Haloperidol Concentrations Research Articles

History of the Discovery of the Antipsychotic Dopamine D2 Receptor: A Basis for the Dopamine Hypothesis of Schizophrenia

The 1975 publication of Seeman et al. (Proc Nat Acad Sci, USA), reporting the discovery of the antipsychotic receptor in the brain, is a classic example of translational medicine research. In searching for a pathophysiological mechanism of psychosis, the team sought to identify sites that bound the antipsychotic drug haloperidol. Their criterion was that haloperidol bound to the site at one to two nanomoles per liter, corresponding to haloperidol concentrations found in spinal fluid or plasma water in treated patients. They requested de novo synthesis of tritiated haloperidol, and it readily detected specific haloperidol binding sites in brain striatum. With dopamine binding the haloperidol-labeled sites with higher potency than other neurotransmitters, the sites were named antipsychotic/dopamine receptors (now designated dopamine D2 receptors). Most significantly, they found that all antipsychotics bound these sites at concentrations and with a rank order of potencies that were directly related to the mean daily antipsychotic dose taken by patients with schizophrenia. Their findings enabled screening for new antipsychotics, initiated D2 receptor measurements in brain of living patients, and determination of minimum occupancy (65%) of D2 receptors for antipsychotic benefit. The collective work is generally viewed as providing a fundamental basis for the dopamine hypothesis of schizophrenia.

Exploration of Optimal Dosing Regimens of Haloperidol, a D2 Antagonist, via Modeling and Simulation Analysis in a D2 Receptor Occupancy Study

To evaluate the potential usage of D(2) receptor occupancy (D2RO) measured by positron emission tomography (PET) in antipsychotic development. In this randomized, parallel group study, eight healthy male volunteers received oral doses of 0.5 (n = 3), 1 (n = 2), or 3mg (n = 3) of haloperidol once daily for 7days. PET's were scanned before haloperidol, and on days 8, 12, with serial pharmacokinetic sampling on day 7. Pharmacokinetics and binding potential to D(2) receptor in putamen and caudate nucleus over time were analyzed using NONMEM, and simulations for the profiles of D2RO over time on various regimens of haloperidol were conducted to find the optimal dosing regimens. One compartment model with a saturable binding compartment, and inhibitory E(max) model in the effect compartment best described the data. Plasma haloperidol concentrations at half-maximal inhibition were 0.791 and 0.650ng/ml, in putamen and caudate nucleus. Simulation suggested haloperidol 2mg every 12h is near the optimal dose. This study showed that sparse D2RO measurements in steady state pharmacodynamic design after multiple dosing could reveal the possibility of treatment effect of D(2) antagonist, and could identify the potential optimal doses for later clinical studies by modeling and simulation.

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.

Enhanced effect of haloperidol and apomorphine after hypophysectomy: pharmacokinetic considerations.

The behavioural effects of both apomorphine (stereotypies) and haloperidol (catalepsy and reversal of stereotypies) were significantly enhanced in hypophysectomized rats compared with sham-operated rats. Both the efficacy and duration of action were increased Hypophysectomized animals had significantly greater brain haloperidol concentrations than did sham-operated animals. The data suggest that changes in brain drug concentrations following hypophysectomy at least partially explain the behavioural alterations seen in this test situation.

Apparent desensitization of the effects of sigma receptor ligand haloperidol in isolated rat and guinea pig hearts after chronic treatmentThis article is one of a selection of papers published in a special issue on Advances in Cardiovascular Research.

The supposed role of cardiac sigma receptors is fine tuning of contractility. Sigma receptors affect several ionic channels and hence their signaling is reflected by the electrophysiological properties of the heart. Numerous ligands of sigma receptors are known to prolong the QT interval and therefore cause a variety of arrhythmias, including severe ones. The effects of the prototypical sigma ligand haloperidol have been studied extensively in humans as well as in various animal models, primarily after acute administration. We examined the incidence of arrhythmias, changes in heart rate, and prolongation of QT interval in isolated Langendorff-perfused rat and guinea pig hearts after they were exposed to nanomolar concentrations of haloperidol. Hearts from both untreated (acute) and pretreated (chronic) animals were investigated. While QT prolongation and arrhythmias due to haloperidol administration were observed in untreated rat and guinea pig hearts, arrhythmias were completely prevented in both species of chronically treated animals. In treated guinea pigs, the results were generally less convincing. Since the hearts were exposed to nanomolar concentration of haloperidol, we conclude that our data may be explained by desensitization of sigma receptors.

Role of CYP2D6 gene polymorphism in individual's ability to quit smoking

In 1980, we published two papers of importance for the future of our research: (i) it was shown that the two polymorphic hydroxylations of debrisoquine and sparteine are catalysed by a common enzyme now called CYP2D6 and (ii) that this polymorphic enzyme also catalysed the metabolism of the tricyclic antidepressant nortriptyline. Later, it was shown that most antidepressants are metabolized by CYP2D6. There are many allelic variants of CYP2D6 causing decreased (e.g. CYP2D6*10 in Asians) or no (*4 in Caucasians) activity of the enzyme. We have identified duplication and amplification of a CYP2D6 gene as a cause of ultrarapid metabolism. There are pronounced interethnic differences in these allelic variants. When nortriptyline was given as single doses to healthy subjects, there was a close relationship between the rate of 10-hydroxylation and the number of functional CYP2D6 genes.Most neuroleptic drugs are also metabolized by CYP2D6. Exceptions are the atypical neuroleptics clozapine and olanzapine, which are mainly metabolized by CYP1A2. When haloperidol was given as a single oral dose to a panel of healthy Swedish Caucasians, PM of debrisoquine eliminated the drug slower than EM (PM=poor, EM=extensive metabolisers). Among eight patients treated with i.m. injection of haloperidol decanoate every 4 weeks, one patient having the genotype CYP2D6*4/*4 and thus a PM, had the highest plasma concentration of haloperidol, highest dopamine D2-receptor occupancy and most pronounced extrapyramidal side-effects. In Japan, plasma concentrations of haloperidol per dose unit have been shown to be related to the CYP2D6*10 allele. In Koreans, this relationship was confirmed at doses of haloperidol below 20 mg per day, but not at higher doses. These and other studies taken together show that at low doses haloperidol is metabolized by CYP2D6, while at high doses, this enzyme is saturated and then enzymes with a higher capacity, e.g. CYP3A4, are taking over.CYP2D6 catalyzes the metabolism of a large number of psychotropic drugs and the pronounced variation in its activity between individuals and populations contributes to the variation in treatment response and side effects. Also, it must be emphasized that when two drugs, both of which are substrates of CYP2D6, are co-administrated they may increase each others' plasma concentrations and potentiate therapeutic effects and adverse drug reactions.

Increased lactate levels and reduced pH in postmortem brains of schizophrenics: Medication confounds

A number of postmortem studies have found decreased pH in brains of patients with schizophrenia. Insofar as lower pH has been associated with decreased mRNA expression in postmortem human brain, decreased pH in schizophrenia may represent an important potential confound in comparisons between patients and controls. We hypothesized that decreased pH may be related to increased concentration of lactic acid. However, in contrast to the previous notion that an increase in lactic acid represents evidence for primary metabolic abnormalities in schizophrenia, we hypothesized that this increase is secondary to prior antipsychotic treatment. We have tested this by first demonstrating that lactate levels in the cerebellum of patients with schizophrenia ( n = 35) are increased relative to control subjects ( n = 42) by 28%, p = 0.001. Second, we have shown that there is an excellent correlation between lactate levels in the cerebellum and pH, and that this correlation is particularly strong in patients ( r = −0.78, p = 3E−6). Third, we have shown in rats that chronic haloperidol (0.8 mg/kg/day) and clozapine (5 mg/kg/day) increase lactic acid concentration in the frontal cortex relative to vehicle (by 31% and 22% respectively, p < 0.01). These data suggest that lactate increases in postmortem human brain of patients with schizophrenia are associated with decreased pH and that these changes are possibly related to antipsychotic treatment rather than a primary metabolic abnormality in the prefrontal cortex of patients with schizophrenia.

Depot Haloperidol Treatment in Outpatients With Schizophrenia on Monotherapy: Impact of CYP2D6 Polymorphism on Pharmacokinetics and Treatment Outcome

Haloperidol and several other antipsychotic drugs are at least partially metabolized by the polymorphic cytochrome P450 2D6 (CYP2D6). The interindividual variation in metabolic capacity of CYP2D6 might be of importance when dosing. In this study, 26 outpatients with schizophrenia and depot haloperidol as monotherapy were genotyped. The authors found 1 patient with no functional alleles, 8 with one functional allele, 16 with two functional alleles, and 1 with three functional alleles. The daily dose of haloperidol ranged from 0.45 to 14.29 mg. Steady state plasma concentrations were measured at peak (range, 1.6-67 nmol/L) and at trough (range, 1.0-49 nmol/L). The Positive and Negative Syndrome scale for Schizophrenia and the Extrapyramidal Symptom Rating Scale were used to evaluate the clinical effect. The authors found a clear correlation between haloperidol plasma concentration and number of active CYP2D6 alleles. No correlation was found between plasma concentration of haloperidol or number of CYP2D6 alleles and treatment outcome or side effects. A model to predict plasma concentration from dose and number of active CYP2D6 alleles was formed from the obtained data by means of multiple linear regression.

Effects of haloperidol and its pyridinium metabolite on plasma membrane permeability and fluidity in the rat brain

The use of antipsychotic drugs is limited by their tendency to produce extrapyramidal movement disorders such as tardive dyskinesia and parkinsonism. In previous reports it was speculated that extrapyramidal side effects associated with the butyrophenone neuroleptic agent haloperidol (HP) could be caused in part by the neurotoxic effect of its pyridinium metabolite (HPP +). Although both HPP + and HP have been shown to induce neurotoxic effects such as loss of cell membrane integrity, no information exists about the difference in the neurotoxic potency, especially in the potency to induce plasma membrane damage, between these two agents. In the present study, we compared the potency of the interaction of HPP + and HP with the plasma membrane integrity in the rat brain. Membrane permeabilization (assessed as [ 18 F]2-fluoro-2-deoxy- d-glucose-6-phosphate release from brain slices) and fluidization (assessed as the reduction in the plasma membrane anisotropy of 1,6-diphenyl 1,3,5-hexatriene) were induced by HPP + loading (at ≥ 100 μM and ≥ 10 μM, respectively), while comparable changes were induced only at a higher concentration of HP (= 1 mM). These results suggest that HPP + has a higher potency to induce plasma membrane damage than HP, and these actions of HPP + may partly underlie the pathogenesis of HP-induced extrapyramidal side effects.

Neuroleptic drugs in the human brain

After discontinuation of neuroleptic agents, their effects are still present for a long time. The exact underlaying mechanisms are still unclear. In two previous studies we measured the concentrations and region-specific distribution of haloperidol (Kornhuber et al. 1999) and levomepromazine (Kornhuber et al. 2006) in postmortem human brain tissues. The aim of the present paper is to compare the results of these two studies. Even after short-term treatment, haloperidol and levomepromazine concentrations reach high levels in human brain tissue. Haloperidol concentrations in brain tissue are 10-30 times higher than the optimum serum concentrations in the treatment of schizophrenia. The brain-to-blood concentration ratio of levomepromazine is about 10. The estimated elimination half-life of these drugs in brain tissue are 6.8 days (haloperidol), 7.9 days (levomepromazine) and 27.8 days for the metabolite desmethyl-levomepromazine, respectively. After two half-lives (about 2 weeks), a considerable amount of drug remains in brain tissue. Haloperidol concentrations appeared to be homogeneously distributed across different brain areas, whereas levomepromazine shows a region-specific distribution, with highest values in the basal ganglia. The persistence of neuroleptic drugs in the human brain might explain their prolonged effects and side effects. The region-specific distribution of levomepromazine may increase our understanding of both the preferential toxicity of neuroleptic drugs against basal ganglia structures and higher basal ganglia volumes in patients treated with neuroleptics.

Correlation of haloperidol levels between submandibular saliva and brain in the rat

The clinical usefulness of therapeutic drug monitoring (TDM) for haloperidol using blood samples has to be validated. Despite the potential advantage of TDM using saliva, there are few reports comparing drug levels in saliva and blood. Additionally, the relation between haloperidol levels in saliva and brain, the target organ of this drug, has not been reported. We compared haloperidol levels in rat submandibular saliva, plasma and brain. Haloperidol was administered through the femoral vein (0.25 mg/kg). Submandibular saliva was collected 30 min after drug administration. To stimulate secretion, the chorda (parasympathetic) and superior cervical ganglion (sympathetic) were electrically stimulated, and pilocarpine was administered. The concentration of haloperidol in saliva, plasma and brain homogenate was determined. Haloperidol levels in saliva elicited by any stimuli significantly correlated with levels in the brain and plasma. The correlation of haloperidol between saliva and brain was higher than that between plasma and brain. Immunohistochemistry showed that haloperidol was secreted from striated duct cells within the submandibular gland. These results suggested that haloperidol was specifically secreted from the striated duct system, and that salivary drug levels reflect the levels in the brain more precisely than plasma.

Iontophoretic Transdermal Delivery of Haloperidol

The in vitro iontophoretic transdermal delivery of haloperidol (HP) across pig skin was investigated. Anodal iontophoresis considerably increased HP skin penetration and accumulation as compared to the passive controls.The effect of NaCl and HP concentrations on the vehicle were also studied. As expected, HP iontophoretic transport decreased with NaCl content. On the other hand, HP concentration did not modify its electrotransport in the range of concentrations between 0.4 and 0.9 mg/mL, except at 24 hours. The influence of the current density (0.20–0.50 mA/cm2) was also investigated. The iontophoretic transport of HP tends to increase with current density. On the whole, this work shows that iontophoresis may be used to improve the topical application of HP for the treatment of chronic psychosis.

Interactions between Antiepileptic and Antipsychotic Drugs

Antiepileptic and antipsychotic drugs are often prescribed together. Interactions between the drugs may affect both efficacy and toxicity. This is a review of human clinical data on the interactions between the antiepileptic drugs carbamazepine, valproic acid (sodium valproate), vigabatrin, lamotrigine, gabapentin, topiramate, tiagabine, oxcarbazepine, levetiracetam, pregabalin, felbamate, zonisamide, phenobarbital and phenytoin with the antipsychotic drugs risperidone, olanzapine, quetiapine, clozapine, amisulpride, sulpiride, ziprasidone, aripiprazole, haloperidol and chlorpromazine; the limited information on interactions between antiepileptic drugs and zuclopenthixol, periciazine, fluphenazine, flupenthixol and pimozide is also presented. Many of the interactions depend on the induction or inhibition of the cytochrome P450 isoenzymes, but other important mechanisms involve the uridine diphosphate glucuronosyltransferase isoenzymes and protein binding. There is some evidence for the following effects. Carbamazepine decreases the plasma concentrations of both risperidone and its active metabolite. It also decreases concentrations of olanzapine, clozapine, ziprasidone, haloperidol, zuclopenthixol, flupenthixol and probably chlorpromazine and fluphenazine. Quetiapine increases the ratio of carbamazepine epoxide to carbamazepine and this may lead to toxicity. The data on valproic acid are conflicting; it may either increase or decrease clozapine concentrations, and it appears to decrease aripiprazole concentrations. Chlorpromazine possibly increases valproic acid concentrations. Lamotrigine possibly increases clozapine concentrations. Phenobarbital decreases clozapine, haloperidol and chlorpromazine concentrations. Phenytoin decreases quetiapine, clozapine, haloperidol and possibly chlorpromazine concentrations. There are major gaps in the data. In many cases there are no published clinical data on interactions that would be predicted on theoretical grounds.

Validation of LC–MS electrospray ionisation method for quantitation of haloperidol in human plasma and its application to bioequivalence study

In the present investigation, a new sensitive LC/MS electrospray ionisation mass spectrometric method has been developed for the quantitation of haloperidol—an antipsychotic drug, in human plasma. The method was developed with the objective of accurately measuring the concentration of haloperidol in the plasma of human subjects enrolled in the bioequivalence study of haloperidol (5 mg) tablets of M/s. Cadila Health Care Ltd. India versus 5 mg haloperidol tablets of Geneva Pharma USA. The sample purification and pre-concentration was performed by liquid–liquid extraction (LLE) using duloxetine as internal standard. The chromatographic separation was achieved using an isocratic mobile phase containing 1.0 mM ammonium acetate pH 3.0 and acetonitrile (70:30, v/v) flowing through Xterra MS C18 100 mm × 2.1 mm, 3.5 μm analytical column, at a flow rate of 0.2 ml/min. The lower limit of quantitation (LLOQ) of 70.0 pg/ml was achieved using mass spectrometric detection in positive mode. The ion signals of m/ z 375.9 and 297.9 were measured for haloperidol and internal standard, respectively. An exhaustive pre-study method validation was performed in accordance with USFDA guidelines. The standard curves were linear in the concentration range of 70.0 pg/ml to 14.0 ng/ml with mean correlation coefficient of 0.998. The method was successfully applied to the bioequivalence study of haloperidol in healthy human male volunteers.

Antipsychotic drugs elevate mRNA levels of presynaptic proteins in the frontal cortex of the rat

Molecular adaptations are believed to contribute to the mechanism of action of antipsychotic drugs (APDs). We attempted to establish common gene regulation patterns induced by chronic treatment with APDs. Gene expression analysis was performed with the Affymetrix U34A array in the frontal cortex (FC) and the striatum of rats chronically treated with two concentrations of either clozapine or haloperidol. Key data were verified with real-time quantitative polymerase chain reaction. Many genes in the FC affected by APD-treatment contribute to similar functions. mRNAs coding for synaptic vesicle docking- and microtubule-associated proteins were upregulated; mRNAs for serine-threonine protein phosphatases were downregulated, whereas the serine-threonine kinases protein kinase A, protein kinase C, and calcium/calmodulin kinase II alpha and IV were upregulated, indicating increased potential for protein phosphorylation. In the striatum, altered gene expression was less focused on genes of particular function or location, and the high concentration of haloperidol had a different gene expression profile than any of the other APD treatments. We found an increase in the transcription of genes coding for proteins involved in synaptic plasticity and synaptic activity in the FC. We furthermore found that the gene expression profile of APDs is different between FC and striatum.

Assay of the anti-psychotic drug haloperidol in bulk form, pharmaceutical formulation and biological fluids using square-wave adsorptive stripping voltammetry at a mercury electrode

The cyclic voltammetric behavior of haloperidol at a hanging mercury drop electrode was studied in Britton–Robinson buffer series of pH 2.5–11 containing 40% (v/v) ethanol. A single two-electron irreversible cathodic peak was obtained which attributed to reduction of the C O double bond. In addition, a small enhanced adsorptive pre-wave was observed at less negative potentials over the pH range 3.5–11. Controlled adsorptive accumulation of haloperidol onto the hanging mercury drop electrode provided the basis for its direct trace assay in bulk form, pharmaceutical formulation and human biological fluids using square-wave adsorptive cathodic stripping voltammetry. Following preconcentration of bulk haloperidol onto the HMDE a well-developed square-wave cathodic peak was generated in Britton–Robinson buffer especially at pH values 9–10; its peak current showed a linear dependence on the concentration of haloperidol over the range 1 × 10 −9 M to 1.5 × 10 −6 M depending on the preconcentration duration. The procedural parameters for assay of haloperidol were studied. The achieved limits of detection (LOD) and quantitation (LOQ) were 3.83 × 10 −10 M and 1.28 × 10 −9 M bulk haloperidol, respectively. The procedure was successfully applied to assay haloperidol in tablets (Safinace ®) and in spiked human serum and urine. LOD of 3.3 × 10 −9 M and 5.46 × 10 −9 M, and LOQ of 1.10 × 10 −8 and 1.82 × 10 −8 M haloperidol were achieved in spiked human serum and urine samples, respectively.

Preliminary Findings in Switching from Parenteral Haloperidol to Oral Quetiapine Treatment in the Management of Acutely Agitated Patients

Agitation is a very common but complex clinical challenge to the hospital psychiatrist. A subset of agitated patients, threatening their life and that of others, unresponsive to verbal interventions, has to be medicated by parenteral administration. For this indication haloperidol is a well studied and routinely prescribed compound despite its limiting side effects. Therefore, switching to 2nd generation antipsychotics after successful treatment of the acute symptoms should be considered. Our prospective naturalistic study describes clinical practice in the management of acutely agitated patients. Fifteen acute agitated psychiatric patients requiring i.v. haloperidol treatment at admission were subsequently switched to oral quetiapine, remaining on this medication until their discharge. Age, gender, weight, diagnoses, dosages of haloperidol and quetiapine, serum concentration analysed by HPLC, duration of i.v. application, smoking behaviour and co-medications were registered. The patients (10 f) were mainly affected by schizophreniform (N=8), affective or schizoaffective (N=6) disorders. The mean age was 38.4 years (25–58), the mean body weight 71.2kg (55–103.5). Eight patients were identified as smokers. Haloperidol was prescribed for a mean duration of 5.8 days (2–11) in a mean dose of 24.6mg (15–30) reaching a mean serum concentration of 19.9 ng/ml (6–47) with a mean C/D ratio of 0.8 (0.3–1.57). Switching to quetiapine was based on clinical improvement. The mean dose of quetiapine was 573.3mg (300–800) resulting in a mean serum concentration of 267.6 ng/ml (57–520) and a mean C/D ratio of 0.5 (0.1–0.9). A subanalysis revealed that patients (N=8) initially treated with high doses of haloperidol (up to 30mg) were switched earlier to quetiapine (average 2 days) and discharged with smaller doses quetiapine of 525mg/d (300–800) than patients (N=7) medicated with haloperidol up to 20mg requiring a mean quetiapine doses of 671.5mg/d (500–800). Additionally smokers showed lower haloperidol but higher quetiapine serum concentration than non smokers. Since significantly more smokers were present in the group treated with high haloperidol doses, the opposite effects of nicotine on haloperidol and quetiapine will be discussed. Our results indicate that the initial dose of parenteral haloperidol has a clinical impact on the switching time to quetiapine and on the final doses of quetiapine.

QT PRODACT: Usability of Miniature Pigs in Safety Pharmacology Studies: Assessment for Drug-Induced QT Interval Prolongation

To investigate whether miniature pigs are useful for evaluating the potential of drugs for drug-induced prolongation of the QT interval, we performed an in vivo QT assay using conscious and unrestricted miniature pigs. Compared with the vehicle average baseline values, haloperidol at 3 and 10 mg/kg, p.o. prolonged the QTcF interval (Fridericia’s formula) by 8% – 16%. The plasma concentration of haloperidol at which QT interval was prolonged (Cmax = 42.9 ng/mL) was almost equal to that in humans. dl-Propranolol at 3, 10, and 30 mg/kg, p.o. caused no alterations in QT interval. dl-Propranolol at 3, 10, and 30 mg/kg, at which plasma concentrations were lower than in humans treated with dl-propranolol at the therapeutic dose level, shortened QTcF interval by 7% – 12%. dl-Sotalol at 10 mg/kg, p.o. prolonged QTcF interval by 7%. From the above results, we considered that the miniature pig can be used for prediction of drug-induced prolongation of QT interval in humans, and thus, it is one of the useful animal species for assessing electrocardiograms in safety pharmacology studies.

Poor reliability of therapeutic drug monitoring data for haloperidol and bromperidol using enzyme immunoassay.

Therapeutic drug monitoring (TDM) services for plasma concentrations of haloperidol and bromperidol using enzyme immunoassay (EIA) methods are available in Japan, whereas high-performance liquid chromatographic (HPLC) methods are preferred in other countries. To compare these methods, we took 54 plasma samples for haloperidol and 91 plasma samples for bromperidol from schizophrenic patients receiving haloperidol or bromperidol, and the samples were measured using both commercial EIA and HPLC methods. Significant linear correlations were found between the two methods in determining haloperidol (EIA = 1.351 x HPLC + 1.39; r = 0.934, P < 0.001) and bromperidol (EIA = 1.420 x HPLC + 0.712; r = 0.956, P < 0.001) concentrations, but plasma concentrations using the EIA kits were approximately 92% (95% CI; 53-131%) and 62% (54-70%) higher than those using HPLC for haloperidol and bromperidol, respectively. Mean (and range) plasma concentrations of reduced metabolites were 54% (30-92%) and 55% (29-111%) of those of haloperidol and bromperidol, respectively. The present study suggests that reduced metabolites are included to a considerable degree in TDM data using the EIA kits. Therefore, some limitation of TDM data of haloperidol and bromperidol using the EIA kits, ie, high precision but poor accuracy, should be kept in mind.

Significant Dose Effect of Carbamazepine on Reduction of Steady-State Plasma Concentration of Haloperidol in Schizophrenic Patients

A reduction in haloperidol concentration induced by carbamazepine coadministration has been consistently reported. However, the degree of this reduction is very different among individuals treated with various doses of carbamazepine. Thus, we investigated dose effect of carbamazepine on the steady-state plasma concentration of haloperidol. Eleven excited schizophrenic inpatients, despite receiving haloperidol 12 mg/d, were treated with incremental doses of carbamazepine for 6 weeks (100, 300, 600 mg/d for 2 weeks each). Plasma drug concentrations were monitored together with clinical assessments before and after each phase of the 3 carbamazepine doses. Mean haloperidol concentrations during coadministration of carbamazepine 100, 300, and 600 mg/d were 75%, 39%, and 15%, respectively, of corresponding variables before carbamazepine coadministration. Negative linear correlations were observed between dose or plasma concentration of carbamazepine and the degree of reduction in haloperidol concentration. Mean carbamazepine dose and plasma carbamazepine concentrations at 50% reduction of haloperidol concentration were 240 mg/d and 3.5 microg/mL, respectively. Scores in total and excitement symptoms were significantly reduced after carbamazepine coadministration, whereas no changes were observed in other clinical symptoms or any of the subgroup side effects. Therefore, this study indicates that carbamazepine decreases plasma haloperidol concentration in a dose-dependent or concentration-dependent manner, and that reduction in haloperidol concentration is apparent even at subtherapeutic dose of carbamazepine.