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PubMed1987

The bioavailability and pharmacokinetics of oral and depot intramuscular haloperidol in schizophrenic patients.

In a four-segment long-term (greater than or equal to 6 mo) study, patients with schizophrenia received oral haloperidol in single daily doses and subsequently depot intramuscular (IM) haloperidol decanoate q28d. For each route of administration, a period of stabilization was followed by a maintenance period. Dosages for both oral haloperidol and IM haloperidol decanoate were determined on the basis of the patient's past psychiatric history and clinical response during the stabilization period. To characterize the concentration-time profile of the two routes of administration, blood samples were obtained on two separate occasions at steady state during maintenance dosing for each route of administration. Examination of values for cumulative area under the plasma concentration-time curves (AUC) to each sampling time indicated a sustained release of haloperidol from the intramuscularly administered haloperidol decanoate. Dose ranges during maintenance periods were 5-35 mg/d for oral haloperidol (mean, 17 mg/d), and 75-500 mg/28 d for IM haloperidol decanoate (mean, haloperidol decanoate was 243 mg equivalents of haloperidol/28 d). The ratio of long-acting to daily oral doses during maintenance therapy ranged from 9.4:1.0 to 15.0:1.0 (mean, 14.1:1.0). At these ratios, plasma concentration data showed that haloperidol decanoate gave lower values than did oral haloperidol for peak plasma, minimum plasma, and mean steady-state plasma concentrations. The absolute concentration swing was significantly less for decanoate than for the oral drug. Dose-normalized AUC values were compared determine the IM dose of haloperidol decanoate that would have yielded haloperidol plasma concentrations equivalent to those resulting from daily oral administration of haloperidol for 28 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1996

Investigation of pharmacokinetic and pharmacodynamic interactions after coadministration of nefazodone and haloperidol.

A double-blind, placebo-controlled study using 12 healthy men was designed to evaluate pharmacokinetic and pharmacodynamic interactions when nefazodone and haloperidol are coadministered. Two groups of six subjects each received a 5-mg oral dose of haloperidol or a placebo on study days 1 and 2. Nefazodone, 200 mg, was administered to all 12 subjects twice daily (every 12 hours) on study days 3 to 9; on study day 10, only the morning dose of nefazodone was administered. On study days 9 and 10, all subjects also received 5 mg of haloperidol or a placebo along with the morning dose of nefazodone. Serial blood samples for pharmacokinetic analysis were collected from each subject over a 12-hour period after the morning dose on study days 1, 2, 9, and 10. Plasma samples were assayed for haloperidol, reduced haloperidol, nefazodone, hydroxynefazodone and m-chlorophenylpiperazine by specific, validated high-performance liquid chromatogoraphy methods. Psychomotor performance tests to evaluate haloperidol pharmacodynamics were also performed on days 1, 2, 9, and 10. Reduced haloperidol in the majority of samples was below the limit of quantitation; therefore, the effect of nefazodone on the pharmacokinetics of reduced haloperidol could not be determined. The administration of 5 mg of haloperidol to subjects dosed with nefazodone to steady state led to a modest pharmacokinetic interaction, as indicated by a 36, 13, and 37% increase in mean area under the curve (AUC0-12), highest concentration, and 12-h concentration values for haloperidol, respectively; only the increase in AUC was statistically significant. In contrast, the steady-state pharmacokinetics of nefazodone, hydroxynefazodone, and m-chlorophenylpiperazine were not affected by the administration of haloperidol. Although there were significant differences observed in some psychomotor performance tests, the effects of nefazodone on the pharmacodynamics of haloperidol could not be consistently demonstrated. The results from this study suggest that nefazodone has only modest pharmacokinetic and pharmacodynamic interactions with haloperidol. Although no specific recommendations can be made, dosage adjustment may be necessary for haloperidol when coadministered with nefazodone.

Adult↗
PubMed2004

Influence of i.v. haloperidol on ventricular repolarization and monophasic action potential duration in anesthetized dogs.

INTRODUCTION: i.v. haloperidol is used commonly for sedation in critically ill patients. However, i.v. haloperidol has been shown to cause the life-threatening ventricular tachyarrhythmia torsades de pointes. Mechanisms by which haloperidol causes torsades de pointes have not been widely investigated in controlled studies. STUDY OBJECTIVES: To determine the effects of i.v. haloperidol on electrophysiologic parameters known to promote torsades de pointes. INTERVENTIONS: Monophasic action potential catheters were guided under fluoroscopy into the right and left ventricles of 14 chloralose-anesthetized dogs (haloperidol, nine dogs; placebo, five dogs). Effective refractory period (ERP), action potential duration at 90% repolarization (APD90), and QTc interval measurements were performed at baseline and after each of four doses of haloperidol (0.15, 0.5, 2.0, and 3.0 mg/kg) or placebo at three different pacing cycle lengths (450, 300, and 250 ms). MEASUREMENTS AND RESULTS: i.v. haloperidol significantly prolonged left and right ventricular ERP by a magnitude of 12 to 20% at all pacing cycle lengths. ERP values in the placebo group did not change significantly from pretreatment values in either ventricle. Haloperidol significantly prolonged left ventricular APD90 at a pacing cycle length of 300 ms. The effects of haloperidol on right ventricular APD90 approached significance at a cycle length of 450 ms. Overall, haloperidol prolonged APD90 by 7 to 11%, with less consistent and more variable effects than those for the ERP. APD90 was not significantly altered in the placebo groups. Haloperidol produced significant prolongation in QTc intervals. The electrophysiologic effects of haloperidol were related to dose, with a plateau reached at the 0.5 mg/kg dose for ERP measurements and at the 2 mg/kg dose for the APD90 and QTc interval measurements. CONCLUSIONS: i.v. haloperidol prolongs ventricular ERP and APD90 in intact canine hearts. These electrophysiologic effects are likely associated with the clinical torsades de pointes-inducing actions of i.v. haloperidol in critically ill patients.

Action Potentials↗
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: II. Functional profile in comparison to clozapine and haloperidol.

S 16924 antagonized locomotion provoked by dizocilpine and cocaine, reduced conditioned avoidance responses and blocked climbing elicited by apomorphine, models predictive of control of the positive symptoms of schizophrenia: its median inhibitory dose (ID)50 was 0.96 mg/kg, s.c. vs. 1.91 for clozapine and 0.05 for haloperidol. Rotation elicited in unilateral, substantia nigra-lesioned rats by the D1 agonist, SKF 38393, and by the D2 agonist, quinpirole, was blocked equipotently by S 16924 (0.8 and 1. 7) and clozapine (0.6 and 2.0), whereas haloperidol preferentially blocked quinpirole (0.02) vs. SKF 38393 (1.8). S 16924 more potently inhibited the head-twitches elicited by 1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the locomotion provoked by phencyclidine than it inhibited the locomotion elicited by amphetamine (ID50s = 0.15 and 0.02 vs. 2.4). Clozapine showed a similar preference (0.04 and 0.07 vs. 8.6), but not haloperidol (0. 07 and 0.08 vs. 0.04). The discriminative stimulus (DS) properties of DOI were also blocked by S 16924 (ID50 = 0.17) and clozapine (0. 05) but not by haloperidol (>0.16). S 16924 fully (100%) generalized [effective dose (ED)50 = 0.7] to a clozapine DS and clozapine (0.23) fully generalized to a S 16924 DS whereas haloperidol (>/=0.08) only partially generalized (</=50%) to their DS in each case. Power spectra analysis of electroencephalograms from frontal cortex showed that both S 16924 (2.0) and clozapine (5.0) reinforced frequencies in the 7 to 8 Hz range whereas haloperidol (0.5) preferentially reinforced frequencies in the 10 to 14 Hz range. In a model of perturbation of cognitive-attentional function, significant latent inhibition was obtained with S 16924 (0.08) and clozapine (0.16), but not haloperidol (0.0063 and 0.04): higher doses of S 16924 (2.5), clozapine (5.0) and haloperidol (0.1) all blocked disruption of latent inhibition by amphetamine (1.5). Catalepsy was provoked by haloperidol (0.04-0.63) but not by S 16924 (>/=80.0) or clozapine (>/=80.0). Further, S 16924 (ID50 = 3.2) and clozapine (5.5) inhibited induction of catalepsy by haloperidol. This action of S 16924 was abolished by the 5-HT1A receptor antagonist, WAY 100,635 (0.16), which less markedly attenuated the anticataleptic action of clozapine. Further, although gnawing elicited by methylphenidate was inhibited by S 16924 (ID50 = 8.4), clozapine (19.6) and haloperidol (0.04), only the action of S 16924 was blocked by WAY 100,635 (0.16). Haloperidol potently (0.01-0.16, approximately 24-fold) increased prolactin levels whereas they were less markedly affected by S 16924 (2.5-40.0, 4-fold) and clozapine (10.0-40.0, 3-fold). Clozapine displayed high affinity at cloned, human, muscarinic (M1) and native, histamine (H1) receptors (Kis = 4.6 and 5.4 nM, respectively), whereas S 16924 (>1000 and 158) and haloperidol (>1000 and 453) displayed low affinity. In conclusion, S 16924 displays a profile of activity in diverse models of potential antipsychotic and extrapyramidal properties similar to that of clozapine and different to that of haloperidol. In particular, reflecting its partial agonist actions at 5-HT1A receptors, S 16924 inhibits rather than induces catalepsy in rats. However, in contrast to clozapine, S 16924 displays only low affinity for muscarinic and histaminic receptors.

Amphetamines↗
PubMed2000

Depot haloperidol decanoate for schizophrenia.

BACKGROUND: The mainstay of treatment for schizophrenia is the antipsychotic group of drugs. These are usually given orally but compliance with medication given by this route may be difficult to quantify. Problems with treatment adherence are common. The development of depot injections in the 1960s gave rise to their extensive use as a means of long-term maintenance treatment. Haloperidol decanoate is one depot drug available in clinical practice. OBJECTIVES: To assess the effects of haloperidol decanoate versus oral anti-psychotics and other depot antipsychotic preparations for people with schizophrenia in terms of clinical, social and economic outcomes. SEARCH STRATEGY: Relevant trials were identified by searching Biological Abstracts (1982-1998), Cochrane Library (Issue 2, 1998), Cochrane Schizophrenia Group's Register (June 1998), EMBASE (1980-1998), MEDLINE (1966-1998) and PsycLIT (1974-1998). References of all identified trials were also inspected for more studies. SELECTION CRITERIA: All relevant randomised trials focusing on people with schizophrenia where haloperidol decanoate, oral anti-psychotics or other depot preparations were compared. Outcomes such as death, clinically significant change in global function, mental state, relapse, hospital admission, adverse effects and acceptability of treatment were sought. DATA COLLECTION AND ANALYSIS: Studies were reliably selected, quality rated and data extracted. For dichotomous data Mantel-Haenszel odds ratios (OR) with the 95% confidence intervals (CI) were estimated. Where possible, the number needed to treat statistic (NNT) was calculated. Analysis was by intention-to-treat. Normal continuous data were summated using the weighted mean difference (WMD). Scale data were presented only for those tools that had attained pre-specified levels of quality. MAIN RESULTS: In a haloperidol decanoate versus placebo comparison, two small studies reported that significantly fewer people on depot left early (OR 0.09 CI 0.03-0.21, NNT 2 CI 1-3) or experienced no important improvement in mental state (OR 0. 04 CI 0.01-0.15). Zississ (1982) suggested that those taking haloperidol decanoate would need less additional antipsychotic medication (OR 0.14 Cl 0.04-0.55, NNT 2 CI 1-5). Haloperidol decanoate was compared to oral haloperidol in a single trial that showed no differences in global impression, mental state or side effects ( approximately approximately Zuardi 1983 approximately approximately , n=22). Compliance with medication was not reported in this study. Eight trials compared haloperidol decanoate to other depot neuroleptics and again no differences were found for the outcomes of death, global impression, mental state, behaviour, or side effects. REVIEWER'S CONCLUSIONS: Haloperidol decanoate may have a substantial effect in improving the symptoms and behaviour associated with schizophrenia in comparison to placebo, but data are remarkably sparse. There are no discernible differences between the depot form of haloperidol and its oral equivalent. For those needing and willing to take the drug, the means of administration is then a matter of individual choice and clinical judgement. As there are no clear differences between haloperidol decanoate and other depots, the choice of depot medication could also be individually tailored and patient preference exercised. Well-conducted and reported randomised trials are needed comparing haloperidol decanoate with other depots but the comparison of haloperidol decanoate to oral antipsychotics is a priority.

Antipsychotic Agents↗
PubMed2004

Combined treatment of quetiapine with haloperidol in animal models of antipsychotic effect and extrapyramidal side effects: comparison with risperidone and chlorpromazine.

RATIONALE: Quetiapine, an atypical neuroleptic, has beneficial antipsychotic effects in schizophrenic patients, but with a lower incidence of extrapyramidal symptoms (EPS) compared with typical antipsychotics. While typical antipsychotics are often switched to atypical agents when adverse effects become limiting, there is little preclinical information to support this strategy, both in terms of efficacy and side effects. OBJECTIVES: The antipsychotic effects and EPS during concomitant administration of quetiapine with haloperidol, a typical antipsychotic agent, were evaluated in mice and compared with chlorpromazine and risperidone. METHODS: We first investigated the antipsychotic effects and EPS liability of quetiapine, risperidone, chlorpromazine, and haloperidol when administered alone to select optimal doses for subsequent combination studies. The second study was designed to evaluate the antipsychotic efficacy and EPS profile of concomitant administration of quetiapine, risperidone, or chlorpromazine with haloperidol. Antipsychotic effects were evaluated with the methamphetamine-induced hyperlocomotion test, and EPS liability was evaluated in a catalepsy-induction model. RESULTS: Quetiapine, risperidone, chlorpromazine, and haloperidol dose-dependently reduced methamphetamine-induced hyperlocomotion, with ED50 values of 5.6, 0.020, 1.8, 0.035 mg/kg, respectively. In the catalepsy test, quetiapine only weakly induced catalepsy at the highest dose of 100 mg/kg, whereas risperidone, chlorpromazine, and haloperidol dose-dependently induced catalepsy with ED50 values of 0.25, 4.6, and 0.10 mg/kg, respectively. While the combination of quetiapine (6 mg/kg) and haloperidol (0.04 mg/kg) significantly reduced methamphetamine-induced hyperlocomotion in comparison with haloperidol alone, quetiapine (10, 32 mg/kg) plus haloperidol did not potentiate the cataleptogenic activity of haloperidol. In contrast, risperidone (0.1, 0.32 mg/kg) or chlorpromazine (3.2 mg/kg) significantly augmented catalepsy induced by haloperidol. Catalepsy induced by co-administration of quetiapine (10 mg/kg) and haloperidol (0.1 mg/kg) was significantly potentiated by WAY100635, a 5-HT1A antagonist, and catalepsy induced by co-administration of risperidone (0.1 mg/kg) and haloperidol (0.1 mg/kg) was significantly antagonized by 8-OH-DPAT, a 5-HT1A agonist. CONCLUSION: The present study demonstrated that the combined administration of quetiapine with haloperidol did not aggravate EPS, possibly because of its affinity for 5-HT1A receptors. This finding may have the clinical implication that quetiapine could provide a successful regimen in switching from typical antipsychotic agents in the symptom management of schizophrenia, or even in adjunctive therapy with other antipsychotic agents.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

Involvement of human cytochrome P450 3A4 in reduced haloperidol oxidation.

OBJECTIVE: The present study was conducted to identify in vitro the cytochrome P450(CYP) isoform involved in the metabolic conversion of reduced haloperidol to haloperidol using microsomes derived from human AHH-1 TK +/- cells expressing human cytochrome P450s. The inhibitory and/or stimulatory effects of reduced haloperidol or haloperidol on CYP2D6-catalyzed carteolol 8-hydroxylase activity were also investigated. RESULTS: The CYP isoform involved in the oxidation of reduced haloperidol to haloperidol was CYP3A4. CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 2E1 were not involved in the oxidation. The kM value for the CYP3A4 expressed in the cells was 69.7 micromol x l(-1), and the Vmax was 4.87 pmol x min(-1) x pmol(-1) P450. Troleandomycin, a relatively selective probe for CYP3A enzymes, inhibited the CYP3A4-mediated oxidation of reduced haloperidol in a dose-dependent manner. Quinidine and sparteine competitively inhibited the oxidative reaction with a k(i) value of 24.9 and 1390 micromol x l(-1), respectively. Carteolol 8-hydroxylase activity, which is a selective reaction probe for CYP2D6 activity, was inhibited by reduced haloperidol with a k(i) value of 4.3 micromol x l(-1). Haloperidol stimulated the CYP2D6-mediated carteolol 8-hydroxylase activity with an optimum concentration of 1 micromol x l(-1), whereas higher concentrations of the compound (> 10 micromol x l(-1)) inhibited the hydroxylase activity. CONCLUSION: It was concluded that CYP3A4, not CYP2D6, is the principal isoform of cytochrome P450 involved in the metabolic conversion of reduced haloperidol to haloperidol. It was further found that reduced haloperidol is a substrate of CYP3A4 and an inhibitor of CYP2D6, and that haloperidol has both stimulatory and inhibitory effects on CYP2D6 activity.

Anti-Arrhythmia Agents↗
PubMed1986

Effects of intermittent and continuous haloperidol administration on the dopaminergic system in the rat brain.

The after-effect of intermittent and of continuous treatment with haloperidol on the dopaminergic system of the rat brain was studied. Each rat was treated for 14 days with either a single daily intraperitoneal injection of haloperidol (intermittent haloperidol group) or with a subcutaneously implanted pump that released haloperidol for 14 days (continuous haloperidol group). The total amount of haloperidol administered was 28 mg/kg in each animal of both groups. On the seventh day after cessation of injections or removal of pumps, the changes in dopamine (DA) metabolism after a challenge dose of haloperidol (1 mg/kg, intraperitoneally) were noted, and the number of [3H]spiperone binding sites in the striatum were recorded. The continuous haloperidol group showed a greater tolerance response to the influence of haloperidol on stimulation of DA turnover and also showed a larger increase in the number of [3H]spiperone binding sites than the intermittent haloperidol group. It is concluded that continuously administered haloperidol exerts a stronger effect on DA transmission, which in turn produces a greater tolerance to an acute dose of haloperidol than intermittent haloperidol administration.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

Glutamatergic regulation of haloperidol-induced c-fos expression in the rat striatum and nucleus accumbens.

Acute administration of haloperidol induces the expression of the immediate-early gene c-fos in the striatum and nucleus accumbens via dopamine D(2) receptor antagonism. Dopaminergic transmission in the striatum and nucleus accumbens is modulated by glutamate via N-methyl-D-aspartate (NMDA) receptors. Indeed, haloperidol-induced c-fos expression is dependent on NMDA receptor activation in the dorsolateral part of the striatum. However, the role that NMDA receptors play in haloperidol-induced c-fos expression in other functionally distinct areas of the striatum and nucleus accumbens has not yet been established. Therefore, in the present study the entire rostrocaudal extent of the rat striatum and nucleus accumbens was examined to determine the role that NMDA receptors play in haloperidol-induced c-fos expression. Pretreatment with MK-801, a non-competitive antagonist of NMDA receptors, significantly reduced the number of neurons showing c-fos immunoreactivity in the rostral aspect of the dorsolateral striatum and the entire rostrocaudal extent of the ventrolateral striatum following an acute injection of haloperidol. However, the same treatment did not modify the pattern of haloperidol-mediated c-fos expression in the medial or central parts of the striatum. Similarly, MK-801 pretreatment significantly suppressed the number of neurons expressing c-fos immunoreactivity following haloperidol injection in the entire rostrocaudal extent of the shell region of nucleus accumbens, but not in the core region. The results indicate that haloperidol-induced c-fos expression is dependent on NMDA receptors only in the rostral aspect of the dorsolateral striatum and the rostrocaudal extent of the ventrolateral striatum, the areas involved in motor function. The differential role that NMDA receptors play in modulating haloperidol-mediated dopamine D(2) receptor antagonism between motor and associative areas of the striatum may contribute to the development of extrapyramidal symptoms following chronic haloperidol treatment. Furthermore, the attenuation of the haloperidol-induced c-fos expression by MK-801 was restricted to the nucleus accumbens shell, an area often implicated in the therapeutic effect of haloperidol. Therefore, the NMDA-dopamine D(2) receptor interaction may also play a role in mediating the therapeutic effects of haloperidol.

Animals↗
PubMed1997

The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes.

1. The antipsychotic drug haloperidol can induce a marked QT prolongation and polymorphic ventricular arrhythmias. In this study, we expressed several cloned cardiac K+ channels, including the human ether-a-go-go related gene (HERG) channels, in Xenopus oocytes and tested them for their haloperidol sensitivity. 2. Haloperidol had only little effects on the delayed rectifier channels Kv1.1, Kv1.2, Kv1.5 and IsK, the A-type channel Kv1.4 and the inward rectifier channel Kir2.1 (inhibition < 6% at 3 microM haloperidol). 3. In contrast, haloperidol blocked HERG channels potently with an IC50 value of approximately 1 microM. Reduced haloperidol, the primary metabolite of haloperidol, produced a block with an IC50 value of 2.6 microM. 4. Haloperidol block was use- and voltage-dependent, suggesting that it binds preferentially to either open or inactivated HERG channels. As haloperidol increased the degree and rate of HERG inactivation, binding to inactivated HERG channels is suggested. 5. The channel mutant HERG S631A has been shown to exhibit greatly reduced C-type inactivation which occurs only at potentials greater than 0 mV. Haloperidol block of HERG S631A at 0 mV was four fold weaker than for HERG wild-type channels. Haloperidol affinity for HERG S631A was increased four fold at +40 mV compared to 0 mV. 6. In summary, the data suggest that HERG channel blockade is involved in the arrhythmogenic side effects of haloperidol. The mechanism of haloperidol block involves binding to inactivated HERG channels.

Animals↗
PubMed1994

Continuous infusion of haloperidol controls agitation in critically ill patients.

OBJECTIVE: To evaluate the safety and efficacy of continuous infusion of haloperidol in treating agitated critically ill adult patients. DESIGN: Case series of patients treated with continuous infusion of haloperidol and followed to hospital discharge, during a 6-month period. SETTING: A 34-bed multidisciplinary intensive care unit (ICU) in a 598-bed nonuniversity, tertiary care teaching hospital. PATIENTS: Consecutive sample of eight patients requiring mechanical ventilation who had severe agitation which was refractory to intermittent bolus treatment with benzodiazepines, narcotics, and haloperidol. INTERVENTIONS: Continuous infusions of haloperidol (range 3 to 25 mg/hr) were supplemented, as required, to maintain adequate sedation. MEASUREMENTS AND MAIN RESULTS: The four men and four women averaged 47 yrs of age, and the average length of hospitalization was 33 days, with 25 days spent in the ICU. On the day continuous infusion of haloperidol was initiated, the average Acute Physiology and Chronic Health Evaluation (APACHE) II and Therapeutic Intervention Scoring System (TISS) scores were 24 and 47, respectively. The Sedation-Agitation Scale score averaged +2.4 (maximum agitation score being +3) before continuous infusion of haloperidol decreasing to +1.8 after 1 day (p = .38) and to +0.8 after 2 days (p = .06) of continuous infusion of haloperidol. The average daily haloperidol dose increased from 68 mg before continuous infusion of haloperidol to 269 mg (p < .008) after 1 day. The daily total of nonhaloperidol sedatives decreased from 18.3 to 10.9 sedation-equivalent units (p = .15) and the daily number of bolus administrations of sedatives decreased from 23 to 7 (p = .01) after 1 day of continuous infusion of haloperidol. Estimated nursing time to prepare, administer, and monitor these bolus medications decreased from 320 to 96 mins per 24 hrs (p = .01). Of the five patients discharged alive (37.5% mortality rate), four were successfully weaned from assisted ventilation during continuous infusion of haloperidol. Two of these four patients were difficult to wean because of agitation and oversedation. Four possible complications were noted: minor tremors (n = 2), atrial dysrhythmias with intermittent third-degree atrioventricular block and QT interval prolongation (n = 1), and ventricular tachycardia (n = 1). CONCLUSIONS: Continuous infusion of haloperidol effectively controls severe agitation in critically ill patients, reduces requirements for bolus administration of sedatives and nursing time lost to that task, and may facilitate ventilator weaning. Parenteral administration of haloperidol was associated with few complications in > 1,340 patient-hours of continuous administration.

Adolescent↗
PubMed2004

Haloperidol half-life after chronic dosing.

In normal subjects after a single oral dose, haloperidol half-life has been reported to range 14.5-36.7 hours (or up to 1.5 days). After chronic administration, half-lives of up to 21 days have been reported. The objective of this study was to evaluate specific factors that might account for differences in haloperidol half-life in patients taking haloperidol chronically, including gender, age, weight, race, CYP2D6 and CYP3A5 genotypes, comedication, and smoking.Thirty-one patients were administered haloperidol for 4 weeks followed by a 1-week washout before administration of clozapine. Haloperidol plasma levels were measured weekly for at least 2 months after discontinuation. The geometric mean for haloperidol half-life and detectable levels duration were 3.9 and 13.8 days, respectively. Within 31 subjects, 58% (18/31) had half-lives <3 days (1.2-2.3 days) and 42% (13/31) had half-lives > or =3 days. Two of 3 patients with half-lives longer than 30 days (720 hours) and levels detectable >2 months had received haloperidol decanoate. Five patients who received haloperidol decanoate in the prior year were excluded from a comparison between patients with long haloperidol half-lives (> or =3 days, n = 10) and patients with short half-lives (<3 days, n = 16). The only significant difference between the two groups was that African-Americans (n = 4) were all found to have a long haloperidol half-life (P = 0.014). CYP3A5 genotype did not appear to influence haloperidol half-life but the two CYP2D6 poor metabolizer had half-lives > or =3 days. This study suggests that haloperidol half-life following repeated drug administration is substantially more prolonged than what has been observed after acute haloperidol administration.

Adult↗
PubMed2001

The effect of intravenous haloperidol on QT interval dispersion in critically ill patients: comparison with QT interval prolongation for assessment of risk of Torsades de Pointes.

The objective of this study was to determine the effect of intravenous haloperidol on QT interval dispersion in critically ill patients and to compare increases in QT interval dispersion and QTc intervals in patients who developed haloperidol-induced Torsades de Pointes versus those in patients who did not. This was a case-controlled study of 30 critically ill patients who received intravenous haloperidol for delusional agitation. Cases were patients (n = 6) who developed Torsades de Pointes during haloperidol therapy. Controls were patients (n = 24) who did not experience haloperidol-induced Torsades dePointes. QTc intervals were measured and QT interval dispersion was calculated. Haloperidol prolonged QTc interval compared to pretreatment values in Torsades de Pointes patients (606 +/- 61 ms vs. 501 +/- 44 ms, p = 0.007) by a greater magnitude than in patients who did not experience Torsades de Pointes (507 +/- 60 ms vs. 466 +/- 44, p = 0.01). Twelve-lead analysis revealed that QT interval dispersion increased in patients who experienced Torsades de Pointes (from 63 +/- 11 to 95 +/- 22 ms, p = 0.03) but not in those who did not (62 +/- 18 vs. 60 +/- 26 ms, p = 0.66). Analysis of precordial leads only showed no significant haloperidol-associated increases in QTinterval dispersion in eithergroup. The odds of developing haloperidol-induced Torsades de Pointes were highest in patients with QTc interval > 521 ms during haloperidol therapy(odds ratio = 12.1). It was concluded that intravenous haloperidol prolongs QTc intervals in critically ill patients. The degree of prolongation is greater in patients who experience Torsades de Pointes. QT interval dispersion may be increased in patients who develop haloperidol-induced Torsades de Pointes compared with those who do not. However, these effects are dependent on the method of measurement (12 leads vs. precordial leads). In addition, the odds of haloperidol-induced Torsades de Pointes are higherin patients with QTc intervalprolongation compared with increased QT interval dispersion. Therefore, QTc interval determination remains preferable to QT interval dispersion as a means assessment of risk for haloperidol-induced Torsades de Pointes.

Aged↗
PubMed1992

Interindividual variabilities in haloperidol interconversion and the reduced haloperidol/haloperidol ratio.

Metabolism of haloperidol in humans includes N-dealkylation to inactive metabolites and reduction to reduced haloperidol; reduced haloperidol is also oxidized back to haloperidol. A single 0.5 mg/kg (0.00133 mmol/kg) oral dose of haloperidol and reduced haloperidol was administered to seven Chinese schizophrenics in a randomized crossover manner separated by a 2-week interval. The clearance values for the different metabolic pathways of haloperidol and reduced haloperidol were determined. There were differences up to 10-fold in both oxidation and reduction capacities. There were also interindividual variabilities in the elimination of reduced haloperidol (0.37 +/- 0.20 L/hr/kg) and the N-dealkylation pathway (0.74 +/- 0.36 L/hr/kg). Four weeks after the single-dose study, the same patients also received haloperidol (10 mg) twice daily for 4 weeks. The reduced haloperidol to haloperidol concentration ratio (0.40 +/- 0.16) after the 4-week therapy is related to individual variabilities in the interconversion process and the N-dealkylation pathway of haloperidol.

Adult↗
PubMed2000

Positron emission tomography of radioligand binding in porcine striatum in vivo: haloperidol inhibition linked to endogenous ligand release.

The ligands N-methylspiperone and haloperidol both bind to D(2)-like dopamine receptors. The competitive nature of the binding over a wide range of haloperidol concentrations and the effect on dopamine release have never been tested in vivo. We determined the competitive interaction between 3-N-[(11)C]methylspiperone ([(11)C]NMSP) and haloperidol binding to striatal dopamine D(2)-like receptors with positron emission tomography (PET) of pig brain. [(11)C]NMSP tomography was performed with haloperidol at five different plasma concentrations maintained constant by programmed infusion. Kinetic parameters of ligand competition for binding in the striatum were determined by deconvolving time-activity curves of the striatum and cerebellum from metabolite-corrected arterial plasma [(11)C]NMSP and haloperidol concentrations. Two types of [(11)C]NMSP-binding sites were evident in the striatum, both saturable by haloperidol administration. The preponderant or primary sites bound [(11)C]NMSP irreversibly, as dopamine D2-like receptors, while the secondary sites bound [(11)C]NMSP reversibly, as do serotonin S2 receptors. Woolf-Hanes plots revealed the predicted approximately linear relationships between the binding indices and the haloperidol plasma concentration. For the irreversible binding sites, this relationship indicated a 50% inhibitory concentration of haloperidol of 2 nM in plasma and a maximum binding capacity of 64 pmol cm(-3) in striatum. For the reversible binding sites, the relationship indicated a 50% inhibitory plasma concentration of haloperidol of 1 nM and a maximum binding capacity of 4.5 pmol cm(-3). Second-order polynomial Eadie-Hofstee-Scatchard plots were consistent with increased competition from an endogenous ligand of the irreversibly binding sites only with increasing doses of haloperidol. At the highest haloperidol dose, this hypothetical endogenous ligand had risen 6-7-fold. We contend that this reveals the release of dopamine by high concentrations of haloperidol.

Animals↗
PubMed2001

Haloperidol versus placebo for schizophrenia.

BACKGROUND: Haloperidol was developed in the late 1950s for use in the field of analgesia. Research subsequently demonstrated effects on hallucinations, delusions, aggressiveness, impulsiveness and states of excitement and led to the introduction of haloperidol as an antipsychotic. OBJECTIVES: To evaluate the clinical effects of haloperidol for the management of schizophrenia and other similar serious mental illnesses compared to placebo. SEARCH STRATEGY: Electronic searches of Biological Abstracts (1985-1998), CINAHL (1982-1998), The Cochrane Library (1998, Issue 4), The Cochrane Schizophrenia Group's Register (December 2000), EMBASE (1980-1998), MEDLINE (1966-1998), PsycLIT (1974-1998), and SCISEARCH (January 1974-December 1998) were undertaken. References of all identified studies were searched for further trial citations. Authors of trials and pharmaceutical companies were contacted for further information and archive material. SELECTION CRITERIA: All relevant randomised controlled trials comparing use of haloperidol (any dose) with placebo for those with schizophrenia or other similar serious, non-affective psychotic illnesses (however diagnosed). The main outcomes of interest were death, loss to follow up, clinical and social response, relapse and severity of adverse effects. DATA COLLECTION AND ANALYSIS: Reviewers evaluated data independently and analysed on an intention-to-treat basis, assuming that people who left the study early, or were lost to follow up, had no improvement. Where possible and appropriate, dichotomous data were analysed using relative risk (RR) and their 95% confidence intervals (CI) calculated. If appropriate, the number needed to treat (NNT) or number needed to harm (NNH) was estimated. For continuous data, weighted mean differences were calculated. Continuous data were excluded if loss to follow up was greater than 50%. All data were inspected for heterogeneity. MAIN RESULTS: Seventy-four trials were identified but only 20 included. More people allocated to haloperidol improved in the first six weeks of treatment than those given placebo (three trials, n=159, RR failing to produce a marked improvement 0.44 CI 0.3 to 0.6, NNT 3 CI 2 to 5). A further eight trials (n=313) also found a difference favouring haloperidol across the 6-24 week period (RR no marked global improvement 0.68 CI 0.6 to 0.8 NNT 3 CI 2.5 to 5) but this may be an overestimate of effect as small negative studies were not identified. About half of those entering studies failed to complete the short trials, although, at 0-6 weeks, 10 studies found a difference that favoured haloperidol (n=686, RR 0.82 CI 0.7 to 0.95, NNT 8 CI 5 to 17). Limited adverse effect data do, nevertheless, support the clinical impression that haloperidol is a potent cause of movement disorders, at least in the short term. Haloperidol promotes acute dystonia (three trials, n=135, RR 4.7 CI 1.7 to 44, NNH 5 CI 3 to 9 - not assuming those who left early from placebo suffered dystonis), akathisia (three trials, n=129, RR 6.5 CI 1.5 to 28, NNH 6 CI 4 to 14) and parkinsonism (four trials, n=165, RR 8.9 CI 2.6 to 31, NNH 3 CI 2 to 5). REVIEWER'S CONCLUSIONS: Haloperidol is a potent antipsychotic drug but with a high propensity to cause adverse effects. Given no choice of drug, use of haloperidol to counter the damaging and potentially dangerous consequences of untreated schizophrenia is justified. If a choice of drug is available, however, people with schizophrenia and clinicians may wish to start another antipsychotic with less likelihood of causing parkinsonism, akathisia and acute dystonias. For countries where haloperidol is not widely used, it should not be a control drug of choice for randomised trials of new antipsychotics.

Antipsychotic Agents↗
PubMed2006

Haloperidol versus placebo for schizophrenia.

BACKGROUND: Haloperidol was developed in the late 1950s for use in the field of anaesthesia. Research subsequently demonstrated effects on hallucinations, delusions, aggressiveness, impulsiveness and states of excitement and led to the introduction of haloperidol as an antipsychotic. OBJECTIVES: To evaluate the clinical effects of haloperidol for the management of schizophrenia and other similar serious mental illnesses compared to placebo. SEARCH STRATEGY: We initially electronically searched the databases of Biological Abstracts (1985-1998), CINAHL (1982-1998), The Cochrane Library (1998, Issue 4), The Cochrane Schizophrenia Group's Register (December 1998), EMBASE (1980-1998), MEDLINE (1966-1998), PsycLIT (1974-1998), and SCISEARCH. We also checked references of all identified studies for further trial citations and contacted the authors of trials and pharmaceutical companies for further information and archive material. For the 2005 update we searched The Cochrane Library (2005, Issue 6). SELECTION CRITERIA: We included all relevant randomised controlled trials comparing the use of haloperidol (any oral dose) with placebo for those with schizophrenia or other similar serious, non-affective psychotic illnesses (however diagnosed). Our main outcomes of interest were death, loss to follow up, clinical and social response, relapse and severity of adverse effects. DATA COLLECTION AND ANALYSIS: We evaluated data independently and analysed on an intention-to-treat basis, assuming that people who left the study early, or were lost to follow-up, had no improvement. Where possible and appropriate, we analysed dichotomous data using Relative Risk (RR) and calculated their 95% confidence intervals (CI). If appropriate, the number needed to treat (NNT) or number needed to harm (NNH) was estimated. For continuous data, we calculated weighted mean differences. We excluded continuous data if loss to follow up was greater than 50% and inspected data for heterogeneity. MAIN RESULTS: Twenty-one trials randomising 1519 people are now included in this review. One new trial, Kane 2002 (n=414) has been added but it did not affect the overall results. More people allocated haloperidol improved in the first six weeks of treatment than those given placebo (3RCTs n=159, RR failing to produce a marked improvement 0.44 CI 0.3 to 0.6, NNT 3 CI 2 to 5). A further eight trials also found a difference favouring haloperidol across the 6-24 week period (8 RCTs n=308 RR no marked global improvement 0.68 CI 0.6 to 0.8 NNT 3 CI 2.5 to 5) but this may be an over estimate of effect as small negative studies were not identified. About half of those entering studies failed to complete the short trials, although, at 0-6 weeks, 11 studies found a difference that marginally favoured haloperidol (11 RCTs n=898, RR 0.8 CI 0.7 to 0.9, NNT 59 CI 38 to 200). Adverse effect data does, nevertheless, support clinical impression, that haloperidol is a potent cause of movement disorders, at least in the short term. Haloperidol promotes acute dystonia (3 RCTs n=93, RR 4.7 CI 1.7 to 44, NNH 5 CI 3 to 9), akathisia (4 RCTs n=333, RR 2.6 CI 1.4 to 4.8, NNH 7 CI 3 to 25) and parkinsonism (4 RCTs n=163, RR 11.7 CI 2.9 to 47, NNH 3 CI 2 to 5). AUTHORS' CONCLUSIONS: Haloperidol is a potent antipsychotic drug but has a high propensity to cause adverse effects. Where there is no treatment option, use of haloperidol to counter the damaging and potentially dangerous consequences of untreated schizophrenia is justified. However, where a choice of drug is available, people with schizophrenia and clinicians may wish to prescribe an alternative antipsychotic with less likelihood of adverse effects such as parkinsonism, akathisia and acute dystonias. Haloperidol should not be a control drug of choice for randomised trials of new antipsychotics.

Antipsychotic Agents↗
PubMed1985

Chronic treatment with clozapine, unlike haloperidol, does not induce changes in striatal D-2 receptor function in the rat.

Comparison has been made of the effects on brain dopamine function of chronic administration of haloperidol or clozapine to rats for up to 12 months. In rats treated for 1-12 months with haloperidol (1.4-1.6 mg/kg/day), purposeless chewing jaw movements emerged. These movements were only observed after 12 months' treatment with clozapine (24-27 mg/kg/day). Apomorphine-induced (0.125-0.25 mg/kg) stereotyped behaviour was inhibited during 12 months treatment with haloperidol. Clozapine treatment was without effect. After 12 months, stereotypy induced by higher doses of apomorphine (0.5-1.0 mg/kg) was enhanced in haloperidol, but not clozapine, treated rats. Bmax for striatal 3H-spiperone binding was elevated throughout 12 months of haloperidol administration, but was not altered by clozapine treatment. Bmax for striatal 3H-NPA binding was only elevated after 12 months of haloperidol treatment; clozapine treatment was without effect. Bmax for 3H-piflutixol binding was not altered by haloperidol treatment, but was increased after 9 and 12 months of clozapine treatment. Dopamine (50 microM)-stimulated adenylate cyclase activity was inhibited after 1 month's haloperidol treatment but normal thereafter. Adenylate cyclase activity was not altered by chronic clozapine treatment. Striatal acetylcholine content was increased after 3 and 12 months of haloperidol or clozapine intake. These findings indicate that the chronic administration of the atypical neuroleptic clozapine does not produce changes in brain dopamine function which mirror those of the typical neuroleptic haloperidol. In particular, chronic administration of clozapine, unlike haloperidol, does not appear to induce striatal D-2 receptor supersensitivity. Unexpectedly, clozapine treatment, unlike haloperidol, altered D-1 receptor function.

Acetylcholine↗