Haloperidol Levels Research Articles

Haloperidol and Reduced Haloperidol Serum Levels: Correlation with Psychopathology in Acute Schizophrenia

Serum levels of haloperidol (HPL) and reduced haloperidol (RHPL) as well as the RHPL/HPL ratio were determined in 55 acute schizophrenics on oral haloperidol medication and correlated over 28 days with psychopathology and extrapyramidal symptom scores. Linear and nonlinear models of serum concentration and psychopathology were tested at several time points. No single consistent model could be established for either HPL or RPHL. However, when non-parametrical methods are used HPL levels between 10 and 25 ng/ml can be shown to be significantly associated with better outcome during the first three weeks of treatment. RHPL is unsuitable for therapy monitoring, since equilibrium is not reached in the first four weeks of treatment. The RHPL/HPL ratio was found to rise continuously during the study, and it neither separated responders from nonresponders nor did it correlate with clinical outcome.

Measurement of Haloperidol in Human Breast Milk by High‐Performance Liquid Chromatography

AbstractA high-performance liquid chromatographic method was developed for the assay of haloperidol in human breast milk. The method involves rapid extraction of haloperidol and chromatography with a reversed-phase C18 column and a mobile phase of phosphate buffer (pH 4.0):acetonitrile (70:30, v/v). Moperone was used as the internal standard. Haloperidol and moperone were detected with ultraviolet detection at 254nm. The sensitivity was 5 ng/mL of milk, and the standard curve was linear in the concentration range 5–250 ng/mL. The average interassay coefficient of variation for samples with drug in the concentration range 25–125 ng/mL was <8.8%. The absolute recovery of haloperidol by the method was >94.4%. No interference with endogenous substances in human milk was observed. The method was used to determine haloperidol levels in breast milk from patients undergoing chronic haloperidol treatment.

Differences between antipsychotic drugs in persistence of brain levels and behavioral effects.

After a single dose of the butyrophenone neuroleptic haloperidol, behavioral effects and detectable drug levels in rat brain can last for several weeks. To determine if such persistence is a general property of neuroleptics, we compared drug levels and effects after IP administration of two butyrophenones (haloperidol and bromperidol), a high potency (fluphenazine) and a low potency (chlorpromazine) phenothiazine. Drug levels in brain tissue were measured by high pressure liquid chromatography and behavioral effects monitored as inhibition of apomorphine-induced stereotypy. Estimated near terminal elimination half-lives (t 1/2) from brain for acutely administered chlorpromazine (20 mg/kg) and fluphenazine (1 mg/kg) were 0.41 and 0.62 days, respectively, and neither drug was detectable after 4 days. Fluphenazine given daily for 5 days showed an only slightly slower elimination (t 1/2 = 1.1 days). In contrast, near-terminal elimination half-lives from brain for haloperidol and bromperidol (both at 1 mg/kg, IP) were much longer (6.6 and 5.8 days, respectively), and each was detectable for 21 days after dosing. Inhibition of apomorphine-induced stereotypy correlated highly (r = 0.95) with brain levels of haloperidol. For fluphenazine, given once or repeatedly, early inhibition was replaced within 1 week by supersensitivity to apomorphine which persisted for up to 3 weeks. These findings, indicating marked differences in clearance and recovery times after dosing with butyrophenones and phenothiazines, have clear implications for studies of the effects of neuroleptic drugs in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of Prophylactic Haloperidol Plasma Levels in Stable Outpatient Schizophrenics

AbstractSchizophrenic patients taking haloperidol prophylactically were screened for a haloperidol monitoring project at four medical centers. Fifty-five patients participated. Most patients had doses and plasma levels below those found in acute treatment studies; however, a sizeable minority had doses and levels that were greater than was probably needed for prophylaxis. Six percent of patients appeared to be rapid metabolizers. A regression formula was calculated for prediction of haloperidol level from daify dose. There were no apparent differences in dosing practices between two university-affiliated medical centers and two nonaffiliated centers. More research is needed to establish optimal prohylactic haloperidol levels. However, hayoperidol monitoring can provide some assistance for choice of dose.

Level of haloperidol in plasma is related to electroencephalographic findings in patients who improve

This study analyzed interrelationships among plasma level of haloperidol (HAL), electroencephalographic (EEG) changes, and clinical response in 37 acutely exacerbated schizophrenic patients after a 6-week period of treatment. Two hypotheses were tested: (1) EEG theta response to HAL depends on levels of HAL in plasma, and this relationship is expressed in patients showing a clear clinical response (responders). (2) Responders and nonresponders are characterized by a different neuroleptic EEG profile. EEG examinations (resting, waking EEG) were performed at study entry, end point of the placebo period (“baseline”), and weekly during the entire HAL treatment period. EEG response was measured by power spectral changes in four frequency bands (delta, theta, alpha, and beta); clinical response was assessed by the Brief Psychiatric Rating Scale. There was a significant relationship between HAL plasma levels and EEG theta activity for treatment responders, whereas no relationship was detected for the nonresponders. Furthermore, there were EEG changes (in the delta and alpha bands) that depended on clinical response but did not show any relationship, either in responders or nonresponders, to HAL plasma levels. These results supported both hypotheses.

Dose-dependent reduced haloperidol/haloperidol ratios in schizophrenic patients

Plasma haloperidol (HAL) and reduced HAL (RHAL) concentrations were measured in 113 Chinese schizophrenic patients. Daily doses of HAL ranged from 8 to 65 mg. Samples were obtained under steady-state conditions and drawn 10–12 hours after the bedtime dose and before the morning dose. In all, 313 blood samples were collected. Multiple samples were obtained at the same doses in 63 patients and at two or three different doses in 31 patients. HAL and RHAL concentrations were assayed by high performance liquid chromatography. Interpatient variation in plasma HAL levels at a given dosage was up to sixfold. However, there was a high positive correlation between plasma levels and daily dosages with the equation of HAL plasma level ( ng/ ml) = 0.88 × dosage ( mg/ day) — 0.56 or 46.0 × dosage ( mg/ day/ kg) + 0.28. The expected values are about 15–55% higher than those obtained from non-Chinese patients as reported in the literature. The RHAL/HAL ratios were dose-dependent. The greater the dose used, the higher the ratio. An upper therapeutic limit of plasma HAL level is suggested to be 25 ng/ml, which can be achieved at dosages about 30 mg/day in most Chinese patients. Based upon the dose-dependent increase in RHAL/HAL ratios, the importance of RHAL in determining the therapeutic benefit of HAL treatment is discussed.

Pharmacokinetics of haloperidol and fluphenazine decanoates in chronic schizophrenia

In a double-blind comparison of haloperidol decanoate and fluphenazine decanoate given 4-weekly for 60 weeks as maintenance therapy in 38 chronic schizophrenic in-patients, plasma haloperidol, fluphenazine and prolactin levels were measured at regular intervals by radioimmunoassay. After the first injection, the mean plasma haloperidol level was highest at week 1 and fell gradually towards week 4. Mean pre-dose haloperidol levels changed little after week 8. Results suggested an absorption half-life of 4 weeks, although, in three cases steady state was only achieved after 11 monthly injections. Steady state levels of both haloperidol and fluphenazine correlated highly with dose. In two sub-groups observed at steady state, both drugs produced a biphasic pattern of plasma drug concentration between injections, a rapid rise on day 1 followed by stable elevated levels and a gradual return to pre-injection concentration by the end of week 4. In the fluphenazine sub-group there was a second peak on day 7 and a steeper decline, so that the mean area-under-curve in week 4 was 64% of that in week 1. Drug injections at steady state induced an increase in prolactin secretion in all of the fluphenazine sub-group and in half of those receiving haloperidol. Plasma prolactin changes resembled those for drug concentrations, but differences in times of peaks on day 1 resulted in weak correlations. Fluphenazine appeared more potent than haloperidol in provoking prolactin secretion.

Direct Radioimmunoassay for Haloperidol in Human Serum

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

Change in Haloperidol Level Due to Carbamazepine???A Complicating Factor in Combined Medication for Schizophrenia

Serum haloperidol levels were measured in patients who received haloperidol alone and, subsequently, haloperidol in combination with carbamazepine or lithium carbonate. Haloperidol levels and the level- dose ratios dropped about 50% in patients receiving carbamazepine. They remained the same in most patients receiving lithium carbonate. One patient receiving added carbamazepine experienced worsening of symptoms; this was associated with a drop in serum haloperidol level. Two other patients receiving added carbamazepine showed significant symptom reduction, although they also sustained drops in serum haloperidol levels. It is not clear whether these two individuals benefited from a primary antipsychotic effect of carbamazepine or from reduction of "toxic" haloperidol levels. Serum levels of antipsychotic medication should be monitored carefully when these medications are prescribed in combination with carbamazepine.

Reduced haloperidol/haloperidol ratios in plasma: Polymorphism in Japanese psychiatric patients

We measured plasma concentrations of haloperidol (HAL) and its metabolite, reduced haloperidol (RHAL), by high performance liquid chromatography (HPLC) in 45 Japanese psychiatric patients receiving HAL. Plasma levels of HAL had a highly positive correlation with daily dose per body weight. Plasma RHAL/HAL ratios had also a dose-dependent relationship, but their distribution was nonnormal and a bimodal pattern with an antimode at 0.7 was apparent by probit analysis. There were 8 subjects (18%) with high RHAL/HAL ratios (mean = 1.26, SD = 0.41) and 37 subjects (82%) with low RHAL/HAL ratios (mean = 0.42, SD = 0.13). RHAL/HAL ratios showed little intraindividual variability (± 10.6%), while interindividual variability was large. This may suggest that pharmacogenetic factors are involved in the metabolism of HAL and RHAL.

Factors Affecting the Clinical Response to Haloperidol Therapy in Schizophrenia

Fifty-one patients diagnosed as schizophrenics or schizoaffective according to DSM-III criteria were treated with conventional haloperidol regimens for 4 or 6 weeks. The clinical picture and extrapyramidal side effects were assessed by means of the Brief Psychiatric Rating Scale (BPRS), and the Simpson and Angus Scale (EPSE). Evaluations were made at admission and after 4 or 6 weeks of treatment. The clinical response to treatment was reported as the percent change in BPRS scores at the end of treatment from the BPRS scores at baseline. Haloperidol (HAL) and hydroxyhaloperidol (REDHAL) were determined by high-performance liquid chromatography (HPLC) with electrochemical detection in plasma. The mean total BPRS item score at the end of the study was significantly lower than at the beginning of the study. HAL and REDHAL levels were significantly related to the dose, and REDHAL levels were also related to HAL levels. There was no correlation between plasma HAL levels and the percent change in BPRS. The percent change in BPRS at the end of the study was negatively correlated with plasma REDHAL levels and REDHAL/HAL ratios and was positively correlated with the baseline BPRS total score. There was no significant correlation between the duration of illness and improvement, but patients with good improvement had significantly shorter duration of illness. Patients who improved also had higher baseline BPRS scores, lower REDHAL levels and REDHAL to HAL ratios, but not significantly different HAL levels. Therefore, the shorter the duration of the disease, the higher the baseline BPRS and the lower the reduced levels of its ratio to haloperidol levels, the higher the percent improvement.(ABSTRACT TRUNCATED AT 250 WORDS)

Human scalp hair as evidence of individual dosage history of haloperidol: prospective study.

The concentration of haloperidol in hair was measured by radioimmunoassay after hairs were dissolved in 2.5 N NaOH solution and the drug was extracted. In patients to whom haloperidol had been administered at fixed daily doses for more than 1 month, and in whom therapy had been just discontinued (group A, n = 5) or the doses cut to half (group B, n = 3), hairs were collected when the dose was changed and at 1 and 2 or 3 months thereafter. A few strands of hair collected on each occasion were cut into 1-cm-long portions from the roots, and the haloperidol concentration was measured in each portion. When hairs were assumed to grow at a rate of 1-1.5 cm/month, the portion of hair that reflected the change of dose was observed to move upward along the hair length in all patients of group A. However, these phenomena were less obvious in group B. These results indicate that at the least, hair could serve as an indicator of individual exposure or nonexposure to haloperidol and could yield retrospective information. In rats whose hairs had been removed by plucking from an area on the back, either saline or 1 mg/kg of haloperidol (i.p., b.i.d.) was administered for 2 weeks (first period), followed by 0, 0.5, 1, or 2 mg/kg b.i.d. for the subsequent 2 weeks (second period). At the end of each period, hairs that had grown in the plucked area were collected. Within-groups, haloperidol levels in hairs collected at the end of each period corresponded to the doses given.(ABSTRACT TRUNCATED AT 250 WORDS)

Haloperidol and reduced haloperidol plasma levels in Chinese vs. non-Chinese psychiatric patients

Haloperidol and reduced haloperidol plasma concentrations were measured in age-matched Chinese and non-Chinese patients ( n = 32). Steady-state plasma concentrations were obtained 10–12 hours after the bedtime dose. Haloperidol and reduced haloperidol concentrations were measured by liquid chromatography and radioimmunoassay. Haloperidol plasma concentrations did not significantly differ between the populations, but reduced haloperidol levels were 3 times greater in non-Chinese patients than in Chinese patients. The incidence of extrapyramidal side effects was higher in Chinese patients (18 vs. 10), while non-Chinese patients with extrapyramidal symptoms had higher reduced haloperidol plasma levels. Logistic regression analysis revealed that ethnicity and reduced haloperidol/haloperidol ratios were important variables in predicting extrapyramidal symptoms. These results suggest that the metabolism and disposition of haloperidol and reduced haloperidol could differ among ethnic populations.

A Systematic Approach to Pharmacotherapy in Patients With Neuroleptic-Resistant Psychoses

The presence or absence of neuroleptic-induced pseudoparkinsonism, the presence or absence of akathisia, and plasma levels of haloperidol are used to distinguish five types of haloperidol-resistant psychotic patients. The five types are patients receiving an inadequate dose, those whose inadequate dose cannot be increased due to the presence of akathisia, those in whom neuroleptic activity at the dopamine type 2 receptors in the brain is inhibited, those receiving a bioavailable but clinically ineffective dose, and those receiving an excessive dose. Management strategies are proposed for each type of patient and include guidelines for adjusting doses of haloperidol, switching to different neuroleptics, and introducing nonneuroleptic somatic therapies.

Clinical response and plasma haloperidol levels in chronic and subchronic schizophrenia

Levels of haloperidol were determined by radioimmunoassay (RIA) in 30 schizophrenic patients (diagnosed according to the criteria of DSM-III), who were treated with fixed doses of this neuroleptic for a period of 21 days. An inverted U-shaped relationship was found between the percent improvement observed in the BPRS global score and the steady state of haloperidol. The interval of effective concentration of haloperidol was set between 12.0 and 35.5. ng/ml. However, the limits of such an interval found in the subchronic schizophrenic subgroup (SS) ranged from 7.4 to 24.9 ng/ml, whereas in the chronic schizophrenic subgroup (CS), it ranged from 14.8 to 38.5 ng/ml. This finding suggests that the interval of effective concentrations may vary as a function of the number of years of evolution of the subjects' illness. This may be compatible with the development of tolerance in the mesolimbic and/or mesocortical dopaminergic systems as a response to prolonged neuroleptic treatments.

Dopamine Receptor Occupancy and Plasma Haloperidol Levels-Reply

<h3>In Reply.—</h3> Our finding of a 65% to 85% D2-dopamine receptor occupancy in schizophrenic patients treated with chemically distinct antipsychotic drugs represents strong support for the hypothesis that the antipsychotic effect is mediated by blockade of D2-dopamine receptors.¹The theoretically expected curvilinear relationship between neuroleptic drug concentration in plasma and D2-dopamine receptor occupancy has now been confirmed in several PET studies of patients receiving neuroleptic therapy.^1,2However, caution must be exercised before accepting the conclusions reached by Wolkin et al regarding the clinical utility of plasma levels. In their letter, Wolkin et al comment on their curve between plasma haloperidol levels and receptor occupancy: "The lack of scatter about the curve implies a close relationship between plasma level and receptor blockade. This is a strong argument for the clinical utility of plasma neuroleptic drug levels." Despite a large number of studies, a generally confirmed relationship between plasma drug concentrations

Clinical implications of determination of plasma haloperidol levels.

The aim of this study was to analyze the clinical utility of monitoring plasma levels, since the utility of monitoring is not yet well established. After a washout period, 30 schizophrenic patients were given fixed doses of haloperidol for 3 weeks. A U-shaped second-grade polynomic relationship (R = 0.69) was found between steady state of haloperidol and percentage improvement in total score on the Brief Psychiatric Rating Scale. The interval of effective concentrations was between 12 and 59 ng/ml. Fourteen of the 15 patients who had a steady state of haloperidol within that therapeutic interval were responders: only 5 out of the 15 patients below the therapeutic interval were responders. None of the 5 patients who had concentrations below 8 ng/ml was a responder. Furthermore, responder patients showed a steady-state level of haloperidol significantly higher than that of nonresponders. These data suggest that plasma levels of haloperidol are predictors of therapeutic response in schizophrenic disorders.

Serum haloperidol and anticholinergic levels in drug-induced parkinsonism

Serum haloperidol and anticholinergic levels in drug-induced parkinsonism

Redistribution of haloperidol after electroshock: Experimental evidence

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

Human scalp hair as evidence of individual dosage history of haloperidol: method and retrospective study.

Hair samples and morning pre-dose plasma were collected from 40 patients who had received fixed daily doses of haloperidol for more than four months and whose compliance was good. After washing, 1 to 2 cm-long portions nearest to the roots of 2 to 3 strands of hair were completely dissolved in 2.5N NaOH. Haloperidol in that sample or alkalinised plasma was extracted and measured by RIA. Haloperidol concentrations in hair correlated well both with the trough concentration in plasma at steady-state (r = 0.772, n = 39) and with the daily dose (r = 0.555, n = 40). Another keratinized tissue, nail, was also collected from 20 of the 40 patients and the haloperidol level was compared with that in hair. The former was only about 4.3% of the latter and was significantly correlated only with the daily dose (r = 0.525, n = 20). Hair from 10 other patients in whom the dosage of haloperidol had been changed within a few months prior to sampling the hair was cut into 0.5 or 1 cm-long portions from the roots and the drug concentration in each portion was measured. If hairs were assumed to grow at 1 cm/month, a history of individual dosage could be deduced in 9 of the 10 patients from the distribution of drug level along the length of the hair. The results suggest that human scalp hair could serve as a useful tool for monitoring individual dosage history over several months, or in demonstrating exposure or non-exposure of a patient to a drug.