Serum Concentrations Of Quetiapine Research Articles

Dose-dependent effect of lamotrigine on quetiapine serum concentration in patients using instant release tablets

PurposeLamotrigine was previously reported to reduce serum concentration of quetiapine. The aim of this study was to investigate whether lamotrigine dose or quetiapine formulation was of importance for the drug interaction.MethodsPatients combining lamotrigine with quetiapine (cases) were included retrospectively from a routine therapeutic drug monitoring (TDM) service, as were a control group of patients using quetiapine without any interacting drugs. The case and control groups were divided into groups using immediate release (IR) and extended release (XR) quetiapine. The case group was further split into high-dose (> 200 mg/day) and low-dose (≤ 200 mg/day) lamotrigine users. Quetiapine concentration-to-dose (C/D) ratio and metabolite-to-parent ratio (MPR) were compared between the control group and dose-separated case groups using ANOVA test and t-tests.ResultsIn total, 406 patients were included. The mean C/D ratio of IR quetiapine was 46% lower in the high-dose lamotrigine group compared with the control group (P < 0.001), while no interaction effect was present in the low dose lamotrigine group (P = 0.7). Regardless of lamotrigine dose, there was no difference in quetiapine C/D ratio for patients using the XR formulation (P = 0.4). The quetiapine MPR was unaffected regardless of formulation and lamotrigine dose (P ≥ 0.06).ConclusionThe effect of lamotrigine in reducing quetiapine concentration is only significant for patients using quetiapine IR tablets who are treated with lamotrigine doses > 200 mg/day. Because of high variability in the interaction effect, TDM of quetiapine should be recommended during co-prescription of high-dose lamotrigine.

Impact of age, sex and cytochrome P450 genotype on quetiapine and N-desalkylquetiapine serum concentrations: A study based on real-world data from 8118 patients.

To investigate the effect of aging, sex and cytochrome P450 (CYP) genotypes on the exposure of quetiapine (QUE) and the pharmacologically active metabolite N-desalkylquetiapine (NDQ). Patients with serum concentrations of QUE and NDQ were included retrospectively from a therapeutic drug monitoring service. The outcome measures were concentration:dose (C:D) ratios of QUE and NDQ, and NDQ:QUE metabolic ratio. Linear mixed model analyses were used to evaluate the effects of age, sex and, subsequently, CYP2D6/3A genotypes. The average age of the included population (n= 8118 patients) was 44 years (13.5% ≥65 years). The C:D ratio of QUE and NDQ gradually increased in patients aged >50 years compared to those aged 18-30 years, with 28 and 29% increase, respectively, for patients aged >70 years (P< .001). Compared to males, females had 15% lower QUE C:D ratio and 10% higher C:D ratio of NDQ (both P< .001). The NDQ:QUE metabolic ratio was 30% higher in females than in males (P< .001). For females ≥65 years, the NDQ C:D ratio was 36% higher compared to males <65 years (P< .001). A significantly higher NDQ C:D ratio was observed for CYP2D6 intermediate (+7%, P= .012) and poor (+17%, P= .001) compared to normal metabolizers. No effects of CYP3A4*22 and CYP3A5*1 allele variants were observed. This study shows an increase of the QUE and NDQ exposures during aging. Old age, female sex and CYP2D6 allele variants encoding reduced activity are factors associated with high NDQ exposure. Therefore, females ≥65 years carrying CYP2D6 allele variants encoding reduced activity have the highest risk of dose-dependent side effects of NDQ during QUE treatment.

Relationship between serum concentration and clinical response of quetiapine in adolescents and adults with bipolar disorders in acute stage: a prospective observational study

BackgroundIt is found that there are great differences in the efficacy of quetiapine at the same dose in many patients with bipolar disorders. Therefore, therapeutic drug monitoring (TDM) is a valuable tool for guiding treatment with quetiapine. The aims of this study were to assess the relationship between serum concentration and clinical response of quetiapine in adolescents and adults with bipolar disorders in acute stage. MethodsThe study design was prospective and observational. Within the naturalistic setting of a routine TDM service at the First Affiliated Hospital, Zhejiang University School of Medicine. Psychiatric symptoms were assessed using the HAMD (Hamilton Depression Scale), YRMS (Young manic rating scale) and CUDOS-M (Clinically Useful Depression Outcome Scale-Mixed Subscale). The decline of HAMD and YMRS scores was were used to assess clinical outcome of bipolar disorders respectively. Results169 inpatients (23.7 % male, 76.3 % female) were enrolled in the study. We found that there was a strong correlation between quetiapine serum concentrations and clinical outcomes (rs = 0.702, p < 0.001). While, quetiapine daily dose was not correlated with clinical outcome. We found that when the quetiapine serum level is >146.85 ng/ml in depression episodes patients could obtain a satisfactory treatment effect after 2 weeks of hospitalization. ConclusionsWe found a significant positive relationship between serum concentration and clinical outcome, and also determined the serum concentration of quetiapine for the treatment of bipolar depression.

Relationship Between Daily Dose, Serum Concentration, and Clinical Response to Quetiapine in Children and Adolescents with Psychotic and Mood Disorders.

Introduction In child and adolescent psychiatry, therapeutic drug monitoring (TDM) is strongly recommended. However, therapeutic ranges (TR) are defined only for adults. The objectives of this naturalistic study were to assess the relationships between serum quetiapine concentration, daily dose, and clinical outcomes as well as the determinants of pharmacokinetic variability. Furthermore, it was elucidated whether the recommended TR for adult patients with psychotic disorders is valid for children and adolescents. Methods TDM was performed in 180 pediatric patients treated with quetiapine. Psychopathological changes were assessed by the Clinical Global Impression - Improvement scale (CGI-I). Adverse drug reactions (ADRs) were assessed by using a short form of the Udvalg for Kliniske Undersogelser (UKU) side effect rating scale. Results A weak positive linear relationship between daily dose (mean 349.9±248.9 mg/day) and serum concentration of quetiapine (rs=0.496, p<0.001) was found (mean age 15.6±1.9 years, 45.6% male, 31.1% monotherapy), but no relationship between serum concentration and clinical outcome was found. Dose variation accounted for only 12.5% (rs2=0.125) of the variability of serum concentrations. No effects by gender, age, body weight, smoking habits, and co-medication were found. The majority of patients with psychotic (67.8%) and mood disorders (74.5%) showed a serum concentration below the suggested lower limit (100 ng/mL) of the TR for adults. Discussion There are several limitations of this study because of the naturalistic design, and our results should therefore be interpreted with caution. Notwithstanding, our data suggest that the lower limit of the TR for quetiapine is lower than the limit in adult patients.

Impact of genetic variability in CYP2D6, CYP3A5, and ABCB1 on serum concentrations of quetiapine and N-desalkylquetiapine in psychiatric patients.

To investigate the impact of genetic variability in CYP2D6, CYP3A5, and ABCB1 on steady-state serum concentrations of quetiapine and the active metabolite, N-desalkylquetiapine, in psychiatric patients. Measured serum concentrations of quetiapine and N-desalkylquetiapine from patients with biobanked DNA samples were included retrospectively from a routine therapeutic drug monitoring database. The impact of CYP2D6, CYP3A5, and ABCB1 (345C>T) genotypes on dose-adjusted serum concentrations (C/D ratios) of quetiapine and N-desalkylquetiapine was investigated by multivariate mixed model analysis. In total, 289 patients with 633 serum measurements were included. In the multivariate analysis, mean C/D ratio of N-desalkylquetiapine was estimated to be 33% and 22% higher in inherent CYP2D6 poor metabolizers (P = 0.03) and heterozygous extensive metabolizers (P < 0.001), respectively, compared with inherent extensive metabolizers. The ABCB1 3435C>T polymorphism and CYP3A5 genotype had no significant influence on either of the substances in the present material. Genetic variability in CYP2D6 contributes to the interindividual variability in steady-state serum concentrations of N-desalkylquetiapine. Although the metabolite exhibits relevant pharmacological activity, the quantitative effect of CYP2D6 genotype on serum concentration of N-desalkylquetiapine is probably of limited clinical relevance for quetiapine treatment.

Relationship between serum concentration and clinical efficacy of quetiapine in treatment of male patients with schizophrenia

Objective To examine the relationship between quetiapine serum concentration, dose, therapeutic efficacy and side effects in male patients with schizophrenia. Methods Sixty- three male patients with schizophrenia were collected. They were treated openly for 8 weeks with quetiapine, the dose was adjusted according to clinical improvement and tolerance. The plasma quetiapine concentrations, therapeutic efficacy and adverse drug reactions were observed after the 4- week treatment period, and at the end of the 8 weeks of the treatment. Results After 4 weeks, the serum concentration had significant correlation with age, the disease duration and education level.After 8 weeks, there was significant correlation between serum concentration and age. We found a correlation between dose and serum concentration of quetiapine, and no relationship between serum concentration and PANSSscores. Side effects were correlated with 4 weeks'serum concentrations. Conclusion Quetiapine is effective for male patients with schizophrenia. Age, quetiapine dose and side effects have significant correlations with the serum concentration. It appears that plasma quetiapine concentration has no effects on therapeutic efficacy. Key words: Schizophrenia; Plasma concentration; Quetiapine

The Influence of the CYP3A4*22 Polymorphism on Serum Concentration of Quetiapine in Psychiatric Patients

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. 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. 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). Being a carrier of the CYP3A4*22 allele increases the serum concentration of quetiapine at comparable doses.

Relation between dosage, serum concentration and therapeutic response of quetiapine in children and adolescents with different psychiatric disorders in clinical practice

Introduction: Quetiapine is used frequently in the treatment of children and adolescents with different psychiatric disorders despite not being licensed for this age group. The aim of this observational study was to examine the relationship between dosage, serum concentration and therapeutic response in children and adolescents treated with quetiapine in daily clinical practice. Methods: Steady state trough serum concentrations of quetiapine were measured in 122 children and adolescents as part of a routine TDM-program. The therapeutic effect was assessed by the Clinical Global Impression Improvement subscale (CGI-I) and side effects by the Udvalg for Kliniske Undersogelser-side effect rating scale (UKU). Results: A weak linear relationship between the bodyweight adjusted daily dose (mean (SD); 6.1 (4.1)mg/kg) and serum concentration (mean (SD); 78.5 (93.1) ng/ml) of quetiapine was found (Pearson r2=0.13). The majority (77.9%) of the measured serum concentrations were below, 20.5% within and 1.6% above the therapeutic window (100–500ng/ml) suggested for adults. Serum concentrations were not significantly influenced by gender, smoking-habits or co-medication. 43% of the patients showed very good or good improvement, 48% little improvement, 7% no change and only 2% deteriorated. 45.1% of the patients had side effects; most of them mild. However, no correlation between serum concentration and neither the therapeutic nor side effects was found. Discussion: Our results suggest a lower therapeutic window of quetiapine for children and adolescents and higher dosing than in adult psychiatric patients. Further studies with greater sample sizes and diagnosis-specific as well as age-specific psychometric instruments are needed to confirm our findings.

Possible drug–drug interaction between quetiapine and lamotrigine – evidence from a Swedish TDM database

The aim of the present study was to investigate a previously proposed interaction between quetiapine and lamotrigine resulting in reduced serum quetiapine concentrations. Data on 402 patients subjected to analysis of quetiapine concentration in serum were extracted from a routine therapeutic drug monitoring database. Among these patients, those concomitantly treated with lamotrigine (n= 22) were identified and matched with 22 controls receiving quetiapine while unexposed to lamotrigine. The dose-corrected quetiapine concentrations (C : D ratios) in the two groups were compared in both paired and unpaired analyses. Patients co-treated with lamotrigine had a lower mean C : D ratio (0.71, 95% CI 0.46, 0.97) compared with controls (1.64, 95% CI 1.00, 2.28). Dose-corrected quetiapine concentrations were 58% lower in patients co-medicated with lamotrigine. This study indicates that lamotrigine exposure is associated with substantially reduced serum concentrations of quetiapine, possibly due to induced glucuronidation. These findings need to be confirmed in experimental studies.

Late-onset seizures associated with quetiapine poisoning

Quetiapine, a second-generation antipsychotic, acts at multiple brain neurotransmitter receptors and has the potential for serious complications. Although seizures have been described in the literature, delayed seizure onset has not been reported. We report the first case of delayed seizures after a significant quetiapine overdose. A 27-year-old female presented to the emergency department following an overdose of approximately 30 g of quetiapine. Twenty-four hours after arrival, the patient had 2 seizures. The patient was then intubated and remained in the ICU for four days. EEG was negative for epileptiform activity. The serum quetiapine levels (MedTox, St. Paul, MN) were 8.67 mg/L on hospital day one and 3.28 mg/L on hospital day three. Quetiapine poisoning, with serum levels, associated with seizures has been reported in one prior case. Our case report represents late-onset seizures with serum levels above therapeutic range (>1 mg/L). The serum concentrations of quetiapine in this case were consistent with those in postmortem case reports.

Drug Interaction Can Lead to Undetectable Serum Concentrations of Quetiapine in the Presence of Carbamazepine

Nickl-Jockschat, Thomas MD; Paulzen, Michael MD; Schneider, Frank MD, PhD; Grözinger, Michael MD Author Information

Therapeutic Drug Monitoring in Children and Adolescent Psychiatry – First Results for Atypical Antipsychotic Drugs

The psychopharmacotherapy of children and adolescents varies from that of adults due to age-dependent and developmental differences in the pharmacokinetics and pharmacodynamics of psychotropic drugs. The aim of this ongoing study was to examine the relationship between serum concentration, treatment response and adverse effects to elucidate the age-specific therapeutic range of several atypical antipsychotic drugs in children and adolescents under naturalistic conditions. Over a period of 4 years Therapeutic Drug Monitoring (TDM) was routinely performed in children and adolescents with schizophrenic disorders treated with atypical antipsychotic drugs according to the guidelines of the AGNP TDM expert group. The psychopathology was assessed by using the Clinical Global Impression Scale (CGI) and the Brief Psychiatric Rating Scale (BPRS), adverse side effects were assessed by the UKU-side effect rating scale. We retrospectively evaluated all TDM-analyses of the atypical antipsychotic drugs risperidone, quetiapine, clozapine, and olanzapine in an unselected sample of paediatric patients with schizophrenic disorders in a standard clinical setting. We found a marked variability of serum concentrations. In 36 patients receiving oral doses of risperidone (mean 4,18mg) 67% of the risperidone serum concentrations were within the recommended concentration ranges for TDM in adults (20–60ng/ml). Only 35% of the serum concentrations of quetiapine in 34 patients were within the recommended ranges for adults (70–170ng/ml), 44% of the patients showed lower serum-levels of quetiapine although 68% received more than the recommended dosage for adults (300–450mg) with a maximum of 1000mg daily. Clozapine therapy with 100 to 600mg daily improved psychotic symptoms in 90,3% of the 32 patients. 47% of clozapine serum concentrations were lower, 25% were higher than the recommended ranges for adults (350–600ng/ml). In the 17 schizophrenic patients receiving olanzapine (2,5–20mg daily) 70,6% of olanzapine serum levels were in the recommended ranges for adults (20–80ng/ml). Our preliminary data of TDM in an average child and adolescent psychiatric population suggest that some therapeutic ranges recommended for adults seem to be quite valid for children and adolescents (e.g. olanzapine), whereas others seem not (e.g. quetiapine). Further studies using larger samples are warranted.

Quetiapine and Drug Interactions

The objective of the present study was to investigate the effect of age, gender, and various comedications on the pharmacokinetics of quetiapine in a naturalistic setting. In total, 2111 serum samples analyzed for quetiapine during the period from June 2001 to December 2004 were included in the study. The samples had been collected for routine therapeutic drug monitoring purposes from 1179 patients treated with quetiapine. A log-linear mixed model was used to identify factors influencing the dose-corrected quetiapine serum concentration, expressed as the quetiapine concentration-to-dose (C/D) ratio. Variables included in the analysis were age, gender, and concomitant treatment with a total of 41 drugs most often used in combination with quetiapine. Age >or= 70 years (p = .001) and comedication with alimemazine (p = .002), fluvoxamine (p = .001), citalopram/escitalopram (p = .041), or clozapine (p < .001) significantly increased the serum concentrations of quetiapine, while age < 18 years (p = .044) and comedication with lamotrigine (p = .024), levomepromazine (p = .011), oxazepam (p < .001), or carbamazepine (p < .001) significantly decreased the serum concentrations. The effects were most pronounced for fluvoxamine (+159%), clozapine (+82%), age >or= 70 years (+67%), and carbamaze-pine (-86%). In 18% of the samples, the daily dose exceeded the currently recommended maximum of 800 mg/day. Due to the increased serum levels of quetiapine, a lower dose than usual should be considered when quetiapine is administered to elderly patients and to patients comedicated with clozapine or fluvoxamine. As the inducing effect of carbamazepine on quetiapine metabolism is very potent, cotreatment with carbamazepine cannot be recommended. On the basis of our data and pharmacokinetic considerations, the majority of drugs commonly used in psychiatry can safely be given in combination with quetiapine.

Therapeutic Drug Monitoring of Quetiapine in Adolescents with Psychotic Disorders

There are developmental and age-dependent differences in the pharmacokinetics and the pharmacodynamics of drugs in children and adolescents. Therefore, there is a need to carry out standardised studies to find out therapeutic ranges of plasma/serum concentrations in psychopharmacotherapy of children and adolescents. The aim of this prospective study was to examine the relationship between quetiapine serum concentration, treatment response, and side effects in a clinical setting to elucidate the age-specific therapeutic range of quetiapine in adolescents. Over a period of two years, therapeutic drug monitoring (TDM) was routinely performed in 21 adolescents (mean age was 15.9+/-1.5 years, 57% male) with psychotic disorders according to the guidelines of the AGNP TDM expert group. The psychopathology was assessed by using the Clinical Global Impression Scale (CGI) and the Brief Psychiatric Rating Scale (BPRS). Side effects were assessed by using the Dose Record and Treatment Emergent Symptom Scale (DOTES). Trough quetiapine concentrations were determined under steady state conditions after multiple-dose regimes (median 600 mg/day; range 100-800 mg/day). There was a marked variability of the serum concentrations, ranging from 19-877 ng/ml. 40.8% of the determined values were below and 24.5% above the therapeutic range (70-170 ng/ml) recommended for adults. None of the patients had severe side effects. We found a weak correlation between dose and serum concentration of quetiapine and no relationship between serum concentration and treatment response. There are several limitations of this study, and our results should therefore be interpreted with caution. Notwithstanding, differences in the ontogenesis of pharmacokinetics and pharmacodynamics may be the reason for the difference in the relationship between blood concentrations and therapeutic response to psychopharmaca in children, adolescents and adults. Further studies using larger samples, baseline assessment of psychopathology, definition of the treatment interval and investigation of clinically relevant interactions with various co-medications are warranted to improve the limitations of this pilot study.

Quetiapine in Overdosage

Data on quetiapine overdosage are only sparsely available in the literature. This study provides additional data on the pharmacokinetics and clinical effects of intoxication with this atypical antipsychotic drug. The authors performed a retrospective analysis of all quetiapine intoxications reported to and screened by the toxicological laboratory of the Central Hospital Pharmacy The Hague between January 1999 and December 2003. Cases with known suggested amount of intake and medical outcome were included. From the patient's medical record and from the toxicological laboratory findings, patient demographic characteristics (gender, age), details of quetiapine intoxication (estimated time of ingestion, estimated amount of ingestion, and coingested drugs) and clinical parameters were obtained. Severity of intoxication was graded by the Poisoning Severity Score (PSS). Individual pharmacokinetic parameter values were calculated using a one-compartment open model and a Bayesian fitting procedure. Out of a total of 21 intoxications with quetiapine, 14 fulfilled the inclusion criteria. The ingested dose ranged from 1200 to 18,000 mg. The blood concentration ranged from 1.1 to 8.8 mg/L with a lag time of 1 to 26.2 hours between time of ingestion and blood sampling at the emergency ward. The most frequent findings were somnolence and tachycardia. The PSS was minor in 6 patients (43%), moderate in 5 patients (36%), and severe in 3 patients (21%). Severity of intoxication was not associated with a higher amount of quetiapine intake. The authors found no correlation between the serum concentration of quetiapine and the amount ingested. Elimination t(1/2) was not prolonged. It can be concluded that quetiapine intoxications appear to proceed mildly. Tachycardia and somnolence were the main clinical symptoms in our case series. No fatalities occurred. The severity of clinical symptoms was not associated with either a high serum concentration or the suggested amount ingested of quetiapine.

Serum Concentrations of Quetiapine and Clinical Effects

Quetiapine is a novel second generation antipsychotic used mainly for the treatment of patients with schizophrenia. Therapeutic serum concentrations are so far unclear. This investigation analyzed data of patients treated with quetiapine and correlated serum concentrations of quetiapine with therapeutic effects and side effects.