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PubMed2000

Factors affecting serum haloperidol level assessed by longitudinal therapeutic monitoring.

1. Since the development of a kit for the assay of haloperidol by enzyme immunoassay, therapeutic monitoring of haloperidol has been utilised in Japan for several years. By retrospectively analysing the accumulated data, this study was carried out to investigate the factors affecting haloperidol level. Especially, the effects of enzyme-inducing comedications were analysed in relation to serum gamma-glutamyltransferase (GGT) level, which has been measured simultaneously with haloperidol. Serum haloperidol level measurements were obtained from medical records of inpatients on multiple medications (n = 102). For each subject, average haloperidol level was computed during the same prescription and doses. The effects of age, sex, smoking status, and the coadministration of carbamazepine and barbiturates (including phenobarbital, amobarbital and pentobarbital) were analysed using correlation, between-group comparison and multiple regression analysis. Separately, the effect of comedications on haloperidol and GGT levels were analysed individually in a small number of patients (n = 5) who had received those comedications intermittently. Significant lowering of serum haloperidol level by the coadministration of carbamazepine and/or barbiturates was observed. The coadministration was also correlated with the elevated GGT level in between-group comparison. In the separate analysis, the change in haloperidol level was correlated with the change in GGT level in some individuals but not in others. None of the other clinical factors investigated in the study showed significant effect on haloperidol level. This study suggests that the lowering of haloperidol level and the elevation of GGT level may often occur coincidentally by the coadministration of enzyme-inducing drugs. However, whether there is a causal relationship between these phenomena and whether elevated serum GGT level could serve as a clinically useful marker need to be clarified by further basic pharmacological research.

Adult↗
PubMed2003

Enhancement of serotonin-1A receptor dependent responses following withdrawal of haloperidol in rats.

Although haloperidol is widely prescribed for the treatment of schizophrenia, its beneficial effects are accompanied by extrapyramidal side effects (EPS). In view of a role of 5-hydroxytryptamine (5-HT; serotonin)-1A receptors in the elicitation of EPS, the present study concerns pre- and postsynaptic responses to a selective 5-HT-1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) following acute and chronic administration of haloperidol in rats. In the acute administration study, effects of 8-OH-DPAT (0.5 mg/kg) were monitored 30 min after single injection of haloperidol (5 mg/kg). In the chronic administration study, effects of 8-OH-DPAT (0.5 mg/kg) were monitored 48 h after withdrawal from repeated (two times a day for 2 weeks) administration of haloperidol (5 mg/kg). The intensity of 5-HT syndrome elicited by 8-OH-DPAT was taken as measure of postsynaptic response. 8-OH-DPAT-induced decreases of 5-HT synthesis were taken as measure of presynaptic response. Results showed that 8-OH-DPAT-induced locomotion was smaller in acute haloperidol-treated rats. Conversely, these effects of 8-OH-DPAT were greater in chronic haloperidol-treated rats. Animals injected acutely or chronically with haloperidol exhibited greater 5-HT synthesis in the striatum. Administration of 8-OH-DPAT did not decrease 5-HT synthesis in the striatum of acute haloperidol-treated rats but decreased it in the striatum of chronic haloperidol-treated rats. The results show an increase in the effectiveness of pre- and postsynaptic 5-HT-1A receptor dependent responses following chronic administration of haloperidol. A causal role of 5-HT-1A receptor responsiveness in the greater incidences of EPS in patients treated with typical neuroleptics such as haloperidol is discussed.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2001

A double-blind, randomized, prospective evaluation of the efficacy and safety of risperidone versus haloperidol in the treatment of schizoaffective disorder.

The relative efficacy and safety of risperidone versus haloperidol in the treatment of schizoaffective disorder was studied. Sixty-two patients (29 depressed type; 33 bipolar type) entered a three-site, randomized, double-blind, 6-week trial of risperidone (up to 10 mg/day) or haloperidol (up to 20 mg/day). Trained raters assessed baseline, weekly, and end-of-study levels of psychopathology with the Positive and Negative Syndrome Scale (PANSS), the 24-item Hamilton Rating Scale for Depression (HAM-D-24) and the Clinician-Administered Rating Scale for Mania (CARS-M). The authors were unable to statistically distinguish between risperidone and haloperidol in the amelioration of psychotic and manic symptoms. In addition, there was no difference in worsening of mania between the two agents in either subgroup (i.e., depressed or bipolar subgroups). For the total PANSS, risperidone produced a mean decrease of 16 points from baseline compared with a 14-point decrease with haloperidol. For the total CARS-M scale, risperidone and haloperidol produced mean change scores of 5 and 8 points, respectively, and for the CARS-M Mania subscale, 3 and 7 points, respectively. Additionally, risperidone produced a mean decrease of 13 points from the baseline 24-item HAM-D, compared with an 8-point decrease with haloperidol. In those patients who had more severe depressive symptoms (i.e., HAM-D baseline score >20), risperidone produced at least a 50% mean improvement in 12 (75%) of 16 patients in comparison to 8 (38%) of 21 patients receiving haloperidol. Haloperidol produced significantly more extrapyramidal side effects and resulted in more dropouts caused by any side effect. There was no difference between risperidone and haloperidol in reducing both psychotic and manic symptoms in this group of patients with schizoaffective disorder. Risperidone did not demonstrate a propensity to precipitate mania and was better tolerated than haloperidol. In those subjects with higher baseline HAM-D scores (i.e., >20), risperidone produced a greater improvement in depressive symptoms than haloperidol.

Adult↗
PubMed2001

Importance of the cytochrome P450 2D6 genotype for the drug metabolic interaction between chlorpromazine and haloperidol.

The authors studied the interactive effects of the coadministration of haloperidol and chlorpromazine on plasma concentrations of haloperidol and reduced haloperidol. The subjects were 43 Japanese male schizophrenic inpatients who were concomitantly treated with chlorpromazine before or after monotherapy with haloperidol. Coadministration of chlorpromazine produced significant increases in the plasma concentrations of haloperidol (P < 0.01) and reduced haloperidol (P < 0.001) by an average of 28.5% +/- 83.3% and 160.8% +/- 288.9%, respectively. However, there were marked interindividual variations in the interactive effects of chlorpromazine. The authors analyzed the importance of five CYP2D6 genotypes, *1/ *1, *1/ *10, *10/ *10, *1/*5, and *5/*10 on the percentage of change in plasma concentrations of haloperidol and reduced haloperidol. Patients with the CYP2D6*5 allele (n = 4) showed a significantly smaller increase in plasma concentrations of haloperidol (P < 0.05) and a slightly smaller increase in those of reduced haloperidol (P = 0.074) in response to the coadministration of chlorpromazine compared than those with the CYP2D6*1/*1 genotype (n = 8). Those with the CYP2D6*1/*1 genotype (n = 8) showed a trend toward greater increases in plasma concentrations of haloperidol than those with other genotypes (P = 0.087).

Adult↗
PubMed1998

In-vitro characterization of the cytochrome P450 isoenzymes involved in the back oxidation and N-dealkylation of reduced haloperidol.

In-vitro studies were performed using human liver microsomes and c-DNA-expressed human P450 isoforms to identify the cytochrome P450 isoenzyme(s) involved in the back oxidation and N-dealkylation of reduced haloperidol. Back oxidation and N-dealkylation of reduced haloperidol were assessed by measuring the formation of haloperidol and 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP), respectively. The haloperidol and CPHP formation rates as a function of substrate concentration, measured in three livers, followed monophasic enzyme kinetics. For haloperidol formation Km values ranged from 51-59 microM, and Vmax values from 190-334 pmol mg(-1) min(-1); for CPHP formation Km values were 44-49 microM, and Vmax values 74-110 pmol mg(-1) min(-1). Haloperidol and CPHP formation rates in the nine liver preparations were significantly correlated with dextromethorphan N-demethylase activity (a marker of CYP3A4 activity), but not with the CYP2D6, CYP1A2 and CYP2C9 activity. Ketoconazole and troleandomycin, inhibitors of CYP3A4, inhibited competitively both haloperidol and CPHP formation, with a Ki value lower than 0.2 microM for ketoconazole and lower than 0.3 microM for troleandomycin. Sulphaphenazole (CYP2C9), furafylline (CYP1A2) and quinidine and paroxetine (CYP2D6) gave only little inhibition (IC50 > 60 microM). CPHP and haloperidol formation were, moreover, enhanced by alpha-naphthoflavone, an effect known for CYP3A4 mediated reactions. Anti-CYP3A4 antibodies strongly inhibited haloperidol and CPHP formation, whereas CYP2D6 antibodies did not. Among the recombinant human CYP isoforms tested, CYP3A4 exhibited the highest activity with respect to haloperidol and CPHP formation rates, with no detectable effect of CYP1A2, CYP2D6 and CYP2C9. These results strongly suggest that back oxidation and N-dealkylation of reduced haloperidol in human liver microsomal preparations are mediated by CYP3A4.

Adolescent↗
PubMed2002

Lack of correlation between the steady-state plasma concentrations of haloperidol and risperidone.

Both haloperidol and risperidone have been widely used in the treatment of schizophrenia. Because of wider therapeutic spectrum of risperidone, switching from haloperidol to risperidone is recommended in patients who do not sufficiently respond to haloperidol. The present study investigated the correlation between the steady-state plasma concentrations of haloperidol and risperidone together with the effects of CYP2D6 status on the steady-state kinetics of both drugs. Subjects were 22 schizophrenic inpatients. Eleven patients first received risperidone 6 mg/day and then haloperidol 12 mg/day, while the remaining 11 patients received these two treatments in the opposite sequence. The steady-state plasma concentrations of risperidone, 9-hydroxyrisperidone, haloperidol, and reduced haloperidol were measured after the subjects had been on the treatment for at least 2 weeks, and CYP2D6 genotypes were identified in all subjects. Neither the correlation between the steady-state plasma concentrations of haloperidol and those of risperidone (r = 0.061, ns) nor the active moiety (sum of concentration of risperidone and 9-hydroxyrisperidone) of risperidone (r = 0.141, ns) was significant. The mean (+/- SD) plasma concentration of risperidone in patients with mutated allele(s)for CYP2D6 was significantly higher than those without mutated allele (1.5 +/- 0.7 vs. 8.5 +/- 11.0, p < 0.05), while such a tendency for haloperidol was not observed. The present study suggests that the steady-state plasma concentration of risperidone is not predicted from that of haloperidol in the same individual, probably because of the much greater involvement of CYP2D6 in the metabolism of risperidone than in that of haloperidol.

Adult↗
PubMed1989

Pharmacokinetics of haloperidol.

Haloperidol has been used extensively for the treatment of psychotic disorders, and it has been suggested that the monitoring of plasma haloperidol concentration is clinically useful. Different assay methodologies have been used in research and clinical practice to examine the relationship between response and plasma concentration of the drug. Chemical assays such as high pressure liquid chromatography (HPLC) and gas-liquid chromatography (GLC) have good precision and sensitivity; radioimmunoassay (RIA) is generally more sensitive, but less precise and specific. Radioreceptor assay quantifies dopaminereceptor blocking activity but does not provide results comparable with those of HPLC, GLC and RIA. Large doses of haloperidol can safely be given intravenously and intramuscularly for rapid neuroleptisation; the bioavailability of this agent administered orally ranges from 60 to 65%. However, there is large interindividual, but not intraindividual, variability in plasma haloperidol concentrations and most pharmacokinetic parameters. This interindividual variability could be partially explained by the reversible oxidation/reduction metabolic pathway of haloperidol: it is metabolised via reduction to reduced haloperidol, which is biologically inactive. Different extents of enterohepatic recycling, and ethnic differences in metabolism, could also account for the observed variability in haloperidol disposition. Although not conclusive from different clinical studies, it appears that a plasma haloperidol concentration range of 4 micrograms/L to an upper limit of 20 to 25 micrograms/L produces therapeutic response. The role of reduced haloperidol in determining clinical response is not clear, although in some studies a high reduced haloperidol/haloperidol concentration ratio has been suggested to be associated with therapeutic failure. Measurements of red blood cell or cerebrospinal fluid haloperidol concentration have also been proposed as determinants of therapeutic response, but results from different studies are inconsistent, and do not seem to provide a significant advantage over plasma concentration monitoring. Physiological parameters such as prolactin and homovanillic acid levels have been evaluated, with the latter showing some promise that warrants further investigation. Haloperidol decanoate can be characterised by a flip-flop pharmacokinetic model because its absorption rate constant is slower than the elimination rate constant. Its plasma concentration peaks on day 7 after intramuscular injection. The elimination half-life is about 3 weeks, and the time to steady-state is about 3 months.

Drug Interactions↗
PubMed2006

Haloperidol dose when used as active comparator in randomized controlled trials with atypical antipsychotics in schizophrenia: comparison with officially recommended doses.

OBJECTIVE: To determine the doses of haloperidol as a comparator drug in randomized controlled trials (RCTs) with atypical antipsychotics in patients with schizophrenia and to compare these doses with the officially recommended doses for haloperidol in the United States and the United Kingdom. DATA SOURCES: We searched for RCTs conducted and published in English in full before January 2005 in which atypical antipsychotics were compared with haloperidol for the treatment of schizophrenia. We searched for Cochrane Reviews in which 1 of the following atypical antipsychotics was evaluated for the treatment of patients with schizophrenia, schizophreniform psychosis, or other primary psychosis: amisulpride, aripiprazole, olanzapine, quetiapine, risperidone, sertindole, and ziprasidone. For the gap between the end point of inclusion of the studies in the Cochrane Reviews and January 2005, we electronically searched the Cochrane Central Register of Controlled Trials for any further RCTs in which atypical antipsychotics were compared with haloperidol for the same indication. Search terms used were haloperidol and schizophren and haloperidol and psychotic, as well as the names of the selected atypical antipsychotics for the years that were not covered by the Cochrane Reviews. For each study, the required dose and mean dose of haloperidol were compared with officially recommended doses of haloperidol in U.S. (Food and Drug Administration) and U.K. (British National Formulary) guidelines. DATA SYNTHESIS: In all of the included studies (N = 49), the midpoints of the required doses were above the midpoint of the official recommended doses in the United States and United Kingdom for moderately ill patients. In 94% (U.S.) and 80% (U.K.) of the studies, they were above the upper border of the recommended doses. Compared with recommended doses for severely ill patients in both the United Kingdom and United States (range, 6-15 mg daily), in 17 studies (35%) the mean actual used dose was above the upper dose border for severely ill patients (15 mg daily). CONCLUSIONS: Nearly all randomized clinical trials used haloperidol in doses that were higher than the official recommended doses for moderately ill or even severely ill patients. Therefore, it is probable that the results of the RCTs were affected by the high dose of haloperidol, hampering the interpretation of the effects of atypical anti-psychotics in their comparison with haloperidol.

Antipsychotic Agents↗
PubMed1982

Stability of haloperidol in 5% dextrose injection.

The stability of haloperidol in 5% dextrose injection using a high-pressure liquid chromatographic (HPLC) method is reported. A solution of haloperidol 10 mg/dl in 5% dextrose injection was prepared using commercially available haloperidol injection. The solution was stored at 24 degrees C, half in an amber glass bottle and half in a plastic bag. These were assayed on days 0, 1, 7, 14, and 38. Solutions prepared from commercial dosage forms of haloperidol (injection, oral liquid concentrate, and tablets) were assayed to verify the accuracy of the HPLC assay to quantify haloperidol. There was no loss of haloperidol potency in 38 days when stored 24 degrees C in either the amber glass bottle or plastic bag. There was a substantial loss of methylparaben and propylparaben (present in commercial haloperidol injection) in the solution stored in the plastic bag. Oxidation products of haloperidol did not interfere with the assay, and the HPLC assay accurately measured haloperidol in solutions prepared from commercial dosage forms. The results show that haloperidol 10 mg/dl in 5% dextrose injection was stable for at least 38 days. While the loss of parabens is not of practical importance, the HPLC method developed provided this information while the previously used USP-NF procedure did not. The assay can be used to quantify haloperidol in commercial dosage forms.

Chemistry, Pharmaceutical↗
PubMed1998

S 16924 ((R)-2-[1-[2-(2,3-dihydro-benzo[1,4] dioxin-5-Yloxy)-ethyl]-pyrrolidin-3yl]-1-(4-fluoro-phenyl)-ethanone), a novel, potential antipsychotic with marked serotonin (5-HT)1A agonist properties: I. Receptorial and neurochemical profile in comparison with clozapine and haloperidol.

S 16924 showed a pattern of interaction at multiple (>20) native, rodent and cloned, human (h) monoaminergic receptors similar to that of clozapine and different to that of haloperidol. Notably, like clozapine, the affinity of S 16924 for hD2 and hD3 receptors was modest, and it showed 5-fold higher affinity for hD4 receptors. At each of these sites, using a [35S]GTPgammaS binding procedure, S 16924, clozapine and haloperidol behaved as antagonists. In distinction to haloperidol, S 16924 shared the marked affinity of clozapine for h5-HT2A and h5-HT2C receptors. However, an important difference to clozapine (and haloperidol) was the high affinity of S 16924 for h5-HT1A receptors. At these sites, using a [35S]GTPgammaS binding model, both S 16924 and clozapine behaved as partial agonists, whereas haloperidol was inactive. In vivo, the agonist properties of S 16924 at 5-HT1A autoreceptors were revealed by its ability to potently inhibit the firing of raphe-localized serotoninergic neurones, an action reversed by the selective 5-HT1A receptor antagonist, WAY 100,635. In contrast, clozapine and haloperidol only weakly inhibited raphe firing, and their actions were resistant to WAY 100,635. Similarly, S 16924 more potently inhibited striatal turnover of 5-HT than either clozapine or haloperidol. Reflecting its modest affinity for D2 (and D3) autoreceptors, S 16924 only weakly blocked the inhibitory influence of the dopaminergic agonist, apomorphine, upon the firing rate of ventrotegmental area-localized dopaminergic neurones. Further, S 16924 only weakly increased striatal, mesolimbic and mesocortical turnover of dopamine (DA). Clozapine was, similarly, weakly active in these models, whereas haloperidol, in line with its higher affinity at D2 (and D3) receptors, was potently active. In the frontal cortex (FCX) of freely moving rats, S 16924 dose-dependently reduced dialysate levels of 5-HT, whereas those of DA and NAD were dose-dependently increased in the same samples. In contrast, although S 16924 also suppressed 5-HT levels in the striatum and nucleus accumbens, DA levels therein were unaffected. Clozapine mimicked this selective increase in DA levels in the FCX as compared to striatum and accumbens. In contrast, haloperidol modestly increased DA levels in the FCX, striatum and accumbens to the same extent. In distinction to S 16924, clozapine and haloperidol exerted little influence upon 5-HT levels. Finally, the influence of S 16924 upon FCX levels of 5-HT, DA (and NAD) was attenuated by WAY 100,635. In conclusion, S 16924 possesses a profile of interaction at multiple monoaminergic receptors comparable to that of clozapine and distinct to that of haloperidol. In addition, S 16924 is a potent, partial agonist at 5-HT1A receptors. Correspondingly, acute administration of S 16924 decreases cerebral serotoninergic transmission and selectively reinforces frontocortical as compared to subcortical dopaminergic transmission. In line with these actions, S 16924 shows a distinctive profile of activity in functional (behavioral) models of potential antipsychotic activity (companion paper).

Animals↗
PubMed1995

Effect of alosetron (a new 5-HT3 receptor antagonist) on the pharmacokinetics of haloperidol in schizophrenic patients.

Alosetron is under clinical development for the treatment of schizophrenia. This study evaluated the effect of oral alosetron dosing on the pharmacokinetics of haloperidol, the latter being administered daily to 13 schizophrenic patients for 56 days. Alosetron 1 mg daily or placebo was given by random assignment for 2 weeks. After a two-week alosetron washout period (during which patients received placebo), patients received the alternate treatment for another two weeks. Serial blood samples were collected for high-performance liquid chromatography determination of plasma haloperidol, reduced haloperidol, and alosetron at selected times for 24 hours after administration of haloperidol and alosetron on study days 21 and 49. Mean pharmacokinetic parameters of haloperidol in the presence of alosetron and placebo treatments were not significantly (P > .05) different: dose-normalized Cmax (6.40 versus 5.75 ng/mL), dose-normalized Cmin (2.00 versus 1.90 ng/mL), dose-normalized AUC (85.97 versus 68.48 ng.hr/mL), and CL/f (78.23 versus 104.7 L/hr). A two-compartment model was used to assess the concentration- and time-independent pharmacokinetics of haloperidol after multiple dosing. The model confirmed that there was no change in the pharmacokinetics of haloperidol when alosetron was administered concomitantly. Mean AUC ratios of reduced haloperidol to haloperidol (0.18) in the presence of alosetron were similar to values obtained in the absence of alosetron, indicating that alosetron had no influence on the metabolism of haloperidol. Mean pharmacokinetic parameters of alosetron were similar to those in previous studies in healthy subjects.

Adult↗
PubMed1996

Lack of pharmacokinetic interaction between buspirone and haloperidol in patients with schizophrenia.

The pharmacokinetic interaction between buspirone and haloperidol was evaluated in schizophrenic patients in two different groups. In both groups, haloperidol doses (10-40 mg/day) remained constant for 6 weeks before the addition of buspirone 10 mg three times daily. Serial blood samples were obtained from the 11 patients in group I at baseline (before addition of buspirone) and after administration for 24 hours. The pharmacokinetic parameters of haloperidol were determined alone and with coadministration of buspirone. In group II, buspirone 10 mg three times daily was added to treatment with haloperidol in 27 patients. Blood samples were obtained before addition of buspirone and at weeks 2 and 6 of treatment with buspirone. Samples were obtained 10 to 12 hours after administration of the evening dose and before the morning dose. Haloperidol and its metabolite, reduced haloperidol (RH), were assayed by means of high-performance liquid chromatography with electrochemical detection. Significant changes in the pharmacokinetic parameters of haloperidol were not found in group I; a mean increase in the half-life (t1/2) of haloperidol from 21.5 to 28.1 hours was observed, but this finding was not statistically significant. Under steady-state conditions, plasma levels of haloperidol in the patients in group II did not change significantly from baseline to week 6. Plasma concentrations of RH remained unaltered in both groups. The results indicate that coadministration of buspirone does not markedly affect the pharmacokinetics or plasma concentrations of haloperidol.

Adult↗
PubMed1990

Direct radioimmunoassay for haloperidol in human serum.

A direct radioimmunoassay for the accurate determination of haloperidol in human serum has been developed. Based on recent information about the metabolism of haloperidol, a new haloperidol hapten, in which a (3-carboxypropionyl)methylamino group was attached as a bridge in the place of fluorine atom, was synthesized and coupled to bovine serum albumin through the bridge to provide a new immunogen. Guinea pigs were used for the immunization. Since the antisera obtained by the new immunogen still cross reacted greater than 10% with reduced haloperidol, the immunological tolerance to reduced haloperidol was induced by administration of a copolymer of D-glutamic acid and D-lysine linked with reduced haloperidol. This gave an antiserum in guinea pigs which was highly specific for unchanged haloperidol with negligible cross reactivity (less than or equal to 1.0%) to any haloperidol metabolites including the newly found ones. With the newly developed antiserum and [3H]haloperidol, serum haloperidol levels can be determined over the concentration range from 0.3 to 20 ng/mL, using 0.1 mL of human serum, without an extraction procedure.

Animals↗
PubMed1999

Potencies of haloperidol metabolites as inhibitors of the human noradrenaline, dopamine and serotonin transporters in transfected COS-7 cells.

Extrapyramidal symptoms, such as tardive dyskinesia, often develop in patients on long-term treatment with haloperidol. It has been proposed that these symptoms could be caused by neurotoxic effects of haloperidol metabolites following uptake by monoamine transporters, in an analogous mechanism to the neurotoxic effect of MPP+ (1-methyl-4-phenylpyridinium) metabolised from MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). In this study, the hypothesis was partially investigated by determining the potencies of haloperidol and reduced haloperidol and the corresponding pyridinium and tetrahydropyridine metabolites, compared with MPP+ and MPTP, as inhibitors of the noradrenaline transporter (NAT), dopamine transporter (DAT) and 5-HT transporter (SERT). Two days after COS-7 cells were transiently transfected with the cDNA for the human NAT, DAT or SERT (Lipofectamine method), the cells were incubated with 10 nM [3H]noradrenaline, dopamine or 5-HT, respectively, for 2 min at 37 C, in the absence or presence of various concentrations of the eight compounds or a specific uptake inhibitor (NAT: nisoxetine 1 microM; DAT: GBR 12909 1 microM; SERT: citalopram 10 microM). Specific amine uptake (fmol/ mg protein) was calculated as the difference in uptake in the absence and presence of the specific uptake inhibitor. Ki values were calculated for the eight compounds for inhibition of NAT, DAT and SERT. Haloperidol, its five metabolites and MPP+ and MPTP all inhibited NAT, DAT and SERT. For the pyridinium and tetrahydropyridine metabolites of haloperidol, there were not marked differences between their potencies as inhibitors between each other for NAT or DAT or between NAT and DAT, with all of the Ki values in the range of 5.8-16 microM. However, there were more marked differences for SERT, with all but one of the metabolites showing selectivity for inhibition of SERT relative to NAT and DAT. Haloperidol and reduced haloperidol had similar inhibitory potencies for all three transporters, and were clearly less potent than the other haloperidol metabolites only for inhibition of SERT. The lack of correlation between the inhibitory potencies of the haloperidol metabolites and their structural analogues, MPTP and MPP+, suggests that they are not likely to cause neurotoxicity by a mechanism analogous to that of the latter neurotoxin.

Animals↗
PubMed2005

Enhanced 5-HT2C receptor signaling is associated with haloperidol-induced "early onset" vacuous chewing in rats: implications for antipsychotic drug therapy.

RATIONALE: Haloperidol is a representative of typical antipsychotics that are still in clinical use and which can lead to abnormal motor activity following repeated administration. The mechanisms underlying antipsychotic-induced dyskinesias are not well understood but are widely held to be related to excessive loss of dopamine function. In several models of dopamine hypofunction, serotonin 5-HT2C receptors have been shown to mediate vacuous chewing movements (VCM), a form of abnormal motor activity. It is well established that repeated haloperidol administration also elicits VCM, but there is no information on how repeated haloperidol administration affects 5-HT2C receptor signaling. OBJECTIVES: In the present study, we tested the hypothesis that repeated daily administration of haloperidol leads to enhanced serotonin 5-HT2C receptor signaling that is associated with increased 5-HT2C-mediated VCM. METHODS: Rats were treated by subcutaneous injection once daily for 21 days with either vehicle, a low dose of haloperidol (0.1 mg kg(-1) day(-1)), or a high dose of haloperidol (1.0 mg kg(-1) day(-1)). Following 1-day withdrawal, rats were either used for behavioral scoring of VCM or sacrificed for biochemical assessment of 5-HT2 receptor-mediated phospholipase C activity and radioligand binding. VCM were scored following two successive "drug" challenges. The first challenge was an injection of vehicle (0.9% saline), and the second challenge was an injection of the 5-HT2C agonist meta-chlorophenylpiperazine (1.0 mg/kg). In this manner, a measure of "spontaneous" and "5-HT2C-elicited" orofacial activity could be made while minimizing animal use. RESULTS: Following 21-day haloperidol treatment at either dose, there was an increase in expression of meta-chlorophenylpiperazine-induced VCM. In a separate experiment, meta-chlorophenylpiperazine-induced VCM were shown to be mediated through 5-HT2C receptors. Striatal 5-HT2C receptor-mediated phospholipase C (PLC) activity and high-affinity agonist-labeled 5-HT2C receptors were also increased following either dose of haloperidol as compared to vehicle treatment. GTP-stimulated PLC activity and striatal Gq proteins were unchanged by haloperidol suggesting that enhanced signaling could be accounted for by alterations at the level of the receptor and not at downstream mechanisms. CONCLUSIONS: Repeated daily administration of haloperidol leads to an adaptive increase in 5-HT2C signaling which may contribute to abnormal motor function associated with antipsychotic use.

Animals↗
PubMed2000

Double blind study of tiapride versus haloperidol and placebo in agitation and aggressiveness in elderly patients with cognitive impairment.

OBJECTIVE: The aim of the present study was to compare the efficacy and safety of tiapride versus haloperidol and placebo in the treatment of agitation and aggressiveness in elderly patients with mild or moderate mental impairment. METHOD: This international, multicentre, randomized, double blind, three parallel groups study compared efficacy and safety of a 21 -day regimen of tiapride 100-300 mg/day versus haloperidol 2-6 mg/day and placebo in 306 elderly patients with mild or moderate dementia according to DSM III R and behavioural troubles with the Multidimensional Observation Scale for the Elderly Subjects (MOSES) irritability/aggressiveness subscore ranging from 16 to 30. RESULTS: The percentage of responders (defined as patients with at least a 25% MOSES irritability/aggressiveness subscore decrease between the inclusion and the end of the treatment) was significantly greater in the tiapride (63%, P=0.04) and haloperidol (69%, P=0.004) groups than in the placebo group (49%), with no significant difference between the active drugs. Similar results were observed for the mean MOSES irritability/aggressiveness subscores on D7, D21 and at D(end) which were significantly smaller in the tiapride and haloperidol groups than in the placebo group. The decrease between D0 and D(end) was significantly greater in the tiapride (6.57, P=0.009) and haloperidol groups (6.75, P=0.005) than in the placebo group (4.71). The global improvement CGI was significantly better in the tiapride and haloperidol groups than in the placebo group (P=0.03 and P=0.02). No significant difference was observed between the two active drugs or among the three treatment groups for the Folstein's Mini Mental Status scale (MMS) total score, and there was no notable change during treatment. The number of patients with adverse events, assessed on the Udvalg Kliniske Undersogelser scale (UKU), and the number of UKU symptoms were smaller in the tiapride group (62 patients, 61%, 212 events) than in the haloperidol group (77 patients, 76%, 305 events) and identical to that observed in the placebo group (69 patients, 67%, 234 events). Of interest, the number of patients with at least one extrapyramidal symptom was significantly lower (P=0.003) in the tiapride group (16 patients, 16%) than in the haloperidol group (34 patients, 34%) and similar to that of the placebo group (18 patients, 17%); the difference observed between the haloperidol and placebo groups was significant (P=0.008). CONCLUSION: Tiapride is not different from haloperidol in the treatment of agitation and aggressiveness in elderly patients and better tolerated, in particular with significantly fewer extrapyramidal symptoms.

Aged↗
PubMed1994

Acute versus chronic haloperidol: relationship between tolerance to catalepsy and striatal and accumbens dopamine, GABA and acetylcholine release.

Using in vivo microdialysis, changes in extracellular dorsolateral striatum and nucleus accumbens dopamine, GABA and acetylcholine following acute and chronic haloperidol (0.25 mg/kg, s.c.) were evaluated in rats concurrent with the measurement of catalepsy. When administered to drug-naive and chronically treated rats, haloperidol was associated with a consistent and prolonged (> 150 min) increase in dorsolateral striatum and nucleus accumbens DA release and a transient (60 min) increase in dorsolateral striatum GABA release. Haloperidol was also associated with a transient (30 min) increase in dorsolateral striatum acetylcholine release in the chronically treated rats. Basal dopamine and acetylcholine levels were similar in both brain regions; however, basal dorsolateral striatum GABA levels were two-fold higher in the chronically treated rats. Administration of haloperidol was associated with a prolonged (> 150 min) catalepsy in the drug-naive rats which was greatly diminished or absent in chronically treated rats. Additionally, serum haloperidol levels were shown to be similar 120 min following administration of haloperidol in both groups. These results indicate a marked behavioral difference in the effects of haloperidol in drug-naive and chronically treated rats which is not related to an altered bioavailability of the drug and which is dissociated from both basal and haloperidol induced effects on dopamine and acetylcholine release in both brain regions. However, the selective elevation of basal dorsolateral striatum GABA release following chronic administration of haloperidol may contribute to the development of tolerance to catalepsy as well as providing an in vivo neurochemical marker of the long-term effects of haloperidol.

Acetylcholine↗
PubMed1989

Redistribution of haloperidol after electroshock: experimental evidence.

We have previously reported that plasma and red blood cell levels of haloperidol, a neuroleptic agent, significantly increased immediately after electroconvulsive shock therapy (ECT) in schizophrenic patients on long term haloperidol treatment. To elucidate the mechanism of this increase, we attempted to reproduce this phenomenon in female Wistar rats. After 4 successive days of ip administration of haloperidol (10 mg/kg body weight, once daily), rats were given ECT through corneal electrodes on the fifth day (a.c. 50 Herz, 55 mA, 2.0 sec). Haloperidol levels were determined in plasma and other major tissues using a radioreceptor assay for haloperidol distribution before and after ECT at appropriate time intervals. Plasma haloperidol level was significantly increased 1 min after ECT but tended to return to the control level (without ECT) after 5 min. A significant decrease in haloperidol concentration in tissues was not observed in any of the tissues examined including frontal cerebrum, striatum, and muscle tissues (gluteal muscles). However, the relatively high haloperidol level and the large volume of muscle tissues suggested that the muscle could be the source of the transient increase in haloperidol levels in plasma. This conclusion was also supported by the data showing no significant rise of plasma haloperidol level after ETC in rats previously given a muscle relaxant, succamethonium chloride.

Animals↗