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The rs1076560 polymorphism of DRD2 (encoding dopamine receptor D2) is associated with alternative splicing and cognitive functioning; however, a mechanistic relationship to schizophrenia has not been shown. Here, we demonstrate that rs1076560(T) imparts a small but reliable risk for schizophrenia in a sample of 616 affected families and five independent replication samples totaling 4017 affected and 4704 unaffected individuals (odds ratio=1.1; P=0.004). rs1076560(T) was associated with impaired verbal fluency and comprehension in schizophrenia but improved performance among healthy comparison subjects. rs1076560(T) also associated with lower D2 short isoform expression in postmortem brain. rs1076560(T) disrupted a binding site for the splicing factor ZRANB2, diminished binding affinity between DRD2 pre-mRNA and ZRANB2 and abolished the ability of ZRANB2 to modulate short:long isoform-expression ratios of DRD2 minigenes in cell culture. Collectively, this work implicates rs1076560(T) as one possible risk factor for schizophrenia in the Han Chinese population, and suggests molecular mechanisms by which it may exert such influence.

Background: Reduced P300 event-related potential (ERP) amplitude and latency prolongation have been reported in patients with schizophrenia compared to healthy controls. However, the influence of antipsychotics (and dopamine) on ERP measures are poorly understood and medication confounding remains a possibility., Method: We explored ERP differences between 36 drug-naive patients with schizophrenia and 138 healthy controls and examined whether P300 performance was related to dopamine transporter (DAT) availability, both without the confounding effects of medication. We also conducted a random effects meta-analysis of the available literature, synthesizing the results of three comparable published articles and our local study., Results: No overall significant difference was found in mean P300 ERP between patients and controls in latency or in amplitude. There was a significant gender effect, with females showing greater P300 amplitude than males. A difference between patients and controls in P300 latency was evident with ageing, with latency increasing faster in patients. No effect of DAT availability on P300 latency or amplitude was detected. The meta-analysis computed the latency pooled standardized effect size (PSES; Cohen's d) of -0.13 and the amplitude PSES (Cohen's d) of 0.48, with patients showing a significant reduction in amplitude., Conclusions: Our findings suggest the P300 ERP is not altered in the early stages of schizophrenia before medication is introduced, and the DAT availability does not influence the P300 ERP amplitude or latency. P300 ERP amplitude reduction could be an indicator of the progression of illness and chronicity.

To compare the prevalence of extrapyramidal syndrome (EPS) between the first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs), the co-prescribing rate of anti-Parkinson drugs (APDs) of each antipsychotic drug was analyzed using population database. Fourteen antipsychotics had been prescribed during the 5-year study period. Among the SGAs, quetiapine had the lowest crude co-prescribing rate of APDs (27.09%), whereas risperidone had the highest rate (66.50%). Among the FGAs, thioridazine and loxapine had the lowest (60.99%) and highest rates (96.35%), respectively. The rankings of the co-prescribing rate of APDs among antipsychotics, in increasing order, were quetiapine, clozapine, olanzapine, thioridazine, zotepine, chlorpromazine, risperidone, sulpiride, clotiapine, flupentixol, haloperidol, zuclopentixol, trifluoperazine, and loxapine. The results indicate that the risk of EPS appears to be lower in SGAs than in FGAs; however, the considerably high rate of EPS in some of the newer generation of antipsychotics warrants clinical attention.

Background: Grapefruit juice can inhibit the gastrointestinal activity of cytochrome P450 (CYP) 3A4, while its effect on CYP1A2 remains controversial. Several grapefruit juice bioflavonoids also modulate the activity of the drug transporter P-glycoprotein in the gut and in the blood-brain barrier. Both CYP1A2 and CYP3A4 are involved in clozapine metabolism. This study investigated the effects of repeated ingestion of grapefruit juice on multiple-dose pharmacokinetics and pharmacodynamics of clozapine in schizophrenic patients., Method: Clozapine therapy was initiated for fifteen treatment-resistant schizophrenic inpatients (DSM-IV criteria). The doses were individually titrated from day -35 to day -15 and then kept unchanged from day -14 to day 49. Regular-strength grapefruit juice (250 mL) was coadministered b.i.d. with each clozapine dose from day 15 to day 28. Plasma levels of clozapine and its main metabolites (norclozapine and clozapine N-oxide) were obtained, and clinical efficacy and safety assessments were completed prior to juice administration (days 0, 7, and 14), during the coadministration (days 17, 21, and 28), and after cessation of the juice (days 35, 42, and 49)., Results: After reaching steady states, plasma concentrations of clozapine and its metabolites and Positive and Negative Syndrome Scale scores were not significantly altered by the effect of grapefruit juice ingestion. The Clinical Global Impressions scale scores, Calgary Depression Scale scores, and side effect profiles (by the Extrapyramidal Symptom Rating Scale, the UKU Side Effect Rating Scale, and thorough examinations including electrocardiography and electroencephalography) also remained constant during the study., Conclusion: Consumption of regular-strength grapefruit juice, 250 mL b.i.d., for 14 days did not significantly impact clozapine metabolism, clinical efficacy, or tolerability. One reason is that enzymes other than CYP3A4 also mediate clozapine disposition. Also, grapefruit juice inhibits CYP3A4 in the gut, but not in the liver. The preliminary results also suggest that clozapine is unlikely to be a P-glycoprotein substrate. Further rigorous studies are necessary to reconfirm these findings.

The drug-food and drug-drug interaction between grapefruit juice (GFJ) and ketoconazole (KETO) was evaluated in schizophrenic patients given a single dose of clozapine (CLZ). CLZ is metabolized primarily by CYP isozymes 3A4 and 1A2 to two principal metabolites, desmethylclozapine (DCLZ) and clozapine N-oxide (CNO). GFJ and KETO are well known potent CYP 3A4 inhibitors in the gastrointestinal tract and hepatic isozymes, respectively. Twenty-one schizophrenic patients participated in the co-administration of CLZ 50 mg and GFJ. After a one-week washout, five patients were given double the GFJ (HGFJ) dose for 7 consecutive days. In another group of five patients, ketoconazole (KETO) 400 mg was given for 7 consecutive days. At the end of the 7-day period for both groups, CLZ was coadministered with the HGFJ and KETO groups. CLZ, DCLZ and CNO were assayed by HPLC. GFJ, HGJF and ketoconazole failed to significantly change CLZ disposition. Metabolites DCLZ and CNO concentrations remained unchanged during the study. The only exception was decreased Cmax in DCLZ and CNO concentrations. These results indicate that CYP 3A4 inhibition may not be clinically significant compared to CYP 1A2, as previous studies show a dramatic increase in CLZ plasma concentrations with fluvoxamine (CYP 1A2 inhibitor). The reasons for the lack of drug-food and drug-drug interactions with CLZ and CYP 3A4 inhibitors can be explained by the higher Ki values for gastrointestinal and hepatic CYP 3A4 isozymes.

The disposition of olanzapine was evaluated in 21 male chronic schizophrenic patients. A single 10 mg dose of olanzapine was administered and blood sampling performed over the following 120 hours. The mean (+/- SD) oral clearance and elimination half-life of olanzapine were 51.5+/-61.6 l/h and 30.9+/-4.3 hours, respectively. A wide interpatient variability was found. Compared to the population norms, no significant differences were observed between different populations and Chinese patients in olanzapine disposition.

Background: Concomitant fluvoxamine use can potentially reduce the dosage of clozapine needed in treatment-refractory patients with schizophrenia. Previous reports have shown that fluvoxamine can increase plasma clozapine concentrations by inhibition of cytochrome P450 (CYP) 1A2. We evaluated the safety and efficacy of fluvoxamine, 50 mg/day, coadministration with clozapine, 100 mg/day, in refractory schizophrenic patients., Method: In this prospective study, 18 treatment-refractory patients with DSM-IV schizophrenia (10 nonsmokers and 8 smokers) were treated with clozapine at a target dose of 100 mg h.s. After steady-state conditions of clozapine had been reached, 50 mg/day of fluvoxamine was then added. Plasma levels of clozapine, norclozapine, and clozapine N-oxide were measured prior to fluvoxamine addition and on days 14 and 28 during combined treatment. Side effects and efficacy were monitored with standardized rating instruments., Results: After 14 days of combined treatment, the mean +/- SD plasma clozapine level increased 2.3-fold to 432.4+/-190.9 ng/mL without further elevation on day 28. All patients completed the study without significant adverse side effects. Twelve of the 18 patients achieved plasma clozapine concentrations of at least 350 ng/mL. While plasma norclozapine levels also rose (but to a smaller extent), plasma clozapine N-oxide levels remained unchanged after the add-on therapy. Patients who smoked had 34% lower plasma clozapine concentrations than nonsmokers (NS). Three of the 4 patients who did not reach clozapine plasma levels of at least 300 ng/mL were smokers. Plasma norclozapine/clozapine ratios, especially in smokers, declined significantly with fluvoxamine addition., Conclusion: The addition of fluvoxamine, 50 mg/day, to low-dose clozapine, 100 mg/day, can raise plasma clozapine levels to at least 300 ng/mL in most patients. Only slight dosage adjustments with clozapine may be needed after fluvoxamine coadministration in some patients who smoke. Plasma clozapine levels remained stable after 14 days of fluvoxamine addition. The combined treatment was well tolerated, and clinical improvement was observed in our patients. Further long-term studies with this drug combination are needed to determine its economic impact.

Background: The optimal risperidone dosing strategy for acute schizophrenia requires elucidation. Furthermore, plasma levels of risperidone and its active metabolite (9-hydroxyrisperidone) at a given dose vary greatly among different individuals. For patients who metabolize risperidone slowly, a medium dose results in excessively high plasma levels, which might be related to adverse events and perhaps poor response. We thus investigated whether dose reduction to diminish adverse reactions associated with ordinary risperidone doses could still yield efficacy for acutely exacerbated schizophrenia., Method: Thirty-one newly hospitalized Chinese patients with acute exacerbation of schizophrenia (DSM-IV) entered this prospective, 6-week open trial. Risperidone doses were titrated to 6 mg/day (if tolerable) over 3 days, but were lowered thereafter if side effects appeared. Efficacy and side effect assessments were conducted on days 0, 4, 14, 28, and 42. Endpoint steady-state plasma levels of risperidone and 9-hydroxyrisperidone were analyzed by high performance liquid chromatography with ultraviolet detection., Results: Thirty patients completed the trial. Of them, 17 tolerated the 6-mg target dose well, while the other 13 received lower final doses (mean +/- SD = 3.6 +/- 0.9 mg, p = .0001) for curtailing treatment-emergent side effects. At endpoint, 92.3% of the 13 low-dose individuals responded to treatment (20% or more reduction in the total Positive and Negative Syndrome Scale score), compared with 52.9% of the 17 high-dose subjects (p < .05). No significant between-group differences were revealed in other minor efficacy measures. Of note, endpoint plasma levels of the active moiety (risperidone plus 9-hydroxyrisperidone) were similar between the low- and high-dose groups (40.4 +/- 31.1 ng/mL vs. 49.7 +/- 13.4 ng/mL, NS)., Conclusion: The results of this preliminary trial suggest that up to 6 mg of risperidone is efficacious in treating patients with acute exacerbation of schizophrenia. Nearly 60% of the patients could tolerate a 6-mg dose. For the other 40%, reducing dosages to 3.6 +/- 0.9 mg for relieving side effects still yielded efficacy. The 2 dose groups were comparable in the endpoint steady-state plasma drug concentrations.

The drug-drug interaction between fluvoxamine (FLV) and clozapine (CLZ) was evaluated by in-vitro and in-vivo methods. In-vitro studies were conducted using human hepatic microsomal preparations with standard chemical inhibitors of the cytochrome P450 (CYP 450) isozyme system. Furafyline, FLV, troleandomycin (TAO) and erythromycin were used as the chemical inhibitors. For the in-vivo study, nine male schizophrenic patients were administered a single dose of CLZ 50 mg on two separate occasions with a 2-week FLV treatment of 50 mg twice a day in between each CLZ dose. Blood samples were obtained over 48 h following CLZ administration. CLZ and its two principle metabolites, clozapine N-oxide (CNO) and desmethylclozapine (DCLZ), were measured by high performance liquid chromatography with ultraviolet detection for both in-vitro and in-vivo studies. The in-vitro formation of DCLZ was inhibited by furafyline and FLV by 42.0% and 48.5% (P<0.01), respectively. TAO and erythromycin had only modest inhibition effects on DCLZ formation of 18.3% and 21.0% (P = NS), respectively. CNO in-vitro formation was significantly reduced by TAO and erythromycin by 44.5% and 45.0% (P<0.01), respectively. Furafyline and FLV had only modest effects of 19.2% and 8.5% (P = NS), respectively. In schizophrenic patients, FLV resulted in a pronounced increased in CLZ plasma concentrations with the total mean CLZ AUC increased by a factor of 2.58 from 780.8 ng/ml per hour to 2218.0 ng/ml per hour (P<0.001). All patients were sedated during combined FLV and CLZ use. During FLV treatment, CNO and DCLZ AUC both decreased by 18.8% (P = 0.07) and 9.0% (P = NS), respectively. These results indicate that in-vitro evaluations may not always accurately reflect changes in drug-drug interaction observed in-vivo. Careful patient monitoring is recommended during FLV/CLZ co-administration.

Background: Previous reports concerning the effects of gender and age on steady-state plasma concentrations of clozapine and its major metabolites, norclozapine and clozapine-N-oxide, have been controversial. Since the frequency distribution of the plasma levels is asymmetrical and skewed to the right, the statistical methods (such as analysis of variance and regression analysis) used earlier are actually inappropriate for analyzing the effects of the variables on the concentrations and might contribute to the inconsistent results. The goal of the present study, with befitting statistics, is to measure the potential effect of dose, gender, age, and body weight on plasma levels of clozapine and its 2 major metabolites., Method: We retrospectively analyzed data from a therapeutic drug monitoring study for steady-state plasma clozapine, norclozapine, and clozapine-N-oxide levels that was conducted in a large group of Chinese schizophrenic inpatients (male:female ratio = 83:79; age range, 33.8 +/- 9.3 years). The daily doses of clozapine had ranged from 100 to 900 mg, with a mean +/- SD value of 379.5 +/- 142.2 mg. Plasma concentrations had been measured using high-performance liquid chromatography with ultraviolet detection. Multiple linear regression was adopted to quantify the effects of various factors on the plasma levels. The natural logarithm of the plasma level was used as the dependent variable to overcome the skewness problem., Results: After adjusting the effects of gender, age, and body weight by multiple linear regression, each 1-mg increment in the daily dose could raise the clozapine level by 0.31%, norclozapine by 0.27%, and clozapine-N-oxide by 0.16%. Female patients had 34.9% higher clozapine levels and 36.3% higher norclozapine, with other variables being controlled. No sex differences were demonstrated for clozapine-N-oxide levels. Each 1-year increment in age would elevate the clozapine level by 1.1%, norclozapine by 1.0%, and clozapine-N-oxide by 1.0%. Body weight could not influence the levels of these compounds., Conclusion: The present results suggest that women possess higher plasma levels (about one third higher) of clozapine and norclozapine, but not the N-oxide metabolite. Each addition of 1 year in age elevated clozapine and either metabolite's levels by about 1%. Furthermore, every 1-mg increase in the daily dose raised clozapine and norclozapine concentrations by approximately 0.3%. These findings could assist clinicians in optimizing clozapine dosing strategies.

1. To characterize the interconversion process between clozapine and its metabolite clozapine N-oxide (CNO), eight healthy male schizophrenics were administered a single dose of clozapine or CNO in a randomized crossover manner. 2. Using a general pharmacokinetic model for the interconversion process, the mean total clearances of clozapine and CNO were 28.45 L/hr and 45.30 L/hr, respectively. These values were similar to the values obtained by the usual model-independent method of pharmacokinetic analysis. 3. When administered clozapine, mean CNO plasma concentrations of 17.7 +/- 16.4 ng/ml were slightly lower than the other clozapine metabolite-desmethylclozapine (DCLOZ) plasma levels of 24.4 +/- 8.6 ng/ml at the 12 hour time point. When CNO was administered, plasma concentrations at the 12 hour time point of clozapine were twice the amount of CNO (28.1 +/- 8.9 ng/ml vs 14.4 +/- 8.8 ng/ml). 4. DCLOZ plasma concentrations were detected in all patients upon clozapine administration. Upon CNO administration, only one patient had detectable plasma DCLOZ levels. 5. The interconversion process of clozapine and CNO could partially account for the wide interpatient variability reported for clozapine plasma concentrations in schizophrenic patients.

Plasma reduced haloperidol (RH) concentrations or RH to haloperidol (HL) ratios have been suggested to be important in determining the clinical efficacy and extrapyramidal side effects of HL. In this study, we measured the steady-state plasma HL and RH levels by high performance liquid chromatography and analyzed the effects of various variables (dose, gender, age, and body weight) on RH/HL ratios in four dose groups of Chinese schizophrenic inpatients: 10 mg/day (n = 84), 20 (n = 111), 30 (n = 29), and 60 (n = 55). In addition, the polymorphic distribution of RH/HL ratios, suggested by previous investigators, was further tested in each dosage group (for controlling the potential dosage effect on RH/HL ratios). As a result, both age and body weight could influence RH/HL ratios. Each year increase in age (after adjusting the effects of gender, body weight, and dosage) would elevate the RH/HL ratio by 0.0067 (P < 0.0001). On the other hand, after adjusting gender, age, and dosage effects, each kg increment in body weight would decrease the RH/HL ratio by 0.0044 (P < 0.01). Gender did not influence the ratio. Furthermore, the high dosage groups had higher RH/HL ratios (even with other variables being controlled). In comparison with the 10 mg group, the 60 mg group exhibited a higher mean RH/HL ratio by 0.84 (P < 0.0001) and the 30 mg group did by 0.31 (P < 0.0001). The 20 mg group was almost equal to the 10 mg group in RH/HL ratios. Besides, at each dosage group, the frequency distribution of RH/HL ratios seemed to be predominantly unimodal with a small proportion of extreme outliers. The results of this study clearly indicate that aging or a high dose (> or = 30 mg/day) of HL could raise the plasma RH/HL ratio, while an increasing body weight would reduce that. In contrast, gender does not affect the ratios.

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.

The pharmacokinetic interaction between buspirone and haloperidol was evaluated in schizophrenic patients in two different groups. In both groups, haloperidol doses (10-40 mg/day) remained constant for 6 weeks before the addition of buspirone 10 mg three times daily. Serial blood samples were obtained from the 11 patients in group I at baseline (before addition of buspirone) and after administration for 24 hours. The pharmacokinetic parameters of haloperidol were determined alone and with coadministration of buspirone. In group II, buspirone 10 mg three times daily was added to treatment with haloperidol in 27 patients. Blood samples were obtained before addition of buspirone and at weeks 2 and 6 of treatment with buspirone. Samples were obtained 10 to 12 hours after administration of the evening dose and before the morning dose. Haloperidol and its metabolite, reduced haloperidol (RH), were assayed by means of high-performance liquid chromatography with electrochemical detection. Significant changes in the pharmacokinetic parameters of haloperidol were not found in group I; a mean increase in the half-life (t1/2) of haloperidol from 21.5 to 28.1 hours was observed, but this finding was not statistically significant. Under steady-state conditions, plasma levels of haloperidol in the patients in group II did not change significantly from baseline to week 6. Plasma concentrations of RH remained unaltered in both groups. The results indicate that coadministration of buspirone does not markedly affect the pharmacokinetics or plasma concentrations of haloperidol.

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.

Plasma concentrations of clozapine and its metabolites desmethylclozapine and clozapine N-oxide were measured in 61 patients with refractory schizophrenia. Before the initiation of clozapine, each patient was given haloperidol (HL) up to 60 mg/day for at least 4 weeks without improvement. Patients were then given a fixed dose of clozapine 400 mg/day. Patients were assessed with the Brief Psychiatric Rating Scale (BPRS) at baseline before HL therapy, at the end of HL at 6 weeks, before clozapine, and after 6 weeks of clozapine therapy. Clozapine and its metabolites were measured by high-performance liquid chromatography with ultraviolet detection. The mean plasma concentrations of clozapine, desmethylclozapine, and clozapine N-oxide were 598 +/- 314, 281 +/- 140, and 90 +/- 29 ng/ml, respectively. The mean decrease in the total BPRS scores from baseline clozapine to the 6-week treatment period was 11 +/- 4. Clinical improvement was noted to occur in most patients with clozapine plasma levels > 300 ng/ml. Improvement diminished in patients with clozapine plasma levels > 700 ng/ml. The most common adverse effects were sedation and hypersalivation. Significant correlations between plasma clozapine concentrations and adverse side effects were not found.

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. Patients 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. 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. A loading dose regimen is needed due to the long elimination half-life of decanoate of 26 days otherwise steady-state condition will not occur until 34 months of therapy. 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. The formation of reduced haloperidol remained consistent for oral and depot haloperidol treatment.

The disposition of remoxipride was evaluated in 13 male chronic schizophrenic patients. A single 150 mg dose of remoxipride was administered and blood sampling performed over the following 48 hours. The mean (SD) oral clearance and half-life of remoxipride were 74.46 (25.9) ml/min and 5.46 (0.87) hours, respectively. The mean (SD) AUC for remoxipride was 25,320 (9,820) ng.h/ml. A wide interpatient variability was observed. Compared to Caucasian studies there were no significant differences in the disposition of remoxipride.

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.

Twenty schizophrenic patients were treated with a fixed haloperidol (HL) dose of 20 mg/day for 4 weeks. The conversion of HL to its reduced metabolite (reduced haloperidol, RH) occurs via the ketone reductase enzyme. RH is also converted back to HL by the cytochrome P450 2D6 isozyme. Ketone reductase activity can be measured in red blood cells. Plasma HL and RH levels were assayed by high performance liquid chromatography. Blood samples were obtained at baseline and during weeks 2 and 4 of HL therapy. Seventeen of 20 patients had ketone reductase values < 3. A significant correlation between ketone reductase and RH/HL plasma ratios was observed at week 4 in these 17 patients. Patients with ketone reductase activity < 3 could represent a subgroup of patients that metabolize HL differently. The wide interpatient variability observed with HL and RH plasma levels in HL-treated patients could reflect differences in ketone reductase activity and the metabolic status of debrisoquin hydroxylase (cytochrome P450IID6) in psychiatric patients.

Steady-state haloperidol and reduced haloperidol concentrations were measured in 250 schizophrenic patients from 4 ethnic groups: 39 Blacks, 66 Caucasians, 82 Chinese, and 63 Mexican Americans. The distribution of the reduced haloperidol to haloperidol concentration (RH/HL) ratios was bimodal in all ethnic groups, with the antimode determined by probit plot as 0.46, 0.51, 0.36, and 0.76, respectively. With these antimodes, the proportion of patients with low RH/HL ratios were 41%, 42%, 73%, and 57% in the four ethnic groups, respectively. Compared with the other three ethnic groups, in the Chinese patients the ratio was lower. The mean RH/HL ratio in the Chinese was 0.34 compared with 0.81 to 0.87 in the non-Chinese groups. In 53 patients who were treated with two or more haloperidol dosage regimens, steady-state haloperidol and reduced haloperidol drug concentrations obtained from the different regimens were positively correlated with the haloperidol dose (R = .79 and R = .62, respectively). Our data suggest not only the existence of a bimodal distribution in the RH/HL ratio, but also that the antimode separating the low and high ratio subgroups is different among the various ethnic groups.

Plasma haloperidol (HL) and reduced haloperidol (RH) levels were measured in 60 schizophrenic patients treated with high to very high HL doses of 40-200 mg/day. Plasma samples were obtained at steady-state conditions and 10-12 h after the evening dose and prior to the morning dose. RH/HL ratios were shown to be dose-dependent. In the lowest dose group of 40-45 mg/day, 77% of the patients had RH/HL ratios < 1.0. At the higher dose of 60-80 mg/day, these results were reversed as 79% of the patients had RH/HL ratios > 1.0. All patients with HL doses greater than 100 mg/day had RH/HL ratios > 1.0. All patients safely tolerated the high haloperidol dosages and only five patients had extrapyramidal side effects that were unresponsive to trihexyphenidyl. Therapeutic improvement was not observed in each patient. Based upon the dose-dependent increase in the RH/HL ratios in schizophrenic patients, the possible mechanism of a 'therapeutic' window for HL is discussed.

The disposition of the atypical clozapine and its desmethyl metabolite were evaluated in fourteen male chronic patients. A single 100 mg dose of clozapine was administered and blood sampling performed over the following 72 hours. The mean (SD) oral clearance and half-life of clozapine were 55.4 (29.7) L/hr and 13.7 (9.9) hours, respectively. The mean (SD) AUC for clozapine and desmethylclozapine was 2389.9 (1406) and 751.1 (622.9) ng.hr/mL, respectively. The elimination of the metabolite is rate limited by its formation from cloza-pine. A wide interpatient variability in clozapine and desmethylclozapine pharmacokinetics was observed.

Plasma levels of homovanillic acid (pHVA), a metabolite of dopamine, were measured in ninety-five Chinese schizophrenic patients free of neuroleptics for at least four weeks. These patients were treated with classical antipsychotics for six weeks. Pretreatment pHVA was positively correlated with the subsequent clinical response (r = 0.408, p < 0.0001). Good responders (BPRS improvement > or = 50%, n = 47) had higher pretreatment pHVA levels than poor responders (BPRS improvement < 50%, n = 48) (15.7 +/- 8.4 ng/ml versus 9.9 +/- 3.7 ng/ml, p < 0.0001). A higher than 15 ng/ml pretreatment pHVA level was associated with a more consistent clinical response to the subsequent treatment. Using a pHVA level of 12 ng/ml as a demarcation point, 72% of patients (34 of 47) who had pHVA > or = 12 responded whereas 65% (31 of 48) who had < 12 did not respond (chi-square = 13.02, p < 0.0001). These results suggest that higher pretreatment pHVA levels may predict a better clinical response to antipsychotics. Based upon the pHVA findings, two hypothetical subtypes of schizophrenia are proposed.

There is a trend in clinical psychiatric practice to make the dosing schedules of psychotropic medications as simple as possible. In this study, the authors measured the steady state haloperidol plasma levels in patients on different dosing schedules. Twenty-three schizophrenic in-patients were placed on haloperidol with a twice-a-day (10 mg bid) schedule for 14 days; the patients were then changed to a once-a-day (20 mg qd) schedule for another 14 days. Plasma haloperidol (HAL) and reduced haloperidol concentrations were measured at the end of each two-week period. The mean HAL plasma concentrations obtained from the bid and qd dosing schedules were 16.6 +/- 4.9 ng/mL and 12.7 +/- 5.3 ng/mL, respectively. These results are reasonable as the elimination half-life of HAL, as reported by most investigators, is about 24 hours. The present study suggests that a once-a-day dosing schedule in HAL treatment is adequate for most chronic patients.

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.

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.

The pharmacokinetics of haloperidol were studied in eight Chinese schizophrenic patients after intravenous administration and in six of the patients who also received oral haloperidol. After intravenous dosing, haloperidol disposition was best characterized by a three compartment model. The mean elimination half-life of 54.8 h determined by model dependent analysis was similar to the mean elimination half-life of 59.9 h determined by model independent analysis. The mean plasma clearance was 21.71/h and the mean volume of distribution during the distribution phase was 1754.3 1. After oral dosing, bioavailability of haloperidol was 35 +/- 8%, suggesting extensive first pass metabolism. Determination of reduced haloperidol concentration confirmed a previous finding of significant variability in haloperidol reductive capacity in individual patients. Comparison of area under the plasma concentration-time curve of reduced haloperidol after intravenous and oral administration of haloperidol suggests that reduction of haloperidol may only account for a small portion of first pass metabolism of haloperidol. However, conversion of reduced haloperidol back to haloperidol necessitates the monitoring of both haloperidol and reduced haloperidol concentrations in clinical practice.

One of the metabolic pathways of haloperidol (HAL) is the reduction of the molecule at the benzylic ketone to form an alcohol metabolite, known as reduced HAL (RHAL). The basic and clinical pharmacology of RHAL is the subject of this review. The investigation of RHAL in biological samples has been suggested to be important, as the reduced metabolite can be reconverted back to the parent drug and is shown to be 20-50% as potent as HAL in some in vivo neuroleptic tests. Nevertheless, the metabolic reduction/oxidation cycle of the drug is unbalanced. The interconversion process largely favours the reduction of HAL to RHAL but not vice versa. The RHAL/HAL ratios are dose and time dependent. The higher the dose or the longer the duration of treatment, the greater the ratio. The results concerning relationship between plasma RHAL level or RHAL/HAL ratio and clinical response are inconsistent, yet interesting. Some studies in schizophrenic patients have suggested a diminished therapeutic response to HAL when elevated plasma RHAL concentrations or RHAL/HAL ratios are presented. However, this finding has not been replicated by other investigations. Possible interference by RHAL with HAL at dopamine receptors thus reducing the effectiveness of HAL treatment has been suggested by some authors. Measurements of RHAL as well as HAL plasma concentrations for evaluating drug level-clinical response might be necessary in psychiatric 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 x dosage (mg/day) -0.56 or 46.0 x 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.

Plasma concentrations of haloperidol (HAL) and reduced haloperidol (RHAL) were measured in 8 schizophrenic patients, neuroleptic-free for at least 4 weeks, after repeated oral administrations of 10 mg HAL and RHAL. Each agent was given for 10 days with a 2-week washout period between the two compounds. HAL and RHAL were interconverted in all subjects. Plasma RHAL/HAL ratios at steady state during HAL treatment were significantly greater than the HAL/RHAL ratios after repeated reduced HAL administration (0.51 +/- 0.12 vs. 0.16 +/- 0.04 SD, p less than 0.0005). This result suggests that the interconversions between HAL and RHAL are apparently not equivalent in humans. A negative correlation was found between RHAL/HAL ratios after HAL administrations and HAL/RHAL ratios after RHAL administrations (r = -0.82, p less than 0.05). Repeated injections of HAL or RHAL at low (0.1 mg/kg) or high (1.0 mg/kg) doses were conducted in guinea pigs. Drug concentrations in striatum and plasma were measured. Both RHAL/HAL ratios after HAL injections and HAL/RHAL ratios after RHAL injections were dose- and time-dependent. High doses and repeated injections produced greater RHAL/HAL ratios after HAL and smaller HAL/RHAL ratios after RHAL than those observed with low doses and single injections, respectively. Compared with the results obtained from schizophrenic patients, the conversion from HAL to RHAL in guinea pigs was greater than that in humans, but the back conversions appeared to be similar between the guinea pigs and humans. Based upon the dose-dependent increase in RHAL/HAL ratios, a hypothesis of the therapeutic window effect for HAL treatment is proposed.

Plasma homovanillic acid (pHVA) and plasma methoxyhydroxyphenyl glycol (pMHPG), as well as plasma haloperidol, were measured in 33 schizophrenic patients before and during 6 weeks of haloperidol treatment. Good responders had higher baseline pHVA values compared with poor responders (17.4 +/- 8.8 ng/ml, n = 22 versus 11.4 +/- 5.0 ng/ml, n = 11, p less than 0.05). A higher than 15 ng/ml pretreatment pHVA level was associated with a more consistent clinical response to the subsequent treatment. Differential pHVA changes during treatment were also found between good and poor responders. Within the good responder group, a significant decline in pHVA over time was found. By contrast, pHVA showed a transient increase in the poor responder group. Plasma MHPG changes showed a similar pattern during treatment in good responders, although no significant differences in baseline values were found between the good (n = 13) and poor (n = 9) responders, and pMHPG showed no change during treatment in poor responders. Significant correlations between baseline pHVA and pMHPG values were found in 22 patients. Good responders and poor responders did not differ significantly in terms of age, duration of illness, severity of presenting symptoms, haloperidol dose, or plasma drug concentration. Two hypothetical subtypes of schizophrenia and both dopamine and norepinephrine systems involved in schizophrenic psychopathology are proposed.

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.

Twelve male chronic schizophrenic inpatients, neuroleptic-free for at least 4 weeks, were given an oral test dose of 10 mg haloperidol (HAL) and reduced HAL (RHAL) in a random order, with a 2-week interval. Two weeks after the last test dose, the patients were given HAL, 5 mg orally twice daily for 7 days. Blood samples were drawn at baseline and between 0.5 and 24 hr after the test doses, and during HAL treatment as well. Plasma drug concentrations and homovanillic acid (HVA) levels were measured with high-performance liquid chromatography using electrochemical detection. HAL, but not RHAL, produced increments in plasma HVA (pHVA) levels at 24 hr after a test dose. pHVA levels remained higher than baseline during HAL treatment. Detectable interconversion between HAL and RHAL was observed in eight patients. The capacity of the reductive drug-metabolizing enzyme system, however, was greater than that of the oxidative processes. The plasma RHAL:HAL ratios on days 6 and 7 were higher than and positively correlated with those at Tmax after a single dose of HAL and were negatively correlated with the HAL:RHAL ratios at Tmax after a single dose of RHAL. Thus, both reductive and oxidative drug-metabolizing systems probably contribute to individual differences in plasma RHAL:HAL ratios in HAL-treated schizophrenic patients.

Concentrations of norepinephrine, 3-methoxy-4-hydroxyphenylglycol, homovanillic acid, and 5-hydroxyindoleacetic acid (5-HIAA) were quantified in the CSF of 28 drug-free schizophrenic patients. Fifteen patients provided more than one drug-free sample on separate occasions. Considerable intraindividual variability over time was found in the concentrations of norepinephrine and these major monoamine metabolites in the repeated samples. This was not explained by assay errors or changes in the patient's global psychosis ratings. The variability in the present sample for CSF 5-HIAA concentrations was almost twice as wide as has been reported for patients with affective disorder. Variables that contribute much of the variability of norepinephrine and major monoamine metabolite concentrations in drug-free CSF samples from schizophrenic patients remain unknown and cannot be controlled.

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.

Plasma levels of homovanillic acid (HVA), a major metabolite of dopamine, were measured in a group of 24 schizophrenic inpatients before and during 6 weeks of haloperidol (HAL) treatment. Steady-state plasma HAL levels were measured in parallel with plasma HVA. Differential plasma HVA responses to HAL treatment were found between good and poor outcome patients. The two groups did not differ significantly in plasma HAL levels. Two hypothetical subtypes of schizophrenia are proposed.

Plasma levels of homovanillic acid (pHVA), a major metabolite of dopamine (DA), were measured in a group of 51 schizophrenic inpatients before and during 6 weeks of neuroleptic treatment. Steady-state plasma drug concentrations were monitored in parallel with pHVA. Good responders (n = 22) had higher pretreatment pHVA levels as compared to poor responders (n = 22). Differential pHVA changes during neuroleptic treatment were also found between each group. The two groups did not differ significantly in terms of age, duration of illness, severity of presenting symptoms, neuroleptic, dose, or plasma drug concentration. Two hypothetical subtypes in the group of schizophrenics were proposed.