clozapine-n-oxide and Schizophrenia

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

To assess the relation between plasma concentrations of clozapine and its 2 main metabolites desmethyl clozapine and clozapine N-oxide, and clinical change in a sample of inpatients with schizophrenia who were resistant to conventional neuroleptics.. Thirty-seven patients (27 men and 10 women, mean age 34.8 yr) with treatment-resistant schizophrenia were treated with clozapine for 18 weeks; dosage was adjusted according to clinical response, and plasma concentrations of clozapine and of its metabolites were measured weekly by high-performance liquid chromatography. Clinical status was also assessed weekly with the Positive and Negative Syndrome Scale (PANSS). Patients were considered "responsive" if they showed at least a 20% improvement over their baseline PANSS ratings.. The mean endpoint clozapine dosage was 486.5 mg/day. There was a significant correlation between the daily dosage of clozapine and the plasma levels of clozapine and of its metabolites (p < 0.05). There was no correlation between the clozapine plasma level and the percent improvement on the PANSS. Clozapine plasma levels were not significantly different between those who responded to clozapine (n = 19) and those who did not (n = 18) and were not significantly different between patients who smoked (n = 28) and those who did not (n = 9). Receiver operating characteristic (ROC) curve analysis determined the plasma level threshold (above which a better clinical response was obtained) to be 550 ng/mL. Using the total of plasma levels of clozapine and its metabolites did not lead to a better sensitivity and specificity.. Our calculated plasma clozapine threshold was higher than that reported by others, but this may be related to the severity of symptoms of our patient sample. Monitoring plasma rates remains a useful tool, together with clinical evaluation, to establish the clozapine dosage for an optimum benefit-risk ratio.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Clozapine; Drug Resistance; Female; Humans; Male; ROC Curve; Schizophrenia; Treatment Outcome

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

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

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

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

Topics: Adult; Antipsychotic Agents; Area Under Curve; Biotransformation; Chromatography, High Pressure Liquid; Clozapine; Cross-Over Studies; Humans; Male; Middle Aged; Models, Biological; Schizophrenia; Spectrophotometry, Ultraviolet

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

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

Schizophrenia is a severely debilitating neurodevelopmental disorder. Establishing a causal link between circuit dysfunction and particular behavioral traits that are relevant to schizophrenia is crucial to shed new light on the mechanisms underlying the pathology. We studied an animal model of the human 22q11 deletion syndrome, the mutation that represents the highest genetic risk of developing schizophrenia. We observed a desynchronization of hippocampal neuronal assemblies that resulted from parvalbumin interneuron hypoexcitability. Rescuing parvalbumin interneuron excitability with pharmacological or chemogenetic approaches was sufficient to restore wild-type-like CA1 network dynamics and hippocampal-dependent behavior during adulthood. In conclusion, our data provide insights into the network dysfunction underlying schizophrenia and highlight the use of reverse engineering to restore physiological and behavioral phenotypes in an animal model of neurodevelopmental disorder.

Topics: 22q11 Deletion Syndrome; Action Potentials; Animals; Animals, Newborn; CA1 Region, Hippocampal; Clozapine; Disease Models, Animal; Female; Humans; Male; Mental Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Net; Neuregulins; Neurons; Nonlinear Dynamics; Parvalbumins; Prepulse Inhibition; Reflex, Startle; Schizophrenia

Hyperactivity within the ventral hippocampus (vHPC) has been linked to both psychosis in humans and behavioral deficits in animal models of schizophrenia. A local decrease in GABA-mediated inhibition, particularly involving parvalbumin (PV)-expressing GABA neurons, has been proposed as a key mechanism underlying this hyperactive state. However, direct evidence is lacking for a causal role of vHPC GABA neurons in behaviors associated with schizophrenia. Here, we probed the behavioral function of two different but overlapping populations of vHPC GABA neurons that express either PV or GAD65 by selectively inhibiting these neurons with the pharmacogenetic neuromodulator hM4D. We show that acute inhibition of vHPC GABA neurons in adult mice results in behavioral changes relevant to schizophrenia. Inhibiting either PV or GAD65 neurons produced distinct behavioral deficits. Inhibition of PV neurons, affecting ∼80% of the PV neuron population, robustly impaired prepulse inhibition of the acoustic startle reflex (PPI), startle reactivity, and spontaneous alternation, but did not affect locomotor activity. In contrast, inhibiting a heterogeneous population of GAD65 neurons, affecting ∼40% of PV neurons and 65% of cholecystokinin neurons, increased spontaneous and amphetamine-induced locomotor activity and reduced spontaneous alternation, but did not alter PPI. Inhibition of PV or GAD65 neurons also produced distinct changes in network oscillatory activity in the vHPC in vivo. Together, these findings establish a causal role for vHPC GABA neurons in controlling behaviors relevant to schizophrenia and suggest a functional dissociation between the GABAergic mechanisms involved in hippocampal modulation of sensorimotor processes.

Topics: Action Potentials; Animals; Clozapine; GABAergic Neurons; Glutamate Decarboxylase; Hippocampus; Interneurons; Locomotion; Maze Learning; Mice; Neural Inhibition; Parvalbumins; Receptor, Muscarinic M4; Reflex, Startle; Schizophrenia; Synaptic Potentials

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-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

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

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

Clozapine is an atypical neuroleptic that is increasingly used for the treatment of schizophrenia. An automated method was developed for the routine quantification of clozapine and its major metabolites, N-desmethylclozapine and clozapine N-oxide, in human serum and urine by column switching and online high-performance liquid chromatography with ultraviolet detection. The method included adsorption of clozapine and its metabolites on a cyanopropyl-coated clean-up column (10 microns; 10 mm x 4.0 mm ID), washing interfering serum constituents to waste by deionized water, and, after column switching, separation on C18 ODS Hypersil reversed-phase material (5 microns; 250 mm x 4.6 mm ID). The compounds of interest were separated and eluted in fewer than 20 minutes, using a mobile phase consisting of 37.5 acetonitril:62.5 water, containing 0.4% (vol/vol) tetramethylethylenediamine and adjusted to pH 6.5 with concentrated acetic acid. Ultraviolet-detection was performed at 254 nm. The determinations exhibited linearity between detector signal and drug concentrations in a range from 5 ng/ml to 50 micrograms/ml. As little as 10 ng/ml of clozapine and 20 or 30 ng/ml of the metabolites was quantifiable. Interferences with other psychotropic drugs, serum, or urine constituents were negligible. The automated procedure enables the analysis of clozapine and metabolites in serum or urine in less than 1 hour.

Topics: Antipsychotic Agents; Chromatography, High Pressure Liquid; Clozapine; Humans; Schizophrenia; Sensitivity and Specificity

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