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PubMed1984

[Sensitive determination of haloperidol in human serum by radioimmunoassay].

An improved procedure for the sensitive determination of the neuroleptic drug, haloperidol, in human serum is described. The method is based on a single hexane extraction procedure and a radioimmunoassay. Antiserum was elicited in guinea pigs immunized with haloperidol hemisuccinate derivative coupled to bovine serum albumin. Any appreciable cross-reactivity was observed neither with known metabolites of haloperidol nor with haloperidol decanoate (KD-136). Some devices in the extraction procedure, e.g. the use of 10 ml of extraction solvent, made it possible to measure haloperidol levels as low as 0.05 ng/ml. The accuracy and reproducibility of the method were shown to be sufficient. The present method can be used to study the pharmacokinetics of haloperidol in the phase 1 study of KD-136. In addition, it is simple enough for use in clinical laboratories that are monitoring haloperidol concentrations in the blood of psychiatric patients.

Evaluation Studies as Topic↗

PubMed1983

Blood levels of haloperidol in schizophrenic patients.

Plasma and red blood cell levels of haloperidol were measured in psychotic patients after an acute dose of haloperidol and during treatment with fixed doses for several weeks. There was wide variability of haloperidol plasma and red blood cell levels at a given dose and a nonlinear relationship between haloperidol dose and blood levels. The red blood cell/plasma ratio (0.40) had a narrow range among different patients. Haloperidol blood levels were not correlated with the age of the patient. Concomitant administration of benztropine mesylate did not decrease plasma haloperidol levels. Steady state plasma or red cell haloperidol levels could not be predicted from levels 24 hours after the acute dose.

Adolescent↗

PubMed1982

Psychopharmacological correlates of post-psychotic depression: a double-blind investigation of haloperidol vs thiothixene in outpatient schizophrenia.

A 24-week double-blind study was conducted to compare haloperidol and thiothixene for efficacy and safety in 46 schizophrenic outpatients. In addition to the standard psychiatric rating scales, Brief Psychiatric Rating Scale (BPRS), Nurses' Observation Scale for Inpatient Evaluation (NOSIE), and Evaluation of Social Functioning Rating (ESFR), two scales more sensitive to the incidence of treatment emergent depression were utilized. They were the Hamilton Depression Scale (HPRSD) and the Zung Self-rating Depression Scale (ZUNG). On the BPRS factors, haloperidol was significantly superior to thiothixene in Thought Disturbance and Hostility-Suspiciousness, and in Total symptomatology. Haloperidol was also significantly superior to thiothixene in Cognitive Disturbance on the HPRSD. Results of global evaluations suggested haloperidol produced slightly more rapid relief of symptoms than did thiothixene. The inclusion of the depression scales was useful in following patients who exhibited depressive symptoms; clinically significant depression was seen in 5 patients receiving haloperidol and 3 receiving thiothixene. A high incidence of akathisia in the thiothixene group was responsible for a statistically significant difference between groups in the number of central nervous system symptoms. Mean doses of test drugs were 17.5 mg/day for haloperidol an 31.8 mg/day for thiothixene. The study showed that haloperidol was equal to and in some parameters superior to thiothixene in producing improvement in the symptoms of psychosis.

Adolescent↗

PubMed1981

Individual differences in the response of dopamine receptor number to chronic haloperidol treatment.

Previous studies of the haloperidol-induced increase in dopamine (DA) receptor number have not emphasized the existence of individual differences. The present study evaluated DA receptor number in individual rat and mouse caudates after haloperidol or drug-free feeding. After 3 months of haloperidol treatment of rats there was a 78% increase in caudate DA receptor number, accompanied by a significantly increased variance in the number of DA receptors in haloperidol-treated compared with control rats. Although three inbred mouse strains (Balb/C, C3H, and CBA) also showed significant increases in DA receptor number after 3 months of haloperidol treatment, no increased variance was observed after haloperidol treatment. Wild-type mice from a genetically heterogenous population showed increases in DA receptor number after chronic haloperidol treatment accompanied by a significantly increased variance in receptor number of the drug-treated group. These findings suggest that pharmacogenetic factors may be important in determining the magnitude of DA receptor response to long-term neuroleptic treatment.

Animals↗

PubMed1994

Plasma clozapine and haloperidol concentrations in adolescents with childhood-onset schizophrenia: association with response.

BACKGROUND: Plasma clozapine and haloperidol concentrations were studied in adolescents being treated for childhood-onset schizophrenia. METHOD: Eleven patients (9 boys, 2 girls; mean age = 14.1 +/- 2.1 years) received a 6-week blinded or open trial of clozapine. Five patients also received 6 weeks of blinded or open haloperidol. Doses were increased on an individual basis to a mean 6-week dose of 5.99 +/- 2.6 mg/kg/day for clozapine and 0.24 +/- 0.20 mg/kg/day for haloperidol. The Brief Psychiatric Rating Scale and Bunney Hamburg Rating Scale were completed weekly for each subject. Weekly blood samples were obtained during therapy and assayed by high performance liquid chromatography. RESULTS: The mean clozapine level at Week 6 was 378.3 ng/mL and ranged from 77.5 to 1050 ng/mL. The mean Week 6 haloperidol level was 23.0 ng/mL (range, 6.2-44.3 ng/mL). The clozapine desmethyl and N-oxide metabolites achieved mean concentrations of 77% and 18%, respectively, of those of the parent compound. The mean ratio of haloperidol/reduced haloperidol was 4.48 (range, 0.76-8.76). Clozapine concentrations versus clinical benefit exhibited a consistent linear relationship among patients (correlation range, 0.26-0.96). Conversely, poor and inconsistent correlations between haloperidol concentrations and clinical effects were observed. No relationships were noted between clozapine or haloperidol dose and clinical effects. CONCLUSION: Adolescents with schizophrenia produce a greater amount of desmethylclozapine than previously seen in adults. Plasma clozapine concentrations appear to be related in a linear fashion to clinical improvement.

Adolescent↗

PubMed1994

Blood levels of haloperidol and clinical outcome in schizophrenia.

Haloperidol levels in blood were measured in 55 acutely psychotic inpatients with schizophrenia, who were randomly assigned to three fixed doses of oral haloperidol. Nineteen of these subjects received 10 mg/day, 18 received 30 mg/day, and 18 of them received 80 mg/day. All of the subjects were treated under double-blind conditions for 6 weeks or until remission. Haloperidol and reduced haloperidol levels were measured in plasma and red blood cells at the end of 2, 4, and 6 weeks of treatment. There were statistically significant linear correlations between the dose of haloperidol and levels in blood. An examination of data for linear and curvilinear relationships between levels in blood and clinical response did not yield any statistically significant relations. The data did not support the concept of a "therapeutic window." The ratio of reduced haloperidol to haloperidol levels in plasma or red blood cells did not yield any statistically significant correlations to clinical outcome.

Adolescent↗

PubMed1994

Induction of neurotensin and c-fos mRNA in distinct subregions of rat neostriatum after acute methamphetamine: comparison with acute haloperidol effects.

Large increases of neurotensin (NT)-like immunoreactivity in the rat neostriatum have been reported previously after treatment with either dopamine D2 receptor antagonists (e.g., haloperidol) or potent indirect dopamine agonists (e.g., methamphetamine). Combined administration of these two opposite classes of drugs results in additive increases in striatal NT-like immunoreactivity suggesting that distinct mechanisms may underlie increases in NT content after haloperidol and methamphetamine. Our recent studies demonstrate that acute haloperidol treatment increases NT immunoreactivity in the striatum, at least in part, by enhancing the expression of the NT/neuromedin N (NT/N) gene in neurons confined to the dorsolateral sector of the striatum. Additionally, this induction of NT/N gene transcription in the dorsolateral striatum by haloperidol appears to involve participation of the immediate early gene, c-fos. The present study investigated alterations in NT/N and c-fos gene expression after acute methamphetamine (10 mg/kg s.c.) treatment and compared these changes to those observed after acute haloperidol (1 mg/kg i.p.) administration. Unlike haloperidol, methamphetamine increased NT/N mRNA expression in the periventricular dorsomedial quadrant of the striatum and induced c-fos mRNA primarily in the medial aspects of the central core of the neostriatum. These data suggest that Fos may not act as a primary transcription factor in methamphetamine-induced NT/N gene expression in the dorsomedial striatum. The results also indicate that additive increases in striatal NT-like immunoreactivity after simultaneous treatment with haloperidol and methamphetamine may be due to induction of NT/N gene expression in distinct neostriatal neuronal populations.

Animals↗

PubMed1993

Haloperidol withdrawal and weight changes in autistic children.

The long-term effects of haloperidol on weight were assessed in 30 children, 25 males and 5 females, diagnosed with autistic disorder whose ages ranged from 3.08 to 8.42 years. They received haloperidol (0.25-3.50 mg/day; mean 1.26 +/- 0.84) for 6 months followed by a 4-week drug withdrawal period. Weights obtained on the last day of the 6-month haloperidol period were compared to weights obtained following drug withdrawal. There was no significant difference between the mean weights obtained on the last day of haloperidol administration (24.799 +/- 9.741 kg) compared to the mean weights at the end of the fourth week of the placebo period (24.644 +/- 9.833 kg). Weights increased during the first week of drug discontinuation (24.879 +/- 9.855 kg), but decreased during each following week of drug withdrawal. Weight was measured monthly during the 6-month haloperidol treatment period for 8 of the 30 subjects. In this subsample, weight gain was greater during the 1-month period lasting from the end of the 4-week drug withdrawal to the end of the first month after resuming haloperidol treatment than weight gain prior to drug withdrawal, between the fifth and sixth month of haloperidol treatment.

Autistic Disorder↗

PubMed1993

Reduced haloperidol/haloperidol ratios after oral haloperidol and decanoate administration in schizophrenics.

1. Haloperidol and reduced haloperidol plasma concentrations were measured in thirteen stable schizophrenic patients that received both oral haloperidol and haloperidol decanoate. 2. Significant correlations between reduced haloperidol/haloperidol ratios from oral haloperidol and haloperidol decanoate occurred at week two and week 16, respectively. 3. The formation of RH was consistent during haloperidol decanoate treatment.

Administration, Oral↗

PubMed1993

The assessment and clinical implications of haloperidol acute-dose, steady-state, and withdrawal pharmacokinetics.

In order to evaluate comprehensively haloperidol pharmacokinetics under fixed-dose treatment conditions, psychiatric patients were studied after treatment with an acute dose, during maintenance therapy, and after withdrawal from haloperidol following steady-state conditions. After single doses, haloperidol appeared rapidly in serum, achieving peak concentration at a mean of 4.5 hours. The range of observed elimination half-life was broad, between 8.5 and 66.6 hours, with a mean of 19.5 hours. Under conditions of chronic dosing, serial measurements of steady-state serum concentration revealed intrapatient coefficients of variation between 2 and 72%. The mean for all patients was 26.4%. Body clearance decreased nonsignificantly, and elimination half-life increased significantly after chronic dosing compared with kinetic parameters determined after a single dose. The concentration of haloperidol in serum obtained at 8 hours after a single dose correlated most strongly (r = 0.73; p < 0.0001) with steady-state concentration resulting from chronic dosing. A value of 4 ng/ml or lower determined 8 hours after a single oral dose of 0.2 mg/kg identified patients who did not accumulate haloperidol during chronic dosing of 0.4 mg/kg per day above a presumed therapeutic range for haloperidol of 5 to 15 ng/ml. The implications of these data for the clinical use of haloperidol are discussed.

Adult↗

PubMed1995

Effects of chronic haloperidol on reaction time and errors in a sustained attention task: partial reversal by anticholinergics and by amphetamine.

The attentional and motor-disruptive effects of low doses of haloperidol were studied in a sustained attention task performed by rats. Five separate groups (n = 7 or 8) of rats were trained to react to a 0.125-sec visual stimulus by executing a nose-poke response within 3 sec of stimulus presentation. Each group of rats received its own dose (0.0, 0.02, 0.04, 0.08 or 0.12 mg/kg) of haloperidol daily for 3 months, and from the 1st week onward dose-effects on reaction time were quite stable across time. Haloperidol treatment disrupted the sustained attention task performance by decreasing the number of behavior-initiated stimulus presentations, decreasing the number of reinforcers earned, increasing the proportion of errors of omission and increasing reaction time to the target stimulus. Testing of challenge drugs began after 23 days of haloperidol treatment. Scopolamine (0.1 and 0.2 mg/kg), benztropine (1.0, 3.0 and 6.0 mg/kg) and d-amphetamine (0.25, 0.5, 1.0 and 2.0 mg/kg) ameliorated haloperidol-induced reaction time slowing, whereas only benztropine and amphetamine lessened haloperidol-induced errors of omission. The 2.0-mg/kg dose of amphetamine by itself produced a significant increase in errors of omission without affecting reaction time. Haloperidol effectively normalized this amphetamine-induced disruption in attention. The results are consistent with a dopaminergic involvement in the expression of both attention and motor processes.

Adrenergic Agents↗

PubMed1996

Absence of effect of sertraline on time-based sensitization of cognitive impairment with haloperidol.

UNLABELLED: This double-blind, randomized, placebo-controlled study evaluated the effects of haloperidol alone and haloperidol plus sertraline on cognitive and psychomotor function in 24 healthy male subjects. METHOD: All subjects received placebo on Day 1 and haloperidol 2 mg on Days 2 and 25. From Days 9 to 25, subjects were randomly assigned to either sertraline (12 subjects) or placebo (12 subjects); the sertraline dose was titrated from 50 to 200 mg/day from Days 9 to 16, and remained at 200 mg/day for the final 10 days of the drug administration period. Cognitive function testing was performed before dosing and over a 24-hour period after dosing on Days 1, 2, and 25. RESULTS: Impairment of cognitive function was observed 6 to 8 hours after administration of haloperidol on Day 2 but was not evident 23 hours after dosing. When single-dose haloperidol was given again 25 days later, greater impairment with earlier onset was noted in several tests in both treatment groups, suggesting enhancement of this effect. There was no indication that sertraline exacerbated the impairment produced by haloperidol since an equivalent effect also occurred in the placebo group. Three subjects (2 on sertraline and 1 on placebo) withdrew from the study because of side effects. Ten subjects in each group reported side effects related to treatment. The side effect profiles of sertraline and of placebo were similar. CONCLUSION: Haloperidol produced a clear profile of cognitive impairment that was not worsened by concomitant sertraline administration.

1-Naphthylamine↗

PubMed1996

A practical loading dose method for converting schizophrenic patients from oral to depot haloperidol therapy.

BACKGROUND: Haloperidol decanoate is a long-acting depot antipsychotic agent used for the treatment of schizophrenic patients. The decanoate formulation was developed to treat schizophrenics who have a history of noncompliance with oral medication. Studies of techniques to convert from oral to depot therapy have not utilized the pharmacokinetics of the decanoate formulation. This study is a prospective evaluation for converting patients from oral to depot treatment. METHOD: Twenty-one patients meeting DSM-III-R criteria for schizophrenia participated in the study. Patients were treated with oral haloperidol for 6 weeks and then were switched to decanoate. Haloperidol decanoate 100 mg was administered on a weekly basis for the first 4 weeks. Afterward, injection intervals were increased to every 2 weeks and then to every 4 weeks. Plasma haloperidol concentrations were obtained prior to the next injection and assayed by HPLC with electrochemical detection. Patients were monitored by the psychiatrists and nursing staff for symptoms of clinical deterioration. RESULTS: All patients completed the conversion trial during the first 4 weeks without any problems or adverse side effects. By the third week, mean plasma haloperidol concentrations from the decanoate injections were comparable with those of the 10-mg oral haloperidol treatment (7.95 +/- 4.94 ng/mL vs. 7.79 +/- 4.79 ng/mL). Steady-state conditions for the decanoate therapy were achieved by the fourth week. CONCLUSION: These findings suggest that schizophrenic patients can be easily converted from oral to depot therapy without problems. Further studies with haloperidol decanoate and its conversion from oral treatment utilizing plasma concentrations are needed.

Administration, Oral↗

PubMed1997

Interaction between fluoxetine and haloperidol: pharmacokinetic and clinical implications.

The extent and clinical significance of the pharmacokinetic interaction between fluoxetine and haloperidol was studied in 13 schizophrenic patients with prominent negative symptoms. Patients stabilized on chronic low-dose haloperidol (3-8 mg day-1) received additional fluoxetine (20 mg day-1) for 12 consecutive weeks. Mean plasma concentrations of haloperidol increased significantly from 6.5 +/- 2.4 nmol l-1 at baseline to 8.8 +/- 3.6 nmol l-1 (P < 0.01) at week 12 of fluoxetine treatment, but this effect was not associated with an increase in mean extrapyramidal side effects score on the Simpson and Angus Scale. The improvement in negative symptomatology, as measured by the Scale for Assessment of Negative Symptoms, did not correlate significantly with the increase in plasma haloperidol levels. Though our findings confirm that fluoxetine impairs haloperidol clearance, this interaction is unlikely to have adverse clinical consequences, at least in patients chronically stabilized on a low dosage of haloperidol. As fluoxetine is a potent inhibitor of cytochrome P450 (CYP) 2D6, these results also provide indirect evidence for an involvement of CYP2D6 in the metabolism of haloperidol.

Adult↗

PubMed1997

Clozapine and haloperidol modulate N-methyl-D-aspartate- and non-N-methyl-D-aspartate receptor-mediated neurotransmission in rat prefrontal cortical neurons in vitro.

The effects of the antipsychotic drugs haloperidol and clozapine on N-methyl-D-aspartate (NMDA) and non-NMDA receptor-mediated neurotransmission were examined and compared in pyramidal cells of the medial prefrontal cortex in rat brain slices by using the techniques of intracellular recording and single-electrode voltage-clamp. The bath administration of either haloperidol or clozapine produced a marked facilitation (300-400%) of NMDA-evoked responses in a concentration-dependent manner. The EC50 values of haloperidol and clozapine were 38 and 14 nM, respectively. At concentrations of > or =100 nM, clozapine, but not haloperidol, produced bursts of excitatory postsynaptic potentials (EPSPs), which were blocked by glutamate receptor antagonists, suggesting that these EPSPs were the result of increasing release of excitatory amino acids. Haloperidol, but not clozapine, produced a concentration-dependent inhibition of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced current with an EC50 value of 37 nM. Haloperidol significantly decreased the amplitude of EPSPs evoked by the electrical stimulation of the forceps minor, whereas clozapine increased the amplitude of these EPSPs. The study of current-voltage relationship indicates that clozapine preferentially potentiates NMDA receptor-mediated transmission, whereas haloperidol depresses the non-NMDA receptor-mediated response, which probably obscures its potentiating effect on NMDA receptor-mediated EPSPs.

Action Potentials↗

PubMed2002

Neurochemical effects of 8-hydroxy-2-di-n-propylamino tetralin in rats treated with haloperidol.

In view of a possible role of presynaptic serotonin (5-hydroxytryptamine, 5-HT) receptors in the precipitation of extrapyramidal side effects (EPS), the present study was designed to investigate the neurochemical effects of a selective 5-HT1A ligand, 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT) in rats following single (5 mg/kg) and repeated (two-times a day for 9 days at dosage of 5mg/kg) haloperidol administration. Haloperidol plus 8-OH-DPAT injected animals exhibited a decrease in dopamine (DA) and an increase in DA metabolite homovanillic acid (HVA) levels in the striatum and rest of the brain. The two groups of animals exhibited comparable levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the striatum and rest of the brain. Animals injected with haloperidol and killed 24 hrs after the last injection of haloperidol exhibited higher DA and HVA levels in the striatum but not in the rest of the brain. Conversely, dihydroxyphenylacetic acid (DOPAC), the other metabolite of DA, decreased in the rest of the brain. 5-HIAA concentrations increased in the striatum but not in the rest of the brain. Administration of 8-OH-DPAT significantly decreased 5-HT and 5-HIAA levels in the rest of brain and did not alter 5-HIAA in the striatum of repeated saline injected rats. Conversely, same dose of 8-OH-DPAT injected to repeatedly haloperidol injected animals did not decrease 5-HT and 5-HIAA concentrations in the rest of the brain but decreased 5-HIAA levels in the striatum. No effect of 8-OH-DPAT injections occurred on striatal or rest of the brain DA metabolism in repeatedly saline injected animals except that DOPAC decreased in the striatum of both groups. The results are discussed in the context of a role of somatodendritic 5-HT1A receptors in the regulation of DA metabolism following single and repeated administration of haloperidol. It is suggested that an increase in the responsiveness of these receptors may be involved in the precipitation of EPS observed in patients on haloperidol therapy.

Journal Article↗

PubMed1980

Serum haloperidol determinations in psychiatric patients. Comparison of methods and correlation with serum prolactin level.

Twenty-one serum samples from 11 schizophrenic patients receiving long-term haloperidol therapy were analyzed for haloperidol concentrations by two different radioimmunoassays (RIAs) and gas chromatography (GC). There was a good correspondence between the RIA and GC values over a wide range of drug concentrations. However, compared with the specific GC technique, both RIA methods overestimated haloperidol concentrations, reflecting differences in the specificities of the two RIA antibodies. One of the RIA methods had the requisite specificity for application to patients treated with long-term haloperidol therapy, although further methodological refinement will be required for its general clinical application. Haloperidol values determined by GC and RIA analyses correlated highly with prolactin concentrations in the same samples, suggesting that the usefulness of prolactin measurement as an "in vivo bioassay" for circulating levels of haloperidol should be further explored.

Chromatography, Gas↗

PubMed1989

Controlled study of haloperidol, pimozide and placebo for the treatment of Gilles de la Tourette's syndrome.

The results of this controlled study of the treatment of 57 patients with Gilles de la Tourette's syndrome suggested that both haloperidol and pimozide were more effective than placebo, but that haloperidol was slightly more effective than pimozide. Adverse effects occurred more frequently with haloperidol vs placebo than with pimozide vs placebo, but the frequency was not significantly different for haloperidol compared with pimozide. Clinically significant cardiac effects did not occur at a maximum dosage of 0.3 mg/kg or 20 mg/d for pimozide and 10 mg/d for haloperidol. However, the QTc interval was prolonged during pimozide treatment compared with that during haloperidol treatment, although the values for both medications were not in an abnormal range.

Adolescent↗