The Efficacy and Tolerability of Once-Daily Extended Release Quetiapine Fumarate in Hospitalized Patients with Acute Schizophrenia: A 6-Week Randomized, Double-Blind, Placebo-Controlled Study
Manhattan Psychiatric Center-Nathan Kline Institute for Psychiatric Research, New York University, New York, NY, USA. Psychopharmacology bulletin
(Impact Factor: 0.5).
This study aimed to demonstrate efficacy of once-daily extended release quetiapine fumarate (quetiapine XR) versus placebo in patients with acute schizophrenia.
In this 6-week, randomized, double-blind study (5077IL/0041) patients were randomized to receive quetiapine XR (300, 600, or 800 mg/day), quetiapine fumarate immediate release (quetiapine IR) [300 or 600 mg/day], or placebo. Primary endpoint was change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score at Day 42. Secondary variables included PANSS response rate at Day 42 (>/=30% decrease in PANSS total score from baseline) and Clinical Global Impressions Severity (CGI-S) and Improvement (CGI-I) ratings. Safety assessments included adverse event (AE) reporting and laboratory measures.
Of 532 patients randomized, 222 (41.7%) completed the study. Improvements in PANSS total scores from baseline to Day 42 across treatment groups were: quetiapine XR 300 mg/day -5.01, 600 mg/day -13.01 and 800 mg/day -11.17, quetiapine IR 300 mg/day -9.42 and 600 mg/day -6.97, and placebo -5.19; the difference in change was statistically significant only for quetiapine XR 600 mg/day (p = 0.033). There were no statistically significant differences between active treatment groups and placebo for PANSS response rates. Several post hoc analyses were conducted to explain the study efficacy outcome but these were inconclusive. Quetiapine XR was generally well tolerated with the majority of AEs being mild or moderate in intensity and no unexpected AEs.
Superior efficacy of quetiapine XR versus placebo in patients with schizophrenia was demonstrated for quetiapine XR 600 mg/day. The safety and tolerability profile of quetiapine XR was similar to that of quetiapine IR.
Available from: Xin Xiong
- "Quetiapine is a psychotropic compound approved for the treatment of schizophrenia   , acute mania   , and acute bipolar depression in the US, and is approved for the treatment of schizophrenia and acute mania in China. It has been proposed that the quetiapine therapeutic activity in schizophrenia and its mood stabilizing properties in bipolar depression and mania are mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) antagonism . "
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Quetiapine is an atypical antipsychotic agent for the treatment of schizophrenia, acute mania, and acute bipolar depression. The antidepressive response is considered to be mediated by the metabolite norquetiapine (N-desalkylquetiapine), and the aim of this study was to develop an LC-MS/MS method to measure concentrations of these compounds in human plasma.
Following one step liquid-liquid extraction, the analytes were separated using an isocratic mobile phase on a Sunfire C18 column (50mm×2.1mm, 5μm). The retention times were 2.12, 2.24, 2.12 and 2.19min for quetiapine, norquetiapine and their respective stable labeled internal standards, respectively. Cycle time was 4min. Selected reaction monitoring (SRM) in positive ion mode was used for quantitation.
The present method exhibited a linear dynamic range of 0.5-500ng/ml for quetiapine and 0.6-600ng/ml for norquetiapine. The applicable range was extended by dilution up to 5-fold with blank matrix. The accuracy and precision for quetiapine were <103.0% and 8.8%, for norquetiapine were <108.8% and 11.1%, respectively.
A rapid, sensitive, and robust LC-MS/MS method for quantifying quetiapine and its metabolite norquetiapine levels in human plasma was validated and successfully applied to samples from schizophrenic patients in clinical pharmacokinetics studies.
Available from: Inger Persson
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ABSTRACT: Introduction: This long-term, randomized, double-blind, placebo-controlled study examined the efficacy of extended release quetiapine fumarate (quetiapine XR) in preventing psychotic relapse in schizophrenia.Methods: Three hundred twenty-seven clinically stable patients with schizophrenia were switched to open-label quetiapine XR (300mg on Day 1, 600mg on Day 2, followed by flexible dosing [400-800mg/day]) for a 16-week stabilization phase. Thereafter, patients who were clinically stable for four months were randomized to flexible doses of quetiapine XR (400-800mg/day) or placebo. Primary endpoint was time to first schizophrenia relapse after randomization. Secondary endpoints included risk of relapse at six months. Interim analyses were planned after 45 and 60 relapses and final analysis after 90 relapses. Maximal treatment time was one year.Results: The study was terminated after the first interim analysis showed a significant difference between randomized treatment groups. Time to relapse was significantly longer in quetiapine XR-treated patients versus placebo (hazard ratio 0.16 [95% confidence interval 0.08, 0.34]; p=0.001). Fewer quetiapine XR-treated patients relapsed versus those receiving placebo (10.7% vs. 41.4%, respectively). Estimated risk of relapse at six months was significantly lower with quetiapine XR (14.3%) compared with placebo (68.2%; p=0.0001). The incidence of treatment-related adverse events (AEs) was similar between quetiapine XR and placebo groups (18% and 21% of patients, respectively) and only one percent of patients in each group withdrew because of AEs.Conclusion: Once-daily quetiapine XR (400-800mg/day) was effective in preventing relapse in patients with clinically stable schizophrenia. Quetiapine XR was well tolerated during longer-term use.
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ABSTRACT: Quetiapine is an atypical antipsychotic agent with well established efficacy and tolerability in the acute and maintenance treatment of adults with schizophrenia. The extended-release formulation of quetiapine (quetiapine XR) was developed to provide more convenient once-daily administration, as well as allowing simple and rapid dose escalation, with the aim of improving compliance (known to be a substantial issue in patients with schizophrenia). In several short-term clinical trials, oral quetiapine XR 400-800 mg once daily was generally effective across a range of symptoms in the acute treatment of schizophrenia. As a long-term maintenance treatment, quetiapine XR prevented relapse in patients with stable disease, with significantly longer times to relapse in patients treated with quetiapine XR compared with placebo. Quetiapine XR was generally well tolerated in clinical trials. According to pooled results from three 6-week trials, events occurring in >or=5% of quetiapine XR recipients with an incidence>or=2-fold that seen in placebo recipients were dry mouth, somnolence and dizziness. A generally low incidence of extrapyramidal symptoms (EPS) is seen in quetiapine XR recipients. The most common potentially EPS-associated adverse events seen with quetiapine treatment were akathisia, restlessness and tremor. Rates of worsening of Simpson-Angus Scale and Barnes Akathisia Rating Scale scores were not dissimilar among quetiapine XR, quetiapine immediate release and placebo.
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