CYP2D6, and wild-type (WT) mice. Our purpose was to develop a method for in vivo manipulation of CYP2D6 enzyme activity which could be used to investigate the role of CYP2D6 in drug-induced behaviours. Dextromethorphan metabolism to dextrorphan was used to measure CYP2D activity and to characterize propranolol inhibition in vitro and in vivo. Effects of propranolol pretreatment (24 hr) on serum levels of the CYP2D6 substrate haloperidol and haloperidol-induced catalepsy were also studied. Dextrorphan formation velocity in vitro was threefold higher in liver microsomes of TG compared to WT mice. Propranolol acted as a mechanism-based inhibitor (MBI), inactivating CYP2D in liver microsomes from TG and WT mice, and humans. Pretreatment (24 hr) of TG and WT mice with 20 mg·kg-1 intraperitoneal propranolol reduced dextrorphan formation in vivo and by liver microsomes in vitro. Serum haloperidol levels and catalepsy were increased. Propranolol was a potent MBI of dextrorphan formation in liver microsomes from TG and WT mice, and humans. The inhibition parameters in TG overlapped with those in WT mice and in humans. Inhibition of CYP2D with propranolol in vivo in TG and WT mice altered drug responses, allowing further investigation of variations in CYP2D6 on drug interactions and drug responses.

Sudden Death Associated with Complex Treatment of Acute Mania: Case Report and Toxicological Findings

Background: Antipsychotic drugs, mood-stabilizers, and sedatives are used routinely to treat acute mania, sometimes in combinations, most of which are poorly evaluated for efficacy and safety. Objective: We report a case of sudden death in a 40-year-old man with acute mania treated aggressively with combinations of drugs that resulted in in potentially toxic, high serum drug concentrations. Method: After the autopsy, analysis were conducted to determine levels of the administered medications using GC-MS and LC-MS/MS. Results: Although dosed within recommended ranges, circulating concentrations of some antipsychotic drugs given were excessive, suggesting possible pharmacokinetic interactions. In particular, valproate may have increased serum levels of haloperidol, clozapine, and promazine. The proposed cause of death was cardiac arrest, to which the high concentrations of antipsychotics may have contributed. Conclusion: This case suggests caution in the aggressive treatment of mania with combinations of psychotropic drugs and highlights the need of further clinical studies to identify consequences of drug-drug interactions of antimanic drugs, even when given at recommended doses.

Highly sensitive and selective method for the rapid determination and preconcentration of haloperidol by using a magnetite-molecularly imprinted polymer.

A sensitive and selective method based on the determination of haloperidol with the usage of magnetite-molecularly imprinted polymer and high-resolution liquid chromatography has been developed. This novel method is rapid as the detection procedure for haloperidol can be completed within a total time of 1h. The same imprinted polymer can be used for the determination of haloperidol at least 20 times. The proposed method has been succesfully applied to synthetic urine and serum samples and the recoveries of the spiked samples were in the range of 94.7-100.7%. The limit of detection and limit of quantification of the method were 2.25 and 7.50μg/L, respectively. Linearity of the calibration graph was observed within the range of 10-250μg/L. By combining the high capacity, high selectivity, and reusability of the magnetic adsorbent with the dynamic calibration range, high sensitivity and high resolution of liquid chromatography with quadrupole time-of-flight mass spectrometry, the proposed method is an ideal method for the determination and preconcentration of trace levels of haloperidol. A magnetite-molecularly imprinted polymer has been used for the first time as a selective adsorbent for the determination of haloperidol.

Antipsychotic-induced disorders: Reported cases and prospective study on muscle biomarkers after high exposure to haloperidol

Antipsychotic drugs are known to induce neuromuscular effects. In this study, we review 13 years (2002–2014) of antipsychotic intoxications reported by the anti-poisoning center of Algiers (APCA). The most recorded symptoms were neuromuscular/muscular disorders, of which haloperidol was the most inducer among all antipsychotics. A prospective study was conducted between December 2012 and January 2017 to evaluate muscle effects generated after intentional or accidental ingestion of haloperidol. Fifty-one patients admitted in different emergency departments in Algiers were included in this study. Urine and blood samples were collected from each patient for biological and toxicological monitoring and a group of healthy volunteers was assessed for comparison purpose. There was no significant difference in plasma lactate dehydrogenase (LDH) activity between healthy volunteers and exposed patients even when high levels of haloperidol were recorded. In contrast, selenium concentration and creatine kinase (CK) activity in plasma samples were significantly higher in patients exposed to high levels of haloperidol compared to healthy volunteers. Large percentage of patients exposed to high levels of haloperidol presented a significant elevated CK activity and high selenium concentration regarding the physiological thresholds. Additionally, CK activity and selenium concentration correlated positively with plasma content of haloperidol suggesting a dose-dependent relationship.In conclusion, some biomarkers (CK and selenium) may reflect muscle adverse effects of high haloperidol exposure that result possibly from muscle rigidity.

1 ハロペリドールの顎下腺唾液と脳組織間の濃度相関(第504回 大阪歯科学会例会)

1 ハロペリドールの顎下腺唾液と脳組織間の濃度相関(第504回 大阪歯科学会例会)

Rat brain CYP2D enzymatic metabolism alters acute and chronic haloperidol side-effects by different mechanisms

Risk for side-effects after acute (e.g. parkinsonism) or chronic (e.g. tardive dyskinesia) treatment with antipsychotics, including haloperidol, varies substantially among people. CYP2D can metabolize many antipsychotics and variable brain CYP2D metabolism can influence local drug and metabolite levels sufficiently to alter behavioral responses. Here we investigated a role for brain CYP2D in acutely and chronically administered haloperidol levels and side-effects in a rat model.Rat brain, but not liver, CYP2D activity was irreversibly inhibited with intracerebral propranolol and/or induced by seven days of subcutaneous nicotine pre-treatment. The role of variable brain CYP2D was investigated in rat models of acute (catalepsy) and chronic (vacuous chewing movements, VCMs) haloperidol side-effects.Selective inhibition and induction of brain, but not liver, CYP2D decreased and increased catalepsy after acute haloperidol, respectively. Catalepsy correlated with brain, but not hepatic, CYP2D enzyme activity. Inhibition of brain CYP2D increased VCMs after chronic haloperidol; VCMs correlated with brain, but not hepatic, CYP2D activity, haloperidol levels and lipid peroxidation. Baseline measures, hepatic CYP2D activity and plasma haloperidol levels were unchanged by brain CYP2D manipulations.Variable rat brain CYP2D alters side-effects from acute and chronic haloperidol in opposite directions; catalepsy appears to be enhanced by a brain CYP2D-derived metabolite while the parent haloperidol likely causes VCMs. These data provide novel mechanistic evidence for brain CYP2D altering side-effects of haloperidol and other antipsychotics metabolized by CYP2D, suggesting that variation in human brain CYP2D may be a risk factor for antipsychotic side-effects.

Delirium Management: Diagnosis, Assessment, and Treatment in Palliative Care

Delirium is a common symptom in patients with terminal cancer. The prevalence increases in the dying phase. Delirium causes negative effects on quality of life for both pa tients and their families, and is associated with higher mortality. However, some studies reported that it tends to rema in unrecognized in palliative care setting. That may be related with difficulties to distinguish the symptom from others with overlapping characteristics such as depression and dementia, and a lack of knowledge regarding assessment and diagnostic tools. We suggest that accurate recognition with validated tools and early diagnosis of the symptom should be highly prioritized in delirium management in palliative care setting. After diagnosing deliriu m, it is important to identify and address reversible precipitants such as medication, dehydration, and infection. Non-pharmacological interventions including comfortable environment for the patient and family education are also essential in the management strategy. If such interventions prove ineffective or insufficient to control hyperactive symptoms, pharmacologic interventions with antipsychotics and benzodiazepine can be considered. Until now, low levels of haloperidol remains the standard treatment despite a lack of evidence. Atypical antipsychotics such as olanzapine, quetiapine and risperidone reportedly have similar efficacy with a stronger sedating prope rty and less adverse effect compared to haloperidol. Currently, delirium medications that can be used in palliative care setting require more clinical trials, and thus, clinical guidelines are not sufficiently available. We suggest that it is warranted to develop clinical guidelines based on well-designed clinical studies for palliative care patients.

The role of Abcb5 alleles in susceptibility to haloperidol-induced toxicity in mice and humans.

BackgroundWe know very little about the genetic factors affecting susceptibility to drug-induced central nervous system (CNS) toxicities, and this has limited our ability to optimally utilize existing drugs or to develop new drugs for CNS disorders. For example, haloperidol is a potent dopamine antagonist that is used to treat psychotic disorders, but 50% of treated patients develop characteristic extrapyramidal symptoms caused by haloperidol-induced toxicity (HIT), which limits its clinical utility. We do not have any information about the genetic factors affecting this drug-induced toxicity. HIT in humans is directly mirrored in a murine genetic model, where inbred mouse strains are differentially susceptible to HIT. Therefore, we genetically analyzed this murine model and performed a translational human genetic association study.Methods and FindingsA whole genome SNP database and computational genetic mapping were used to analyze the murine genetic model of HIT. Guided by the mouse genetic analysis, we demonstrate that genetic variation within an ABC-drug efflux transporter (Abcb5) affected susceptibility to HIT. In situ hybridization results reveal that Abcb5 is expressed in brain capillaries, and by cerebellar Purkinje cells. We also analyzed chromosome substitution strains, imaged haloperidol abundance in brain tissue sections and directly measured haloperidol (and its metabolite) levels in brain, and characterized Abcb5 knockout mice. Our results demonstrate that Abcb5 is part of the blood-brain barrier; it affects susceptibility to HIT by altering the brain concentration of haloperidol. Moreover, a genetic association study in a haloperidol-treated human cohort indicates that human ABCB5 alleles had a time-dependent effect on susceptibility to individual and combined measures of HIT. Abcb5 alleles are pharmacogenetic factors that affect susceptibility to HIT, but it is likely that additional pharmacogenetic susceptibility factors will be discovered.Conclusions ABCB5 alleles alter susceptibility to HIT in mouse and humans. This discovery leads to a new model that (at least in part) explains inter-individual differences in susceptibility to a drug-induced CNS toxicity.

Examining dopamine D3 receptor occupancy by antipsychotic drugs via [3H]7-OH-DPAT ex vivo autoradiography and its cross-validation via c-fos immunohistochemistry in the rat brain

Dopamine D3 receptors are a major target for drug discovery programs related to psychiatric disorders such as schizophrenia. The ability of a compound to occupy significant levels of D3 receptors is important for achieving therapeutic efficacy in both pre-clinical and clinical settings. Here we attempt to characterise antipsychotic drug-effects at D3 receptors by measuring receptor occupancy via ex-vivo [3H]7-OH-DPAT autoradiography, and further validating this outcome via analysis of Fos-like immunoreactivity (Fos-LI) in the rat major islands of Calleja (ICjM), a brain structure with high D3 expression. Rats were treated subcutaneously with haloperidol (0.04mg/kg), clozapine (20mg/kg) and olanzapine (0.63mg/kg), the selective D2 antagonist L-741626 (2.5mg/kg) and the selective D3 antagonist SB-277011-A (10mg/kg). Doses were based on levels of D2 occupancy considered clinically relevant (60–80%). When measuring D3 occupancy, clozapine and SB-277011-A displayed meaningful levels of occupancy (60% and 77%, respectively), haloperidol and olanzapine showed limited occupancy (16% and 27%, respectively), whereas L-741626 showed no occupancy. There were no significant changes in ICjM Fos-LI after L-741626 and haloperidol treatment, minor but significant increases after olanzapine treatment, whereas highly significant increases were seen with SB-277011-A and clozapine. Additionally, pre-treating clozapine with the D1 antagonist SCH23390 caused a significant, albeit non-complete, reduction in Fos-LI, highlighting the D1 agonist property of clozapine. In conclusion, it appears that drugs occupying >50% D3 receptors produce robust increases in ICjM Fos-LI. This study may help to identify the appropriate D3 receptor antagonists that have the potential to be tested in the clinic.

Brain levels of the neurotoxic pyridinium metabolite HPP+ and extrapyramidal symptoms in haloperidol-treated mice

The typical antipsychotic haloperidol is a highly effective treatment for schizophrenia but its use is limited by a number of serious, and often irreversible, motor side effects. These adverse drug reactions, termed extrapyramidal syndromes (EPS), result from an unknown pathophysiological mechanism. One theory relates to the observation that the haloperidol metabolite HPP+ (4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium) is structurally similar to MPP+ (1-methyl-4-phenylpyridinium), a neurotoxin responsible for an irreversible neurodegenerative condition similar to Parkinson's disease. To determine whether HPP+ contributes to haloperidol-induced EPS, we measured brain HPP+ and haloperidol levels in strains of mice at high (C57BL/6J and NZO/HILtJ) and low (BALB/cByJ and PWK/PhJ) liability to haloperidol-induced EPS following chronic treatment (7–10 adult male mice per strain). Brain levels of HPP+ and the ratio of HPP+ to haloperidol were not significantly different between the haloperidol-sensitive and haloperidol-resistant strain groups (P=0.50). Within each group, however, strain differences were seen (P<0.01), indicating that genetic variation regulating steady-state HPP+ levels exists. Since the HPP+ levels that we observed in mouse brain overlap the range of those detected in post-mortem human brains following chronic haloperidol treatment, the findings from this study are physiologically relevant to humans. The results suggest that strain differences in steady-state HPP+ levels do not explain sensitivity to haloperidol-induced EPS in the mice we studied.

Patterns of Opiate, Benzodiazepine, and Antipsychotic Drug Dosing in Older Patients in a Medical Intensive Care Unit

Anecdotal observation suggests that older patients in medical intensive care units receive higher doses of psychoactive medications during evening shifts than day and night shifts. To determine the dosing patterns and total doses of fentanyl, lorazepam, and haloperidol according to nursing shift in a cohort of older patients in a medical intensive care unit. The sample consisted of 309 patients 60 years and older admitted to the medical intensive care unit at Yale-New Haven Hospital, New Haven, Connecticut. Data on time, dosage, and route of administration of the drugs were collected. Data were analyzed by using a Bayesian random effects Poisson model adjusted for individual heterogeneity, excess zero doses, and important clinical covariates. Mean age of the patients was 75 years; 58% received fentanyl, 55% received lorazepam, and 32% received haloperidol. Although dosing with fentanyl did not differ according to shift, doses of both lorazepam and haloperidol were higher during the evening shifts (4 pm to midnight) than during the day or night shifts. Compared with women, men received higher doses of both haloperidol and lorazepam and variability between shifts was greater. In this longitudinal, observational sample of older patients, data indicated a positive association between dose levels of lorazepam and haloperidol during the evening nursing shifts relative to other shifts. Further investigation is needed to determine potential causes and to evaluate the impact on outcomes of sleep deprivation and delirium.

The FORTA Project 2013, “Fit for the aged”: Clinical approaches based on an innovative concept in geriatric pharmacology

Introduction.– Haloperidol is the first choice antipsychotic medication in treatment of delirium. In elderly there is a large, not well understood, inter-individual variation in effect and side effects (in particular antipsychotic induced Parkinsonism). There are three possible explanations. First, variation in transport over the bloodbrain barrier (BBB). Second, differences in pharmacogenetics. The genetically polymorphic enzymeCytochroomP516 (CYP)-2D6 contributes to the biotransformation of haloperidol. Last, the number of dopamine-2 (D2) receptors in the brain. This is the first study that investigates, if variability can be explained by transport over the BBB. Methods.– This cross-sectional study included 20 elderly patients above 65years (average 78.9 years), with an elevated risk of a delirium who were prescribed haloperidol 1mg/day five days before an elective surgery with spinal anaesthesia. Introductory the surgery, cerebrospinal fluid (CSF) (2mL) and a blood sample (2mL) were taken. Sample analysis was done by a validated liquid chromatography–mass spectrometry. Thecorrelationofplasma and CSF concentration of haloperidol was investigated by linear regression analysis. Results.– Serum and cerebrospinal fluid levels of haloperidol averaged 0.52mcg/L (distribution 0.17–0.99mcg/L) and 0.04 (distribution<0.01–0.09mcg/L) (ratio averaged 11.45%). The correlation of CSF and serum levels was significant (r=0.853, P<0.05). There is a large variation in serum levels (factor 6). Conclusions.– Variability in transport over the BBB is not the explanatory factor for inter-individual variation in response. Alternative explanations are variation in serum levels (due to cytochroom P516-2D6 polymorfisms) and variation in the number of remaining D2 receptors in the brain.

Correlation of haloperidol levels in blood and cerebrospinal fluid: A pharmacokinetic study

Correlation of haloperidol levels in blood and cerebrospinal fluid: A pharmacokinetic study

Acutely administered antipsychotic drugs are highly selective for dopamine D2 over D3 receptors

We showed previously, using [3H]-(+)-4-propyl-9-hydroxynaphthoxazine ([3H]-(+)-PHNO) autoradiography, that several antipsychotic drugs do not occupy dopamine D3 receptors at clinically-relevant doses in rat. This is an unexpected finding considering the near-equivalent in vitro affinity of these drugs for D2 and D3 receptors. The purpose of the current study was to address two possible methodological limitations of our previous report, namely that (1) [3H]-(+)-PHNO may have been administered at non-tracer dose, potentially causing underestimate of D3 receptor occupancy, and (2) antipsychotic drugs were administered chronically, potentially causing increased D3 receptor expression not accounted for in the vehicle-treated control group. We found that decreasing [3H]-(+)-PHNO dose from 5.6nmol/kg (our previous dose) to 0.6nmol/kg caused a >60% increase in [3H]-(+)-PHNO binding to D3 receptors in cerebellar lobes 9 and 10, indicating that our previous study was indeed conducted under non-tracer dose conditions. However, neither reducing [3H]-(+)-PHNO dose further to 0.3nmol/kg (a tracer dose), nor administering antipsychotics acutely affected antipsychotic receptor occupancy. At clinically-relevant levels of D2 occupancy (57–82% inhibition of striatal binding), neither olanzapine nor haloperidol occupied D3 receptors, while clozapine occupied D3 receptors at levels similar to our previous report (33%). Risperidone moderately occupied D3 receptors (40%), but at a dose occupying >90% of D2 receptors and therefore of questionable clinical relevance. These findings demonstrate that the lack of antipsychotic occupancy of D3 receptors is not attributable to limitations of our previous study. These results suggest that D3 receptor blockade is not necessary for the therapeutic effects of the antipsychotic drugs examined.

Determination of oxidative stress and activities of antioxidant enzymes in guinea pigs treated with haloperidol

Guinea pigs (Cavia porcellus) were treated with haloperidol (HP), and free radical (FR) and ferric reducing antioxidant power (FRAP) assays were used to determine oxidative stress levels. Furthermore, the superoxide dismutase (SOD), glutathione reductase (GR) and glutathione-S-transferase (GST) activity levels were detected and glucose levels and the reduced and oxidized glutathione (GSH/GSSG) ratio were measured in HP-treated and untreated guinea pigs. The present study demonstrated that the administration of HP causes significant oxidative stress in guinea pigs (P=0.022). In animals treated with HP, the activity of GST was significantly increased compared with a placebo (P= 0.007). The elevation of SOD and GR activity levels and increase in the levels of glutathione (GSH) in HP-treated animals were not statistically significant. In the HP-untreated animals, a significant positive correlation was observed between oxidative stress detected by the FR method and GST (r=0.88, P=0.008) and SOD (r=0.86, P= 0.01) activity levels, respectively. A significant negative correlation between the levels of plasma glucose and oxidative stress detected by the FRAP method was observed (r=−0.78, P=0.04). Notably, no significant correlations were observed in the treated animals. In the HP-treated group, two subgroups of animals were identified according to their responses to oxidative stress. The group with higher levels of plasma HP had higher enzyme activity and reactive oxygen species production compared with the group with lower plasma levels of HP. The greatest difference in activity (U/μl) between the two groups of animals was for GR.

The blood concentration and organ distribution of haloperidol at therapeutic and toxic doses in severe fatty liver disease

The aim of this study was to investigate the difference between the pharmacokinetics of haloperidol in normal rats and in rats with fatty liver disease. A therapeutic dosage (0.1 mg/kg) and a toxic dose (15 mg/kg) of haloperidol were administrated to normal 9-week-old male rats or those with severe fatty liver disease, and the blood concentration of haloperidol was determined 15 min, 1, 2, and 3 h following haloperidol administration. The concentration of haloperidol in the organs was determined 1, 2, and 3 h after the haloperidol administration. Additionally, the volume of the portal vein blood flow was measured 3 h after haloperidol administration. When given at the therapeutic dosage, the concentrations of haloperidol in both the blood and organs of the rats with fatty liver disease were significantly higher than those in the normal rats. However, when given at the toxic level, the blood and organ haloperidol concentrations 1 h after administration tended to be lower in the rats with fatty liver disease than those in the normal rats; these lower haloperidol levels returned to be the levels in the normal rats 3 h after the administration of haloperidol. The volume of the portal vein blood flow significantly increased following the toxic haloperidol dose as compared with the volume pre-administration and following the therapeutic haloperidol dose in the normal rats. However, the volume did not change after the toxic or the therapeutic dose of haloperidol compared with pre-administration in rats with severe fatty liver disease, although it was significantly higher than in the normal rats. The pathway for haloperidol metabolism might have been saturated before the administration of haloperidol in rats with fatty liver disease; thus, it is possible that the blood concentration of haloperidol tends to be much higher in individuals with severe fatty liver disease than in those with normal livers in an inverse proportion to the dosage of haloperidol.

Body Mass Index Increase, Serum Leptin, Adiponectin, Neuropeptide Y and Lipid Levels during Treatment with Olanzapine and Haloperidol

Body mass index (BMI) increase is an undesired effect associated with antipsychotics, and crucial for patients' global health and treatment compliance. We aimed to investigate the relation between BMI during olanzapine or haloperidol treatments and leptin, neuropeptide Y (NPY), adiponectin and lipid serum levels. In this 9-month, randomized and naturalist study, 34 male patients, 18 on olanzapine and 16 on haloperidol group were enrolled, all were under monotherapy. Patient outcome was evaluated with positive and negative syndrome scale (PANSS) at every 3-month period. In each visit, BMI, leptin, NPY, lipid, olanzapine or haloperidol levels were also monitored. Leptin levels positively correlated with BMI in olanzapine (r=0.64, p<0.001) and haloperidol (r=0.73, p<0.001) groups; only in olanzapine patients, the former also correlated with PANSS score (r=0.54, p<0.05). NPY levels negatively correlated with olanzapine levels (r=− 0.65, p<0.01). Adiponectin levels had not significantly varied. Antipsychotics probably interfere on leptin and NPY signalling ways and disturb these hormones in eating behaviour control.