Pharmacokinetic, bioavailability, & bioequivalenceOriginal researchSelf-Reported Sedation Profile of Quetiapine Extended-Release and Quetiapine Immediate-Release During 6-Day Initial Dose Escalation in Bipolar Depression: A Multicenter, Randomized, Double-Blind, Phase IV Study
Introduction
The extended-release formulation of quetiapine fumarate (quetiapine XR) provides a more gradual release of quetiapine compared with the immediate-release (IR) formulation.1 Quetiapine XR has been reported to possess efficacy as monotherapy in the treatment of bipolar depression and mania, as well as schizophrenia, major depressive disorder, and generalized anxiety disorder.2, 3, 4, 5, 6, 7 Quetiapine is the only atypical antipsychotic agent with reported efficacy as monotherapy for both manic and depressive symptoms in patients with bipolar disorder.8
The recommended dosage for quetiapine XR and IR in bipolar depression is 300 mg once daily in the evening (XR) or at bedtime (IR). Treatment is initiated at 50 mg on the first day, increasing to the target dose of 300 mg by the fourth day. A crossover study of this dose escalation regimen in healthy volunteers reported statistically significantly lower sedation intensity with the XR than the IR formulation 1 hour after administration of the 50-mg dose (the primary study measure).9 The overall incidence of adverse events was also numerically lower with the XR than the IR formulation.
These observed differences between the XR and IR formulations may be explained by differences in their pharmacokinetic profile.9 A crossover study comparing quetiapine XR and IR at the same daily dose (300 mg) in patients with schizophrenia, schizoaffective disorder, or bipolar disorder confirmed that quetiapine XR once daily provides a longer time to peak concentration (5 hours vs 2 hours) and a lower peak plasma concentration, with comparable overall exposure in terms of AUC relative to quetiapine IR BID.1 The pharmacokinetic profile of quetiapine XR translates to reduced fluctuations in the occupancy of receptors in the central nervous system over time compared with IR.10
If these possible differences in tolerability profile between quetiapine XR and IR during treatment initiation are confirmed, they may have clinical relevance (eg, for patient acceptance). The present randomized, parallel-group study examined the hypothesis that the profile of tolerability, including sedation intensity, differs between quetiapine XR and IR during initial dose escalation in patients with bipolar depression.
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Patients and Methods
This double-blind, double-dummy, randomized, parallel-group, Phase IV inpatient study was conducted at 15 medical centers in the United States between June 15, 2009, and July 22, 2009. Male and female patients aged 18 to 50 years with a Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) diagnosis of bipolar I or II disorder, most recent episode depressed, and with outpatient status at enrollment were recruited.
Patients were excluded if they had >8 mood
Study Patients
Of 198 patients screened, 139 (70.2%) were randomized, and 134 of these (96.4%) completed the study (Figure 2). The tolerability population included 139 patients (70 receiving the XR formulation and 69 receiving the IR formulation). The MITT population included 134 patients (69 receiving the XR formulation and 65 receiving the IR formulation), with the exclusion of 5 patients due to participation in another clinical study within 30 days, and the PP population included 128 patients (65 receiving
Discussion
The results of this randomized double-blind study indicate that sedation intensity measured by the modified Bond-Lader VAS is statistically significantly lower with quetiapine XR than with quetiapine IR during initial dose escalation in patients with bipolar depression, confirming the findings of the study by Datto et al.9
Inclusion criteria for the patients recruited to the study included a Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) diagnosis of
Conclusions
Patients with bipolar depression reported statistically significantly lower sedation intensity with quetiapine XR than with quetiapine IR in the first 1 to 3 hours after taking each dose during the initial dose-escalation period. These results are consistent with those of a volunteer study that compared sedation intensity during dose escalation of quetiapine XR and IR at the same doses.9 The overall incidence of adverse events was numerically lower with quetiapine XR than with quetiapine IR in
Conflicts of Interest
Funding support for this study was provided by AstraZeneca (Study D1443C00040). AstraZeneca provided support in the design and conduct of the study; the collection, management, and analysis of the data; and review of the manuscript. Dr. Riesenberg is the principal investigator at the Atlanta Center for Medical Research, a research center funded for this study by AstraZeneca. Ms. Baldytcheva and Dr. Datto are full-time employees and stockholders of AstraZeneca. The authors have indicated that
Acknowledgments
We thank Bill Wolvey, from PAREXEL International Corp, who provided medical writing support funded by AstraZeneca.
Dr. Riesenberg, Ms. Baldytcheva, and Dr. Datto were responsible for the study design, data interpretation, and critical revision of the publication for intellectual content. Drs. Riesenberg and Datto were responsible for the study concept. Dr. Riesenberg was responsible for the data acquisition. Ms. Baldytcheva was responsible for the data analysis.
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Change in daytime sleepiness and cognitive function in a 6-month, double-blind study of lurasidone and quetiapine XR in patients with schizophrenia
2016, Schizophrenia Research: CognitionCitation Excerpt :Significantly greater improvement from baseline to week 32 (month 6 of the continuation study) in favor of lurasidone compared with quetiapine XR was observed in neurocognitive performance before and after adjustment for daytime sleepiness effects. We note that while the current study evaluated quetiapine XR, similar comparative findings versus lurasidone would be expected for quetiapine IR, which has been shown to be associated with higher sedation intensity and less patient satisfaction compared to the XR formulation (Datto et al., 2009; Riesenberg et al., 2012; Riedel et al., 2015). Across all treatment groups, we found that increased daytime sleepiness was significantly related to reduced neurocognitive performance and quality of well-being, assessed over the acute phase study and longer-term extension.
Comparison of the effects of quetiapine extended-release and quetiapine immediate-release on cognitive performance, sedation and patient satisfaction in patients with schizophrenia: A randomised, double-blind, crossover study (eXtRa)
2015, Schizophrenia ResearchCitation Excerpt :Patients receiving quetiapine XR reported lower daytime sedation compared with quetiapine IR. Previous studies comparing the two formulations in terms of sedation showed that in both healthy subjects and patients with bipolar depression, quetiapine XR resulted in less daytime sedation than IR (Datto et al., 2009; Riesenberg et al., 2012), which in is keeping with the results of the current study. Patients receiving quetiapine XR also reported higher overall treatment satisfaction and satisfaction relating to side effects compared with quetiapine IR.