Reduced Haloperidol Plasma Concentrations Research Articles

Smoking among Male Psychiatric Outpatients in Saudi Arabia

The prevalence rate of smoking among psychiatric patients has been shown to be higher than that among the general population, and this may have several neuropsychiatric implications. This cross-sectional study examines the prevalence, sociodemographic variables and pattern of smoking among psychiatric outpatients in Saudi Arabia. Over a period of 18 months (January 1996 to June 1997), 505 outpatients from five different hospitals were randomly selected to participate in the study. It was observed that 292 patients (57.83%) were current smokers, 199 (39.4%) were nonsmokers and 14 patients (2.77%) were ex-smokers. Besides revealing certain attitudes towards smoking and religious antismoking notions, it was observed that unemployment, low education status, rural background, and drug abuse were significantly associated with smoking. The prevalence rate of smoking revealed in this study is consistent with international data, and probably has implications similar to those reported in other studies. This study also found certain patterns of tobacco use in psychiatric outpatients characterized by certain sociodemographic variables and drug abuse.

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.

Dextromethorphan phenotyping and haloperidol disposition in schizophrenic patients

This study examined the relationship between the metabolic ratios of dextromethorphan/dextrorphan, haloperidol disposition, and the incidence of extrapyramidal side effects in schizophrenic patients. Eighteen schizophrenic patients were phenotyped with a test dose of dextromethorphan prior to the initiation of haloperidol treatment. The metabolic ratio of dextromethorphan/dextrorphan was determined in each patient. Patients were treated with oral haloperidol 10 mg/day for 2 weeks. Blood samples for haloperidol and reduced haloperidol were obtained at week 2 of haloperidol treatment. Haloperidol and reduced haloperidol plasma concentrations were assayed by HPLC with electrochemical detection. Significant correlations of dextromethorphan/dextrorphan metabolic ratios vs. plasma haloperidol concentrations, reduced haloperidol concentrations, and reduced haloperidol/haloperidol ratios were found ( r = 0.726, P = 0.0007; r = 0.782, P = 0.0001; and r = 0.619, P = 0.006, respectively). Ten patients who experienced extrapyramidal side effects had higher reduced haloperidol concentrations and reduced haloperidol/haloperidol ratios than the other patients (2.49 ± 1.42 [S.D.] ng/ml vs. 1.10 ± 0.46 ng/ml, P = 0.014 and 0.287 ± 0.102 vs. 0.192 ± 0.065, P = 0.030). The former also had a trend to have higher haloperidol concentrations and dextromethorphan/dextrorphan ratios than the latter (8.04 ± 2.91 ng/ml vs. 5.83 ± 1.79 ng/ml, P = 0.066 and 0.023 ± 0.017 vs. 0.011 ± 0.010, P = 0.077). Phenotyping patients has the potential to assist clinicians in predicting plasma drug concentrations during the subsequent neuroleptic drug treatment. Further research with phenotyping and psychotropic drug metabolism in psychiatric patients is needed.

Haloperidol and reduced haloperidol plasma concentrations after a loading dose regimen with haloperidol decanoate

1. 1. Haloperidol and reduced haloperidol plasma levels were measured in schizophrenic patients who received both oral (10 mg, N=16 and 20 mg, N=4)and depot haloperidol treatment 2. 2. Patiente were of Asian ethnicity and were safely and effectively converted from oral to depot therapy using a loading dose regimen using a 100 mg weekly injection interval for 4 weeks, biweekly for one month and then monthly. 3. 3. Significant correlations were found for plasma haloperidol and reduced haloperidol levels and reduced haloperidol/haloperidol ratios between oral and depot therapy In these non-smoking patients. 4. 4. A loading dose regimen to needed due to the long elimination half-life of decanoate of 26 days otherwise steady-state condition will not occur until 3–4 months of therapy. 5. 5. Patients were maintained on monthly depot treatment for 40 weeks after the loading dose regimen and only one patient relapsed during treatment despite dosage Increases. 6. 6. The formation of reduced haloperidol remained consistent for oral and depot haloperidol treatment.

Plasma haloperidol and reduced haloperidol concentrations in a geriatric population.

Haloperidol (HL) and reduced haloperidol (RH) plasma concentrations were measured in geriatric patients (n = 45) and schizophrenic patients (n = 8). In the elderly patients, HL doses were 1-4 mg/day while only 2 mg/day was used in the schizophrenics. At HL 2 mg/day dose in both age groups, mean plasma HL levels were approximately twice as high in the elderly patients compared to the schizophrenics (1.39 +/- 0.82 vs. 0.56 +/- 0.23 ng/ml, p < 0.02). RH plasma concentrations were almost 5 times greater in the elderly patients (0.54 +/- 0.35 vs. 0.09 +/- 0.05 ng/ml, p < 0.0001). These results suggest that HL plasma concentrations in the elderly are greater than in adult schizophrenic patients treated with similar HL doses.

Prolonged haloperidol and reduced haloperidol plasma concentrations after decanoate withdrawal

Haloperidol and reduced haloperidol plasma concentrations were measured in twelve schizophrenic patients upon cessation of haloperidol decanoate (HLD) treatment. Each patient received HLD 100 mg every 4 weeks for five injections. After the fifth injection, HLD was discontinued.Haloperidol and reduced haloperidol plasma concentrations were obtained prior to cessation and at weeks 1, 3, 4, 5, 7, 9, 11, and 13 post-injection. Haloperidol and reduced haloperidol plasma concentrations were assayed by HPLC. Both haloperidol and reduced haloperidol plasma concentrations were detectable 13 weeks post HLD discontinuation. Maximal haloperidol plasma concentrations were observed at one week post cessation and gradually declined. The mean elimination half-life for haloperidol was 27.4 ± 8.6 days (range 19.0– 47.0 days). Reduced haloperidol plasma concentrations declined very slowly. Our results show that both haloperidol and reduced haloperidol plasma concentrations can remain for extended time periods after HLD is discontinued.

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.

Haloperidol and reduced haloperidol plasma concentrations in schizophrenic patients: Oral versus depot : Wen-Ho Chang, Shih-Ku Lin, Li-Chin Chen, Chih-Hsien Yang, Dong-Juiing Juang Taipei City Psychiatric Center, Taipei, Taiwan, Republic of China 10510

Haloperidol and reduced haloperidol plasma concentrations in schizophrenic patients: Oral versus depot : Wen-Ho Chang, Shih-Ku Lin, Li-Chin Chen, Chih-Hsien Yang, Dong-Juiing Juang Taipei City Psychiatric Center, Taipei, Taiwan, Republic of China 10510

Reduced haloperidol plasma concentration and clinical response in acute exacerbations of schizophrenia

Twenty-nine hospitalized patients suffering acute exacerbations of schizophrenia were treated for 2 weeks with fixed daily oral doses of haloperidol prospectively calculated to achieve a haloperidol plasma concentration of either 8-18 ng/ml or 25-35 ng/ml. Reduced haloperidol as well as haloperidol concentrations were assayed to determine if the former enhanced the predictability of response. Wee 2 haloperidol plasma concentrations were negatively correlated to clinical response as measured by the percentage change in the BPRS score from baseline (r = -0.43, P less than 0.05). In contrast, week 2 plasma concentrations of reduced haloperidol, total haloperidol (haloperidol + reduced haloperidol), and reduced haloperidol/haloperidol ratio did not correlate with the change in the BPRS score. Chi-square analysis concluded that patients with ratios greater than one were no less likely to be treatment responders (less than 25% improvement in BPRS from baseline and week 2 BPRS less than 55) than those with ratios less than one. Although these data lend additional support to reports of a curvilinear relationship between haloperidol plasma concentration and clinical response, they also suggest that reduced haloperidol plasma concentrations are of no value in predicting treatment response.

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.

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.

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 less than 0.01, P less than 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 nonsmokers. Plasma concentrations should be carefully monitored when patients either start or stop smoking.