Single dose kinetics of thioridazine and its two psychoactive metabolites in healthy humans: a dose proportionality study

Dose proportionality in some pharmacokinetic parameters for thioridazine and its two active metabolites (mesoridazine and sulforidazine) was investigated in 11 healthy human subjects following oral administration of three single doses (25, 50, and 100 mg) of thioridazine hydrochloride separated in each case by an interval of two weeks. Also, after a further two weeks, another 100-mg dose of thioridazine (divided as 5 mg every 0.5 h) was administered to all the volunteers to investigate the effect of a slow rate of dosage input on the pharmacokinetic parameters of this drug. An HPLC method was used to measure concentrations of thioridazine, mesoridazine, and sulforidazine in plasma samples collected up to 72 h following each dose. Dose proportionality for the three single doses of thioridazine was observed for all three analytes in the area under the plasma concentration versus time curves (AUC infinity 0 or AUCt0) and the maximum plasma concentration (Cmax) in that the relationships between the dose and these parameters were each describable by an equation for a straight line (r2 greater than or equal to 0.8). However, the mean apparent distribution and elimination rate constants for thioridazine and mesoridazine and the mean apparent oral clearance for thioridazine decreased significantly with increasing dose. This suggests nonlinear trends in the elimination kinetics at high doses of thioridazine. When a 100-mg divided oral dose of thioridazine was administered, no statistically significant differences between single and divided doses were observed in the mean AUC infinity 0 or AUCt0 for thioridazine or sulforidazine. A significant decrease in the mean AUC infinity 0 or AUCt0 was observed for mesoridazine after the administration of the divided dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Radioimmunoassay for psychotropic drugs. III: Synthesis and properties of haptens for trifluoperazine and fluphenazine

For the development of radioimmunoassay procedures for trifluoperazine and fluphenazine, three haptens, N-(2-carboxyethyl)desmethyltrifluoperazine, N-(4-carboxybutyl)desmethyltrifluoperazine, and 10-[3-(4-carboxyethylpiperazinyl)-3-oxopropyl]-2-trifluoromethyl-+ ++10H- phenothiazine, were synthesized and characterized. Each hapten was coupled to bovine serum albumin, and the number of hapten residues per mole of bovine serum albumin was calculated by UV spectrophotometric methods. Antibodies to each hapten-protein conjugate were developed in rabbits, and titers of the antisera were checked by evaluating their binding characteristics to the tritiated drug.     

Identification of lactams as in vitro metabolites of piperidine-type phenothiazine antipsychotic drugs

The metabolism of the piperidine-type phenothiazine antipsychotic agents thioridazine, mesoridazine and sulforidazine was studied in vitro with 10 000g liver supernatants obtained from rats and dogs. After incubations at 37°C for different time intervals, the incubates were extracted with dichloromethane and the isolated compounds analyzed by HPLC, direct probe MS and on-line HPLC-MS. Five lactam metabolites of these three drugs were unequivocally identified in the rat in vitro system, but none was found in dog preparations; at least one lactam metabolite was identified for each drug in the rat. The lactams of thioridazine and thioridazine ring sulfoxide were characterized as metabolites of thioridazine for the first time in any system. The other three lactam metabolites, namely the lactams of mesoridazine, sulforidazine and mesoridazine ring sulfoxide, were found in vitro for the first time, although they have been previously reported as in vivo metabolites of these drugs. The results indicate that rat would be a more suitable animal model than dog for further studies on the formation of lactam metabolites of these drugs.     

Thioridazine steady-state plasma concentrations are influenced by tobacco smoking and CYP2D6, but not by the CYP2C9 genotype

BACKGROUND: Approximately 7% of Caucasians have genetically impaired activity of the cytochrome P450 enzyme CYP2D6 and are classified as poor metabolizers (PM). The disposition of thioridazine has been related to the CYP2D6 phenotype. The present study aimed to evaluate the influence of CYP2D6 and CYP2C9 genotypes, and tobacco smoking on steady-state thioridazine plasma levels. METHODS: Seventy-six Caucasian psychiatric patients receiving thioridazine monotherapy were studied. Debrisoquine metabolic ratio (MR) and steady-state plasma levels of thioridazine and its metabolites, mesoridazine and sulforidazine, as well as CYP2D6 (in 74 patients) and CYP2C9 (in 63 patients) genotypes were determined. RESULTS: The median dose-corrected, steady-state plasma concentrations (C/D) of thioridazine were related to the number of functional CYP2D6 alleles ( P<0.01), being 15.2, 7.2, 4.0, 4.2 nmol/l per milligram in subjects with no, one, two, and three or more functional CYP2D6 genes, respectively. No significant differences were found in the C/Ds of mesoridazine or sulforidazine. No relationship was found between CYP2C9 genotype and plasma levels of thioridazine or its metabolites. The median C/D of thioridazine was significantly ( P<0.001) lower in smokers (4.0 nmol/l per milligram, range: 1.0-15.5; n=58) than in nonsmokers (7.4 nmol/l per milligram, range: 2.8-23.6; n=18). Also, the C/Ds of mesoridazine and sulforidazine were lower in smokers ( P<0.01). The plasma thioridazine/mesoridazine ratio significantly correlated with the debrisoquine MR ( r(2)=0.30, P<0.001). CONCLUSION: The results show that the plasma concentrations of thioridazine and its metabolites are influenced by tobacco smoking and the CYP2D6 genotype, and support the dose-dependent inhibition of CYP2D6 by thioridazine. CYP2C9 does not play an important role in thioridazine metabolism.     

Use of the mesoridazine/thioridazine ratio as a marker for CYP2D6 enzyme activity

Thioridazine is metabolized in humans by CYP2D6 to mesoridazine, which is an active metabolite. Two or more CYP2D6 substrates are seldom given simultaneously to elderly patients because potentially dangerous metabolic interactions may occur. It may be valuable to know the CYP2D6 metabolic capacity of such patients to avoid drug interactions, which depend on the metabolic phenotype. The goal of this study was to evaluate the use of the mesoridazine/thioridazine ratio for the estimation of CYP2D6 enzyme capacity. A sensitive and reliable method has been developed for the determination of thioridazine and its metabolites, mesoridazine and sulforidazine. Commonly used central nervous system (CNS) comedications do not interfere with the method. A group of 27 chronic patients with mental illness receiving monotherapy with thioridazine were studied. There were 23 men and 4 women between 37 and 80 years old (mean +/- SD: 61.2 +/- 10.2). The thioridazine/mesoridazine ratio correlated with the debrisoquine metabolic ratio (r = 0.74, p < 0.001). Therefore, the authors suggest that the measurement of thioridazine and its metabolite might be a useful tool to assess CYP2D6 activity during treatment.     

A fixed dose study of the plasma concentration and clinical effects of thioridazine and its major metabolites

Fifty-three patients in an acute episode or exacerbation of psychosis were given thioridazine 200 or 400 mg daily for 2 weeks. Thioridazine and its active metabolites, mesoridazine and sulforidazine, were estimated in plasma by high performance liquid chromatography (HPLC) and radioreceptor assay (RRA). One week after institution of treatment, plasma concentrations of drug were stable in the morning 12 h after dosing. Drug levels varied widely between patients, but in all patients the relative level of thioridazine to mesoridazine was about one half and thioridazine to sulforidazine was about two fold. Estimates of neuroleptic activity by RRA and the weighted sum of thioridazine, mesoridazine and sulforidazine by HPLC were very similar. Plasma concentration of parent compound, metabolites, or the sum of active substances as estimated by HPLC or RRA, showed only modest correlations (r _s=0.10–0.22, all NS) to the degree of improvement as measured by change on the Brief Psychiatric Rating Scale. Significant correlations were observed between plasma concentrations of drug and side effects, including dry mouth, blurred vision, or total rating on the Somatic Symptoms Scale. Even patients receiving the lowest dose and achieving the lowest plasma concentrations of drug showed considerable improvement. There was suggestive evidence that the patients achieving the highest plasma levels of drug did not have the best clinical outcome. These and similar observations from other studies suggest that currently used doses of neuroleptics may be excessive. Optimal drug effects as well as stronger relationships between dose, drug concentration, and clinical therapeutic effects might best be sought at doses below those in common use.     

S-oxidation of thioridazine to psychoactive metabolites: an oral dose-proportionality study in healthy volunteers

Thioridazine has two major active metabolites, which are formed from S-oxidation of its 2-methylthio group; the sulphoxide, mesoridazine, and the sulphone, sulforidazine. Dose proportionality of the three compounds was investigated for the first time in 11 males after administration of three single oral doses (25, 50, and 100 mg) of thioridazine hydrochloride separated in each case by two weeks. Based on the plasma concentrations of the three analytes over 72 h following each dose, large intersubject variabilities in such parameters as AUCot and Cmax were observed for each of the three compounds. The relationships between dose and parameters such as AUCot and Cmax for each analyte were described by an equation for a straight line (r2 greater than or equal to 0.8). However, the mean apparent distribution and elimination rate constants for thioridazine and mesoridazine and the mean apparent oral clearance for thioridazine decreased significantly with increasing dose, suggesting non-linearity in the elimination of thioridazine at high dose.     

Pharmacokinetic interaction of fluvoxamine and thioridazine in schizophrenic patients

This study investigated to what extent fluvoxamine affects the pharmacokinetics of thioridazine (THD) in schizophrenic patients under steady-state conditions. Concentrations of THD, mesoridazine, and sulforidazine were measured in plasma samples obtained from 10 male inpatients, aged 36 to 78 years, at three different time points: A, during habitual monotherapy with THD at 88 +/-54 mg/day; B, after addition of a low dosage of fluvoxamine (25 mg twice a day) for 1 week; and C, 2 weeks after fluvoxamine discontinuation. After the addition of fluvoxamine, THD concentrations relative to time point A significantly increased approximately threefold from 0.40 to 1.21 micromol/L (225%) (p < 0.002), mesoridazine concentrations increased from 0.65 to 2.0 micromol/L (219%) (p < 0.004), and sulforidazine levels increased from 0.21 to 0.56 micromol/L (258%) (p < 0.004). The THD-mesoridazine and THD-sulforidazine ratios remained unchanged during the study. Mean plasma THD, mesoridazine, and sulforidazine levels decreased at time point C, but despite fluvoxamine discontinuation for 2 weeks, three patients continued to exhibit elevated concentrations of THD and its metabolites. In conclusion, fluvoxamine markedly interferes with the metabolism of THD, probably at the CYP2C19 and/or CYP1A2 enzyme level. Therefore, clinicians should be aware of the potential for a clinical drug interaction between both compounds, and careful monitoring of THD levels is valuable to prevent the accumulation of the drug and resulting toxicity.     

Development of a radioimmunoassay procedure for sulforidazine and its comparison with a high-performance liquid chromatographic method

A radioimmunoassay (RIA) procedure for the determination of sulforidazine in human plasma was developed using an antiserum raised in rabbits immunized with N-(2-carboxyethyl)desmethylsulforidazine-porcine thyroglobulin conjugate. The RIA procedure can measure as low as 40 pg of sulforidazine in a 200-microliter human plasma sample with a coefficient of variation of less than 6%. The antiserum did not show any marked cross reaction with any available potential cross reactant. Also, there were no significant differences between the concentrations of sulforidazine determined in the presence or absence of thioridazine and/or mesoridazine. This RIA procedure was compared with a high performance liquid chromatographic (HPLC) method by determining concentrations of sulforidazine in plasma samples from human volunteers over 72 h after administration of single 50-mg oral doses of thioridazine hydrochloride. The two methods showed a good correlation for the assay values (n = 55; r2 = 0.926) and the slope of the regression line was not significantly different from 1.0 (p greater than 0.30 when RIA values were plotted on the gamma-axis and HPLC values on the chi-axis; p greater than 0.30 when HPLC values were plotted on the gamma-axis and RIA values on the chi-axis). The plot of the differences between these two assay values against the average of the assay values showed that the differences were independent of the concentration range studied. Also, statistically favorable comparisons were obtained for area under the plasma concentration-time curve to 48 h (AUC48(0)), Cmax, and Tmax calculated from the data obtained by the two methods.     

Development of a radioimmunoassay procedure for mesoridazine and its comparison with a high-performance liquid chromatographic method

A radioimmunoassay (RIA) procedure for mesoridazine was developed using an antiserum raised in rabbits immunized with N-(2-carboxyethyl) desmethylmesoridazine-porcine thyroglobulin conjugate. The RIA procedure enabled the quantitation of 40 pg of mesoridazine in a 200-microliters human plasma sample with a coefficient of variation of less than 5%. Except for N-desmethylmesoridazine, the antiserum showed no marked cross-reaction with any of the other available potential cross-reactants. Furthermore, statistically indistinguishable results were obtained for the determination of mesoridazine in the presence or absence of a fivefold excess of thioridazine or sulforidazine. This RIA procedure was compared with a high-performance liquid chromatographic (HPLC) method by determining concentrations of mesoridazine in plasma samples from human volunteers over 72 h after administration of single 50-mg oral doses of thioridazine hydrochloride. Good correlation existed between the assay values (n = 55) determined by the RIA and HPLC methods (r2 = 0.940), but the slope of the regression line was significantly different from 1.0 (p less than 0.05, when RIA values were plotted on the gamma axis and HPLC values were plotted on the chi axis; p less than 0.001, when HPLC values were plotted on the gamma axis and RIA values were plotted on the chi axis). The plot of the differences between these two assay values against the average of the assay values showed, however, that the differences were independent of the concentration range studied. Moreover, statistically favorable comparisons were obtained for area under the plasma level/time curve to 48 h (AUC0(48)), Cmax, and Tmax calculated from the data obtained by the two methods.     

Characterization of human cytochrome p450 enzymes involved in the metabolism of the piperidine-type phenothiazine neuroleptic thioridazine.

The aim of the present study was to identify human cytochrome P450 enzymes (P450s) involved in mono-2-, di-2-, and 5-sulfoxidation, and N-demethylation of the piperidine-type phenothiazine neuroleptic thioridazine in the human liver. The experiments were performed in vitro using cDNA-expressed human P450s (Supersomes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4), liver microsomes from different donors, and P450-selective inhibitors. The results indicate that CYP1A2 and CYP3A4 are the main enzymes responsible for 5-sulfoxidation and N-demethylation (34-52%), whereas CYP2D6 is the basic enzyme that catalyzes mono-2- and di-2-sulfoxidation of thioridazine in human liver (49 and 64%, respectively). Besides CYP2D6, CYP3A4 contributes to a noticeable degree to thioridazine mono-2-sulfoxidation (22%). Therefore, the sulforidazine/mesoridazine ratio may be an additional and more specific marker than the mesoridazine/thioridazine ratio for assessing the activity of CYP2D6. In contrast to promazine and perazine, CYP2C19 insignificantly contributes to the N-demethylation of thioridazine. Considering serious side-effects of thioridazine and its 5-sulfoxide (cardiotoxicity), as well as strong dopaminergic D2 and noradrenergic alpha1 receptor-blocking properties of mono-2- and di-2-sulfoxides, the obtained results are of pharmacological and clinical importance, in particular, in a combined therapy. Knowledge of the catalysis of thioridazine metabolism helps to choose optimum conditions (a proper coadministered drug and dosage) to avoid undesirable drug interactions.     

Effect of thioridazine dosage on the debrisoquine hydroxylation phenotype in psychiatric patients with different CYP2D6 genotypes.

Sixteen hospitalized white European Spanish psychiatric patients treated with thioridazine alone were studied with respect to CYP2D6 genotype, debrisoquine metabolic ratio (MR), and the plasma levels of thioridazine and its metabolites mesoridazine and sulforidazine. After decreasing the dose of thioridazine the debrisoquine MR and thioridazine plasma levels were redetermined. At the initial determination (regular clinical doses, 20-300 mg/day), 14 of 16 patients (88%) were classified as poor metabolizers of debrisoquine (PMs). However, after complete withdrawal of thioridazine in 10 patients, all 10 became extensive metabolizers except two who were genotypically PMs (*4/*4). The inhibition of debrisoquine metabolism was genotype dependent. All patients with wt/wt genotype treated with a dose 150 mg/d were phenotypically PMs, all patients with wt/*4 genotype treated with a dose of 50 mg/d or greater were PMs. The debrisoquine MR from all dose changes correlated with the dose (p < 0.001) and plasma level (p < 0.001) of thioridazine. The CYP2D6 hydroxylation capacity was inhibited by thioridazine as determined by the debrisoquine MR. This inhibition was reversible by thioridazine withdrawal, and thus seems to be dose dependent and related to CYP2D6 genotype. One must consider the effects of thioridazine dosage on CYP2D6, because it may influence the metabolism of concomitant drugs or produce clinically important adverse effects such as cardiotoxicity. An awareness of this problem and cautious dosage adjustment of other drugs metabolized by the same enzyme are recommended during treatment with thioridazine.     

Metabolism of thioridazine in the elderly

Metabolism of drugs may change with age. Yet, there are few studies that provide data to help define appropriate doses of neuroleptic drugs in the treatment of the elderly. To address this issue, we determined serum concentrations of thioridazine and its active metabolites, mesoridazine and sulforidazine, by high performance liquid chromatography in young adult (mean age, 28 +/- 7.6 years) and elderly (mean age, 76 +/- 7.7 years) patients after single 25-mg oral doses of thioridazine. At both times measured, 4 and 8 hours after dosing, the concentrations of parent compound and metabolites in serum were 1.5- to twofold higher, and side effects (especially postural hypotension and dry mouth) were more frequent and severe in the elderly patients. These results, along with those reported in a small number of studies of serum drug levels during extended treatment of the elderly, support the practice of using smaller doses of phenothiazine neuroleptics in older patients.     

Dextromethorphan and mephenytoin phenotyping of patients treated with thioridazine or amitriptyline.

The metabolism of most tricyclic antidepressants and some phenothiazine neuroleptics is under the genetic control of hepatic cytochrome P-450IID6, which also regulates the metabolism of dextromethorphan. This study investigated the effect of treatment with amitriptyline or thioridazine on testing for genetically regulated efficiency of the metabolism of dextromethorphan and mephenytoin. One group of 33 patients was treated with 150 mg amitriptyline a day (the AMI group); 25 other patients received a daily dose of thioridazine, either 200 mg (200-THD group; n = 7) or 400 mg (400-THD group; n = 18). Before and after 10 days of this treatment, all patients were tested with 25 mg dextromethorphan and 100 mg mephenytoin to determine their pharmacogenetic status with respect to their hepatic drug oxidizing systems (cytochrome P-450IID6 and P-450 MP). Two patients were poor metabolizers (PMs) of dextromethorphan and three of mephenytoin. Treatment with either psychotropic drug was without significant effect on the metabolism of mephenytoin, but both amitriptyline and thioridazine increased significantly the metabolic ratio of dextromethorphan/dextrorphan. Thioridazine had the effect of changing the pharmacogenetic status of 15 efficient metabolizers of dextromethorphan to poor metabolizers; amitriptyline did not have such an effect. There was no significant correlation between day-11 plasma levels of thioridazine, mesoridazine, or sulforidazine and the metabolism of dextromethorphan, but there was a correlation between the metabolism of dextromethorphan and plasma levels of amitriptyline and nortriptyline. Amitriptyline (p less than 0.05), but not thioridazine, decreases the ratio of conjugated/total dextrorphan in urine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Facile synthesis of tilmicosin and tylosin related haptens for use as protein conjugates

Synthesis is described for the haptens 23-demycinosyl-23-deoxy-23-(3-aminoprop-1-yl)-aminotilmicosin (6) from 5-O-mycaminosyltylonolide (OMT) and for 23-demycinosyl-23-deoxy-23-(3-aminoprop-1-yl)-amino-20-dihydrotylosin (10) from demycinosyltylosin (DMT), respectively. The mild reaction conditions used to synthesize the second hapten, DMT derivative 10, were necessary to overcome instabilities and acid lability of DMT. The haptens synthesized here may be further used to produce protein conjugates useful in developing antibodies against the antibiotics tilmicosin and tylosin.     

Red blood cell and plasma levels of thioridazine and mesoridazine in schizophrenic patients

Thioridazine and mesoridazine levels and levels of thioridazine plus metabolites were determined in plasma and red blood cells (RBC) by gas-liquid chromatography (GLC) and spectrofluorometry (SP), respectively, in schizophrenic patients treated with fixed doses of thioridazine. There was wide interpatient variability in RBC:plasma ratios for thioridazine and mesoridazine, a higher ratio of thioridazine to mesoridazine in RBC than plasma, and a higher ratio of GLC total (thioridazine plus mesoridazine), to SP-determined total drug constituents in RBC than in plasma. RBC showed a monotonic increase in drug levels with dose, whereas levels of drug in the plasma began to level off above the 250 mg/day dose. Drug levels 24 h after the acute dose did not predict steady-state blood levels in plasma or RBC.     

Synthesis of a deuterated 6-AmHap internal standard for the determination of hapten density in a heroin vaccine drug product

A deuterated hapten was designed and synthesized that will be essential for a future study of residual hapten and stability of a hapten-protein conjugate. This hapten, 6-AmHap, was chosen for a heroin vaccine that is now slated for a Phase 1 clinical trial. A maleimide-thiol bioconjugation strategy was successfully applied to our heroin vaccine to connect the hapten 6-AmHap with an immunogenic carrier protein (tetanus toxoid, TT) through a trityl-protected 3-mercaptopropanamide linker. The antibodies induced by the vaccine have been found to have activity against several opioids, including heroin and its metabolites, and, importantly, leave alternate pain treatment medications such as methadone untouched. To the best of our knowledge, no other hapten for a heroin vaccine has been deuterated, yet this tool may prove to be of great importance in the study of residual hapten during product release and the long-term stability program of a hapten-protein conjugate as part of FDA regulatory requirements. Hydrocodone was the starting material for the synthesis of the deuterated 6-AmHap, with a stable amide at C6 and a 3-mercaptopropanamide linker attached at C3. The desired deuterated product was prepared as the disulfide, 3,3′-disulfanediylbis(N-((7S,7aR,12bS)-7-acetamido-3-[²H₃]methyl)-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)propanamide), that could be easily reduced to form the needed hapten, N-((4aR,7S,7aR,12bS)-7-acetamido-3-[²H₃]methyl]-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)-3-mercaptopropanamide.     

Serum neuroleptic concentrations and tardive dyskinesia

Using a liquid chromatographic assay, we measured serum neuroleptic concentrations in eight middle-aged or elderly female inpatients with tardive dyskinesia (TD) and eight controls. All 16 patients were receiving either thioridazine or mesoridazine at stable doses. TD patients were found to have a significantly higher ratio of serum concentration to daily dose of neuroleptics compared with controls. A 1-year follow-up revealed that this ratio did not change appreciably in those patients who continued to receive neuroleptics. Differences in serum neuroleptic levels were not related to peripheral inflammatory activity as indicated by serum -1-acid glycoprotein concentrations. Of the various thioridazine metabolites, sulforidazine (which is reportedly the most potent in terms of affinity for dopaminergic and -noradrenergic receptors) seemed to be significantly elevated in the serum of TD patients as compared with non-TD patients. Our data suggest a need for further pharmacokinetic investigations to study neuroleptic metabolism in patients with TD.     

Partitioning of thioridazine and mesoridazine in human blood fractions

The partitioning of 3H-thioridazine and 3H-mesoridazine in fresh human whole blood was studied. The packed red blood cells were solubilized using the New England Nuclear protocol for whole blood solubilization. The plasma fraction was further fractionated into protein bound and free drug by molecular ultrafiltration. All solutions were counted in Biofluor LSC cocktail and corrected for quenching. Greater than 99% of the labeled drug was bound to the red blood cells and plasma protein. For thioridazine, 59% is bound to RBC, 41% is bound to plasma protein and 0.7% is free; for mesoridazine, 63% is bound to RBC, 37% is bound to plasma protein and 0.9% is free. Though substantial overlap is found in the bound percentage for mesoridazine and thioridazine, more mesoridazine binds to RBC than thioridazine (p less than 0.01). There is no statistically significant relationship between the amount of drug bound to the RBC or to plasma protein and the percent free drug. Though the total drug concentration is the same (1 microgram/ml) the percent free drug is quite variable across subjects by as much as a factor of three. Since free drug is the pharmacologically active portion and therefore determinant of clinical response, the reported variation in free drug concentration at the same total blood concentration invalidates the measurements of total serum or plasma drug concentration as predictive of clinical response.     

Blood levels of haloperidol and thioridazine during maintenance neuroleptic treatment of schizophrenic outpatients

Plasma and red blood cell levels of haloperidol, thioridazine, and thioridazine's main metabolite mesoridazine were measured in schizophrenic outpatients during treatment with fixed doses of haloperidol or thioridazine for several months. These drug levels were compared to those in schizophrenic inpatients treated with fixed doses of the same neuroleptics. There were large interpatient variations in plasma and red blood cell levels at a given dose for schizophrenic outpatients as well as for inpatients. The intrapatient day-to-day fluctuation was much greater in the outpatients. The mean coefficient of variation of thioridazine or mesoridazine levels was about two-fold higher in schizophrenic outpatients than in inpatients. Differences in blood sampling time or compliance in medication ingestion do not fully explain the issue. The factors accounting for the increased intrapatient variability of plasma levels of thioridazine, mesoridazine, and haloperidol in schizophrenic outpatients remain unclear.