norclozapine and Schizophrenia

Clozapine is the most effective antipsychotic for treatment-refractory schizophrenia for reducing positive psychotic symptoms. It is associated with a reduction in hospitalisation and overall mortality. In spite of this, clozapine remains underutilised due to its complex adverse drug reaction (ADR) profile.. This systematic review aims to investigate the association of clozapine and norclozapine serum levels, and peripheral ADRs.. Studies were searched from four electronic databases (PubMed, EMBASE, PsycINFO and CINAHL) from inception to 12 June 2020. Studies were included if they had adult patients, provided data on steady-state trough clozapine or norclozapine levels and reported on clozapine-associated ADRs. Pregnant women, case reports and series were excluded.. A statistically significant correlation was found for clozapine serum levels and triglycerides (n = 70; r = 0.303, 95% CI 0.0119-0.546, p = 0.042), heart rate (n = 137; r = 0.269, 95% CI 0.0918-0.486, p = 0.035), and overall combined ADRs (n = 160; r = 0.264, 95% CI 0.110-0.405, p = 0.001), but not for absolute neutrophil count (n = 223; r = - 0.164, 95% CI - 0.529-0.253, p = 0.444) or total white cell count (n = 18; r = 0.0176, 95% CI - 0.203-0.237, p = 0.878). Interestingly, norclozapine serum levels were found to be statistically correlated to triglycerides (n = 120; r = 0.211, 95% CI 0.0305-0.378, p = 0.022), total cholesterol (n = 120; r = 0.272, 95% CI 0.0948-0.432, p = 0.003) and weight gain (n = 118; r = 0.208, 95% CI 0.0261-0.377, p = 0.025).. Heart rate, triglycerides and combined ADRs are significantly correlated with clozapine levels, and triglycerides, total cholesterol and weight gain with norclozapine levels. Future prospective, randomised controlled studies are needed to identify the cause-effect relationship between clozapine levels and peripheral ADRs.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug-Related Side Effects and Adverse Reactions; Female; Heart Rate; Humans; Pregnancy; Schizophrenia; Schizophrenic Psychology; Triglycerides; Weight Gain

Topics: Antipsychotic Agents; Clozapine; Cognition; Drug Monitoring; Humans; Schizophrenia

Currently available treatments for schizophrenia have limited efficacy and are generally poorly tolerated. However, among these antipsychotic agents, clozapine stands apart in having generally superior motoric tolerability and efficacy. One intriguing possibility, based on clinical correlations, receptor activity profiles and studies with animal models predictive of antipsychotic or cognitive action is that the activity of N-desmethylclozapine (NDMC), a major metabolite of clozapine, may, at least in part, underlie the unique efficacy of clozapine. In this review we compare the pharmacological properties of NDMC to those of clozapine and consider how they may contribute to the overall clinical properties of clozapine. We also consider whether NDMC, in its own right, might be a superior antipsychotic drug.

Topics: Animals; Antipsychotic Agents; Clozapine; Humans; Receptors, Adrenergic, alpha; Receptors, Dopamine; Receptors, Histamine; Receptors, Muscarinic; Receptors, Opioid; Receptors, Serotonin; Schizophrenia

Social inequality in medical rehabilitation is receiving increasing attention. The present study examined the impact of the social status on the long-term effectiveness of the pain competence and depression prevention training "Debora" among patients with chronic low back pain (CLBP) in an inpatient multidisciplinary rehabilitation.. In general, patients of the lower class showed significantly worse values in depressive symptoms, functional capacity, and subjective work ability compared to the upper class. In addition, positive long-term effects could not be found among patients of the lower class. In contrast, patients of the middle and upper class improved, especially in the IG. Furthermore, only the IG showed long-term improvements in subjective work capacity.. This study confirms the influence of the social status on the psychophysical health. Moreover, social inequality in long-term success of rehabilitation of CLBP was suggested, which could be mediated by health literacy. Therefore, these aspects should be taken into account already in the conception and especially in the application of psychological group trainings in inpatient rehabilitation.. Die soziale Ungleichheit in der medizinischen Rehabilitation findet zunehmend Beachtung. Die vorliegende Studie untersuchte die langfristige Wirksamkeit des Schmerzkompetenz- und Depressionspräventionstrainings Debora bei Rehabilitanden mit chronischen Rückenschmerzen in der stationären verhaltensmedizinisch orthopädischen Rehabilitation (VMO) in Abhängigkeit von der sozialen Lage.. Rehabilitanden der Unterschicht wiesen in der Depressivität, Funktionskapazität und subjektiven Arbeitsfähigkeit generell signifikant schlechtere Werte im Vergleich zur Oberschicht auf. Zudem blieben positive Langzeiteffekte bei Rehabilitanden der Unterschicht eher aus. Dagegen verbesserten sich Rehabilitanden der Mittel- und Oberschicht insbesondere in der IG. Ferner zeigte sich, dass lediglich die IG langfristig in der subjektiven Arbeitsfähigkeit profitierte.. Die Studie belegt den Einfluss der sozialen Lage auf die psychophysische Gesundheit. Ferner wird eine soziale Ungleichheit im langfristigen Rehabilitationserfolg bei chronischen Rückenschmerzen nahegelegt, die durch die Gesundheitskompetenz vermittelt sein könnte. Somit sollten diese Aspekte bereits bei der Konzeption und insbesondere bei der Durchführung von psychologischen Gruppentrainings in der stationären medizinischen Rehabilitation bei chronischen Rückenschmerzen berücksichtigt werden.

Topics: Age Factors; Antipsychotic Agents; Chronic Pain; Clozapine; Cytochrome P-450 CYP1A2; Female; Follow-Up Studies; Functional Status; Germany; Health Literacy; Humans; Inpatients; Low Back Pain; Male; Patient Care Team; Psychological Distress; Rehabilitation; Return to Work; Schizophrenia; Self Efficacy; Sex Factors; Smoking; Social Class; Treatment Outcome

Clozapine (CZP) is an atypical antipsychotic agent commonly used in the treatment of schizophrenia. It is metabolized primarily by CYP1A2 enzyme, yielding a pharmacologically active metabolite, norclozapine (NCZP). Significant intra- and interindividual pharmacokinetic (PK) variability for CZP and NCZP has been observed in routine therapeutic drug monitoring. So the goal of this study was to evaluate the magnitude and variability of concentration exposure to CZP and its active metabolite NCZP on pharmacokinetic parameters in Uruguayan patients with schizophrenia with a focus on covariates such as cigarette smoking, age, sex, caffeine consumption, brands available of CZP, and comedication using population PK (PPK) modeling methodologies. Patients with a diagnosis of schizophrenia treated with brand-name CZP (Leponex®) for more than a year were included in the study. Then these patients were switched to the similar brand of CZP (Luverina®). Morning predose blood samples for determination of CZP and NCZP using a HPLC system equipped with a UV detector were withdrawn on both occasions at steady state and under the same comedication. Ninety-eight patients, 22 women and 76 men, took part in the study. Mean ± standard deviation for CZP and NCZP concentration was 421 ± 262 ng/mL and 275 ± 180 ng/mL, respectively. After covariate evaluation, only smoking status remained significant in CZP apparent clearance, inducing a mean increment of 32% but with no clinical impact. The results obtained with the two brands of CZP should ensure comparable efficacy and tolerability with the clinical use of either product. Smoking was significantly associated with a lower exposure to CZP due to higher clearance. The results obtained with the two brands commercialized in our country hint a bioequivalence scenario in the clinical setting.

Topics: Adult; Aged; Clozapine; Female; Humans; Male; Middle Aged; Models, Biological; Schizophrenia; Uruguay

Clozapine is the sole antipsychotic agent effective for the treatment of refractory schizophrenia. Sixty percent of clozapine-treated patients, however, fail to adequately respond. Minocycline, a tetracycline antibiotic, possesses antiinflammatory and neuroprotective properties that may play a role in schizophrenia. Clozapine is mainly metabolized by CYP1A2 enzymes, and minocycline may potentially inhibit CYP1A2 as hypothesized by case report data. To date, no pharmacokinetic interaction has been reported between minocycline and clozapine. This is a secondary analysis of a 10-week controlled study of adjunctive minocycline to clozapine in treatment refractory schizophrenia. Clozapine plasma levels were collected every two weeks during the study. 28 participants assigned to receive minocycline and 22 assigned to placebo were included. No differences existed in baseline demographics, clozapine dose or plasma levels. Average changes from baseline in clozapine plasma level (p = 0.033) were significantly higher in the minocycline group despite maintenance of stable doses. No statistically significant treatment differences were found in the norclozapine (p = 0.754) or total clozapine (p = 0.053) changes in plasma levels, although possible changes in total clozapine levels require further investigation. This analysis suggests that minocycline administration may lead to increased clozapine plasma levels. Further study is needed to examine possible explanations.

Topics: Adult; Antipsychotic Agents; Clozapine; Drug Interactions; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Minocycline; Neuroprotective Agents; Schizophrenia

Therapeutic drug monitoring (TDM) of clozapine is standardized to 12-h postdose samplings. In clinical settings, sampling time often deviates from this time point, although the importance of the deviation is unknown. To this end, serum concentrations (s-) of clozapine and its metabolite N-desmethyl-clozapine (norclozapine) were measured at 12 ± 1 and 2 h postdose.. Forty-six patients with a diagnosis of schizophrenia, and on stable clozapine treatment, were enrolled for hourly, venous blood sampling at 10-14 h postdose.. Minor changes in median percentage values were observed for both s-clozapine (-8.4%) and s-norclozapine (+1.2%) across the 4-h time span. Maximum individual differences were 42.8% for s-clozapine and 38.4% for s-norclozapine. Compared to 12-h values, maximum median differences were 8.4% for s-clozapine and 7.3% for s-norclozapine at deviations of ±2 h. Maximum individual differences were 52.6% for s-clozapine and 105.0% for s-norclozapine. The magnitude of s-clozapine differences was significantly associated with age, body mass index and the presence of chronic basophilia or monocytosis.. The impact of deviations in clozapine TDM sampling time, within the time span of 10-14 h postdose, seems of minor importance when looking at median percentage differences. However, substantial individual differences were observed, which implies a need to adhere to a fixed sampling time.

Topics: Adult; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Female; Humans; Male; Middle Aged; Schizophrenia; Young Adult

This preliminary prospective study evaluated cardiac status in 15 treatment-resistant schizophrenia patients (aged 18-55 years) without evidence of cardiovascular disease. Patients underwent clinical assessment, blood tests, ECG, and echocardiography before and during clozapine treatment for 4 weeks as doses increased from 25 to 100 mg/day. Serum concentrations of high-sensitivity C-reactive protein, troponin-I, brain natriuretic peptide, and clozapine+norclozapine were assayed at week 3; ECG and echocardiography were repeated at week 4. At moderate serum drug concentrations (124 ng/ml), the heart rate increased by 10% and high-sensitivity C-reactive protein levels were slightly elevated, but troponin-I and brain natriuretic peptide levels were not elevated. Echocardiographic indices indicated declining left ventricular (LV) diastolic and systolic function in 60-80% of participants, with an increase in systolic pulmonary artery pressure, A-wave velocity, and LV myocardial performance index by 16-24% in 60-80% of participants and a decrease in the E/A ratio by 29% in 73% of participants - all uncorrelated with drug concentrations. Early treatment with moderate doses of clozapine was associated with subclinical but substantial decreases in LV functioning in surprisingly high proportions of participants. Studies with more participants, higher drug doses, and long-term follow-up are needed to confirm and determine the course of the observed abnormalities and to evaluate their relationship with rare clinical cardiotoxicity associated with clozapine.

Topics: Adolescent; Adult; Antipsychotic Agents; C-Reactive Protein; Clozapine; Drug Resistance; Echocardiography; Female; Heart Rate; Humans; Middle Aged; Natriuretic Peptide, Brain; Prospective Studies; Schizophrenia; Treatment Outcome; Troponin I; Ventricular Function, Left; Young Adult

To develop a combined population pharmacokinetic model (PPK) to assess the magnitude and variability of exposure to both clozapine and its primary metabolite norclozapine in Chinese patients with refractory schizophrenia via sparse sampling with a focus on the effects of covariates on the pharmacokinetic parameters.. Relevant patient concentration data (eg, demographic data, medication history, dosage regimen, time of last dose, sampling time, concentrations of clozapine and norclozapine, etc) were collected using a standardized data collection form. The demographic characteristics of the patients, including sex, age, weight, body surface area, smoking status, and information on concomitant medications as well as biochemical and hematological test results were recorded. Persons who had smoked 5 or more cigarettes per day within the last week were defined as smokers. The concentrations of clozapine and norclozapine were measured using a HPLC system equipped with a UV detector. PPK analysis was performed using NONMEM. Age, weight, sex, and smoking status were evaluated as main covariates. The model was internally validated using normalized prediction distribution errors.. A total of 809 clozapine concentration data sets and 808 norclozapine concentration data sets from 162 inpatients (74 males, 88 females) at multiple mental health sites in China were included. The one-compartment pharmacokinetic model with mixture error could best describe the concentration-time profiles of clozapine and norclozapine. The population-predicted clearance of clozapine and norclozapine in female nonsmokers were 21.9 and 32.7 L/h, respectively. The population-predicted volumes of distribution for clozapine and norclozapine were 526 and 624 L, respectively. Smoking was significantly associated with increases in the clearance (clozapine by 45%; norclozapine by 54.3%). The clearance was significantly greater in males than in females (clozapine by 20.8%; norclozapine by 24.2%). The clearance of clozapine and norclozapine did not differ significantly between Chinese patients and American patients.. Smoking and male were significantly associated with a lower exposure to clozapine and norclozapine due to higher clearance. This model can be used in individualized drug dosing and therapeutic drug monitoring.

Topics: Adolescent; Adult; Antipsychotic Agents; Asian People; China; Clozapine; Drug Monitoring; Female; Humans; Male; Middle Aged; Models, Biological; Nonlinear Dynamics; Prospective Studies; Schizophrenia; Sex Factors; Smoking; Tissue Distribution; Young Adult

This study compared the bioequivalence of FazaClo (clozapine orally disintegrating tablets) 100 mg to Clozaril (clozapine standard oral tablets) 100 mg after multiple doses in patients with schizophrenia.. This was a randomized, open-label, multiple-dose study in which patients with schizophrenia received FazaClo or Clozaril 100 mg twice daily for 5 days before crossing over to the alternate therapy. Blood samples were obtained at regular intervals during and after the completion of treatment, and standard pharmacokinetic parameters were calculated. Safety and patient satisfaction with FazaClo were also assessed.. Thirty-six patients were enrolled, of whom 33 completed the study and 30 were included in the steady-state analyses. All pharmacokinetic parameters for clozapine and desmethylclozapine (the major metabolite of clozapine) were similar between FazaClo and Clozaril in both the completer and steady-state populations. Geometric mean values for steady-state maximum and minimum concentrations and area under the plasma concentration-time curve for FazaClo were all within 95-105% of those for Clozarilwell within the range considered by the US FDA as acceptable for bioequivalence (80-125%). Patients also expressed a high level of satisfaction with the FazaClo orally disintegrating tablet formulation.. FazaClo produced pharmacokinetic profiles almost identical to those of Clozaril. This should provide clinicians with reassurance that patients who receive FazaClo will achieve plasma drug concentrations similar to those produced by the same daily dose of Clozaril, and that no cross-titration is necessary when switching from one of these clozapine formulations to the other.

Topics: Administration, Oral; Adolescent; Adult; Antipsychotic Agents; Area Under Curve; Clozapine; Cross-Over Studies; Disorders of Excessive Somnolence; Dose-Response Relationship, Drug; Drug Administration Schedule; Drugs, Generic; Female; Half-Life; Humans; Intestinal Obstruction; Intestine, Small; Male; Metabolic Clearance Rate; Middle Aged; Patient Dropouts; Patient Satisfaction; Schizophrenia; Sweating; Tablets; Therapeutic Equivalency

Schizophrenic outpatients (n=102) whose condition had stabilized with clozapine (CLZ) therapy and were being maintained on CLZ were followed for 1 year. Clinical status and concentrations of serum clozapine (CLZ) and its metabolite norclozapine (NCLZ) were evaluated periodically or when relapse occurred. Relapse was defined as a significant exacerbation of psychotic symptoms or hospitalization. Thirty-three patients relapsed and 69 did not. Relapse patients displayed significantly lower serum concentrations of CLZ and a sum of CLZ and NCLZ at endpoint than non-relapses (CLZ: 162 ng/ml vs. 237 ng/ml, p<0.001; CLZ+NCLZ: 225 ng/ml vs. 301 ng/ml, p<0.001). When all subjects were pooled together, a significant inverse correlation was observed between percent increase in the total score on the Brief Psychiatric Rating Scale (BPRS) from baseline and serum levels of CLZ alone (r=0.404, p<0.001) and the sum of CLZ and NCLZ (r=0.364, p<0.001). Relapses and non-relapses were well separated by a threshold CLZ serum concentration of 200 ng/ml with a sensitivity of 73% and a specificity of 80%. The threshold value represented about a 40% lower serum CLZ level than concentration achieved in acute treatment. Survival analysis showed a similarity of the relapse risk over time defined by the CLZ serum threshold and by symptomatic criteria. These results suggest that effective relapse prevention may require maintenance of patients at CLZ serum concentrations above 200 ng/ml and above 60% of the acute-phase level during long-term maintenance treatment of schizophrenia.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Recurrence; Schizophrenia; Statistics as Topic; Time Factors

Kurz et al. conducted the first study of the intra-individual variability of clozapine plasma concentrations but did not take into account the effect of smoking and co-medication. As patients were receiving varying doses, Kurz et al. standardized plasma levels by using a plasma level/dose/kg ratio. In 15 patients, the mean coefficient of variation (CV) was 53% (S.D. = 21). In this new study, plasma clozapine and norclozapine concentrations were measured every 2 weeks in 47 patients randomized to 100, 300, or 600 mg/day for 16-week double-blind clozapine trials under controlled conditions (stable smoking, limited co-medication and absence of caffeinated beverages). For 100, 300 and 600 mg/day, the respective mean CVs for plasma clozapine concentrations were 23% (S.D. = 14), 19% (S.D.= 11) and 18% (S.D. = 8). For the combined concentrations of clozapine and norclozapine, the respective mean CVs were 20% (S.D. = 13), 16% (S.D. = 9) and 15% (S.D. = 7). Under 100 mg/day, the mean CV for clozapine concentrations was significantly higher for heavy smokers than non-heavy smokers (32%, S.D. = 3 vs. 19%, S.D. = 8) (p = 0.03). Studies of CVs in other environments are needed. Clozapine CVs may be important in order to understand the importance of variations around the therapeutic range and to interpret drug interactions above the usual noise of measuring plasma concentrations.

Topics: Adult; Antipsychotic Agents; Clozapine; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Schizophrenia; Severity of Illness Index; Smoking; Time Factors

Recent reports implicate clozapine in heart rate variability, QTc prolongation, torsade de pointes and sudden death at therapeutic doses, even in physically healthy patients. This study aims to examine whether autonomic (vital) signs are correlated with clozapine dose titration and blood levels of clozapine and nor-clozapine during clozapine therapy.. Thirty-seven consecutive patients with diagnosis of schizophrenia treated with clozapine were included in this prospective longitudinal study. The study was restricted to only the first 8 weeks of treatment. After obtaining informed consent, serum concentrations of clozapine and nor-clozapine were determined weekly at trough, as doses were administered q12h and adjusted according to clinical guidelines for clozapine use. Autonomic signs including BP (supine and erect), pulse (supine and erect) and temperature were monitored daily each morning before and one hour after the morning's dose of clozapine was administered.. We calculated analyses of covariance (ANCOVAs) to evaluate the changes in vital signs parameters, from baseline to week 8, with clozapine variables as covariates (i.e, the dose of clozapine, as well as the levels of serum clozapine and nor-clozapine). The blood pressure and pulse did not change significantly (p<0.01) from baseline to weeks 8. The temperature was inversely related to clozapine dose (p<0.003). Higher nor-clozapine to clozapine ratios were associated with higher BP measures (p=0.002). The magnitude of these relationships is weak (r<0.30).. There is a tendency to autonomic dysregulation during clozapine use. This has cardiac function implications, justifying cautious dose adjustment with frequent monitoring of vital signs.

Topics: Analysis of Variance; Antipsychotic Agents; Blood Pressure; Body Temperature; Clozapine; Drug Administration Schedule; Drug Monitoring; Female; Heart Rate; Humans; Longitudinal Studies; Male; Prospective Studies; Schizophrenia

Hypersalivation is known as a frequent, disturbing, and socially stigmatizing side effect of therapy with the atypical antipsychotic clozapine. It has been shown that the addition of the anticholinergic pirenzepine is able to reduce clozapine-induced hypersalivation, probably by blocking M4-receptors. Nevertheless, a pharmacokinetic interaction between both compounds cannot be excluded.. In this pilot study, 29 schizophrenic patients (ICD-10; 51.7 % female; age: 36.7 +/- 8.7 years [mean +/- SD]) were included. Serum concentrations of clozapine and its pharmacologically active metabolite N-desmethylclozapine were determined under steady-state conditions by automated HPLC with UV detection before and after addition of pirenzepine for 3 days.. Significantly fewer patients reported hypersalivation after addition of pirenzepine (69 % vs. 34.5 %, P = 0.002). No significant differences of clozapine and N-desmethylclozapine serum levels before (329 +/- 181 ng/ml and 218.0 +/- 123.4 ng/ml, respectively) and 3 days after (336 +/- 215 ng/ml and 235.9 +/- 164.4 ng/ml, respectively) addition of pirenzepine were found. In three patients, however, clozapine serum levels increased; this was probably unrelated to pirenzepine.. In conclusion, treatment of clozapine-induced hypersalivation with pirenzepine is a recommendable combination with low risk of additional side effects.

Topics: Adult; Antipsychotic Agents; Chromatography, High Pressure Liquid; Clozapine; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Interactions; Female; Humans; Male; Middle Aged; Muscarinic Antagonists; Pilot Projects; Pirenzepine; Schizophrenia; Sialorrhea; Spectrophotometry, Ultraviolet

Topics: Antipsychotic Agents; Clozapine; Drug Resistance, Multiple; Humans; Schizophrenia; Treatment Outcome

This study attempts: (1) to verify that serum antimuscarinic activity is related to clozapine dose, and more importantly to clozapine plasma concentrations; (2) to explore whether norclozapine has serum antimuscarinic activity; (3) to explore whether antimuscarinic activity is related to clozapine side effects; and (4) to compare the serum antimuscarinic activities of clozapine with those of antiparkinsonian drugs and other antipsychotics. In 39 patients participating in a double-blind clozapine study, the [3H]QNB assay was used to measure serum antimuscarinic activity: (1) on baseline medications; (2) after a 4-week haloperidol trial; (3) after a 16-week clozapine trial of either 100, 300, or 600 mg/d; and (4) after 1 or 2 consecutive 16-week clozapine trials with remaining doses in nonresponders. Clozapine levels predicted serum antimuscarinic activity better than clozapine dose. At the end of the 1st clozapine trial, the correlation with the levels explained 69% of the variance of serum antimuscarinic activity (r = 0.83, P < 0.001, N = 34). Clozapine levels were good predictors of serum antimuscarinic activity only in patients taking 300 or 600 mg/d. After correcting for clozapine levels, the within-subject correlation between norclozapine levels and serum antimuscarinic activity was relatively high and significant (r = 0.54, F = 26.7, df = 1.65, P < 0.001). Constipation was significantly associated with higher serum antimuscarinic activity during the 1st clozapine trial. Clozapine was associated with clearly higher antimuscarinic activity than other antipsychotics or low doses of antiparkinsonians. In vitro studies and new clinical studies are needed to verify whether norclozapine may significantly contribute to antimuscarinic activity during clozapine treatment.

Topics: Antipsychotic Agents; Clozapine; Double-Blind Method; Humans; Muscarinic Antagonists; Psychiatric Status Rating Scales; Quinuclidinyl Benzilate; Receptors, Muscarinic; Schizophrenia

Topics: Adult; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Clozapine; Drug Therapy, Combination; Fluvoxamine; Humans; Male; Schizophrenia

Clozapine is an atypical antipsychotic drug and displays efficacy in 30% to 60% of patients with schizophrenia who do not respond to traditional antipsychotics. A clozapine concentration greater than 1,150 nmol/L increases the probability of antipsychotic efficacy. However, plasma clozapine concentration can vary more than 45-fold during long-term treatment. The aim of this study was to assess the contribution of CYP1A2 to variability in steady-state concentration of clozapine and its active metabolite norclozapine. Patients with schizophrenia or schizoaffective disorder were prospectively monitored during clozapine treatment (N = 18). The in vivo CYP1A2 activity was measured using the caffeine metabolic ratio (CMR) in overnight urine. Trough plasma samples were drawn after at least 5 days of treatment with a constant regimen of clozapine. A significant negative association was found between the CMR and the dose-corrected clozapine (r(s) = -0.87,p < 0.01) and norclozapine (r(s) = -0.76,p < 0.01) concentrations. Nonsmokers displayed a higher clozapine (3.2-fold) and norclozapine (2.3-fold) concentration than smokers (p < 0.05). Furthermore, there was marked person-to-person variation in CYP1A2 activity during multiple-dose clozapine treatment (coefficient of variation = 60%). Age, weight, serum creatinine, and grapefruit juice consumption did not significantly contribute to variability in clozapine and norclozapine concentration (p > 0.05). In conclusion, CYP1A2 is one of the important contributors to disposition of clozapine during multiple-dose treatment. Although further in vitro experiments are necessary, the precise metabolic pathways catalyzed by CYP1A2 seem to be subsequent to the formation of norclozapine, hitherto less recognized quantitatively important alternate disposition routes, or both. From a clinical perspective, an environmentally induced or constitutively high CYP1A2 expression can lead to a decrease in steady-state concentration of clozapine as well as its active metabolite norclozapine. Thus, interindividual variability in CYP1A2 activity may potentially explain treatment resistance to clozapine in some patients. CYP1A2 phenotyping with a simple caffeine test may contribute to individualization of clozapine dosage and differentiate between treat ment noncompliance and high CYP1A2 activity.

Topics: Adult; Aged; Antipsychotic Agents; Caffeine; Clozapine; Cytochrome P-450 CYP1A2; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Phosphodiesterase Inhibitors; Psychotic Disorders; Reference Values; Schizophrenia; Smoking

To study the effect of influenza vaccine on serum clozapine, N-desmethylclozapine and clozapine-N-oxide steady-state concentrations in patients with schizophrenia.. This was an open-label study in 14 schizophrenic inpatients (with 2 drop-outs) using clozapine. Serum trough concentrations of clozapine. N-desmethylclozapine and clozapine-N-oxide, as well as the concentration of c-reactive protein (CRP), were measured immediately before conventional trivalent influenza vaccination and 2, 4, 7 and 14 days after the vaccination.. Influenza vaccination had no significant effect on serum concentrations of clozapine, N-desmethylclozapine or clozapine-N-oxide. No changes in the clinical effects of clozapine were observed after vaccination. Influenza vaccination did not increase CRP. However, two drop-out patients who developed upper respiratory and abdominal symptoms had increased and elevated serum concentrations of clozapine, compared with the baseline.. Influenza vaccination using conventional trivalent influenza vaccine does not affect serum concentrations of clozapine or its main metabolites. However, an infection-related increase in CRP may be associated with increased serum concentration of clozapine.

Topics: Adult; Antipsychotic Agents; C-Reactive Protein; Clozapine; Drug Interactions; Female; Humans; Influenza Vaccines; Male; Middle Aged; Schizophrenia; Vaccination

A possible pharmacokinetic interaction between a CYP1A2 inhibitor, ciprofloxacin, and clozapine was studied in schizophrenia patients with stable clozapine treatment.. A randomised double-blind cross-over study design with two phases was used. Seven schizophrenic inpatients volunteered to receive, in addition to their previous drug regimen, either 250 mg ciprofloxacin or placebo twice daily (b.i.d.) for 7 days. The phases were separated by a 7-day wash-out period. Serum concentrations of clozapine and its main metabolite N-desmethylclozapine were measured during both phases before the first dose on day 1 and on days 3 and 8.. Ciprofloxacin increased mean serum concentration of clozapine and N-desmethylclozapine by 29% (P < 0.01) and 31% (P < 0.05), respectively. There was a significant positive correlation (r = 0.90, P < 0.01) between the individual concentrations of serum ciprofloxacin and the increase in concentrations of clozapine plus N-desmethylclozapine. The increase in serum clozapine concentrations correlated significantly (r = 0.89, P < 0.01) with the ratios of N-desmethylclozapine to clozapine concentrations.. Even a low dose of ciprofloxacin can moderately increase serum concentrations of clozapine and N-desmethylclozapine. A probable mechanism of interaction is an inhibition of CYP1A2 enzyme by ciprofloxacin. The possibility of clinically significant interaction should be considered, especially when higher doses of ciprofloxacin are used concomitantly with clozapine.

Topics: Adult; Anti-Infective Agents; Antipsychotic Agents; Ciprofloxacin; Clozapine; Cross-Over Studies; Cytochrome P-450 CYP1A2 Inhibitors; Double-Blind Method; Drug Interactions; Enzyme Inhibitors; Female; Humans; Individuality; Male; Middle Aged; Placebos; Schizophrenia

Two separate studies were carried out to assess the effect of valproic acid on the steady-state plasma concentrations of clozapine and its major metabolites norclozapine and clozapine N-oxide in psychotic patients. In the first study, concentrations of clozapine and metabolites were compared between patients treated with clozapine in combination with sodium valproate (n = 15) and control patients treated with clozapine alone (n = 22) and matched for sex, age, body weight, and antipsychotic dosage. Patients comedicated with valproate tended to have higher clozapine levels and lower norclozapine levels, but the differences did not reach statistical significance. In a subsequent study, plasma concentrations of clozapine and its metabolites were determined in 6 patients with schizophrenia stabilized on clozapine therapy (200-400 mg/d) before and after treatment with sodium valproate (900-1200 mg/d) for 4 weeks. Mean plasma concentrations of clozapine and its metabolites did not change significantly throughout the study, but there was a trend for clozapine levels to be higher and for norclozapine levels to be lower after valproate. Overall, these findings suggest that valproic acid may have an inhibiting effect on the CYP1A2- or CYP3A4-mediated conversion of clozapine to norclozapine. However, the interaction is unlikely to be clinically significant.

Topics: Adult; Anticonvulsants; Antipsychotic Agents; Clozapine; Drug Interactions; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Mood Disorders; Schizophrenia; Valproic Acid

1. The aim of the study was to determine if a more rational therapeutic approach could be devised for neuroleptic resistant psychotic patients treated for months and years with clozapine. Clozapine is an atypical antipsychotic medication, but its therapeutic benefit has been limited by a high incidence of agranulocytosis and seizures. 2. The study has been performed in an open setting and included 12 patients. Some of them developed a secondary depression and were treated with fluoxetine. 3. Pharmacokinetic analysis were conducted at the same time as clinical evaluations, grading using the BPRS, the PDS, and QLS, and determinations of plasma and red blood cell clozapine and desmethylclozapine, plasma and RBC fluoxetine and norfluoxetine, whole blood serotonin and tryptophan. 4. A positive linear correlation was found only between RBC concentration and the evolution of the QLS. 5. Clozapine is efficacious both on positive and negative symptoms but its mechanism of action remains unclear. Positive symptoms disappear more quickly, sometimes followed by a post psychotic depression. Negative symptoms improve more slowly but regularly. They seem to be correlated with serotoninergic mechanisms. For whole blood 5HT, an important increase was seen about 4 weeks after Cloza administration, and then a decrease. 6. Therapeutic drug monitoring (on the same sample drawn for haematological monitoring providing) could play a useful role in the management of patients treated by clozapine: compliance, lowest dose, possible toxicity, drug interaction, lack of efficacy, relapse predictivity.

Topics: Adult; Antidepressive Agents, Second-Generation; Antipsychotic Agents; Brief Psychiatric Rating Scale; Clozapine; Depressive Disorder; Drug Monitoring; Female; Fluoxetine; Humans; Male; Middle Aged; Schizophrenia; Serotonin; Tryptophan

Results presented in this article are focused on the variability in pharmacokinetics. The purpose of this study was (1) to investigate intra- and interindividual variabilities of pharmacokinetic parameters of clozapine and its two main metabolites in plasma after multiple oral administration in 8 chronic schizophrenic patients (Study 1) and (2) to gain more information regarding plasma concentrations of these drugs after multiple doses in a group of 25 treatment-responsive patients (Study 2). Patients were treated with clozapine in fixed daily doses (given every 8-12 hours) between 200 and 900 mg. Plasma drug concentrations were determined by high-performance liquid chromatography. The mean volume of distribution and the total plasma clearance of clozapine, uncorrected for bioavailability, were 7 L/kg and 40.5 L/h, respectively. The terminal elimination half-lives averaged 10.5 hours for clozapine, 19.2 hours for norclozapine, and 8.6 hours for the N-oxide metabolite. Significant relationships were observed between clozapine and norclozapine (or clozapine N-oxide) plasma concentrations. Large inter- and intrapatient variations in pharmacokinetics were observed. Clozapine was generally well tolerated by the patients, with sedation, hypersialorrhea, and tiredness as the most common side effects encountered.

Topics: Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Dose-Response Relationship, Drug; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Schizophrenia; Time Factors

We studied a possible pharmacokinetic interaction between clozapine and itraconazole, a potent CYP3A4 inhibitor.. A double-blind randomized study design was used. Seven schizophrenic inpatients volunteered to receive, in addition to their previous drug regimen, either 200 mg itraconazole or placebo for 7 days. For the next 7 days, itraconazole was changed to placebo and vice versa. Serum concentrations of clozapine and its main metabolite desmethylclozapine were measured on days 0, 3, 7, 10 and 14.. Concomitant administration of itraconazole had no significant effect on serum concentrations of clozapine or desmethylclozapine.. CYP3A4 seems to be of minor importance in clozapine metabolism in humans. Itraconazole, and probably also other inhibitors of CYP3A4, can be used concomitantly with clozapine.

Topics: Adult; Antifungal Agents; Antipsychotic Agents; Clozapine; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Double-Blind Method; Drug Interactions; Female; Humans; Itraconazole; Male; Mixed Function Oxygenases; Schizophrenia

Therapeutic drug monitoring of clozapine as an aid in the treatment of schizophrenic states is commonly used in our hospital.. Development of a high-performance liquid chromatographic method for the determination of clozapine (CLZ) and its major metabolite desmethylclozapine (DMCLZ) in plasma and saliva, and investigation of the relationship between plasma concentrations of CLZ and DMCLZ and concentrations in saliva in patients treated with clozapine.. Subjects were either inpatients or outpatients with a DSM IV diagnosis of schizophrenia (n=34). Determination of CLZ and DMCLZ saliva concentrations appeared to be a satisfactory method to check compliance to treatment, particularly in outpatients.. Mean CLZ and DMCLZ plasma concentrations were 432+/-264 ng/ml (+/-SD) (range 90-1310 ng/ml) and 257+/-144 ng/ml (range 55-580 ng/ ml), respectively. The CLZ/DMCLZ plasma ratio was equal to 1.7+/-0-5 (daily dosage 7.2+/-2.3 mg/kg, n=34). Mean CLZ plasma and saliva levels were 336+/-157 ng/ ml (range 90-580 ng/ml) and 159+/-86 ng/ml (range 40-364ng/ml), respectively (r=0.56, n=14). Mean DMCLZ plasma and saliva levels were 196+/-112 ng/ ml (range 55-481 ng/ml) and 109+/-67ng/ml (range 40-250ng/ml), respectively (r=0.73, n=14). Mean CLZ/DMCLZ ratios determined in plasma and saliva were 1.9+/-0.6 (range 1.0-3.4) and 1.7+/-0.6 (range 1.0-3.2), respectively (r=0.85, n=14). CLZ and DMCLZ saliva concentrations appear to be useful for checking compliance to treatment, in particular among outpatients.

Topics: Adult; Antipsychotic Agents; Chromatography, High Pressure Liquid; Clozapine; Drug Monitoring; Female; Humans; Male; Middle Aged; Patient Compliance; Saliva; Schizophrenia

N-Desmethylclozapine and clozapine N-oxide are major metabolites of the atypical neuroleptic clozapine in humans and undergo renal excretion. The aim of this study was to investigate to what extent the elimination of these metabolites in urine contributes to the total fate of clozapine in patients and how they are handled by the kidney.. From 15 psychiatric patients on continuous clozapine monotherapy, blood and urine samples were obtained during four 2 h intervals, and clozapine and its metabolites were assayed in serum and urine by solid-phase extraction and h.p.l.c. Unbound fractions of the compounds were measured by equilibrium dialysis.. The following unbound fractions in serum were found (geometric means): clozapine 5.5%, N-desmethylclozapine 9.7%, and clozapine N-oxide 24.6%. Renal clearance values calculated from unbound concentrations in serum and quantities excreted in urine were for clozapine on average 11% of the creatinine clearance, whereas those of N-desmethylclozapine and clozapine N-oxide amounted to 300 and 640%, respectively. The clearances of unbound clozapine and N-desmethylclozapine increased with increasing urine volume and decreasing pH. All renal clearance values exhibited large interindividual variations. The sum of clozapine and its metabolites in urine represented on average 14% of the dose.. Clozapine, N-desmethylclozapine and clozapine N-oxide are highly protein-bound in serum. Clozapine is, after glomerular filtration, largely reabsorbed in the tubule, whereas the metabolites undergo net tubular secretion. Metabolic pathways alternative or subsequent to N-demethylation and N-oxidation must make major contributions to the total fate of clozapine in patients.

Topics: Adult; Antipsychotic Agents; Blood Proteins; Clozapine; Female; Humans; Kidney; Male; Metabolic Clearance Rate; Middle Aged; Schizophrenia

The pharmacokinetic parameters of clozapine and its two main metabolites, N-desmethylclozapine (norclozapine, active metabolite) and clozapine N-oxide, were evaluated, after oral administration, in 19 patients with chronic schizophrenia. Plasma and red blood cell (RBC) drug concentrations were determined by high-performance liquid chromatography. Large interpatient variations in pharmacokinetic parameters of clozapine and its two metabolites were observed. Plasma clozapine concentration peaked, on average, at 2.3 hours. The mean volume of distribution and the total plasma clearance, uncorrected for bioavailability, were 6 L/kg and 38 L/hr, respectively. The terminal elimination half-lives averaged 7.6 hours for clozapine, 13 hours for norclozapine, and 7 hours for the N-oxide metabolite. The mean RBC/plasma concentration ratios were 23, 61, and 81% for clozapine, N-desmethylclozapine, and clozapine N-oxide, respectively. From RBC concentration data, the mean elimination half-lives were 7.6 hours for clozapine, 16 hours for N-desmethylclozapine, and 8 hours for the N-oxide metabolite. The average value for blood clearance of clozapine was 54.7 L/hr. Significant correlations were observed between dose and maximum plasma concentrations and between dose and area under the curve concentrations; these results suggested linear steady-state pharmacokinetics over the range of concentrations studied.

Topics: Adolescent; Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Female; Humans; Male; Middle Aged; Schizophrenia

Plasma levels of clozapine and its major metabolites, N-desmethylclozapine and clozapine-N-oxide, were measured in 18 schizophrenic patients at different times (4, 6 and 24 weeks) during the course of treatment with multiple doses of the drug, by using high performance liquid chromatography (HPLC) with UV detection. Plasma levels of clozapine and N-desmethylclozapine were significantly higher in females than in males after 4 and 6 weeks, but not after 24 weeks, of treatment. No sex difference was found at any time with respect to plasma levels of clozapine-N-oxide.

Topics: Adolescent; Adult; Antipsychotic Agents; Chronic Disease; Clozapine; Female; Humans; Male; Schizophrenia; Sex Factors; Time Factors

Serum clozapine (S-Cloza) and serum desmethyl-clozapine concentrations (S-Descloza) were measured in 30 chronic schizophrenic in- and out-patients on a variable dose regimen. All patients were in steady state with respect to clozapine therapy and in a stable condition with respect to psychotic illness. The 24-h clozapine dose (median with interquartile range in parenthesis) was 350 (228-425) mg/24 h (range 100-700). There was a weak positive correlation between doses and the BPRS total score (r = 0.44, P < 0.05). The median S-Cloza was 1076 (706-1882) nmol/l (range 196-5581 corresponding to 64-1824 ng/ml). The S-Cloza was linearly correlated to dose but with a high interindividual variation at equal doses, e.g. a factor of 8 at 400 mg/24 h, but a low intraindividual variability of 20%. The S-Descloza averaged 77% of the S-Cloza and was highly correlated to S-Cloza (r = 0.90; P < 0.001). The S-Descloza/dose ratio increased with age and duration of treatment. The side effects registered were EEG abnormalities (83%), tachycardia (23%), increased liver enzyme activity (60%), orthostatic hypotension (17%), and moderate leucocytosis (17%). Only EEG changes were correlated to S-Cloza (r = 0.43; P < 0.05). The score values of the UKU Side Effect Scale were weakly (r = 0.36) correlated to S-Cloza. No side effects were correlated to S-Descloza, doses, or treatment duration. The frequency of side effects was higher than in studies using lower mean doses indicating a correlation between doses or S-Cloza and the frequency of side effects. It is concluded that clozapine fulfils the criteria for therapeutic drug monitoring. TDM may contribute to finding the lowest effective dose with the fewest possible side effects.

Topics: Adolescent; Adult; Blood Pressure; Clozapine; Cross-Sectional Studies; Electrocardiography; Electroencephalography; Female; Humans; Individuality; Male; Psychiatric Status Rating Scales; Schizophrenia

With the aim of exploring putative correlations between serum and CSF levels of clozapine and its demethyl metabolite, lumbar puncture was performed on four male and five female schizophrenic patients during long-term treatment with clozapine. Three consecutive 6-ml fractions were collected after at least 8 h of bedrest and fasting. On comparing serum and CSF levels, a correlation was found for norclozapine in the third (13-18 ml) CSF fraction. Norclozapine in the first (0-6 ml) CSF correlated significantly with height. The CSF/serum ratio of clozapine in the first fraction was correlated significantly with body weight. No correlations were found between serum levels of clozapine and norclozapine, or between the serum and CSF levels of clozapine. The study suffers from a small number of patients (for ethical reasons), but the present results might be explicable if the first (0-6 ml) CSF fraction represents a cul-du-sac of the CSF, mirroring the previous day's drug levels. The second fraction, then, will represent the CSF level in the steady state during the night.

Topics: Adult; Antipsychotic Agents; Biotransformation; Body Weight; Clozapine; Dealkylation; Female; Humans; Male; Middle Aged; Pilot Projects; Schizophrenia

Plasma clozapine and haloperidol concentrations were studied in adolescents being treated for childhood-onset schizophrenia.. Eleven patients (9 boys, 2 girls; mean age = 14.1 +/- 2.1 years) received a 6-week blinded or open trial of clozapine. Five patients also received 6 weeks of blinded or open haloperidol. Doses were increased on an individual basis to a mean 6-week dose of 5.99 +/- 2.6 mg/kg/day for clozapine and 0.24 +/- 0.20 mg/kg/day for haloperidol. The Brief Psychiatric Rating Scale and Bunney Hamburg Rating Scale were completed weekly for each subject. Weekly blood samples were obtained during therapy and assayed by high performance liquid chromatography.. The mean clozapine level at Week 6 was 378.3 ng/mL and ranged from 77.5 to 1050 ng/mL. The mean Week 6 haloperidol level was 23.0 ng/mL (range, 6.2-44.3 ng/mL). The clozapine desmethyl and N-oxide metabolites achieved mean concentrations of 77% and 18%, respectively, of those of the parent compound. The mean ratio of haloperidol/reduced haloperidol was 4.48 (range, 0.76-8.76). Clozapine concentrations versus clinical benefit exhibited a consistent linear relationship among patients (correlation range, 0.26-0.96). Conversely, poor and inconsistent correlations between haloperidol concentrations and clinical effects were observed. No relationships were noted between clozapine or haloperidol dose and clinical effects.. Adolescents with schizophrenia produce a greater amount of desmethylclozapine than previously seen in adults. Plasma clozapine concentrations appear to be related in a linear fashion to clinical improvement.

Topics: Adolescent; Age of Onset; Child; Clozapine; Drug Administration Schedule; Female; Haloperidol; Humans; Male; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenia, Childhood; Schizophrenic Psychology; Treatment Outcome

Serum concentrations of clozapine, norclozapine, and clozapine-N-oxide were assayed in psychotic patients treated with clozapine alone (N = 17), clozapine with fluoxetine added (N = 6), or clozapine with valproic acid added (N = 11). Subjects were matched for age and other treatments, and concentrations were corrected for daily dose of clozapine (milligrams per kilogram of body weight). With valproic acid, there was a minor increase in total clozapine metabolites, which was even less with dose correction. Fluoxetine increased all clozapine analytes, in some cases to twice the levels in the subjects given only clozapine.

Topics: Adult; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluoxetine; Humans; Male; Psychotic Disorders; Schizophrenia; Stimulation, Chemical; Valproic Acid

Topics: Antipsychotic Agents; Clozapine; Cognition; Humans; Schizophrenia

Clozapine (CLZ) demonstrates a unique clinical efficacy relative to other antipsychotic drugs. Previous work has linked the plasma ratio of CLZ and its major metabolite, N-desmethylclozapine (NDMC), to an inverse relationship with cognition via putative action on the cholinergic system. However, neuroimaging correlates of CLZ/NDMC remain unknown. Here, we examined changes in basal forebrain functional connectivity with the dorsolateral prefrontal cortex, and secondly, cognition in relation to the CLZ/NDMC ratio. A cohort of nineteen chronically ill participants with treatment-resistant schizophrenia (TRS) undergoing 12 weeks of CLZ treatment were included. Measures of cognition and plasma CLZ/NDMC ratios were obtained in addition to resting-state functional neuroimaging scans, captured at baseline and after 12 weeks of CLZ treatment. We observed a significant correlation between basal forebrain-DLPFC connectivity and CLZ/NDMC ratios across CLZ treatment (p = 0.02). Consistent with previous findings, we also demonstrate a positive relationship between CLZ/NDMC ratio and working memory (p = 0.03). These findings may reflect the action of CLZ and NDMC on the muscarinic cholinergic system, highlighting a possible neural correlate of cognition across treatment.

Topics: Antipsychotic Agents; Basal Forebrain; Cholinergic Agents; Clozapine; Dorsolateral Prefrontal Cortex; Humans; Schizophrenia; Schizophrenia, Treatment-Resistant

Clozapine (CLZ), the sole antipsychotic with superior efficacy for ultra-treatment resistant schizophrenia (TRS), is limited by adverse effects, including metabolic dysregulation. Clozapine's main metabolite, N-desmethylclozapine (NDMC), has potent 5-HT2C antagonist properties which may explain this metabolic dysfunction, thus the CLZ:NDMC ratio is of particular interest. High insulin resistance states could be associated with CYP1A2 induction and lower CLZ:NDMC ratios. Additionally, lower CLZ:NDMC ratios have been associated with better cognitive, but worse metabolic functioning. This study investigated associations between metabolic and cognitive parameters with the CLZ/NDMC ratio. Primary outcomes included relationships between the CLZ:NDMC ratio to the homeostatic model assessment for insulin resistance (HOMA-IR) and Brief Assessment of Cognition in Schizophrenia (BACS) composite z-scores. Secondary outcomes assessed relationships between CLZ:NDMC ratios to fasting insulin, BMI, weight, fasting glucose, and BACS digit sequencing z-scores. 38 patients who were overweight or obese with schizophrenia or schizoaffective disorder completed fasting bloodwork, anthropometric, psychopathological, and cognitive assessments. Multivariate regressions found a statistically significant inverse association between the CLZ/NDMC ratio and HOMA-IR (B = - 1.028, SE B = .473, β = - 0.348 p = 0.037), which may have been driven by fasting insulin levels (B = - 27.124, SE B = 12.081, β = - 0.351 p = 0.031). The CLZ/NDMC ratio may predict insulin resistance/metabolic comorbidity among patients with TRS receiving clozapine.

Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Cognition; Female; Humans; Insulin Resistance; Male; Middle Aged; Obesity; Obesity, Morbid; Psychotic Disorders; Schizophrenia; Young Adult

Clozapine is the drug of choice for treatment-resistant schizophrenia. The primary objective of this study was to compare plasma clozapine and N-desmethylclozapine levels in patients switched between 2 liquid formulations [Denzapine suspension and clozapine oral solution (St George's ZTAS)]. Secondary objectives included comparison of safety, tolerability, and patient acceptability.. This was a noninterventional, observational, prospective follow-up of patients consecutively switched between formulations of clozapine liquid in a large inner-city NHS mental health trust. The authors also performed retrospective analysis of outcomes from patient case notes.. The authors identified 43 patients receiving Denzapine suspension in the trust. Data were available for 43 patients switched from Denzapine to clozapine oral solution (St George's ZTAS), among whom, 15 (32%) were excluded from the analysis. Of the 28 patients for whom data were available, the 90% confidence interval for the ratio of mean values for corrected Cmin 91.5 (85.2%-98.4%) and uncorrected Cmin 91.2 (84.4%-98.6%) were within the guideline range of bioequivalence (80%-125%). Safety and tolerability profiles were comparable between the 2 formulations (P = 0.10). Patient acceptability was also similar between the brands in most domains. However, there was a taste preference for Denzapine suspension.. No significant difference in clozapine plasma levels was observed after switching from Denzapine suspension to a recently introduced clozapine solution. This study also highlights the significance of medicinal characteristics such as taste for patient acceptability and compliance.

Topics: Antipsychotic Agents; Clozapine; Drug Monitoring; Female; Humans; Male; Prospective Studies; Schizophrenia; Therapeutic Equivalency

Clozapine is one of the most effective drugs for resistant schizophrenia, but its severe metabolic and hematological side effects limit the use of clozapine. It has been reported that clozapine blood concentrations should be maintained between 350-600 ng/mL. Our aim was to develop a determination method for clozapine and its main metabolites norclozapine and clozapine-N-oxide, to perform validation studies and to investigate the change of various biochemical parameters in patients using clozapine.. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for clozapine measurement. Thus, blood samples were collected from 38 patients with schizophrenia and 32 healthy volunteers. Biochemical and hematological parameters were measured by Beckman-Coulter AU 5800 (Beckman Coulter, Brea, USA) and Beckman Coulter LH 780 analyzer (Beckman Coulter, Miami, FL, USA), respectively. Hormone levels were analyzed using Cobas 6000 analyzer (Roche Diagnostics, Germany).. The LCMS/MS method was linear between 1.22-2500 ng/mL (r. This LC-MS/MS method was rapid, simple, cost-effective and suitable for the routine clozapine monitoring. Furthermore, norclozapine and clozapine-N-oxide were also determined. Monitoring of metabolic and hematological parameters with clozapine levels is very important. However, the limitations of the study were that the method was not validated for norclozapine and clozapine-N-oxide, so the validation parameters were not evaluated for these two metabolites.

Topics: Adult; Antipsychotic Agents; Blood Cell Count; Blood Glucose; Case-Control Studies; Cholesterol; Chromatography, Liquid; Clozapine; Drug Monitoring; Hemoglobins; Humans; Limit of Detection; Reproducibility of Results; Schizophrenia; Tandem Mass Spectrometry; Triglycerides

Previous cross-sectional studies have found clozapine to N-desmethylclozapine (CLZ:NDMC) ratio to be negatively correlated with cognition in clozapine-treated patients with schizophrenia. However, no work has examined the association between CLZ:NDMC ratio and cognition using a within-subjects design. Here, we investigate the longitudinal effects of changes in the clozapine load and the CLZ:NDMC ratio on cognition whilst controlling for a range of independent factors. We analyzed data from a cohort of seventeen clozapine-treated patients who have been repeatedly assessed with the Brief Assessment of Cognition for Schizophrenia (BACS). The Positive symptoms sub-score of the Clinical Global Impression for Schizophrenia (CGI-P) was used to assess severity of psychosis. Blood samples were collected to measure the plasmatic levels of clozapine (CLZ) and of N-desmethylclozapine, allowing calculation of the CLZ:NDMC ratio. Our analyses included bivariate and partial correlations, along with a mediation model analysis. We found that both plasmatic levels of CLZ and the CLZ:NDMC ratio were negatively correlated with cognitive performance, and that these associations were independent of changes in both daily clozapine dose and severity of psychotic symptoms. Mediation analyses further revealed the association between CLZ concentration and cognition to be partially mediated by changes in the CLZ:NDMC ratio. This is the first longitudinal analysis of the influence of CLZ concentration and CLZ:NDMC ratio on cognition. Our findings suggest that reduction of CLZ concentration and the CLZ:NDMC ratio might favorably affect cognition. Thus, the CLZ:NDMC ratio may represent a promising target for novel therapeutic strategies aiming to ameliorate cognitive impairment in clozapine-treated patients.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition; Humans; Longitudinal Studies; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Studies that examined the effect of clozapine on cognitive functions in schizophrenia provided contradictory results. N-desmethylclozapine (NDMC) is the major metabolite of clozapine and have procognitive effects via agonistic activity in the M1 cholinergic receptors. The rs2067477 polymorphism in the M1 receptors may play role in cognitive profile in schizophrenia. We investigated the association of plasma clozapine (PClz), NDMC (PNdmc) levels and the rs2067477 polymorphism with cognitive functions and cortical activity measured by functional near infrared spectroscopy during the N-Back task in subjects with schizophrenia (N = 50) who are under antipsychotic monotherapy with clozapine. We found that PClz and PNdmc levels were negatively, PNdmc/PClz ratio was positively correlated with immediate recall score in the Rey Auditory Verbal Learning Test. PNdmc/PClz ratio was positively correlated with cortical activity during the N-back task. M1 wild-type group (CC: wild-type) produced higher cortical activity than M1 non wild-type group (CA: heterozygote / AA: mutant) in cortical regions associated with working memory (WM). These results suggest that individual differences in clozapine's effect on short term episodic memory may be associated with PClz and PNdmc. Higher activity in the M1 wild-type group may indicate inefficient use of cortical resources and/or excessive use of certain cognitive strategies during WM performance.

Topics: Adult; Antipsychotic Agents; Cerebral Cortex; Clozapine; Cognition; Female; Humans; Male; Memory, Short-Term; Middle Aged; Polymorphism, Single Nucleotide; Receptor, Muscarinic M1; Schizophrenia; Spectroscopy, Near-Infrared

The aim of present study is to measure plasma clozapine (CLZ) and N-desmethyl clozapine (DMC) as biomarkers to correlate drug concentrations with the appearance of preclinical adverse hematic effects.. A high-performance liquid chromatographic method, using a diode-array (ultraviolet) detector, was validated to obtain reliable concentrations of CLZ and DMC, its main metabolite, in plasma of 41 schizophrenic patients taking CLZ. Blood neutrophils and leucocytes counting were concurrently assessed as a proxy to subclinical adverse reactions.. The analytical method employed was linear, reproducible, and stable to measure concentrations of CLZ between 30 and 1000 ng/mL, while 12.5-560 ng/mL of the metabolite. The method allowed us to correlate CLZ plasma concentrations, the time taking CLZ and CLZ dose as determinants of neutrophils' counting with a R. The findings of this study, demonstrate for the first time, that plasma levels of CLZ and time taking the drug are independent determinants of blood neutrophils and leucocytes, so the monitoring of plasma CLZ may be useful in the clinic practice to determine safe dosing of the drug.

Topics: Adult; Antipsychotic Agents; Chromatography, High Pressure Liquid; Clozapine; Female; Humans; Leukocytes; Male; Mexico; Middle Aged; Neutrophils; Schizophrenia; Young Adult

Clozapine is the only effective medication for treatment-resistant schizophrenia, but its worldwide use is still limited because of its complex titration protocols. While the discovery of pharmacogenomic variants of clozapine metabolism may improve clinical management, no robust findings have yet been reported. This study is the first to adopt the framework of genome-wide association studies (GWASs) to discover genetic markers of clozapine plasma concentrations in a large sample of patients with treatment-resistant schizophrenia.. The authors used mixed-model regression to combine data from multiple assays of clozapine metabolite plasma concentrations from a clozapine monitoring service and carried out a genome-wide analysis of clozapine, norclozapine, and their ratio on 10,353 assays from 2,989 individuals. These analyses were adjusted for demographic factors known to influence clozapine metabolism, although it was not possible to adjust for all potential mediators given the available data. GWAS results were used to pinpoint specific enzymes and metabolic pathways and compounds that might interact with clozapine pharmacokinetics.. The authors identified four distinct genome-wide significant loci that harbor common variants affecting the metabolism of clozapine or its metabolites. Detailed examination pointed to coding and regulatory variants at several CYP* and UGT* genes as well as corroborative evidence for interactions between the metabolism of clozapine, coffee, and tobacco. Individual effects of single single-nucleotide polymorphisms (SNPs) fine-mapped from these loci were large, such as the minor allele of rs2472297, which was associated with a reduction in clozapine concentrations roughly equivalent to a decrease of 50 mg/day in clozapine dosage. On their own, these single SNPs explained from 1.15% to 9.48% of the variance in the plasma concentration data.. Common genetic variants with large effects on clozapine metabolism exist and can be found via genome-wide approaches. Their identification opens the way for clinical studies assessing the use of pharmacogenomics in the clinical management of patients with treatment-resistant schizophrenia.

Topics: Adult; Antipsychotic Agents; Clozapine; Coffee; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1A2; Drug Interactions; Female; Genome-Wide Association Study; Glucuronosyltransferase; Humans; Male; Nicotiana; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Schizophrenia

Topics: Adult; Antipsychotic Agents; Clozapine; Humans; Male; Schizophrenia; Weight Gain

Clozapine (CZ) is the most effective drug for managing treatment-resistant schizophrenic disorders. Its use has been limited due to adverse effects, which include weight gain and new-onset diabetes, but the incidence of these varies between patients.. We investigated 187 Clozapine Clinic patients (of whom 137 consented for genotyping) for the presence of CYP2C19*17 and its association with CZ and norclozapine (NCZ) levels, and clinical outcomes.. Thirty-nine percent of genotyped patients were carriers of the CYP2C 19*17 polymorphism. This group demonstrated significantly higher NCZ serum levels, and significantly lower fasting glucose (5.66 ± 1.19 vs 6.72 ± 3.01 mmol/l, P = 0.009) and Hb1Ac (35.36 ± 4.78 vs 49.40 ± 20.60 mmol/mol, P = 0.006) levels compared to non-carriers of this polymorphism. CZ-treated patients with CYP2C19*17/*17 had a significantly lower prevalence of diabetes as well as a higher likelihood of clinical improvement of their schizophrenia, compared to those without this polymorphism (P = 0.012 and P = 0.031, respectively).. Our data suggest that CYP2C19*17 ultra-rapid-metaboliser status is a protective factor against the development of diabetes during clozapine treatment, and increases the likelihood of improvement in schizophrenia. The role of NCZ in treatment response and side effects, including metabolic syndrome, warrants further pharmacogenetic, pharmacokinetic and pharmacodynamic studies.

Topics: Adult; Antipsychotic Agents; Clozapine; Cytochrome P-450 CYP2C19; Diabetes Mellitus; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Protective Factors; Schizophrenia

Cognitive symptoms play a central role in schizophrenia and are strongly associated with social functioning. Treatment with clozapine presents controversial results regarding its effects on cognition. The opposite effects of clozapine and n-desmethylclozapine (NDMC) on cholinergic system have been suggested to underlie these inconclusive findings. The aim of this study is to determine whether clozapine/NDMC ratio can predict cognitive performance in patients with treatment-resistant psychosis. Nineteen clinically stable patients with schizophrenia or schizoaffective disorder treated with clozapine monotherapy completed demographic and clinical interviews. For the purpose of the study, patients were assessed with a neuropsychological battery and on the same day a blood sampling was obtained from each patient to measure plasma levels of clozapine and NDMC. Our results showed that clozapine/NDMC ratio, but not clozapine or NDMC plasma levels separately, was a predictive factor of cognitive performance, specifically of executive functioning. Our results showed that lower clozapine/NDMC ratios are associated with better executive functioning in clinically stable patients. These findings could be interpreted by the different pharmacodynamic properties on cholinergic, dopaminergic and serotonergic systems of NDMC compared to clozapine.

Topics: Adult; Aged; Antipsychotic Agents; Choline; Clozapine; Cognition; Cross-Sectional Studies; Dopamine; Female; Humans; Male; Middle Aged; Prognosis; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Serotonin

Clozapine is associated with subjectively unpleasant or clinically serious side-effects, which may affect treatment adherence. The aims of the study were to explore the association of clozapine+ norclozapine serum concentration and other factors with subjective side-effects in schizophrenia patients.. In this cross-sectional study, 237 patients with a diagnosis of schizophrenia, schizo-affective or other non-organic psychoses completed the Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS), a self-report scale measuring side-effects of antipsychotics and a clinical questionnaire. Clozapine+ norclozapine serum concentration of 190 patients was measured. Of the patients 80 (33.7%) were on antipsychotic combination therapy.. Higher clozapine+ norclozapine concentrations were associated with the depression-anxiety factor of LUNSERS and antipsychotic combination treatments were associated with sympatichotonia-tension factor. Younger patients reported sedation more often than older patients.. According to the present results, high clozapine concentrations were associated with depression-anxiety symptoms, but the causality remains unknown.

Topics: Adult; Aged; Antipsychotic Agents; Anxiety; Causality; Clozapine; Cross-Sectional Studies; Depression; Female; Humans; Male; Medication Adherence; Middle Aged; Psychotic Disorders; Risk Factors; Schizophrenia; Self Report; Sleep Stages; Surveys and Questionnaires; Young Adult

Clozapine's potent antagonism of muscarinic M1 receptors is thought to worsen working memory deficits associated with schizophrenia. In contrast, its major metabolite, N-desmethylclozapine (NDMC), is thought to enhance working memory via its M1 receptor agonist activity. The authors hypothesized that the ratio of serum clozapine and NDMC concentrations would be inversely associated with working memory performance in schizophrenia.. Thirty patients with schizophrenia or schizoaffective disorder who were receiving clozapine monotherapy at bedtime completed the MATRICS Consensus Cognitive Battery (MCCB) on the day their blood was collected to assess concentrations of clozapine and NDMC as well as serum anticholinergic activity.. The clozapine/NDMC ratio was significantly and negatively associated with working memory performance after controlling for age, gender, education, and symptom severity. No significant associations were found between individual clozapine and NDMC concentrations and working memory performance. Serum anticholinergic activity was significantly associated with clozapine concentration, but not with working memory performance or NDMC concentration. No significant associations were found between any pharmacological measure and performance on other MCCB cognitive domains.. This hypothesis-driven study confirms that clozapine/NDMC ratio is a strong predictor of working memory performance in patients with schizophrenia. This finding suggests that manipulating the clozapine/NDMC ratio could enhance cognition in patients with schizophrenia treated with clozapine. It also supports the study of procholinergic agents, such as M1 receptor-positive allosteric modulators, to enhance cognition in schizophrenia.

Topics: Adult; Aged; Clozapine; Female; Humans; Male; Memory, Short-Term; Middle Aged; Neuropsychological Tests; Psychometrics; Psychotic Disorders; Schizophrenia; Treatment Outcome; Young Adult

Although clozapine is the only antipsychotic agent to have demonstrated superior efficacy in treatment-refractory schizophrenia, one- to two-thirds of patients do not respond adequately despite acceptable dosages and plasma levels. Moreover, a significant number of patients stop the therapy for various reasons, including its side effects, many of which are thought to be related to its active metabolite, norclozapine. However, combining clozapine with the SSRI antidepressant fluvoxamine decreases norclozapine formation by inhibiting the CYP450 1A2 isoenzyme. Lowering norclozapine levels in this way while maintaining therapeutic clozapine levels increases the clozapine: norclozapine ratio; the potential benefits include both a reduction of such side effects as sedation, weight gain, metabolic disturbances, and neutropenia, and an increase in efficacy. The optimal ratio of clozapine to norclozapine has not yet been defined, but a ratio of two or more implies that saturation of clozapine metabolism has been reached. We hypothesize that co-administration of clozapine and fluvoxamine at dosages that will produce therapeutic plasma levels of clozapine and a clozapine: norclozapine ratio of two or more will increase efficacy and tolerability of clozapine therapy in treatment-resistant schizophrenic patients.

Topics: Clozapine; Cytochrome P-450 CYP1A2 Inhibitors; Drug Combinations; Fluvoxamine; Humans; Schizophrenia

Clozapine is used in children and adolescents to treat early onset schizophrenia, but data on efficacy and on the plasma clozapine concentrations attained are limited.. We studied data from a clozapine therapeutic drug monitoring (TDM) service, patients in the UK and Eire aged <18 years, 1994-2010. Multiple linear regression analysis was performed to investigate the relationship between plasma clozapine concentration and dose, age, sex, body weight, plasma clozapine:norclozapine ratio (clozapine metabolic ratio (MR)) and smoking habit.. There were 1408 samples from 454 patients, 267 (59%) males aged at time of first sample (median = 17; range = 8-17 years) and 187 (41%) females aged 16 (10-17) years. The plasma clozapine concentration was <0.35 mg L(-1) in 36%, and ≥0.60 mg L(-1) in 31% of samples (6.4% samples ≥1.0 mg L(-1) ). Although plasma clozapine was broadly related to prescribed dose, there was much variation: 10% of samples had plasma clozapine >0.60 mg L(-1) at prescribed clozapine doses of 50-150 mg d(-1) (66% <0.35 mg L(-1) ), while 12% of samples had plasma clozapine <0.35 mg L(-1) at doses ≥650 mg d(-1) (62% >0.6 mg L(-1) ). The covariates studied in the 16-17-year-olds had proportionately similar influences to those observed in adults. Together they explained 48% of the variance observed in plasma clozapine, with dose, smoking habit, MR and sex being major influences. In the younger patients, there were very few smokers, and the influence of sex did not reach statistical significance.. As in adults, clozapine TDM may help in assessing adherence and in dose adjustment, for example if smoking habit changes.

Topics: Adolescent; Age Factors; Antipsychotic Agents; Body Weight; Child; Clozapine; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Male; Schizophrenia; Sex Characteristics; Smoking

Although clozapine is primarily used in a younger to mid-life population of patients with psychosis, there are limited data on the clinical pharmacology of clozapine later in life. The objective of this study was to assess the magnitude and variability of plasma concentrations of clozapine and norclozapine across the lifespan in a real-world clinical setting.. A population pharmacokinetic study using nonlinear mixed effect modeling (NONMEM). Age, sex, height, weight, and dosage formulation were covariates.. Inpatients and outpatients at the Centre for Addiction and Mental Health, Toronto, from 2001 to 2007.. Patients ranging in ages from 11 to 79 with schizophrenia spectrum disorders and prescribed clozapine (Clozaril).. A total of 1142 plasma clozapine and norclozapine concentrations (2,284 concentration measurements) from 391 patients with schizophrenia spectrum disorder.. A one-compartment model with first-order absorption and elimination best described the data. The population predicted clearance of clozapine for females was 27.1 L/h (SE 11.1%) and 36.7 L/h (SE 9.7%) for males. For norclozapine, clearance in females was 48.6 L/h (SE 10.8%) and 63.1 L/h (SE 9.3%) in males. The only covariates with a significant effect on clearance were age and sex: clearance for both parent and metabolite decreased exponentially with age at least 39 years.. Decreased clearance of clozapine and norclozapine with age results in increased blood concentrations and, hence, the potential for adverse drug reactions. These findings have particular clinical relevance for the dosing and safety monitoring of clozapine in older adults, highlighting a need for increased vigilance.

Topics: Adolescent; Adult; Age Factors; Aged; Antipsychotic Agents; Child; Clozapine; Female; Humans; Inpatients; Male; Middle Aged; Models, Statistical; Outpatients; Schizophrenia; Sex Factors

Clozapine (CLZ) is an FDA approved second-generation antipsychotic for refractory schizophrenia, and glucuronidation is an important pathway in its metabolism. The aim of this study was to fully characterize the CLZ glucuronidation pathway and examine whether polymorphisms in active glucuronidating enzymes could contribute to variability in CLZ metabolism.. Cell lines overexpressing wild-type or variant uridine diphosphate-glucuronosyltransferase (UGT) enzymes were used to determine which UGTs show activity against CLZ and its major active metabolite N-desmethylclozapine (dmCLZ). Human liver microsomes (HLM) were used to compare hepatic glucuronidation activity against the UGT genotype.. Several UGTs including 1A1 and 1A4 were active against CLZ; only UGT1A4 showed activity against dmCLZ. UGT1A1 showed a 2.1-fold (P <0.0001) higher V(max)/K(M) for formation of the CLZ-N⁺-glucuronide than UGT1A4; UGT1A4 was the only UGT for which CLZ-5-N-glucuronide kinetics could be determined. The UGT1A4(24Pro/48Val) variant showed a 5.2-, 2.0-, and 3.4-fold (P < 0.0001 for all) higher V(max)/K(M) for the formation of CLZ-5-N-glucuronide, CLZ-N⁺-glucuronide, and dmCLZ-5-N-glucuronide, respectively, as compared with that of wild-type UGT1A4(24Pro/48Leu). There was a 37% (P< 0.05) decrease in the rate of CLZ-N⁺-glucuronide formation in HLM with the UGT1A1 (*28/*28)/UGT1A4 (*1/*1) genotype, and a 2.2- and 1.8-fold (P < 0.05 for both) increase in the formation of CLZ-5-N-glucuronide and CLZ-N⁺-glucuronide in UGT1A1 (*1/*1)/UGT1A4 (*3/*3) HLM compared with UGT1A1 (*1/*1)/UGT1A4 (*1/*1) HLM. The UGT1A1*28 allele was a significant (P = 0.045) predictor of CLZ-N⁺-glucuronide formation; the UGT1A4*3 allele was a significant (P < 0.0001) predictor of CLZ-5-N-glucuronide and dmCLZ-glucuronide formation.. These data suggest that the UGT1A1*28 and UGT1A4*3 alleles contribute significantly to the interindividual variability in CLZ and dmCLZ metabolism.

Topics: Alleles; Antipsychotic Agents; Cell Line; Clozapine; Genotype; Glucuronides; Glucuronosyltransferase; Humans; Kinetics; Microsomes, Liver; Polymorphism, Genetic; Schizophrenia

The aim of the present study was to determine the prescribing practice for clozapine (CAS 5786-21-0) as well as the plasma levels of clozapine and its main metabolite norclozapine (CAS 6104-71-8) in Mexican patients. A prospective study was performed in 69 in and out psychotic patients taking clozapine. Blood samples were taken at steady state. Plasma concentrations of clozapine and norclozapine were determined by HPLC. The results showed that the mean daily dose administered was 250 mg/d. Plasma levels showed a large interindividual variability. Mean plasma levels were 411.3 +/- 328.12 ng/mL, for clozapine and 172.0 +/- 129.9 ng/mL for norclozapine. When data were compared with those reported in other populations, it was found that although the dose was lower than that reported in Caucasians, the plasma levels were similar. As a result, the predictive models for the estimation of clozapine concentration in Caucasians were not appropriate for application in Mexican patients. The findings suggest ethnic differences in the ratio dose/plasma levels of clozapine in Mexican patients. Further studies are required to expand the observations.

Topics: Adult; Aged; Antipsychotic Agents; Chromatography, High Pressure Liquid; Clozapine; Drug Monitoring; Ethnicity; Female; Humans; Male; Mexico; Middle Aged; Prospective Studies; Schizophrenia

Topics: Adult; Antipsychotic Agents; Biotransformation; Chemical and Drug Induced Liver Injury; Clozapine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Isoxazoles; Liver Function Tests; Paliperidone Palmitate; Pyrimidines; Reference Values; Risperidone; Schizophrenia

Clozapine (CLZ) has been shown to have a beneficial effect on cognition in schizophrenia in some studies and a detrimental effect in others. The relative effect and exposure to CLZ and its major metabolite-N-desmethylclozapine (NDMC)-could explain these discrepancies.. Using a validated measure of global cognition, we performed 2 binary logistic regression models to assess the relationship among cognition, age, sex, CLZ dose, CLZ and NDMC plasma levels, and their ratio (CLZ/NDMC) in individuals with schizophrenia spectrum disorders. Model 1 included age, sex, CLZ dose, and CLZ and NDMC levels. Model 2 included age, sex, CLZ dose, and CLZ/NDMC.. Among 73 subjects (mean [SD] age, 41.6 [12.0] years), 16 (21.9%) had high cognitive impairment, whereas the rest had low cognitive. In model 1, age and CLZ level were associated with high cognitive impairment (odds ratio [95% confidence interval] for age, 1.079 [1.011-1.152]; CLZ level, 1.010 [1.003-1.017]), whereas NDMC level was associated with its absence (NDMC level, 0.987 [0.977-0.997]). In model 2, age, male sex, and CLZ/NDMC were associated with cognitive impairment (age, 1.083 [1.015-1.154]; sex, 0.178 [0.032-0.994]; CLZ/NDMC, 7.302 [1.823-29.253]). Clozapine dose was not associated with cognition in either model.. After controlling for age, sex, and dose, CLZ/NDMC was more strongly associated with cognition than CLZ or NDMC levels. N-desmethylclozapine agonist activity versus CLZ antagonist activity at the muscarinic receptors could explain the strength of the association of CLZ/NDMC with cognition.

Topics: Adult; Antipsychotic Agents; Clozapine; Cognition Disorders; Cross-Sectional Studies; Databases, Factual; Dose-Response Relationship, Drug; Female; Humans; Logistic Models; Male; Middle Aged; Receptors, Muscarinic; Retrospective Studies; Schizophrenia; Severity of Illness Index

Patients may fail to respond to clozapine treatment despite use of the maximum licensed UK dosage (900 mg/day) because of ultra-rapid metabolism of the drug. We present the findings of a study of a national clozapine/norclozapine assay service for the period 1997-2005 and three individual case studies of patients treated with clozapine in doses greater than 900 mg/day. Clinicians should be alert to the possibility of treatment failure because of rapid clozapine clearance secondary to genetic factors and heavy cigarette consumption. This may necessitate the use of clozapine in doses up to 1400 mg/day, notably in young male smokers. Doses of greater than 900 mg/day are rarely justified in women. Anyone given relatively high-dose clozapine (600 mg/day or more) should be monitored regularly for adverse events and changes in smoking habit.

Topics: Adult; Antipsychotic Agents; Clozapine; Cytochrome P-450 Enzyme System; Drug Administration Schedule; Drug Interactions; Humans; Male; Schizophrenia; Sex Factors; Smoking

There is a wide interethnic variance in the pharmacokinetic profile of clozapine (CLZ), but the accumulated data are limited to some regional populations. In this study, we investigated the pharmacokinetic profile of CLZ in Korean patients and examined the association between serum CLZ parameters and clinical outcome. We assessed 78 Korean patients with schizophrenia who had been taking CLZ medication for more than 6 months. The patients were classified into three groups (good, moderate, and poor responders) according to their Clinical Global Impressions-Improvement scores. The serum concentrations of CLZ and norclozapine were 610.7+/-368.4 and 314.5+/-163.0 ng/ml (mean+/-SD), respectively, showing a large interindividual variation that was affected by dose, age, smoking habits, and sex by variable degrees. The pharmacokinetic profiles of Koreans were similar to those observed in Asians but quite different from those in Caucasians. Investigation on clinical responses revealed that the good or moderate responders clinically improved at a relatively low serum CLZ levels, whereas the poor responders showed less improvement despite the higher doses and serum levels. The metabolic ratio of the good responders was 0.65+/-0.20, higher than the poor responders (P=0.033). In this study, we identified a pharmacokinetic profile of CLZ in Korean schizophrenia patients and found a wide interindividual difference affected by various factors.

Topics: Adult; Aging; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Female; Humans; Korea; Male; Psychiatric Status Rating Scales; Regression Analysis; Retrospective Studies; Schizophrenia; Schizophrenic Psychology; Smoking; Treatment Outcome

A rapid, sensitive, and specific method was developed and validated using ultra-performance liquid chromatography- tandem mass spectrometry (UPLC-MS-MS) for simultaneous determination of clozapine and its major metabolite norclozapine in human serum. The compounds were extracted from serum by a single step protein precipitation and analyzed using a UPLC-triple-quadrupole detection (TQD) system. Separation of compounds was achieved on a BEH C18 (50 mm x 2.1 mm, 1.7 microm) analytical column using methanol and water (both containing 0.2% ammonium hydroxide) as the mobile phase at a flow rate of 0.40 mL/min. The compounds were ionized in the electrospray ionization ion source of the TQD and were detected in the multiple reaction monitoring (MRM) mode. The MRM transitions m/z 327 --> 270 and m/z 313 --> 192 for clozapine and norclozapine, respectively, were used for the quantification ions. Clozapine transition 327 --> 192 and norclozapine transition 313 --> 270 were used as confirmation ions. Linear calibration curves in human serum were generated over the range of 10-2000 ng/mL for both clozapine and norclozapine with a correlation coefficient (r(2)) > 0.9970. Calibration curves exhibited consistent linearity and reproducibility. Interassay coefficients of variation (CV) (n = 20) were 3.04-4.94% for clozapine and 2.84-6.07% for norclozapine. Intra-assay CVs (n = 6, 20 days) were 0.61-1.26% and 1.62-2.21% for clozapine and norclozapine, respectively. The extraction recoveries were larger than 95% for both clozapine and norclozapine. The method was applied to the quantification of clozapine and norclozapine in the sera of schizophrenic patients, and the data revealed that the concentrations of two compounds varied significantly in the patients treated with clozapine.

Topics: Antipsychotic Agents; Biotransformation; Calibration; Chromatography, Liquid; Clozapine; Drug Monitoring; Drug Stability; Humans; Reproducibility of Results; Schizophrenia; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Temperature; Time Factors

Clozapine is indicated for the treatment of schizophrenia and related psychotic disorders. Several methods have been developed for monitoring Clozapine levels; however, they possess limited specificity and are often laborious. This study describes a simple liquid chromatography/tandem mass spectrometer (LCMS) method in human serum. The ion transitions monitored were m/z 327, 270, 296 for Clozapine, m/z 313, 192, 227 for Norclozapine and m/z 328, 271 for Loxapine. The assay is linear (25-1000 ng/ml) and showed a good correlation (r=0.98) within the analytical range of 79-1210 ng/ml in human serum. This assay is highly specific and sensitive for the simultaneous measurements of Clozapine and Norclozapine. The simplification of this assay makes it ideal for high throughput analyses of the patient samples in a routine clinical laboratory staffed with general medical technologists.

Topics: Chromatography, High Pressure Liquid; Chromatography, Liquid; Clozapine; Humans; Loxapine; Schizophrenia; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

At present, the determination of steady-state trough serum/plasma concentrations of clozapine is considered a useful tool for the clinical management of schizophrenic patients treated with this drug. In a previously published study, it was indicated that only plasma should be used to avoid a significant underestimation of clozapine and norclozapine concentrations; however, a formal evaluation of this topic has still not been made, and a consensus on the use of plasma or serum for therapeutic clozapine monitoring may be desirable. Paired samples of serum and plasma (K3EDTA solution contained in Vacutainer tubes) were obtained from 40 schizophrenic patients, and clozapine and norclozapine concentrations were determined by high-performance liquid chromatography. For the parent drug and its metabolite, serum concentrations were higher than in plasma (approximately 7%), although the correction of plasma concentrations in function of hematocrit values reduced this difference to 3%. High correlation coefficients were found between the serum and uncorrected or corrected plasma clozapine concentrations (r = 0.996, P < 0.001), with clinically acceptable differences between the means and standard error of the estimate and consequently with transferability of the results. The clozapine and norclozapine concentrations in five lithium heparin-containing plasma samples (371.9 +/- 226.7 ng/mL and 217.9 +/- 113.1 ng/mL) were analogous to the corresponding hematocrit-corrected EDTA-containing plasma values (374.4 +/- 225.4 ng/mL and 223.5 +/- 115.2 ng/mL), with correlation coefficients of r > or = 0.998 (P < 0.001). Serum or plasma samples may be used for the therapeutic monitoring of clozapine, and no practical advantages have been found with regard to the stability of the drug or imprecision obtained by using either type of biological matrix.

Topics: Antipsychotic Agents; Chromatography, High Pressure Liquid; Clozapine; Humans; Plasma; Schizophrenia; Serum

To study the relationship between age, gender, cigarette smoking and plasma concentrations of clozapine (CLZ) and its metabolite, norclozapine (NCLZ) in Chinese patients with schizophrenia.. Data from a therapeutic drug monitoring programme were analysed retrospectively. One hundred and ninety-three Chinese inpatients with schizophrenia were assessed using clinical data forms. Steady-state plasma concentrations of CLZ and NCLZ were assayed using high-performance liquid chromatography. Comparisons of dosage and plasma CLZ concentrations were undertaken between males (n = 116) and females (n = 77), younger (40 years, n = 111) and current male smokers (n = 50) and nonsmokers (n = 66).. (i) Plasma CLZ concentrations demonstrated large interindividual variability, up to eightfold at a given dose; (ii) there were significant effects of gender on plasma CLZ concentrations (relative to dose per kg of body weight) with female patients having significantly higher concentrations than males (30.09 +/- 24.86 vs. 19.87 +/- 3.55 ng ml(-1) mg(-1) day(-1) kg(-1); P < 0.001); (iii) there were no significant differences in plasma CLZ concentrations between those patients 40 years; and (iv) there were no significant differences in plasma CLZ concentrations between male smokers and nonsmokers, despite the CLZ dosage for smokers being significantly higher.. Plasma CLZ concentrations vary up to eightfold in Chinese patients. Among the patient-related factors investigated, only gender was significant in affecting CLZ concentrations in Chinese patients with schizophrenia, with female patients having higher levels.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antipsychotic Agents; Asian People; Clozapine; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Retrospective Studies; Schizophrenia; Sex Factors; Smoking

Clozapine is associated with non-neurological side effects that can be subjectively unpleasant and/or clinically serious. We sought to: (i) assess the nature and prevalence of side effects experienced by patients receiving maintenance treatment with clozapine and (ii) explore the relationship between clozapine plasma concentration and side effect burden. Patients were receiving clozapine maintenance treatment. Open questioning followed by systematic enquiry using the Antipsychotic Non-neurological Side Effects Rating Scale were used to assess side effects. Trough plasma clozapine and norclozapine concentrations were measured. One hundred and three patients participated. On open questioning, 61 patients reported a total of 117 side effects, whereas systematic enquiry identified an additional 649 side effects, with each patient reporting at least one. Clozapine plasma concentrations were significantly but weakly correlated with total Antipsychotic Non-neurological Side Effects Rating Scale score (Pearson correlation=0.29, P<0.004). Patients with a plasma clozapine concentration >0.25 mg/l were significantly more likely to have moderate/severe side effects than patients with lower plasma concentrations (63/76 vs. 12/23, chi=9.07, d.f.=1, P<0.01). The side-effect burden associated with maintenance clozapine treatment is high and the true extent can only be ascertained by systematic inquiry. The use of target plasma concentrations below those used for acute treatment should be explored as a strategy for minimizing side effects.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clozapine; Disorders of Excessive Somnolence; Female; Humans; Male; Middle Aged; Prevalence; Psychotic Disorders; Schizophrenia; Sexual Dysfunction, Physiological; Sialorrhea

The report presents a fatal poisoning of a neonate occurring in the final stage of gestational life and evoked by his mother, who, while 9 months pregnant, took a toxic dose of clozapine aiming at committing suicide. She was also severely poisoned, but ultimately was saved. The woman had been taking the medication due to schizophrenia and depression prior to conception, and the discontinuation of the drug in the course of pregnancy increased the risk of the woman attempting suicide. In the course of comprehensive toxicological analysis based on the developed analytical procedure with the use of LC-APCI-MS, clozapine and its two metabolites, norclozapine and clozapine-N-oxide, were determined in postmortem blood, liver and kidney in concentrations explaining the death of the neonate. The interpretation of the above-described case is complex and--apart from toxicological aspects--also involves issues associated with psychiatry, pharmacotherapy in pregnancy and medicolegal problems.

Topics: Adult; Antipsychotic Agents; Clozapine; Depression; Fatal Outcome; Female; Humans; Infant, Newborn; Kidney; Liver; Male; Pregnancy; Prenatal Exposure Delayed Effects; Schizophrenia; Suicide, Attempted

Clozapine-induced obsessive/compulsive symptoms (OCS) have been reported by many authors. This study investigated the incidence of these side effects, together with the relation between these side effects and the plasma concentration (Cps) of clozapine and its metabolites norclozapine and clozapine-N-oxide in schizophrenic patients. One hundred and two schizophrenic patients treated with clozapine were interviewed and screened with questionnaires testing for OCS during a 1-year study period. Cps of clozapine and the metabolites were monitored using reversed-phase high-performance liquid chromatography with ultraviolet detection. Thirty-nine patients (38.2%) presented with OCS, and, of these, 29 patients (28.4%) were classified as clozapine-induced, with an average latent period of 39.8+/-22.5 months. The Cps of clozapine and norclozapine were significantly higher in patients with OCS than in those without (595.1+/-364.9 vs. 433.5+/-252.8 ng/mL, P=0.001 and 266.4+/-144.4 vs. 203.1+/-119.8 ng/mL) OCS. Clozapine-induced OCS were not uncommon side effects. The authors suggest that the emergence of these side effects may be related to higher Cps of clozapine and clinicians should routinely check for and manage these side effects.

Topics: Adult; Antipsychotic Agents; Clozapine; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Male; Obsessive-Compulsive Disorder; Schizophrenia

To determine the relation between serum clozapine and nor-clozapine levels and blood cell counts during clozapine treatment.. We undertook a prospective longitudinal study of 37 consecutive patients with a diagnosis of schizophrenia treated with clozapine. We obtained informed consent and then determined serum concentrations of clozapine and nor-clozapine weekly. Clozapine was administered daily in divided doses given every 12 hours and adjusted according to clinical guidelines for its use. Samples for serum concentrations were taken at steady state, immediately before the next morning's dose, for 4 to 8 weeks. Complete blood counts (CBC), weight, and vital signs (that is, blood pressure, pulse, and temperature) were also monitored weekly before the morning's dose of clozapine was administered.. Analyses of variance showed no significant changes over the 8-week treatment course in the observed mean white blood count (WBC), red blood count (RBC), neutrophils, and lymphocytes counts, or in the hemoglobin and hematocrit. Only a few weak correlations (r < 0.21) were found between these hematological parameters and the measures of serum clozapine and nor-clozapine.. The mechanism of clozapine-induced hematotoxicity at the therapeutic dosage range is probably not by direct toxicity of clozapine or nor-clozapine to the blood cells or their precursors. The formation of the cytotoxic nitrenium compound from clozapine by neutrophils may be necessary.

Topics: Adolescent; Adult; Blood Cell Count; Clozapine; Dose-Response Relationship, Drug; Erythrocyte Count; Female; Half-Life; Hematocrit; Hemoglobinometry; Humans; Inactivation, Metabolic; Leukocyte Count; Male; Middle Aged; Schizophrenia; Schizophrenic Psychology

A liquid chromatography tandem mass spectrometry (LC-MS-MS) assay method for the simultaneous determination of clozapine and its N-desmethyl (norclozapine) and N-oxide metabolites in human plasma is described. The compounds were extracted from plasma by a single step liquid-liquid extraction procedure and analyzed using a high performance liquid chromatography electrospray tandem mass spectrometer system. The compounds were eluted isocratically on a C-18 column, ionized using positive ion atmospheric pressure electrospray ionization method by a TurboIonspray source and analyzed using multiple reaction monitoring mode. The ion transitions monitored were m/z 327 --> m/z 270 for clozapine, m/z 313 --> m/z 192 for norclozapine, m/z 343 --> m/z 256 for clozapine-N-oxide and m/z 421--> m/z 201 for internal standard. The standard curves of clozapine, norclozapine and clozapine-N-oxide were linear over the range of 1 ng/ml to 1000 ng/ml when 0.5 ml of plasma was used for the analysis (r(2) >0.998). Three pooled plasma samples collected from patients who were treated with clozapine were used as long-term quality control samples to check the validity of spiked standard curve samples made at various times. The intra- and inter-assay variations for the spiked standard curve and quality control samples were less than 14%. These variations for the long-term patient quality control samples were less than 11%. The LC-MS-MS assay for simultaneous determination of clozapine, norclozapine and clozapine-N-oxide reported here is highly specific, sensitive, accurate and rapid. This method is currently being used for the plasma level monitoring of clozapine and its N-desmethyl and N-oxide metabolites in patients treated with clozapine. The plasma levels of clozapine, norclozapine and clozapine-N-oxide varied widely within and among patients. The data revealed that the norclozapine and clozapine N-oxide metabolites were present at about 58%+/-14% and 17%+/-6% of clozapine concentrations in plasma, respectively.

Topics: Antipsychotic Agents; Chromatography, Liquid; Clozapine; Drug Monitoring; Humans; Reproducibility of Results; Schizophrenia; Spectrometry, Mass, Electrospray Ionization

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.. 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).. 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.. 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.

Topics: Adult; Beverages; Citrus; Clozapine; Female; Food-Drug Interactions; Humans; Male; Middle Aged; Prospective Studies; Psychiatric Status Rating Scales; Schizophrenia

Monitoring plasma clozapine concentrations may play a useful role in the management of patients with schizophrenia, but information on the relationship between the plasma levels of the drug and response is still controversial.. The purpose of this study was to assess the relationship between plasma concentrations of clozapine and its weakly active metabolite norclozapine and clinical response in patients with schizophrenia resistant to conventional neuroleptics.. Forty-five patients, 35 males and ten females, aged 19-65 years, were given clozapine at a dosage up to 500 mg/day for 12 weeks. Steady-state plasma concentrations of clozapine and norclozapine were measured at week 12 by a specific HPLC assay. Psychopathological state was assessed at baseline and at week 12 by using the Brief Psychiatric Rating Scale, and patients were considered responders if they showed a greater than 20% reduction in total BPRS score compared with baseline and a final BPRS score of 35 or less.. Mean plasma clozapine concentrations were higher in responders (n=18) than in non-responders (n=27) (472+/-220 versus 328+/-128 ng/ml, P<0.01), whereas plasma norclozapine levels did not differ between the two groups (201+/-104 versus 156+/-64 ng/ml, NS). A significant positive correlation between plasma levels and percent decrease in total BPRS score was found for clozapine (r(s)=0.371, P<0.02), but not for norclozapine (r(s)=0.162, NS). A cutoff value at a clozapine concentration of about 350 ng/ml differentiated responders from non-responders with a sensitivity of 72% and a specificity of 70%. At a cutoff of 400 ng/ml, sensitivity was 67% and specificity 78%. The incidence of side effects was twice as high at clozapine concentrations above 350 ng/ml compared with lower concentrations (38% versus 17%).. These results suggest that plasma clozapine levels are correlated with clinical effects, although there is considerable variability in the response achieved at any given drug concentration. Because many patients respond well at plasma clozapine concentrations in a low range, aiming initially at plasma clozapine concentrations of 350 ng/ml or greater would require in some patients use of unrealistically high dosages and imply an excessive risk of side effects. Increasing dosage to achieve plasma levels above 350-400 ng/ml may be especially indicated in patients without side effects who failed to exhibit amelioration of psychopathology at standard dosages or at lower drug concentrations.

Topics: Adult; Aged; Antipsychotic Agents; Clinical Trials as Topic; Clozapine; Conscious Sedation; Constipation; Dizziness; Dose-Response Relationship, Drug; Drug Resistance; Female; Follow-Up Studies; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Sialorrhea; Tachycardia; Treatment Outcome; Weight Gain

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.. 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.. 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.. 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.

Topics: Adult; Age Factors; Body Weight; Chromatography, High Pressure Liquid; Clozapine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Linear Models; Male; Retrospective Studies; Schizophrenia; Sex Factors

Both clozapine (CLZ) and caffeine are CYP1A2 substrates. This study raises the hypothesis of whether caffeine withdrawal from the diet alters the metabolism and/or clinical status of patients receiving CLZ. Seven schizophrenic patients (six men and one woman) receiving monotherapy with CLZ at 271+/-102 mg/day (3.73+/-1.4 mg/kg) participated in the study. CLZ, norclozapine (NOR), and clozapine-N-oxide (NOX) were assayed in plasma by high-performance liquid chromatography at three different time points: A, with concomitant intake of caffeine from the diet; B, after caffeine withdrawal for 5 days; and C, after 2 weeks of rechallenge to habitual caffeine intake. The CYP1A2 activity was determined by means of a urinary caffeine test. After a caffeine-free diet for 5 days, CLZ concentrations relative to time point A decreased from 486 to 306 ng/mL (-47%) (p < 0.02), NOX levels decreased from 66 to 49 ng/mL (-31%) (p < 0.03), and the NOR/CLZ ratio significantly increased from 0.47 to 1.04 (185%) (p < 0.02). All parameters returned to initial figures at time point C. The NOR/CLZ ratio was significantly correlated to the CYP1A2 index (rs = 0.96, p < 0.0005). In conclusion, changes in the habitual caffeine intake alter the metabolism of CLZ in schizophrenic patients. Thus, patient intake of caffeine should be medically supervised, and the monitoring of CLZ and metabolite levels may be warranted. Furthermore, in those patients who receive therapy with CLZ, the NOR/CLZ ratio may provide an additional and valuable estimate of CYP1A2 activity.

Topics: Adult; Antipsychotic Agents; Biological Availability; Biotransformation; Caffeine; Chromatography, High Pressure Liquid; Clozapine; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP1A2 Inhibitors; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Male; Psychiatric Status Rating Scales; Schizophrenia; Substance Withdrawal Syndrome

Clozapine is a diabenzodiazepine derivative characterized by a high therapeutic index in schizophrenic patients resistant to traditional neuroleptic drugs, because of the rarity of any extrapyramidal side effects, and its particular hematologic toxicity. According to the international literature, clozapine-induced neutropenia occurs mainly during the first 4-6 months of treatment, and its incidence decreases considerably over time. This neutropenic effect is not dose-dependent and normally clears up after drug discontinuation, although it may evolve into agranulocytosis. The aim of this study is to evaluate the in vitro toxic effect of clozapine and N-desmethylclozapine on both committed and immature human hematopoietic progenitor cells.. Cytotoxic assays were performed in vitro on normal human bone marrow samples treated with clozapine or with its metabolite N-desmethylclozapine. The clonogenic potential after treatment with both compounds was assessed on low density mononuclear cells (LD-MNC), purified CD34+ cells, cytokine driven liquid cultures and long term culture initiating cell (LTC-IC).. Clozapine and N-desmethylclozapine had a dose-dependent inhibitory effect on in vitro growth of CFU-GM and BFU-E from normal bone marrow. The two drugs had toxic effects on purified CD34+ progenitor cells but no significant effect on LTI-IC.. Our data indicate a cytotoxic effect, which is more pronounced with N-desmethylclozapine and at high doses, on the committed progenitor cell compartment but not on primitive hematopoietic cells. Furthermore, our data show that clozapine and N-desmethylclozapine have a direct effect on treated cells and do not induce apoptotic death.

Topics: Antipsychotic Agents; Cells, Cultured; Clozapine; Colony-Forming Units Assay; Hematopoietic Stem Cells; Humans; Schizophrenia

The steady state plasma concentrations of clozapine and its two major metabolites, norclozapine and clozapine N-oxide, were compared in patients with schizophrenia treated with clozapine in combination with phenobarbital (n=7), and in control patients treated with clozapine alone (n=15). Patients were matched for sex, age, body weight, and antipsychotic dosage. Patients comedicated with phenobarbital had significantly lower plasma clozapine levels than those of the controls (232+/-104 versus 356+/-138 ng/ml; mean, SD, p < 0.05). Plasma norclozapine levels did not differ between the two groups (195+/-91 versus 172+/-61 ng/ml, NS), whereas clozapine N-oxide levels were significantly higher in the phenobarbital group (115+/-49 versus 53+/-31 ng/ml, p < 0.01). Norclozapine/clozapine and clozapine N-oxide/ clozapine ratios were also significantly higher (p < 0.001) in patients comedicated with phenobarbital. These findings suggest that phenobarbital stimulates the metabolism of clozapine, probably by inducing its N-oxidation and demethylation pathways.

Topics: Adult; Clozapine; Cytochrome P-450 Enzyme System; Drug Interactions; Enzyme Induction; Female; Humans; Male; Middle Aged; Phenobarbital; Schizophrenia

A high-performance liquid chromatographic method with UV detection has been developed for the analysis of clozapine and its active N-desmethylated metabolite (N-desmethylclozapine = DMC) in human plasma. A liquid/liquid procedure was used to extract clozapine and DMC from human plasma. The analysis was performed on a C8 Nucleosil column and the mobile phase comprised acetonitrile-water-Pic B5 diethylamine (63:37:25:0.04, v/v/v/v). The detection wavelength was 245 nm. The intra-assay and inter-assay precision was satisfactory within the concentration range 10-900 ng ml-1. The lower detection limit for clozapine and for DMC was 5 ng ml-1. The recovery and reproducibility values of this method were better or similar to those found by other authors. This method, which is simple, selective and avoids an evaporation step, can be used routinely for therapeutic drug monitoring.

Topics: Antipsychotic Agents; Chromatography, High Pressure Liquid; Clozapine; Drug Monitoring; Drug Stability; Humans; Schizophrenia

The selective serotonin reuptake inhibitor (SSRI) fluoxetine can increase serum levels of clozapine and norclozapine, but effects of other SSRIs are unknown. Thus, the authors evaluated interactions of clozapine with fluoxetine, paroxetine, and sertraline.. Serum clozapine and norclozapine concentrations were assayed in 80 psychiatric patients, matched for age and clozapine dose, given clozapine (mean dose = 279 mg/day) alone or with fluoxetine (mean dose = 39.3 mg/day), paroxetine (mean = 31.2 mg/day), or sertraline (mean = 92.5 mg/ day). Each patient's dose of clozapine was stable for at least a month before serum sampling.. Concentrations of clozapine plus norclozapine averaged 43% higher, and the risk of levels higher than 1000 ng/ml was 10-fold greater (25%), in the patients taking SSRIs, with minor differences between patients taking the individual SSRIs.. SSRIs can increase circulating concentrations of clozapine and norclozapine, sometimes to potentially toxic levels.

Topics: 1-Naphthylamine; Adult; Affective Disorders, Psychotic; Aged; Ambulatory Care; Clozapine; Drug Interactions; Drug Therapy, Combination; Fluoxetine; Humans; Middle Aged; Paroxetine; Schizophrenia; Selective Serotonin Reuptake Inhibitors; Sertraline; Stimulation, Chemical

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.

Topics: Adult; Antipsychotic Agents; Chromatography, High Pressure Liquid; Clozapine; Female; Haloperidol; Humans; Male; Schizophrenia

Clozapine is an antipsychotic drug with few extra-pyramidal motor side-effects, used to treat schizophrenia which is resistant to classical neuroleptic therapy. This report shows that norclozapine but not clozapine-N-oxide has the same D2 receptor affinity as clozapine. Assay results suggest a bimodal distribution which may be explained by CYP1A2 polymorphism. Extensive metabolizers could produce other active metabolites, probably other hydroxy-clozapine derivatives.

Topics: Animals; Antipsychotic Agents; Chromatography, High Pressure Liquid; Clozapine; Corpus Striatum; Female; Humans; Hydroxylation; Male; Radioligand Assay; Rats; Receptors, Dopamine D2; Schizophrenia

Topics: Clozapine; Depression, Chemical; Drug Therapy, Combination; Humans; Schizophrenia; Seizures; Valproic Acid

Clozapine may produce agranulocytosis in 1-2% of patients treated with it for 4 weeks or longer. Three mechanisms have been suggested: a direct toxic effect of metabolite of clozapine, an immunologic mechanism or a combination of both. N-desmethylclozapine, the major metabolite of clozapine, has been reported to be more toxic than clozapine itself (Gerson et al., 1994). In this study, plasma levels of clozapine and desmethylclozapine were measured in five patients who developed agranulocytosis. The levels of both parent compound and metabolite were within the range found in other patients and below the toxic range. If a toxic mechanism is involved in clozapine-induced agranulocytosis, an additional vulnerability factor must be important.

Topics: Adult; Agranulocytosis; Clozapine; Female; Humans; Male; Schizophrenia

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.

Topics: Adult; Chronic Disease; Clozapine; Dextromethorphan; Half-Life; Homovanillic Acid; Humans; Male; Metabolic Clearance Rate; Middle Aged; Phenotype; Schizophrenia

Concentrations in plasma of clozapine and norclozapine, the major metabolite of clozapine, were measured in 59 treatment-resistant schizophrenic patients at a random time period during the course of treatment. A lower sum of the concentrations of clozapine and norclozapine or either alone predicted less improvement in the Brief Psychiatric Rating Scale (BPRS) Total and Positive symptoms in a multivariate analysis that controlled for baseline BPRS rating and dose. The mean doses of clozapine after 6 months of treatment and at the time of blood sampling were not significantly different in 30 responders and 29 nonresponders to clozapine, on the basis of the decrease in BPRS Total scores, whereas the concentrations in plasma in clozapine of norclozapine and the sum of their concentrations were significantly higher in responders. Clozapine and norclozapine concentrations in plasma correlated both with dose at the time of sampling and with dose at 6 months. A clozapine concentration of 370 ng/ml was the optimal cutoff for distinguishing responders from nonresponders. Clozapine and norclozapine concentrations did not differ in male smokers and nonsmokers.

Topics: Adult; Chromatography, High Pressure Liquid; Clozapine; Female; Humans; Male; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Smoking

A method using reversed-phase high-performance liquid chromatography for the simultaneous determination of clozapine and its desmethyl metabolite in human plasma has been established. Clozapine and N-desmethylclozapine were extracted with n-hexane-isoamyl alcohol (98.5:1.5, v/v). Protriptyline served as the internal standard. The limits of detection for clozapine and desmethylclozapine are 2 and 1 ng/ml, respectively. The sensitivity and precision of this method can be utilized for pharmacokinetic studies and therapeutic drug monitoring regimens.

Topics: Adult; Chromatography, High Pressure Liquid; Clozapine; Humans; Male; Schizophrenia; Spectrophotometry, Ultraviolet

Clozapine, an atypical antipsychotic, has been estimated to be effective in 30% of treatment-refractory schizophrenic patients. The authors hypothesized that if a dose-response relationship was obvious for this drug, the response rate could be significantly amplified.. Following an 8-24-day dose titration phase, 29 inpatients with treatment-resistant schizophrenia diagnosed according to DSM-III-R were given a clozapine dose of approximately 400 mg/day for 4 weeks; blood samples were obtained weekly during this period.. A receiver operator curve demonstrated that the threshold clozapine plasma concentration for therapeutic response was 350 ng/ml. Sixty-four percent of the patients with clozapine plasma concentrations greater than 350 ng/ml responded, whereas only 22% of the patients with concentrations less than 350 ng/ml responded.. Use of clozapine blood levels as a predictor for treatment response in treatment-refractory schizophrenic patients appears worthwhile, since the measurement's sensitivity for response was 64% and the specificity for nonresponse was 78%.

Topics: Adult; Antipsychotic Agents; Chromatography, High Pressure Liquid; Clinical Protocols; Clozapine; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; ROC Curve; Schizophrenia; Schizophrenic Psychology; Sensitivity and Specificity

Topics: Clozapine; Humans; Neuroleptic Malignant Syndrome; Psychiatric Status Rating Scales; Regression Analysis; Schizophrenia; Schizophrenic Psychology

A gas chromatographic-mass spectrometric method with single ion detection has been developed for determination of clozapine and its N-demethylated metabolite norclozapine in plasma. Propylnorclozapine was used as internal standard and the mass spectrometer was adjusted to record the ion m/z 373 for the compounds analyzed. The precision of the method was found to be high, with a relative standard deviation of 6% or less for replicated samples. The limit of determination was 1.0 ng/ml for clozapine and 5.0 ng/ml norclozapine. A significant correlation was obtained between the daily oral dose of clozapine within the dose interval 100-800 mg/day and the plasma level of clozapine in 22 chronic schizophrenic patients. The plasma levels of clozapine and norclozapine were also significantly correlated. The quotient norclozapine/clozapine showed great interindividual variation and was not correlated to the daily dose of clozapine. The method is rapid and sensitive to allow evaluation of the pharmacokinetic properties of clozapine in the treatment of schizophrenic patients.

Topics: Adult; Clozapine; Dibenzazepines; Female; Gas Chromatography-Mass Spectrometry; Humans; Indicators and Reagents; Male; Schizophrenia