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PubMed2002

The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and on the outcome of haloperidol treatment.

OBJECTIVES: The genetically polymorphic enzyme cytochrome P450 (CYP) 2D6 contributes to the biotransformation of the antipsychotic drug haloperidol. The impact of the polymorphism on haloperidol pharmacokinetics, adverse events, and efficacy was prospectively evaluated under naturalistic conditions in 172 unselected psychiatric inpatients with acute psychotic symptoms. METHODS: Serum trough levels of haloperidol and reduced haloperidol of patients receiving clinically adjusted doses were analyzed on days 3, 14, and 28 after hospital admission. Adverse events such as extrapyramidal symptoms were assessed by standardized rating scales. Efficacy was documented by recording the change in positive and negative schizophrenic symptoms. These parameters were correlated with the CYP2D6 genotype determined by polymerase chain reaction analysis for alleles *1 to *15 and *17. RESULTS: The serum concentrations showed wide interindividual variation. Reduced haloperidol trough levels and haloperidol total clearance correlated significantly with the number of active CYP2D6 genes. In addition, body weight and smoking had significant effects on haloperidol kinetics, whereas age, gender, and comedication showed only slight effects. The ratings for pseudoparkinsonism were significantly higher in poor metabolizers of substrates of CYP2D6. On the other hand, there was a trend toward lower therapeutic efficacy with increasing number of active CYP2D6 genes. CONCLUSIONS: Treatment with haloperidol should be avoided in extremely slow and extremely rapid metabolizers of CYP2D6 substrates. Both genotyping and blood concentration measurement explained only a fraction of the adverse events; about 20 patients would have to be genotyped to achieve a significant benefit in 1 patient. It is interesting that genotyping was at least as good a predictor of adverse events as the measured drug concentrations.

Adult↗
PubMed1989

Intersubject variation in the pharmacokinetics of haloperidol and reduced haloperidol.

Single oral doses (5 mg) of haloperidol were administered to 36 healthy men (26 black, 10 white) of whom 28 (22 black, 6 white) completed the study. Plasma samples harvested over 96 hours were analyzed for haloperidol and reduced haloperidol by means of a new high performance liquid chromatographic method. Reduced haloperidol was detectable in the plasma of only six of the 28 subjects (five blacks, one white). In these individuals reduced haloperidol plasma concentrations were generally much lower than those of the parent drug. This finding in the present single-dose study is in contrast to literature reports that have described levels of reduced haloperidol higher than those of the parent drug in some patients chronically mediated with haloperidol. There was wide intersubject variation in area under the plasma concentration versus time curve and apparent oral clearance values for haloperidol. The distributions of these pharmacokinetic parameters about their respective means were each leptokurtotic and skewed toward higher values. In each case the geometric mean gave a better estimate of central tendency than the arithmetic mean. Wide intersubject variation prevented the detection of significant differences in these pharmacokinetic parameters between black and white subjects or between smokers and nonsmokers.

Adolescent↗
PubMed1988

Controlled study of extrapyramidal reactions in the management of delirious, medically ill patients: intravenous haloperidol versus intravenous haloperidol plus benzodiazepines.

In a prospective study, the intensity of extrapyramidal symptoms (EPS) was rated in two groups of delirious, medically ill patients. Fourteen patients received intravenous (IV) haloperidol and benzodiazepines for control of severe agitation and four received IV haloperidol alone. Patients were rated daily by a standardized scale for EPS by raters blind to the dose of haloperidol and benzodiazepines. Patients receiving haloperidol and benzodiazepines had significantly (p less than 0.001) less EPS than patients receiving IV haloperidol alone. In the haloperidol and benzodiazepine group there were only one case of very mild parkinsonian-like EPS and no cases of akathisia or dystonia. No adverse respiratory or cardiac reactions were seen in any patients. The literature on the use of IV haloperidol alone and in combination with benzodiazepines is briefly reviewed and possible explanations of the lower intensity of EPS with IV haloperidol in combination with benzodiazepines are discussed.

Aged↗
PubMed1987

Plasma haloperidol and clinical response: a role for reduced haloperidol in antipsychotic activity?

Seventeen hospitalized psychotic patients were treated with a fixed oral dose of haloperidol, 5 mg twice daily for 28 days. Most were chronic schizophrenics with an acute exacerbation of their illness. All patients also received benztropine 3 mg twice daily during the last 11 days of the study, regardless of the presence or absence of extrapyramidal side effects. No significant linear or curvilinear relationship was found between steady state plasma levels of haloperidol and clinical response measured by total Brief Psychiatric Rating Scale score. At 28 days, the correlations between plasma levels and percent improvement were rs = 0.187 (not significant) for haloperidol and rs = 0.582 (p = 0.04) for the hydroxymetabolite, reduced haloperidol. The correlation for the sum was rs = 0.511 (p = 0.078). Metabolite levels were substantially higher than plasma haloperidol, on the average 2.7 times greater. Eleven days of benztropine treatment had no significant effect on haloperidol or metabolite plasma levels or on clinical status. At the end of the study, nine of 17 patients (53%) had recovered as judged by discharge readiness. Within the limitations implied by the small number of patients, these data suggest that reduced haloperidol is an important component of plasma antipsychotic activity and cannot be neglected in correlative studies, and that a substantial proportion of patients--about half--can be successfully treated with only 10 mg of haloperidol. The routine use of large doses is thus not necessary for many patients.

Adult↗
PubMedDate not supplied

[Value of the determination of erythrocyte haloperidol ketone reductase activity in the evaluation of haloperidol therapy].

Serum levels of haloperidol and reduced haloperidol as well as the reduced haloperidol/haloperidol ratios were determined in nine acute schizophrenics on oral haloperidol medication and correlated over 21 days with psycho pathology and extra-pyramidal symptom scores. We have investigated red blood cells haloperidol reductase activity in the group of patients. Significant correlations were found between haloperidol plasma levels and positive sub scale for each patient (r = 0.86 and p < 0.01; r = 0.70 and p < 0.05). We found a correlation between red blood cells reductase activity and the improvement of the psychotic anxiety scale (r = 0.64/and p < 0.05; r = 0.67 and p < 0.05), but not with reduced haloperidol/haloperidol ratios in plasma. The knowledge of reductase activity could predict the treatment response in acute schizophrenic patients. We suggest that the reported inter individual and inter ethnic differences in haloperidol and reduced haloperidol and in clinical response and adverse effects may be a reflection of genetic control of the two oxidative pathways mediated by cytochrome P450 isozyme and/or the reductase pathway mediated by haloperidol reductase in individual subject.

Adult↗
PubMed1990

Human scalp hair as evidence of individual dosage history of haloperidol: a possible linkage of haloperidol excretion into hair with hair pigment.

We report a method for determining haloperidol concentration in human scalp hair and discuss a possible linkage of haloperidol excretion into hair with the hair pigment melanin. First, an animal study was conducted to support the idea that hair contains amounts of haloperidol corresponding to the doses given and pigmented hair contains much more drug than does unpigmented hair. The haloperidol concentration was measured using a radioimmunoassay technique after hairs were dissolved in 2.5 N NaOH solution and the drug extracted. Pigmented and albino rats, whose hair from an area on the back had been removed beforehand by plucking, were administered either 1, 3, or 10 mg of haloperidol (i.p.) per kg body weight every day for 3 weeks. At the end of the administration period hair which had newly grown on the denuded area was plucked and collected. In each of the two groups classified by hair color the drug levels in the hair correlated with the doses given; however, the concentrations in the hair from the albino rats were much lower than those in the hair from the pigmented rats (which was less than 8.5%). Second, black and white hair was collected from each of seven human subjects with grizzled hair, who were receiving or had been administered haloperidol at fixed daily doses for more than 1 month, and the concentration of haloperidol in each type of hair was measured. In the same subject the concentration in the white hair was found to be much lower than that in the black (less than 10%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1997

Genetics, haloperidol-induced catalepsy and haloperidol-induced changes in acoustic startle and prepulse inhibition.

The acoustic startle response (ASR), prepulse inhibition (PPI) of the ASR and the effects of haloperidol on the ASR and PPI were examined in C57BL/6J (B6) and DBA/2 (D2) inbred mouse strains and their F1 and F2 progeny. The startle stimulus was a 60-ms, 110-dB, 10-kHz tone; the prepulse stimuli were 20-ms, white noise bursts at 56, 68 and 80 dB against a 50-dB background presented 100-ms before the startle pulse. The B6 strain showed modest PPI (25-40%); in contrast, the D2 strain showed on average no PPI and numerous individuals showed prepulse augmentation (PPA). The F2 progeny showed an intermediate PPI; however, the extreme values ranged from 200% PPA to essentially 100% PPI. Haloperidol in dose-dependent fashion, increased PPI in both the B6 and D2 strains; the threshold dose was in the range of 0.1-0.2 mg/kg. Raclopride (0.3 mg/kg), clozapine (2 mg/kg) and risperidone (0.4 mg/kg) also increased PPI in both strains. The effects of haloperidol (0.4 mg/kg) on PPI in 140 F2 progeny were examined. For all prepulse intensities, there were highly significant (r > 0.80) and negative correlations between baseline PPI and the haloperidol-induced change in PPI. Thus, those animals that showed the greatest PPA showed the greatest haloperidol-induced increase in PPI. There was, however, significant variance in the haloperidol response; plots of the regression residuals showed the most and least responsive animals differed by almost 100% in effect on PPI. The F2 progeny were subsequently phenotyped for haloperidol-induced catalepsy. There was no association between the variation in effects on catalepsy and PPI. However, it was observed that those individuals with the poorest baseline PPI were catalepsy non-responsive.

Acoustic Stimulation↗
PubMed2004

Neurotoxic potential of haloperidol in comparison with risperidone: implication of Akt-mediated signal changes by haloperidol.

The neurotoxicity of conventional antipsychotic drugs has emerged as a potential pathogenic event in extrapyramidal side effects (EPS) and in their limited efficacy for negative-cognitive symptoms in schizophrenic patients. The atypical antipsychotics, recently developed, have superior therapeutic efficacy to treat not only positive symptoms but negative symptoms and cognitive dysfunctions with much lower potentials of side effects, although the influence of atypical antipsychotics on the regulation of neuronal survival has been less investigated. It is important to clarify the effects of typical and atypical antipsychotics on neuronal survival and their contributions to the therapeutic development and understanding of the pathophysiology of schizophrenia. We measured the neurotoxicity of two antipsychotic drug treatments, haloperidol and risperidone, in primary cultured rat cortical neurons. Immunoblotting and pharmacological agent analyses were used to determine the signal transduction changes implicated in the mechanisms of the neurotoxicity. Haloperidol induced apoptotic injury in cultured cortical neurons, but risperidone showed weak potential to injure the neurons. Treatment with haloperidol also led the reduction of phosphorylation levels of Akt, and activated caspase-3. The D2 agonist bromocriptine and 5-HT2A antagonist, ketanserin attenuated the haloperidol-induced neuronal toxicity. Moreover, brain-derived neurotrophic factor (BDNF) reduced the caspase-3 activity and protected neurons from haloperidol-induced apoptosis. BDNF also reversed the reduced levels of phosphorylation of Akt caused by treatment with haloperidol. Haloperidol but not risperidone induces caspase-dependent apoptosis by reducing cellular survival signaling, which possibly contributes to the differential clinical therapeutic efficacy and expression of side effects in schizophrenia.

Animals↗
PubMed1985

Electrophysiological interactions between haloperidol and reduced haloperidol, and dopamine, norepinephrine and phencyclidine in rat brain.

Haloperidol and its metabolite, reduced haloperidol, were compared as antagonists of catecholaminergic neurotransmission in central nervous system of the rat. Agonists and antagonists were applied from multibarrelled micropipettes, which were also used to record extracellularly the effects of these substances on neuronal discharge. Haloperidol antagonized dopaminergic inhibition of caudate neurons and inhibition of cerebellar Purkinje neurons induced by noradrenaline, whereas reduced haloperidol was an ineffective antagonist. Phencyclidine, which is an indirect dopaminergic agonist in the caudate, caused inhibition of the discharges of caudate neurons resembling that induced by dopamine itself. These indirect effects of phencyclidine were also antagonized by haloperidol but not by reduced haloperidol. The data suggest that the metabolite, reduced haloperidol, is not an effective neuroleptic drug in the central nervous system.

Animals↗
PubMed1996

Effects of chronic methamphetamine on SCH23390- or haloperidol-induced catalepsy, and effects of coadministration of SCH23390 or haloperidol in mice.

The influence of chronic treatment of mice with methamphetamine, an indirect dopamine agonist, on the cataleptic effects of R-(+)-chloro-2,3,4,5,-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin -7ol hydrochloride (SCH23390), a D1 receptor agonist, or haloperidol, a mainly D2 antagonist, was investigated. Once every other day treatment with 3 mg/kg SC methamphetamine for 15 days resulted in an increase in the catalepsy produced by haloperidol (0.3 mg/kg IP) (haloperidol catalepsy), but in a decrease in the catalepsy produced by SCH23390 (0.3 mg/kg IP) (SCH23390 catalepsy), 24 h and 7 days after withdrawal of methamphetamine. These effects of chronic methamphetamine were antagonized by coadministration of either SCH23390 (0.5 mg/kg SC) or haloperidol (1.0 mg/kg SC). These results suggest that the decreased responsiveness to SCH23390 in chronic methamphetamine-pretreated mice results from a supersensitivity of D1 receptors, and that the increased responsiveness to haloperidol catalepsy results from a subsensitivity of D2 receptors. The attenuated response to SCH23390 may be interpreted as an example of sensitization to methamphetamine, and the enhanced haloperidol response as an example of tolerance to methamphetamine, based on the development of supersensitivity and subsensitivity of D1 and D2 receptors, respectively, after chronic methamphetamine administration. Furthermore, it is suggested that coadministration of either SCH23390 or haloperidol could prevent the development of D1 receptor supersensitivity and D2 receptor subsensitivity induced by chronic methamphetamine.

Animals↗
PubMed1989

Haloperidol and reduced haloperidol concentrations and psychiatric ratings in schizophrenic patients treated with ascorbic acid.

Recent reports have suggested an augmentation by ascorbic acid of haloperidol treatment of schizophrenic patients. This study was designed to examine whether pharmacokinetic interactions between ascorbic acid and haloperidol occur in this population. Eight male inpatients diagnosed as having chronic schizophrenia by DSM-III-R criteria and stabilized on a fixed dose of haloperidol were given oral doses of ascorbic acid, 4.5 grams daily, for 2 weeks in an open trial. Serum concentrations of haloperidol and is metabolite, reduced haloperidol, were measured by high performance liquid chromatography. Psychiatric symptoms were monitored using the Psychiatric Symptom Assessment Scale performed by nursing staff blind to the haloperidol status but not to the ascorbic acid dosage. The addition of ascorbic acid was not associated with any change in psychopathology in this group of patients, nor was there any apparent pharmacokinetic interaction with haloperidol.

Ascorbic Acid↗
PubMed1989

Haloperidol and reduced haloperidol concentrations in plasma and red blood cells from chronic schizophrenic patients.

In a double-blind, placebo-controlled study, 15 drug-free chronic schizophrenic inpatients were treated with a fixed dose of haloperidol for 6 weeks. Haloperidol and its metabolite, reduced haloperidol, were measured in plasma and red blood cells after 2, 4, and 6 weeks of treatment. Behavioral change was rated using the Brief Psychiatric Rating Scale (BPRS). Not only the raw concentrations, but also blood compartment sums and ratios of these four drug measurements were tested for their strength of association with behavioral improvement. Positive associations with some BPRS subscales at some time points emerged; however, no significant correlations were found to extend across all time points measured. There was a trend in this cohort for negative symptom improvement to be associated with the ratio of haloperidol to reduced haloperidol in red blood cells. The ratio of haloperidol to reduced haloperidol in plasma was always greater than that in the red blood cells for all patients, reflecting an accumulation of the metabolite in red blood cells.

Adolescent↗
PubMed1984

Carbamazepine and haloperidol v placebo and haloperidol in excited psychoses. A controlled study.

Carbamazepine has recently been reported to have therapeutic potential in mania. We studied carbamazepine plus haloperidol v placebo plus haloperidol in excited psychoses in a controlled double-blind design. Twenty-three patients completed five weeks of carbamazepine-haloperidol therapy, and 20 patients placebo-haloperidol therapy. Brief Psychiatric Rating Scale ratings showed superior improvement in the group receiving carbamazepine plus haloperidol. This benefit was as apparent in excited schizophrenia as in mania. No unusual toxicity was observed because of the combination of haloperidol with carbamazepine.

Adult↗
PubMed1982

Effects of haloperidol and apomorphine on catecholamine metabolism in brain slices. Reserpine-like effects of haloperidol.

The accumulation, release and catabolism of [3H]dopamine (DA) and [3H]norepinephrine (NE) synthesized from [3H]tyrosine were measured in mouse striatal and substantia nigral slices. Apomorphine inhibited both [3H]NE and [3H]DA accumulation (IC50 less than 10(-6) M), presumably by acting on a presynaptic receptor. Haloperidol (10-8M) caused a small, but significant increase in [3H]DA accumulation from [3H]tyrosine in the presence of 26 mM K+, possible reflecting blockade of presynaptic receptors activated by release DA. However, at higher concentrations (10(-6) to 10(-5) M), haloperidol inhibited [3H]DA and [3H]NE accumulation. Reserpine also potently inhibited catecholamine synthesis; chlorpromazine had only a weak effect, and fluphenazine was ineffective. Both haloperidol (10(-5) M) and reserpine (10(-7) M), but not chlorpromazine and fluphenazine, markedly increased the formation of labeled dihydroxyphenylacetic acid (DOPAC) and increased the spontaneous release of labeled DA from striatal slices preloaded with [3H]tyrosine or [14C]DA. These data suggest that haloperidol has some direct effects on DA metabolism that are unrelated to DA-receptor blockade. Because the effects of haloperidol are apparently independent of DA release, haloperidol may elevate cytoplasmic DA by altering its vesicular storage. This would, in turn, increase the spontaneous release of labeled DA by diffusion, the oxidation of DA to DOPAC by monoamine oxidase, and the end-product inhibition of tyrosine hydroxylase.

Animals↗
PubMed1991

Simultaneous determination of haloperidol and its metabolite, reduced haloperidol, in plasma, blood, urine and tissue homogenates by high-performance liquid chromatography.

A high-performance liquid chromatographic method was developed for the simultaneous determination of haloperidol and reduced haloperidol in human plasma, urine and rat tissue homogenates using bromperidol as an internal standard. The method involved extraction followed by injection of 50-80 microliters of the aqueous layer onto a C18 reversed-phase column. The mobile phase was 0.5 M phosphate buffer-acetonitrile-methanol (58:31:11, v/v/v) and the flow-rate was 0.6 ml/min. The column effluent was monitored by ultraviolet detection at 214 nm. The retention times for reduced haloperidol, haloperidol and bromperidol were 5.4, 7.2 and 8.4 min, respectively. The detection limits for haloperidol and reduced haloperidol in human plasma were both 0.5 ng/ml, and the corresponding values in human urine were both 5 ng/ml. The coefficients of variation of the assay were generally low (below 10.7%) for plasma, urine, blood and tissue homogenates. No interferences from endogenous substances or any drug tested were found.

Animals↗
PubMed1995

Megabore capillary gas-liquid chromatographic method with nitrogen-phosphorus selective detection for the assay of haloperidol and reduced haloperidol in serum: results of therapeutic drug-monitoring during acute therapy of eight schizophrenics.

A gas chromatographic method using a HP-5 megabore capillary and nitrogen-phosphorus selective detection for the quantitative analysis of haloperidol (H) and reduced haloperidol (RH) in human serum or plasma is described. A 3-step liquid-liquid extraction is applied. The extraction yield of this procedure is 63% for haloperidol at 20 ng/ml. The limits of detection are 0.4 ng/ml for haloperidol and 1.0 ng/ml for the metabolite if 2 ml of body fluid are applied. At 10 ng/ml the within-day precision is 4.5% for H and 8.3% for RH. Serum levels of eight schizophrenic patients have been monitored weekly over a therapeutic period of six weeks. Seven patients mainly had metabolite ratios RH/H < 1 over the entire period of investigation. They exhibited a linear correlation between dose and serum concentration of haloperidol. In contrast, one patient had metabolite ratios RH/H > 1 over the entire period of the study. Due to considerable increased serum concentrations this patient did not show a linear correlation between the dose and the serum level of haloperidol.

Adult↗
PubMed1995

Haloperidol plasma 'threshold' levels for relapse prevention in schizophrenia: a study with haloperidol decanoate.

Forty-eight schizophrenic outpatients treated with flexible doses of haloperidol decanoate were followed up in a naturalistic fashion for 3 years with periodic monitoring of clinical symptoms, side effects and haloperidol plasma concentrations. There was no relationship between plasma level and clinical response, however categorical data analysis showed that patients with plasma levels over 4 ng/ml had a significantly reduced relapse rate compared with patients with plasma levels below this plasma 'threshold' level. This effect could be observed during the first, second as well as third year of treatment. The relapse rate did not change significantly in relation to time (during years 1, 2, 3), when patients with haloperidol plasma levels below and equal to or over 4 ng/ml were considered separately. In patients with haloperidol equal to or over 4 ng/ml, the variability (measured as coefficient of variation %) in the total scores of SAPS and SANS was lower, indicating a better clinical stability. These data are in fairly good agreement with other literature findings showing that an indiscriminate dose reduction strategy during long-term treatment of schizophrenic disorders with haloperidol decanoate should be discouraged, since it leads to an increase in the relapse rate. Before deciding about a dose reduction, clinicians should take into careful consideration some clinically relevant variables (i.e. frequency of previous relapses, severity of symptoms, iatrogenic depression, risk for development of extrapyramidal side effects) for each patient. A better clinical stability during treatment with haloperidol decanoate can be obtained when plasma 'threshold' levels for response are reached.

Adult↗
PubMed2005

Production of haloperidol-loaded PLGA nanoparticles for extended controlled drug release of haloperidol.

This study developed an emulsion-solvent evaporation method for producing haloperidol-loaded PLGA nanoparticles with up to 2% (wt/wt. of polymer) drug content, in vitro release duration of over 13 days and less than 20% burst release. The free haloperidol is removed from the nanoparticle suspension using a novel solid phase extraction technique. This leads to a more accurate determination of drug incorporation efficiency than the typical washing methods. It was discovered that PLGA end groups have a strong influence on haloperidol incorporation efficiency and its release from PLGA nanoparticles. The hydroxyl-terminated PLGA (uncapped) nanoparticles have a drug incorporation efficiency of more than 30% as compared to only 10% with methyl-terminated PLGA (capped) nanoparticles. The in vitro release profile of nanoparticles with uncapped PLGA has a longer release period and a lower initial burst as compared to capped PLGA. By varying other processing and materials parameters, the size, haloperidol incorporation and haloperidol release of the haloperidol-loaded PLGA nanoparticles were controlled.

Delayed-Action Preparations↗