A Positron Emission Tomography Study of Norepinephrine Transporter Occupancy and Its Correlation with Symptom Response in Depressed Patients Treated with Quetiapine XR.

Background: Quetiapine is effective in treating depressive symptoms in major depressive disorder and bipolar disorder, but the mechanisms underlying its antidepressants effects are unknown. Norquetiapine, a metabolite of quetiapine, has high affinity for norepinephrine transporter, which might account for its therapeutic efficacy. Methods: In this study, we used positron emission tomography with (S,S)-[11C]O-methyl reboxetine to estimate norepinephrine transporter density and assess the relationship between norepinephrine transporter occupancy by quetiapine XR and improvement in depression in patients with major depressive disorder (n=5) and bipolar disorder (n=5). After the baseline positron emission tomography scan, patients were treated with quetiapine XR with a target dose of 150 mg in major depressive disorder and 300 mg in bipolar disorder. Patients had a second positron emission tomography scan at the end of week 2 and a final scan at week 7. Results: Norepinephrine transporter density was significantly lower in locus ceruleus in patients compared with healthy subjects. Further, there was a significant positive correlation between quetiapine XR dose and norepinephrine transporter occupancy in locus ceruleus at week 2. The norepinephrine transporter occupancy at week 2 in hypothalamus but not in other regions predicted improvement in depression as reflected by reduction in MADRS scores from baseline to week 7. The estimated dose of quetiapine XR associated with 50% norepinephrine transporter occupancy in hypothalamus at week 2 was 256 mg and the estimated plasma levels of norquetiapine to achieve 50% norepinephrine transporter occupancy was 36.8 µg/L. Conclusion: These data provide preliminary support for the hypothesis that norepinephrine transporter occupancy by norquetiapine may be a contributor to the antidepressant effects of quetiapine.

Influence of ABCB1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of quetiapine in healthy volunteers.

BACKGROUND AND OBJECTIVES: Quetiapine is an atypical antipsychotic drug used to treat schizophrenia and acute episodes of mania. Quetiapine is metabolized by CYP3A enzymes including CYP3A5 and is a substrate of P-glycoprotein, an efflux drug transporter encoded by the ABCB1 gene. We assessed the effects of ABCB1 [c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), c.3435C>T (rs1045642)] and CYP3A5*3 (6986A>G) (rs776746) polymorphisms on the pharmacokinetics of quetiapine in humans. MATERIALS AND METHODS: Forty healthy male individuals were enrolled, and their ABCB1 and CYP3A5 polymorphisms were assessed. After a single dose of 100 mg quetiapine was administered, plasma concentrations of quetiapine were measured for 24 h and pharmacokinetic analysis was carried out. RESULTS: The ABCB1 polymorphisms including c.1236C>T, c.2677G>T/A, and c.3435C>>T did not affect plasma levels of quetiapine, and its pharmacokinetic parameters did not differ among ABCB1 genotype groups. However, the CYP3A5*3 polymorphism significantly affected the plasma level of quetiapine and its pharmacokinetics. The peak plasma concentration of quetiapine was 208.39 ng/ml for CYP3A5*1/*1, 243.46 ng/ml for CYP3A5*1/*3, and 332.94 ng/ml for CYP3A5*3/*3 (P=0.0118). The mean AUC(inf) (area under the time vs. concentration curve from 0 to infinity) value was 627.3, 712.77, and 1045.29 ng h/ml, respectively (P=0.0017). CONCLUSION: The results indicated that the genetic polymorphism of CYP3A5*3 but not ABCB1 significantly influences the plasma level of quetiapine and its pharmacokinetics. These findings suggest that the CYP3A5 genetic polymorphism affects the disposition of quetiapine and provide a plausible explanation for interindividual variation in the disposition of this drug.

The influence of the CYP3A4*22 polymorphism on serum concentration of quetiapine in psychiatric patients.

BACKGROUND: Besides dietary, hormonal, or pathological factors, mutations in cytochrome P450 enzymes are thought to be responsible for the interindividual differences in serum concentrations of cytochrome P450 (CYP450)-dependent drugs. Cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of greater than 50% of the prescribed drugs. Recently, a new single-nucleotide polymorphism (SNP) was found (CYP3A4*22), which results in a decreased enzyme activity, in contrast to the other known SNPs in CYP3A4. We investigated to which degree the CYP3A4*22 SNP affects serum concentrations of patients receiving quetiapine, a drug exclusively metabolized by CYP3A4. METHODS: Two hundred thirty-eight adult patients receiving quetiapine were included in this study, based on availability of DNA, serum quetiapine levels, and information on dose. Patients were genotyped for CYP3A4*22 using allele-specific polymerase chain reaction, and, as a control, restriction fragment length polymorphism analysis. RESULTS: Carriers of the CYP3A4*22 allele (*1/*22 and *22/*22, n = 31) had 2.5-fold higher serum levels of quetiapine than did wild-type patients (n = 207; P = 0.03) when using a comparable dose (median, 300 mg/d for both wild-type and carriers; P = 0.67). The dose-corrected serum concentration (C/D) was 67% higher in carriers than in wild-type patients (P = 0.01). The number of patients who achieved serum levels above the therapeutic range (>500 µg/L) was also higher in *22-allele carriers (16.1% vs 2.9%; P = 0.007). CONCLUSION: Being a carrier of the CYP3A4*22 allele increases the serum concentration of quetiapine at comparable doses.

Parallel electromembrane extraction in a multiwell plate.

This paper describes the concept of parallel electromembrane extraction (Pa-EME) with flat membranes in a multiwell format for the first time. The setup is based on a multiwell plate and provided simultaneous and selective isolation, cleanup, and enrichment of several human plasma samples as well as LC-MS-compatible extracts within 8 min of extraction. Undiluted human plasma samples spiked with four antidepressant drugs were added to separate wells in the donor plate. Subsequently, the samples were extracted with Pa-EME. The four drugs migrated electrokinetically from undiluted human plasma through a flat polypropylene membrane impregnated with 2-nitrophenyl octyl ether, and were isolated into formic acid. Extraction time, extraction voltage, agitation rate, sample volume, and acceptor solution volume were all optimized with an experimental design. The optimal conditions were as follows: The agitation rate was 1,040 rpm, and an extraction voltage of 200 V was applied. The sample volume and acceptor solution volume was 240 and 70 µL, respectively. The extraction was continued for 8 min. Eventually, the extracts were analyzed by LC-MS/MS. The combination of Pa-EME with LC-MS/MS provided quantitation limits below the therapeutic level and reported relative standard deviations in the range 5-13 %. Linear calibration curves were obtained for all analytes, and the correlation coefficients were above 0.9974 in the range 1-400 ng mL(-1). The drug concentrations from two subjects treated with quetiapine and sertraline were successfully determined with Pa-EME combined with LC-MS/MS. Post-column infusion experiments demonstrated that Pa-EME provided extracts free from interfering matrix components.

Rapid determination of quetiapine in blood by gas chromatography-mass spectrometry. Application to post-mortem cases.

A simple, fast and sensitive method for the determination of quetiapine in human blood has been developed and validated. The method involved a basic liquid-liquid extraction procedure and subsequent analysis by gas chromatography-mass spectrometry, previous derivatization with bis(trimethylsilyl)-trifluoro-acetamide and chorotrimethylsilane (99 : 1). The methods of validation included linearity with a correlation coefficient > 0.99 over the range 0.02-1 µg ml(-1), intra- and interday precision (always < 12%) and accuracy (mean relative error always < 12%) to meet the bioanalytical acceptance criteria. The limit of detection was 0.005 µg ml(-1). The procedure was further applied to post mortems from the Institute of Legal Medicine, University of Santiago de Compostela.

Development of physiologically based pharmacokinetic model to evaluate the relative systemic exposure to quetiapine after administration of IR and XR formulations to adults, children and adolescents.

Quetiapine is an atypical antipsychotic drug with a high permeability, moderate solubility and defined as a Biopharmaceutics Classification System class ll compound. The pharmacokinetics (PK) of the quetiapine immediate-release (IR) formulation has been studied in both adults and children, but the quetiapine extended-release (XR) formulation has only been conducted in adults. The purpose of the current study was to use physiologically based pharmacokinetic modeling (PBPK) quantitatively to predict the PK of the XR formulation in children and adolescents. Using a 'learn and confirm' approach, PBPK models were developed employing in vitro ADME and physicochemical data, clinical PK data of quetiapine IR/XR in adults and clinical PK data of quetiapine IR in children. These models can predict well the effects of CYP3A4 inhibition and induction on the PK of quetiapine, the PK profile of quetiapine IR in children and adults, and the PK profile of quetiapine XR in adults. The AUC and Cmax ratios (children vs adults) for the different age groups were in reasonable agreement with the observed ratios. In addition, the PBPK model predicted that children and adolescents are likely to achieve a similar exposure following administration of either the XR formulation once daily or the IR formulation twice daily at similar total daily doses. The results from the study can help inform dosing regimens in pediatrics using the quetiapine XR formulation.

Pharmacobezoar Associated Prolonged Clinical Course in a Patient with Immediate Release Quetiapine Overdose.

INTRODUCTION: Quetiapine is available in both immediate-release (IR) and extended-release (XR) formulations. Quetiapine XR overdose is known to cause delayed increase in serum quetiapine concentrations. However, it is not certain whether quetiapine IR overdose would similarly cause a delayed increase in serum quetiapine concentrations. CASE REPORT: A 57-year-old woman with depression who was taking half a tablet of 25 mg quetiapine IR daily was transported to our emergency department with a complaint of disturbance of consciousness 12 h after a quetiapine IR overdose. On arrival, her initial vital signs were heart rate of 116 beats per minute, blood pressure of 77/43 mm Hg, and oxygen saturation of 91% under 10 L oxygen administration. Whole body plain computed tomography showed a large amount of gastric hyperdense content suggesting pharmacobezoar with a volume of 71.2 ml. After treatment with respiratory and circulatory support, gastric lavage was performed. Her disturbance of consciousness persisted until day 5, and she was extubated on day 7. The serum concentrations of quetiapine were 2690 ng/mL at 12 h after overdose, 5940 ng/mL at 40 h, and 350 ng/mL at 124 h after overdose. Serum concentrations of other co-ingestions were all below lethal levels. CONCLUSION: A massive quetiapine IR overdose with pharmacobezoars can cause a delayed increase in serum quetiapine concentrations.

Norepinephrine transporter occupancy in the human brain after oral administration of quetiapine XR.

Quetiapine, originally developed as an antipsychotic, demonstrates efficacy in clinical studies of schizophrenia, bipolar mania and depression, major depressive disorder and generalized anxiety disorder. This broad spectrum of efficacy was not predicted from the preclinical pharmacology of quetiapine. Binding studies in vitro show that quetiapine and its major active human metabolite, norquetiapine, have moderate to high affinity for dopamine D2 and serotonin 5-HT2A receptors, while norquetiapine alone has high affinity for the norepinephrine transporter (NET). This positron emission tomography (PET) study measured NET occupancy in human subjects treated with extended-release quetiapine (quetiapine XR) at doses relevant in the treatment of depression. PET measurements using the specific NET radioligand (S,S)-[(18)F]FMeNER-D2 were performed before and after quetiapine XR treatment at 150 and 300 mg/d for 6-8 d in nine healthy males (aged 21-33 yr). Regions of interest were defined for the thalamus, using the caudate as reference region. NET occupancy was calculated using a target:reference region ratio method. Plasma concentrations of quetiapine and norquetiapine were monitored during PET measurements. Following quetiapine XR treatment, the mean NET occupancy in the thalamus was 19 and 35%, respectively, at quetiapine XR doses of 150 and 300 mg/d. The estimated plasma concentration of norquetiapine corresponding to 50% NET occupancy was 161 ng/ml. This is the first demonstration of NET occupancy by an antipsychotic in the human brain. NET inhibition is accepted as a mechanism of antidepressant activity. NET occupancy may therefore contribute to the broad spectrum of efficacy of quetiapine.

A thorough QTc study of 3 doses of iloperidone including metabolic inhibition via CYP2D6 and/or CYP3A4 and a comparison to quetiapine and ziprasidone.

The potential for iloperidone, a D2/5-HT2A antipsychotic, to affect the heart rate-corrected QT interval (QTc) was assessed in the absence and presence of metabolic inhibitors in a randomized, open-label, multicenter study. QT interval prolongation by medications, including both conventional and atypical antipsychotic drugs, can predispose patients to cardiac arrhythmias and result in sudden death. Adults with schizophrenia or schizoaffective disorder and normal electrocardiograms at baseline (N = 188) were randomized 1:1:1:1:1 to iloperidone, 8 mg twice daily (BID), 12 mg BID, 24 mg once daily (QD); quetiapine, 375 mg BID; or ziprasidone, 80 mg BID during period 1 (no metabolic inhibitors present). Iloperidone BID produced mean changes in QTc Fridericia correction (QTcF) interval (8.5-9.0 milliseconds [ms]) similar to those produced by ziprasidone (9.6 ms) and higher than those produced by quetiapine (1.3 ms). Iloperidone, 24 mg QD, produced a mean QTcF change of 15.4 ms. Coadministration of metabolic inhibitors with iloperidone during periods 2 (paroxetine) and 3 (paroxetine and ketoconazole) resulted in greater increases in the QTc interval. Increased QTc was observed in individuals with specific cytochrome P450 2D6 polymorphisms. Up to 10% of patients on iloperidone experienced QTc intervals of 60 ms or longer in the presence of metabolic inhibition and QD dosing. However, no patients experienced QTc changes of clinical concern (QTc ≥ 500 ms). The most common adverse events with iloperidone were headache, anxiety, and dyspepsia. The only cardiovascular adverse events with iloperidone were non-concentration-dependent tachycardia that was mild in most patients and did not lead to further sequelae. Pharmacogenetics and recommendations are discussed.

Quetiapine and norquetiapine serum concentrations and clinical effects in depressed patients under augmentation therapy with quetiapine.

BACKGROUND: Quetiapine has been recently approved as an add-on therapy in the treatment of major depressive disorders in the case of inadequate response to antidepressant monotherapy. Thereby the antidepressant potential is attributed to the N-demethylated metabolite norquetiapine (NQ). The aim of this cross-sectional analysis was to relate quetiapine (Q) doses to serum concentrations of Q and its active metabolite and clinical effects. METHODS: Data were obtained from patients who had been treated with different antidepressants and augmented under naturalistic conditions with Q for whom blood level measurements were requested. RESULTS: For this analysis, 105 depressed patients were included who had been augmented with Q. The mean daily doses of Q were 222 ± 125 mg. Doses correlated significantly (P < 0.001) with the highly variable serum concentrations of both Q and NQ. Median serum concentrations of Q and NQ were 46 ng/mL (25th to 75th percentile 20-91 ng/mL) and 59 ng/mL (25th to 75th percentile 26-133 ng/mL), respectively. Concentrations per dose ranged from 0.10 to 0.58 ng·ml·mg for Q and from 0.17 to 0.59 ng·ml·mg for NQ. Most patients (55%) received comedications in addition to the antidepressant drug and Q. According to the clinical global impressions scale, 60% of the patients were either much (36%) or very much improved (24%). Receiver-operating characteristic analysis revealed no significant differences of serum concentrations between responders and nonresponders for NQ (P = 0.835) but a trend for Q (P = 0.056). CONCLUSIONS: Due to marked variability of Q and NQ concentrations in the blood, therapeutic drug monitoring may be helpful to identify pharmacokinetic peculiarities. The lack of correlation between serum concentrations of NQ and clinical improvement casts doubts on the concept that NQ is the pharmacologically active principle for the augmentation therapy.

The toxicology and comorbidities of fatal cases involving quetiapine.

The use of quetiapine in Australia has increased rapidly in recent years. Anecdotal and post-marketing surveillance reports indicate an increase in quetiapine misuse in prisons as well as an increase in its availability on the black-market. This study examined a cohort of quetiapine-associated deaths occurring in Victoria, Australia, between 2001 and 2009, to determine the prevalence of deaths associated with this drug and to determine whether misuse represents a legitimate concern. Case details were extracted from the National Coronial Information System. There were 224 cases with an average age of 43 years of age (range 15-87 years). The cause of death was mostly drug toxicity (n = 114, 51 %), followed by natural disease (n = 60, 27 %), external injury (n = 31, 14 %) and unascertained causes (n = 19, 8 %). Depression and/or anxiety were common, observed in over a third of the cohort (80 cases, 36 %). About 20 % of cases did not mention a psychiatric diagnosis at all which raises the question of whether quetiapine had been prescribed correctly in these cases. Cardiovascular disease was the most commonly reported illness after mental disease. Quetiapine ranged in concentration from the limit of reporting (0.01 mg/L) to 110 mg/L. The median concentration of quetiapine was much lower in the natural disease deaths (0.25 mg/L) compared with drug caused deaths (0.7 mg/L). The most commonly co-administered drug was diazepam in 81 (36 %) cases. There were a small number of cases where quetiapine contributed to a death where it had not apparently been prescribed, including the death of a 15 year old boy and one of a 34 year old female. Overall, misuse of quetiapine did not appear to be a significant issue in this cohort; use of the drug only occasionally led to fatalities when used in excess or concomitantly with interacting drugs. However, considering that it is a recent social concern, it is possible that analysis of cases post 2009 would reveal more cases of quetiapine abuse. Close monitoring of quetiapine is therefore advised to prevent adverse outcomes, particularly in vulnerable populations such as substance abusers.

Plasma concentrations of quetiapine, N-desalkylquetiapine, o-desalkylquetiapine, 7-hydroxyquetiapine, and quetiapine sulfoxide in relation to quetiapine dose, formulation, and other factors.

BACKGROUND: N-Desalkylquetiapine may be a pharmacologically active quetiapine metabolite. However, information on plasma concentrations of N-desalkylquetiapine and other quetiapine metabolites attained during quetiapine therapy is scant. The aim of this study was to investigate plasma concentrations of quetiapine, N-desalkylquetiapine, O-desalkylquetiapine, 7-hydroxyquetiapine, and quetiapine sulfoxide attained during therapy and analyze the data with respect to prescribed dose and other variables. METHOD: Quetiapine and its metabolites were measured in plasma samples submitted for quetiapine therapeutic drug monitoring (2009-2011). Concentration, metabolic ratio, and concentration corrected for dose (C/D) were investigated against quetiapine dose, age, sex, and formulation. Sample results were excluded if nonadherence with therapy was queried. RESULTS: There were 99 samples from 59 patients. N-Desalkylquetiapine plasma concentrations showed the strongest correlation with dose of all analytes, but O-desalkylquetiapine and quetiapine sulfoxide were strongly correlated to plasma quetiapine concentrations. There was no significant difference in C/D for any analyte between males and females and no correlation to age. Quetiapine and quetiapine sulfoxide C/D were significantly different (P < 0.01) between patients prescribed immediate- and extended-release formulations. Quetiapine, 7-hydroxyquetiapine and quetiapine sulfoxide C/D showed significant variation (P < 0.02) between those samples taken 10-14 hours postdose as compared with that of 16-24 hours postdose, but there was no significant effect as regards N-desalkylquetiapine. CONCLUSIONS: Plasma quetiapine, O-desalkylquetiapine, 7-hydroxyquetiapine, and quetiapine sulfoxide concentrations were significantly affected by formulation and/or time since last dose. Plasma N-desalkylquetiapine concentrations were not affected by either factor therefore may be a better marker for quetiapine exposure than plasma quetiapine concentrations.

Combined therapy with thioridazine decreases plasma levels of quetiapine inTaiwanese schizophrenic patients.

BACKGROUND: In this study, the authors studied the effect of thioridazine (TDZ) on the pharmacokinetic profile of quetiapine (QTP) in Taiwanese patients with schizophrenia. METHODS: Sixteen subjects with schizophrenia were recruited for this study. The authors pretreated 8 patients with TDZ 50 mg daily continuously given until the end of the study. QTP was administered to all the participants, and their doses were escalated to 300 mg once daily over a 7-day period and maintained for another week. On day 15, blood samples were collected at 12 time points within an 8-hour interval. The authors assayed the plasma levels of QTP with a high-performance liquid chromatography system coupled with ultraviolet detector. RESULTS: Significantly decreased plasma levels of QTP after oral administration were observed in patients comedicated with TDZ compared with the QTP monotherapy group at 1.5, 2, and 2.5 hours, and the P values were 0.046, 0.001, and 0.005, respectively. The Cmax of QTP was significantly lower in the group comedicated with TDZ (776.9 ± 175.2 versus 1452.3 ± 707.5 ng/mL; P = 0.002). The oral clearance of QTP was significantly higher in the combined group than in the monothreapy group (123.3 ± 66.8 versus 60.3 ± 28.5 L/h; P = 0.03). Other pharmacokinetic parameters were not significantly different. CONCLUSIONS: The coadministration of TDZ significantly decreased plasma QTP level and significantly increased the oral clearance of QTP. Although TDZ is switched to QTP, choosing larger doses of QTP for titration may be necessary to avoid the emergence of psychotic symptoms among schizophrenic patients.

Measurement of quetiapine and four quetiapine metabolites in human plasma by LC-MS/MS.

There is interest in monitoring plasma concentrations of N-desalkylquetiapine in relation to antidepressant effect. A simple LC-MS/MS method for quetiapine and four metabolites in human plasma (50 µL) has been developed to measure concentrations of these compounds attained during therapy. Analytes and internal standard (quetiapine-d8) were extracted into butyl acetate-butanol (10:1, v/v) and a portion of the extract analysed by LC-MS/MS (100 × 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 calibrators) was linear across the ranges studied (quetiapine and N-desalkylquetiapine 5-800, quetiapine sulfoxide 100-15,000, others 2-100 µg/L). Assay validation was as per FDA guidelines. Quetiapine sulfone was found to be unstable and to degrade to quetiapine sulfoxide. In 47 plasma samples from patients prescribed quetiapine (prescribed dose 200-950 mg/day), the (median, range) concentrations found (µg/L) were: quetiapine 83 (7-748), N-desalkylquetiapine, 127 (7-329), O-desalkylquetiapine 12 (2-37), 7-hydroxyquetiapine 3 (<1-48), and quetiapine sulfoxide 3,379 (343-21,704). The analyte concentrations found were comparable to those reported by others except that the concentrations of the sulfoxide were markedly higher. The reason for this discrepancy in unclear.

A fast, sensitive and simple method for mirtazapine quantification in human plasma by HPLC-ESI-MS/MS. Application to a comparative bioavailability study.

In the present study a simple, fast, sensitive and robust method to quantify mirtazapine in human plasma using quetiapine as the internal standard (IS) is described. The analyte and the IS were extracted from human plasma by a simple protein precipitation with methanol and were analyzed by high-performance liquid chromatography coupled to an electrospray tandem triple quadrupole mass spectrometer (HPLC-ESI-MS/MS). Chromatography was performed isocratically on a C(18), 5 µm analytical column and the run time was 1.8 min. The lower limit of quantitation was 0.5 ng/mL and a linear calibration curve over the range 0.5-150 ng/mL was obtained, showing acceptable accuracy and precision. This analytical method was applied in a relative bioavailability study in order to compare a test mirtazapine 30 mg single-dose formulation vs a reference formulation in 31 volunteers of both sexes. The study was conducted in an open randomized two-period crossover design and with a 14 day washout period. Since the 90% confidence interval for C(max) , AUC(last) and AUC(0-inf) were within the 80-125% interval proposed by the Food and Drug Administration and ANVISA (Brazilian Health Surveillance Agency), it was concluded that mirtazapine 30 mg/dose is bioequivalent to the reference formulation, according to both the rate and extent of absorption.

Comparison of D2 dopamine receptor occupancy after oral administration of quetiapine fumarate immediate-release and extended-release formulations in healthy subjects.

Quetiapine is an established drug for treatment of schizophrenia, bipolar disorder, and major depressive disorder. While initially manufactured as an immediate-release (IR) formulation, an extended-release (XR) formulation has recently been introduced. Pharmacokinetic studies show that quetiapine XR provides a lower peak and more stable plasma concentration than the IR formulation. This study investigated if the pharmacokinetic differences translate into different time curves for central D2 dopamine receptor occupancy. Eleven control subjects were examined with positron emission tomography (PET) and the radioligand [11C]raclopride. Eight subjects underwent all of the scheduled PET measurements. After baseline examination, quetiapine XR was administered once-daily for 8 d titrated to 300 mg/d on days 5-8, followed by 300 mg/d quetiapine IR on days 9-12. PET measurements were repeated after the last doses of quetiapine XR and IR at predicted times of peak and trough plasma concentrations. Striatal D2 receptor occupancy was calculated using the simplified reference tissue model. Peak D2 receptor occupancy was significantly higher with quetiapine IR than XR in all subjects (50 ± 4% and 32 ± 11%, respectively), consistent with lower peak plasma concentrations for the XR formulation. Trough D2 receptor occupancy was similarly low for both formulations (IR 7 ± 7%, XR 8 ± 6%). The lower peak receptor occupancy associated with quetiapine XR may explain observed pharmacodynamic differences between the formulations. Assuming that our findings in control subjects are valid for patients with schizophrenia, the study supports the view that quetiapine, like the prototype atypical antipsychotic clozapine, may show antipsychotic effect at lower D2 receptor occupancy than typical antipsychotics.

Pharmacokinetic variability of quetiapine and the active metabolite N-desalkylquetiapine in psychiatric patients.

BACKGROUND: Quetiapine is an atypical antipsychotic drug that was recently also approved for the treatment of uni- and bipolar depression. The antidepressive response is considered to be mediated by the metabolite N-desalkylquetiapine, and the aim of this study was to assess the interindividual pharmacokinetic variability of quetiapine and N-desalkylquetiapine in psychiatric patients based on therapeutic drug monitoring samples. METHODS: Serum measurements of quetiapine and N-desalkylquetiapine performed between October 2007 and July 2008 were retrospectively included from a routine therapeutic drug monitoring database. Pharmacokinetic variability was expressed as the 5-95 percentile range in dose-adjusted serum concentrations (C/D ratios). The impact of age (65 years or older), gender, and sampling time on the C/D ratios was studied by linear mixed model analysis. Samples from patients comedicated with CYP3A4 inducers or inhibitors were examined separately. RESULTS: In total, 927 serum samples from 601 patients were included (all using quetiapine immediate-release tablets). The 5-95 percentiles of the C/D ratio ranged 15-fold (0.14-2.1 nmol/L/mg) for quetiapine and fivefold (0.44-2.1 nmol/L/mg) for N-desalkylquetiapine. Elderly (65 years or older) obtained 1.5- and 1.2-fold higher C/D ratios of quetiapine (P = 0.002) and N-desalkylquetiapine (P = 0.03) compared with younger patients, respectively. Sampling time was also found to significantly affect the C/D ratios of quetiapine (P = 0.001), whereas gender was not a significant variable (P > 0.13). In three patients treated with potent CYP3A4 inducers, the observed C/D ratios of quetiapine and N-desalkylquetiapine were 77% and 11% lower than the mean C/D ratio in the study population, respectively. CONCLUSION: The pharmacokinetic variability was greater for quetiapine compared with N-desalkylquetiapine. Age 65 years or older and comedication with CYP3A4 inducers affected the serum levels of both agents, but the relative impact was greater on quetiapine.

Quetiapine in adolescents with non-affective psychotic disorders: an open-label trial.

INTRODUCTION: There is a need for more studies on the clinical effectiveness, tolerability and pharmacokinetics of atypical antipsychotics in adolescents with psychotic disorders, as this represents a vulnerable and difficult population to treat. According to recent concerns regarding disabling side effects of antipsychotics, particularly weight gain, further monitoring of their safety profiles is needed. This situation prompted the authors to carry out an investigation on the clinical effectiveness of quetiapine in psychotic adolescents. METHODS: 23 adolescents (13-18 years old) with psychotic disorders participated in a 12-week open label trial, including 6 visits assessing clinical efficacy, tolerability and safety of quetiapine (50-750 mg daily). RESULTS: Adolescents were treated with lower doses compared to adults. Significant decreases in CGI and PANSS total scores were observed after both 4 and 12 weeks of quetiapine treatment compared to baseline. Sedation was the main adverse effect, but medication was generally well tolerated. Irregular compliance, (as assessed by pill counts, a questionnaire and by plasma quetiapine concentration monitoring), and alcohol and/or cannabis consumption were factors identified in this study which add to the difficulty in treating this population. DISCUSSION: The results of the present study help to consolidate evidence of the usefulness of quetiapine as a treatment for adolescents with psychotic disorders. However, this study also highlights the issues encountered in treating this group, including the presence of comorbidities such as drug abuse.

Quetiapine and norquetiapine in plasma and cerebrospinal fluid of schizophrenic patients treated with quetiapine: correlations to clinical outcome and HVA, 5-HIAA, and MHPG in CSF.

This study investigated concentrations of quetiapine and norquetiapine in plasma and cerebrospinal fluid (CSF) in 22 schizophrenic patients after 4-week treatment with quetiapine (600 mg/d), which was preceded by a 3-week washout period. Blood and CSF samples were obtained on days 1 and 28, and CSF levels of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations were measured at baseline and after 4 weeks of quetiapine, allowing calculations of differences in HVA (ΔHVA), 5-HIAA (Δ5-HIAA), and MHPG (ΔMHPG) concentrations. Patients were assessed clinically, using the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression Scale at baseline and then at weekly intervals. Plasma levels of quetiapine and norquetiapine were 1110 ± 608 and 444 ± 226 ng/mL, and the corresponding CSF levels were 29 ± 18 and 5 ± 2 ng/mL, respectively. After the treatment, the levels of HVA, 5-HIAA, and MHPG were increased by 33%, 35%, and 33%, respectively (P < 0.001). A negative correlation was found between the decrease in PANSS positive subscale scores and CSF ΔHVA (r(rho) = -0.690, P < 0.01), and the decrease in PANSS negative subscale scores both with CSF Δ5-HIAA (r(rho) = -0.619, P = 0.02) and ΔMHPG (r(rho) = -0.484, P = 0.038). Because, unfortunately, schizophrenic patients experience relapses even with the best available treatments, monitoring of CSF drug and metabolite levels might prove to be useful in tailoring individually adjusted treatments.