olanzapine and norclozapine

The combination of atypical antipsychotics and selective serotonin reuptake inhibitors is an effective strategy in the treatment of certain psychiatric disorders. However, pharmacokinetic interactions between the two classes of drugs remain to be explored. The present study was designed to determine whether there were different effects of steady-state fluvoxamine on the pharmacokinetics of a single dose of olanzapine and clozapine in healthy male volunteers. One single dose of 10 mg olanzapine (n = 12) or clozapine (n = 9) was administered orally. Following a drug washout of at least 4 weeks, all subjects received fluvoxamine (100 mg/day) for 9 days, and one single dose of 10 mg olanzapine or clozapine was added on day 4. Plasma concentrations of olanzapine, clozapine, and N-desmethylclozapine were assayed at serial time points after the antipsychotics were given alone and when added to fluvoxamine. No bioequivalence was found in olanzapine alone and cotreatment with fluvoxamine for the mean peak plasma concentration (C(max)), the area under the concentration-time curve from time 0 to last sampling time point (AUC(0-t)), and from time 0 to infinity (AUC(0- infinity )). Under the cotreatment, C(max) of olanzapine was significantly elevated by 49%, with a 32% reduced time (t(max)) to C(max), whereas the C(max) and t(max) of clozapine were unaltered. The cotreatment increased the AUC(0-t) and AUC(0- infinity ) of olanzapine by 68% and 76%, respectively, greater than those of clozapine (40% and 41%). The presence of fluvoxamine also prolonged the elimination half-life (t(1/2)) of olanzapine by 40% and, to a much greater extent, clozapine by 370% but reduced the total body clearance (CL/F) of clozapine (78%) more significantly than it did for olanzapine (42%). The apparent volume of distribution (V(d)) was suppressed by 31% in olanzapine combined with fluvoxamine but was unaltered in the clozapine regimen. A significant reduction in the N-desmethylclozapine to clozapine ratio was present in the clozapine with fluvoxamine regimen. The effects of fluvoxamine on different aspects of pharmacokinetics of the two antipsychotics may have implications for clinical therapeutics.

Topics: Adult; Antidepressive Agents; Antidepressive Agents, Second-Generation; Area Under Curve; Benzodiazepines; Clozapine; Drug Interactions; Fluvoxamine; Half-Life; Humans; Male; Metabolic Clearance Rate; Olanzapine

Therapeutic drug monitoring (TDM) of atypical antipsychotics is common, but published methods often specify relatively complex sample preparation and analysis procedures. The aim of this work was to develop and validate a simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the analysis of amisulpride, aripiprazole and dehydroaripiprazole, clozapine and norclozapine, olanzapine, quetiapine, risperidone and 9-hydroxyrisperidone, and sulpiride in small (200 μL) volumes of plasma or serum for TDM purposes. The applicability of the method as developed to haemolysed whole blood and to oral fluid was also investigated. Analytes and internal standards were extracted into butyl acetate:butanol (9+1, v/v) and a portion of the extract analysed by LC-MS/MS (100 mm × 2.1 mm i.d. Waters Spherisorb S5SCX; eluent: 50 mmol/L methanolic ammonium acetate, pH* 6.0; flow-rate 0.5 mL/min; positive ion APCI-SRM, two transitions per analyte). Assay calibration (human plasma, oral fluid, and haemolysed whole blood calibration solutions) was performed by plotting the ratio of the peak area of the analyte to that of the appropriate internal standard. Assay validation was as per FDA guidelines. Assay calibration was linear across the concentration ranges studied. Inter- and intra-assay precision and accuracy were within 10% for all analytes in human plasma. Similar results were obtained for oral fluid and haemolysed whole blood, except that aripiprazole and dehydroaripiprazole were within 15% accuracy at low concentration (15 μg/L) in oral fluid, and olanzapine inter-assay precision could not be assessed in these matrices due to day-by-day degradation of this analyte. Recoveries varied between 16% (sulpiride) and 107% (clozapine), and were reproducible as well as comparable between human plasma, human serum, calf serum and haemolysed whole blood. For oral fluid, recoveries were reproducible, but differed slightly from those in plasma suggesting the need for calibration solutions to be prepared in this medium if oral fluid is to be analysed. LLOQs were 1-5 μg/L depending on the analyte. Neither ion suppression/enhancement, nor interference from some known metabolites of the antipsychotics studied has been encountered. The method has also been applied to the analysis of blood samples collected post-mortem after dilution (1+1, 1+3; v/v) in analyte-free calf serum.

Topics: Amisulpride; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Chromatography, Liquid; Clozapine; Dibenzothiazepines; Female; Forensic Toxicology; Hemolysis; Humans; Isoxazoles; Male; Olanzapine; Paliperidone Palmitate; Piperazines; Pyrimidines; Quetiapine Fumarate; Quinolones; Reproducibility of Results; Risperidone; Saliva; Serum; Sulpiride; Tandem Mass Spectrometry

Long-term stability data of atypical antipsychotics in different matrices are not widely available. The aim of this work was to assess the stability of amisulpride, aripiprazole and dehydroaripiprazole, clozapine and norclozapine, olanzapine, quetiapine, risperidone and 9-hydroxyrisperidone, and sulpiride in human EDTA plasma, heparinised haemolysed human whole blood, oral fluid, human serum, and newborn calf serum stored in tightly capped plastic containers under a range of conditions. Measurements were performed by LC-MS/MS. Analyte instability was defined as a deviation of 15% or greater from the expected concentration. All analytes were stable following 3 freeze-thaw cycles in human plasma, and were stable in this matrix for at least 5 days at ambient temperature (olanzapine, 3 days); 4 weeks at 2-8°C (olanzapine, 2 weeks), and 2 years at -20°C (except for dehydroaripiprazole, olanzapine, and quetiapine, 1 year). In human serum, aripiprazole, dehydroaripiprazole, norclozapine, olanzapine, quetiapine, risperidone, 9-hydroxyrisperidone, and sulpiride were unstable after 5 days at ambient temperature, 3 weeks at 2-8°C, and 9 months at -20°C. Olanzapine was unstable in whole blood and oral fluid under most conditions studied, although prior addition of ascorbic acid had a moderate stabilising effect. All other analytes were stable in whole blood and oral fluid for at least 2 days at ambient temperature, 1 week at 2-8°C, and 2 months at -20°C (clozapine and norclozapine, 1 month whole blood). These results confirm that plasma (EDTA anticoagulant) is the sample of choice for TDM of atypical antipsychotics. Delayed (more than 1 week) analysis of patient samples should be undertaken with caution, especially with serum and with haemolysed whole blood. With olanzapine, only plasma collected and stored appropriately is likely to give reliable quantitative results.

Topics: Amisulpride; Animals; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Cattle; Chromatography, Liquid; Clozapine; Dibenzothiazepines; Drug Stability; Female; Forensic Toxicology; Hemolysis; Humans; Isoxazoles; Male; Olanzapine; Paliperidone Palmitate; Piperazines; Pyrimidines; Quetiapine Fumarate; Quinolones; Reproducibility of Results; Risperidone; Saliva; Serum; Sulpiride; Tandem Mass Spectrometry

Interactive context processing is a cognitive ability that is altered in psychotic states, including schizophrenia. This deficit has been linked to prefrontal cortical dysfunction in humans. The degraded contingency effect (DCE) is a simple form of interactive context processing by which contextual information interferes with a target conditioned stimulus for control over conditioned responding. We have previously shown that the DCE was disrupted by the muscarinic receptor antagonist atropine and that this disruption was specifically restored by cholinergic drugs displaying an antipsychotic-like profile, such as physostigmine or xanomeline. The DCE was selectively associated with an increase in Fos immunoreactivity in the medial prefrontal cortex (mPFC), an increase that was not observed in the presence of atropine. Here, we set out to test the actions of typical, atypical and potential antipsychotics on atropine-induced disruption of the DCE and the related mPFC Fos-immunoreactivity profile. Low doses of haloperidol, olanzapine, clozapine and N-desmethylclozapine reversed atropine-induced disruption of the DCE, but with different dose-dependent curves (linear shapes for haloperidol and N-desmethylclozapine, inverted U shapes for olanzapine and clozapine). The level of Fos within the mPFC paralleled the pharmacological profile of the different drugs. Compared to contingent control groups, an increased level of Fos immunoreactivity within the mPFC was observed only with doses that reversed atropine-induced disruption of the DCE. These results suggest that the deficit of interactive context processing, which is a hallmark of psychotic states, might originate from a mere deficit of fundamental associative processes. This deficit might result from a cholinergic blockade of the PFC.

Topics: Animals; Antipsychotic Agents; Atropine; Benzodiazepines; Clozapine; Conditioning, Classical; Drug Interactions; Haloperidol; Male; Muscarinic Antagonists; Olanzapine; Prefrontal Cortex; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley

1. Several studies suggest an association between venous thromboembolism and the use of antipsychotic drugs, especially clozapine, but the biological mechanisms are unknown. It has been suggested that antipsychotic drugs enhance aggregation of platelets and thereby increase the risk of venous thrombosis. The purpose of the present study was to examine the effects of clozapine and its main metabolite, N-desmethyl clozapine, as well as olanzapine, risperidone and haloperidol, on platelet adhesion and aggregation and on plasma coagulation in vitro. 2. Blood was collected from healthy subjects free of medication. Platelet adhesion to different protein surfaces and aggregation were measured in microplates. The coagulation methods of activated partial thromboplastin time (APTT) and prothrombin time were performed in platelet-poor plasma. 3. Clozapine was the only compound that increased platelet adhesion and aggregation and shortened APTT. The effect appeared at therapeutic concentrations and was significant but weak. 4. This weak effect of clozapine on haemostasis may explain, in part, the association of this compound and venous thromboembolism.

Topics: Adult; Aged; Antipsychotic Agents; Benzodiazepines; Blood Coagulation; Blood Platelets; Clozapine; Dose-Response Relationship, Drug; Female; Haloperidol; Humans; In Vitro Techniques; Male; Middle Aged; Olanzapine; Partial Thromboplastin Time; Platelet Adhesiveness; Platelet Aggregation; Prothrombin Time; Risperidone; Thromboembolism; Venous Thrombosis

A specific and sensitive direct-injection high performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC/ESI-MS/MS) method has been developed for the rapid identification and quantitative determination of olanzapine, clozapine, and N-desmethylclozapine in human plasma. After the addition of the internal standard dibenzepin and dilution with 0.1% formic acid, plasma samples were injected into the LC/MS/MS system. Proteins and other large biomolecules were removed during an online sample cleanup using an extraction column (1 x 50 mm i.d., 30 microm) with a 100% aqueous mobile phase at a flow rate of 4 mL/min. The extraction column was subsequently brought inline with the analytical column by automatic valve switching. Analytes were separated on a 5 microm Symmetry C18 (Waters) analytical column (3.0 x 150 mm) with a mobile phase of acetonitrile/0.1% formic acid (20:80, v/v) at a flow rate of 0.5 mL/min. The total analysis time was 6 min per sample. The inter- and intra-assay coefficients of variation for all compounds were <11%. By eliminating the need for extensive sample preparation, the proposed method offers very large savings in total analysis time.

Topics: Antipsychotic Agents; Benzodiazepines; Chromatography, High Pressure Liquid; Clozapine; Humans; Olanzapine; Pirenzepine; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization

In order to analyze clozapine, N-desmethyl clozapine and olanzapine, their detection characteristics with high performance liquid chromatograph-electrochemical detector (HPLC-ECD) were investigated. The separation was performed on an ODS-3 column with the mobile phase of methanol and 0.1 mol/L phosphate buffer(60:40, V/V). The retention times of clozapine, N-desmethyl clozapine and olanzapine were all prolonged with higher pH of the mobile phase. These three compounds could be separated on the baseline at pH 4.56 and 5.56. The relationships of peak heights and detection voltages shown typical "S" shaped curves, and these curves shifted to the left with higher pH. To get stable detection current, the detection voltages for clozapine, N-desmethyl clozapine and olanzapine must be higher than 0.60 V, 0.60 V and 0.35 V at pH 4.56, and 0.48 V, 0.48 V and 0.30 V at pH 5.56, respectively. The typical "S" shaped ampere-volt curves were very important for the selection of suitable voltage for quantitative detection, and could be used for the qualitative detection of these three compounds.

Topics: Antipsychotic Agents; Benzodiazepines; Chromatography, High Pressure Liquid; Clozapine; Electrochemistry; Olanzapine; Pirenzepine