Haloperidol and reduced haloperidol plasma levels in selected schizophrenic patients

The first measurements of haloperidol (HL) and its reduced metabolite hydroxyhaloperidol (RH) in plasma versus clinical response in five chronic schizophrenic patients are reported. HL and RH were measured by a radioimmunoassay with a low coefficient of variation. Patients were selected based on poor response or the need for high dosage and were rated with the Clinical Global Impression Scale. Daily HL dosage range was 0.5 to 1.5 mg/kg. HL plasma concentrations ranged from 14 to 98 ng/ml. RH plasma concentrations ranged from 10 to 319 ng/ml. Four patients did not respond to HL therapy; two of these improved dramatically when switched to fluphenazine. The four nonresponding patients had higher RH than HL concentrations. RH seems to be present in plasma in significant concentrations, and further investigation of the relationships of RH and HL plasma levels versus response is needed.     

Effects of carbamazepine and valproate on haloperidol plasma levels and on psychopathologic outcome in schizophrenic patients.

The objective of this study was to compare the effects of carbamazepine (CBZ) and valproate (VPA) cotreatment on the plasma levels of haloperidol and on the psychopathologic outcome in schizophrenic disorders. In this controlled clinical trial, 27 patients with an ICD-10 diagnosis of schizophrenia (N = 24) or schizoaffective disorder (N = 3) were randomly assigned to receive 4 weeks of treatment with either haloperidol alone, haloperidol with CBZ, or haloperidol with VPA. Whereas the haloperidol dose remained stable, the antiepileptic drug doses were adjusted to achieve therapeutic plasma levels. Clinical state was rated by the Positive subscale of the Positive and Negative Syndrome Scale and the Inpatient Multidimensional Psychiatric Scale. The use of CBZ was associated with significantly lower haloperidol plasma levels and with a worse clinical outcome compared with antipsychotic monotherapy. VPA had no significant effect on either plasma levels or on psychopathology. Our results suggest that comedication with haloperidol and CBZ is associated with a high risk for treatment failure. This might be a result of a pharmacokinetic interaction on the hepatic level. The concomitant use of VPA with neuroleptic therapy is not impaired by clinically significant drug interactions, but it is not associated with a better outcome under our conditions.     

Serum haloperidol levels and clinical response in chronic, treatment-resistant schizophrenic patients

Eleven chronic treatment-resistant schizophrenic in-patients were treated with haloperidol (HPL) or placebo with a fixed ascending dose schedule for 20 weeks. Seven patients relapsed and were withdrawn and five of these re-entered, single-blind, on known active treatment. Two weekly clinical ratings and weekly serum HPL levels were carried out throughout the study. More patients on placebo dropped out and at an earlier stage than those on active treatment but the difference was not statistically significant. Despite wide individual variations in both serum HPL levels and clinical response, these were positively correlated. HPL appeared to be of more value in the prevention of relapse than in symptom reduction. Overall, the clinical response was poor and a 'therapeutic window' could not be demonstrated either for the group as a whole or in any individual patient. There was no additional therapeutic benefit in exceeding serum HPL levels of 20 ng/ml in any of our patients. Since this serum level was achieved by daily doses of 10-40 mg HPL and the relationship between dose and serum level is linear, the use of serum HPL estimations is not likely to be of value in the routine clinical management of treatment-resistant patients.     

Clozapine serum concentrations are lower in smoking than in non-smoking schizophrenic patients

Serum concentrations of clozapine and its main metabolite demethylclozapine were measured in 44 schizophrenic inpatients, of whom ten were non-smokers and 34 smokers. When comparing their clozapine dose and body weight-related serum drug levels, we found that clozapine and demethylclozapine concentrations were about 40% lower in the smoking than in the non-smoking group, probably due to an inducing effect of smoking on the cytochrome P450 (CYP) 1A2, which is involved in the metabolism of clozapine. We conclude that dosage adjustment may be necessary in clozapine-treated smokers.     

Effects of debrisoquin and haloperidol on plasma homovanillic acid concentration in schizophrenic patients

Plasma levels of the dopamine metabolite homovanillic acid (pHVA) may potentially reflect upon central dopamine activity. This study examines the effects of debrisoquin, haloperidol, and the two drugs combined on pHVA concentrations of schizophrenic patients. Debrisoquin is a drug that suppresses the peripheral formation of homovanillic acid without affecting the central formation. Acute haloperidol administration consistently increased pHVA concentrations in patients pretreated or not pretreated with debrisoquin, suggesting that this increment reflects haloperidol's central and not peripheral effects.     

Reversible metabolism of haloperidol and reduced haloperidol in Chinese schizophrenic patients

Haloperidol disposition has been associated with reversible metabolism: it is reversibly reduced to its metabolite, reduced haloperidol, which has less pharmacologic activity than the parent compound. To characterize the interconversion process, six healthy male schizophrenics were administered a single dose of 10 mg haloperidol or reduced haloperidol in a randomized crossover manner. Using a general pharmacokinetic model for the interconversion process, the clearances of haloperidol and reduced haloperidol are 1.15±0.32 l/h/kg and 0.76±54 l/h/kg, respectively. These clearances are similar to that obtained by the usual mammillary model analysis. With a single 10 mg dose administration of either drug, about 23% of the biotransformation of haloperidol involves the reduction pathway. Back conversion from the reduced metabolite to the parent drug through oxidation contributes even less to the total biotransformation of reduced haloperidol. This action of interconversion or saturation under chronic drug administration is unknown. Reversible metabolism of haloperidol could partially account for the wide therapeutic range for haloperidol as reported in the literature.Presented at the 10th Annual Meeting of the American College of Clinical Pharmacy August 6–9, 1989     

Effects of smoking on haloperidol and reduced haloperidol plasma concentrations and haloperidol clearance

Plasma concentrations of haloperidol and its reduced metabolite (reduced haloperidol) were investigated in cigarette smokers (N=23) and nonsmokers (N=27). Steady-state plasma concentrations were obtained 12 h post bedtime dose. Haloperidol and reduced haloperidol concentrations were determined by RIA. Reduced haloperidol was separated by selective succinylation and liquid chromatography. Patients were clinically assessed with the Clinical Global Impression Scale (CGIS). Smokers had significantly lower haloperidol and reduced haloperidol plasma concentrations than nonsmokers (P<0.01, P<0.05). Clearance of haloperidol was significantly greater in smokers compared to nonsmokers (P=0.0052). CGIS assessments did not show significant differences between smokers and non-smokers. Plasma concentrations should be carefully monitored when patients either start or stop smoking.Presented at the IV World Congress of Biological Psychiatry, Philadelphia, PA, September 8–13, 1985     

The plasma haloperidol and reduced haloperidol concentrations in chinese schizophrenic patients: Relationship between reduced haloperidol/haloperidol ratio and red blood cell haloperidol reductase activity

Fifteen chinese schizophrenic patients were given titrated doses of haloperidol (0.05-0.42 mg/kg) for two weeks. All these 15 patients were in clinical remission on maintenance dose of haloperidol. The mean plasma haloperidol and reduced haloperidol concentrations were 16.8 ± 4.8 ng/ml and 13.6- 5.7 ng/ml respectively. The plasma RHAL/HAL ratio was in the range of 0.13±1.94. These values were similar to that reported for the Japanese population. The frequency distribution appeared to be bimodal. RBC reductase activity were found to be distributed normally and no correlation was found between plasma RHAL/HAL ratio and RBC reductase activity.     

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.     

Effects of smoking, CYP2D6 genotype, and concomitant drug intake on the steady state plasma concentrations of haloperidol and reduced haloperidol in schizophrenic inpatients.

The effects of smoking, CYP2D6 genotype, and concomitant use of enzyme inducers or inhibitors on the steady state plasma concentrations of haloperidol (HAL) and reduced haloperidol (RHAL) were evaluated in 92 schizophrenic inpatients. All but three of these patients received concomitant medication, in many cases with drugs potentially interacting with HAL. Of the 92 patients, 63 were treated orally with HAL in a daily dose of 0.4 to 50 mg; 29 patients were treated intramuscularly with a daily equivalent dose of HAL decanoate (expressed as HAL) of 1.8 to 17.9 mg. A wide interindividual variation in HAL dose and in steady state plasma concentrations of HAL and RHAL was observed. In the patients treated orally, the daily oral dose was about 4 times higher and the dose-normalized HAL (but not RHAL) plasma concentrations were significantly lower in smokers (n = 40) than in nonsmokers (n = 23) (p < 0.01). The dose-normalized RHAL (but not HAL) plasma concentrations and the RHAL/HAL ratio were significantly higher in poor metabolizers (PMs) than in extensive metabolizers (EMs). There was a trend toward an effect of potentially interacting drugs (inducers or inhibitors) on dose, dose-normalized HAL and RHAL plasma concentrations, and the RHAL/HAL ratio. In the patients treated intramuscularly, the dose-normalized HAL (but not RHAL) plasma concentrations were significantly lower in smokers than in nonsmokers, but no differences in doses were observed. This naturalistic study of modest sample size in a polymedicated population shows an effect of smoking and CYP2D6 genotype (and to a lesser extent, of interacting drugs) on the kinetics of HAL.     

Significant dose effect of carbamazepine on reduction of steady-state plasma concentration of haloperidol in schizophrenic patients

A reduction in haloperidol concentration induced by carbamazepine coadministration has been consistently reported. However, the degree of this reduction is very different among individuals treated with various doses of carbamazepine. Thus, we investigated dose effect of carbamazepine on the steady-state plasma concentration of haloperidol. Eleven excited schizophrenic inpatients, despite receiving haloperidol 12 mg/d, were treated with incremental doses of carbamazepine for 6 weeks (100, 300, 600 mg/d for 2 weeks each). Plasma drug concentrations were monitored together with clinical assessments before and after each phase of the 3 carbamazepine doses. Mean haloperidol concentrations during coadministration of carbamazepine 100, 300, and 600 mg/d were 75%, 39%, and 15%, respectively, of corresponding variables before carbamazepine coadministration. Negative linear correlations were observed between dose or plasma concentration of carbamazepine and the degree of reduction in haloperidol concentration. Mean carbamazepine dose and plasma carbamazepine concentrations at 50% reduction of haloperidol concentration were 240 mg/d and 3.5 microg/mL, respectively. Scores in total and excitement symptoms were significantly reduced after carbamazepine coadministration, whereas no changes were observed in other clinical symptoms or any of the subgroup side effects. Therefore, this study indicates that carbamazepine decreases plasma haloperidol concentration in a dose-dependent or concentration-dependent manner, and that reduction in haloperidol concentration is apparent even at subtherapeutic dose of carbamazepine.     

Effects of carbamazepine on plasma haloperidol levels

Plasma haloperidol levels were monitored in three schizophrenic patients when carbamazepine was either added or discontinued. The percent decrease in plasma haloperidol levels due to concomitant carbamazepine therapy was between 59% and 61%. The effects of carbamazepine on plasma haloperidol levels were noted to occur in 2 to 3 weeks. Although no adverse effects occurred in the patients during therapy, careful monitoring of clinical symptoms and plasma haloperidol levels is recommended.     

Disposition of haloperidol and reduced haloperidol plasma levels after single dose haloperidol decanoate administration

A single dose of haloperidol decanoate 100 mg was administered to 15 schizophrenic patients. Blood samples were obtained prior to injection, 1 h, 3 h, 6 h, 8 h, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, one week, two weeks, three weeks and four weeks post-injection. Haloperidol and its reduced metabolite, reduced haloperidol, plasma levels were assayed by HPLC with electrochemical detection. The pharmacokinetic parameters of haloperidol were determined. The mean time of maximal (T_max) plasma levels for haloperidol was 5·73 ± 0·80 days. The haloperidol plasma levels showed a biexponential decline with an elimination half-life of 15·78 ± 5·90 days. Reduced haloperidol was rapidly formed from the haloperidol. The T_max of reduced haloperidol was 7·00 ± 2·35 days. The mean ratio reduced haloperidol/haloperidol was 0·155 ± 0·111. Since the T_max occurs at approximately six days, a weekly loading dose of haloperidol decanoate is feasible during the transition from oral to depot therapy.     

Relationship of butaperazine blood levels to plasma prolactin in chronic schizophrenic patients

The relationship of plasma prolactin to plasma or red blood cell butaperazine levels was investigated in chronic schizophrenic patients treated with clinical doses of butaperazine, both after a single acute dose of the drug and during regular, twice daily butaperazine administration. Although there was a significant curvilinear relationship between peak plasma butaperazine levels after an acute single oral dose of butaperazine and the maximum prolactin response that we measured, steady-state levels of plasma or red cell butaperazine and plasma prolactin were not related. We conclude that plasma prolactin cannot be used as a substitute for or even as a rough indicator of butaperazine blood levels in chronic schizophrenic patients being treated with clinical doses of butaperazine.     

Gender differences in plasma clozapine levels and its metabolites in schizophrenic patients

Forty refractory schizophrenic patients (21 females and 19 males) participated in a fixed-dose study with clozapine. After a 6-week trial of haloperidol and a 1-week washout time period, non-responding patients were placed on clozapine and the dosage titrated up to 400 mg/day for the next 5 weeks. Plasma clozapine levels and its two metabolites desmethylclozapine (DCLOZ) and clozapine N-oxide (CNO) were measured at weeks 2, 4 and 6. Blood samples were obtained 10–12 h post-evening dose and prior to the morning dose. Clozapine and its metabolites were assayed by HPLC with UV detection. Patients were assessed for clinical response with the Brief Psychiatric Rating Scale (BPRS) at baseline and at weeks 2, 4 and 6. BPRS scores were also divided into positive (+) and negative (−) symptoms subscales. Plasma clozapine and DCLOZ levels were significantly lower in males. Plasma CNO levels were slightly lower in males but it was not statistically significant. Decreased total BPRS, (+) and (−) symptoms subscale scores occurred during the study for both gender groups. A greater magnitude of change for the (−) symptom subscale score was observed in the male group. Gender was not a significant factor in the incidence or severity of side-effects. © 1997 John Wiley & Sons, Ltd.     

Steady-state pharmacokinetics of haloperidol and reduced haloperidol in schizophrenic patients: analysis of factors determining their concentrations in hair.

Profiles of the steady-state concentrations of haloperidol (HL) and its major metabolite, reduced haloperidol (RHL), in plasma versus time were determined in 10 Japanese patients whose schizophrenic symptoms were clinically controlled by fixed, oral maintenance doses (4-30 mg/day, three times a day) for greater than 4 months. These data were used to determine the pharmacokinetic factor(s) that correlate best with HL and RHL concentrations in hair. The concentrations of HL and RHL in plasma or hair were simultaneously measured by high-performance liquid chromatography with an electrochemical detector. The observed values of minimal and maximal concentrations in plasma (Cmin and Cmax, respectively) varied widely among patients: 3.0-22.9 and 6.2-32.7 ng/mL for HL and 2.8-21.4 and 5.7-33.3 ng/ml for RHL, respectively. The ratio of the area under the plasma concentration-time curve (AUC) of RHL for 1 day to that of HL also ranged widely from 0.39 to 1.99 (1.04 +/- 0.48, mean +/- standard deviation). When the concentration of HL or RHL in hair was compared with the daily dose of HL and respective AUC, Cmax, or trough concentration in the plasma in the morning, the parameter that best correlated with the concentration of HL in hair was AUC. The concentration of RHL in hair correlated with all three parameters, but the correlation with AUC was better than that with Cmax. Therefore, the concentrations of these substances in hair were considered to be representative of their mean amounts in the body.     

Prolactin levels in male schizophrenic patients treated with risperidone and haloperidol: a double-blind and randomized study

Rationale There are few data from systematic, double-blind clinical trials that have compared the effect of the typical and the atypical antipsychotics on serum prolactin (PRL) levels in patients with schizophrenia.Objectives The goal of this study was to compare the effect of risperidone and haloperidol on serum PRL and investigate the relationship between serum PRL levels and clinical response in patients with schizophrenia.Methods Seventy-eight inpatients with a diagnosis of schizophrenia (according to DSM-III-R) were randomly assigned to 12 weeks of treatment with 6 mg/day of risperidone or 20 mg/day of haloperidol after a 2-week washout period, using a randomized, double-blind design. Clinical efficacy was determined using the positive and negative syndrome scale (PANSS). Their serum PRL was assayed by means of radioimmunometric assay (RIA) between pre-treatment and post-treatment, and compared with 30 sex-matched and age-matched normal subjects.Results Both risperidone and haloperidol treatment significantly increased serum PRL levels in drug-free chronic schizophrenia patients (both P<0.001). Hyperprolactinemia induced by risperidone 6 mg/kg was comparable to levels produced by haloperidol 20 mg/day. Considering dose-adjusted serum PRL levels, risperidone treatment induced a significant elevation of PRL levels compared with haloperidol treatment at the haloperidol equivalent (P<0.001). Change in PRL levels at pre-treatment and post-treatment were related to positive symptom improvement seen in the risperidone group (r=0.51, P=0.016), but not in the haloperidol group (P>0.05). Female patients showed both a higher baseline and post-treatment PRL level and a greater increase in PRL than men (all P<0.05).Conclusions Risperidone is associated with a robust effect on prolactin secretion in contrast to the conventional antipsychotic haloperidol. Prolactin monitoring during risperidone treatment should be performed.     

Effect of a drug holiday on plasma chlorpromazine levels in chronic schizophrenic patients

Low chloropromazine (CPZ) levels have been measured in chronically treated schizophrenics. We tested six such patients to determine whether a 2-week CPZ-free period (drug holiday) would improve plasma CPZ levels. We also monitored psychiatric symptoms, autonomic function, and extrapyramidal signs. We found these patients to have low predose CPZ levels that did not change appreciably after the drug holiday. Peak levels following the holiday averaged 28 ±7 ng/ml higher than those measured prior to the holiday. Drug holidays are safe and should be examined more thoroughly as a means of improving plasma neuroleptic levels in chronically treated schizophrenics.Apreliminary report of this work was presented at the 81st Meeting of the American Society for Clinical Pharmacology and Therapeutics, March 21, 1980, San Francisco, California, USA