Self-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

doi:10.1016/j.clinthera.2012.09.002

Clinical Therapeutics

Volume 34, Issue 11, November 2012, Pages 2202-2211

Data from this trial were presented at the 11th International Forum on Mood and Anxiety Disorders, November 9–11, 2011, Budapest, Hungary; and at the 24th Annual US Psychiatric and Mental Health Congress, November 7–10, 2011, Las Vegas, Nevada.

https://doi.org/10.1016/j.clinthera.2012.09.002 Get rights and content

abstract

Background

A human-volunteer study reported lower sedation intensity during escalation of the extended-release formulation of quetiapine fumarate (quetiapine XR) than the immediate-release (IR) formulation.

Objective

To test the hypothesis that the profile of initial tolerability, including sedation, differs between the extended-release (XR) and immediate-release (IR) formulations of quetiapine in patients with bipolar depression.

Methods

In a randomized, double-blind, double-dummy, parallel-group, Phase IV study, male and female inpatients aged 18 to 50 years with a Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) diagnosis of bipolar I or II depression were randomized after washout to receive placebo on day 1 and quetiapine XR or IR at escalating doses of 50, 100, 200, 300, and 300 mg once daily on the evenings of days 2 to 6, with hospital discharge on day 7. Sedation intensity was assessed by a self-reported modified Bond-Lader visual analog scale (VAS) score.

Results

Of 139 randomized patients, 134 completed the study. Mean patient age was 39.0 years; mean weight, 91.3 kg; and mean body mass index (calculated as weight in kilograms divided by height in meters squared), 31.0. Sedation intensity 1 hour after administration of the 50-mg dose (the primary study measure) was statistically significantly lower with quetiapine XR versus IR (mean [SD] VAS score: 33.4 [26.92] vs 44.0 [31.76]; least squares mean difference: 12.55, P = 0.009; modified intention-to-treat population). Sedation intensity was found in secondary analyses to be significantly lower with quetiapine XR than with quetiapine IR 1, 2, and 3 hours after each dose on days 2 to 6 (P ≤ 0.05), with similar sedation intensity between the treatment groups 4 to 14 hours postdose. Rates of treatment-related adverse events were 47.1% with quetiapine XR versus 59.4% with quetiapine IR. Three serious adverse events (4.3%) occurred in the quetiapine XR group. Adverse events led to study discontinuation in 1 patient (1.4%) in the quetiapine XR group and in 2 patients (2.9%) in the IR group.

Conclusions

During the initial dose-escalation period studied, patients with bipolar depression reported statistically significantly lower sedation intensity in the 1 to 3 hours after taking quetiapine XR compared with the IR formulation. Overall tolerability for both formulations was consistent with the known profile of quetiapine. ClinicalTrials.gov identifier: NCT00926393.

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.

Section snippets

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.

References (30)

C. Figueroa et al.
Pharmacokinetic profiles of extended release quetiapine fumarate compared with quetiapine immediate release
Prog Neuropsychopharmacol Biol Psychiatry
(2009)
M. Bauer et al.
A pooled analysis of two randomised, placebo-controlled studies of extended release quetiapine fumarate adjunctive to antidepressant therapy in patients with major depressive disorder
J Affect Disord
(2010)
T. Suppes et al.
Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression
J Affect Disord
(2010)
A.J. Cutler et al.
Extended-release quetiapine as monotherapy for the treatment of adults with acute mania: a randomized, double-blind, 3-week trial
Clin Ther
(2011)
C. Datto et al.
Self-reported sedation profile of immediate-release quetiapine fumarate compared with extended-release quetiapine fumarate during dose initiation: a randomized, double-blind, crossover study in healthy adult subjects
Clin Ther
(2009)
C.H. Mallinckrodt et al.
Assessing and interpreting treatment effects in longitudinal clinical trials with missing data
Biol Psychiatry
(2003)
R.S. Kahn et al.
Efficacy and tolerability of once-daily extended release quetiapine fumarate in acute schizophrenia: a randomized, double-blind, placebo-controlled study
J Clin Psychiatry
(2007)
B. Bandelow et al.
Extended-release quetiapine fumarate (quetiapine XR): a once-daily monotherapy effective in generalized anxiety disorder: data from a randomized, double-blind, placebo- and active-controlled study
Int J Neuropsychopharmacol
(2010)
R. Weisler et al.
Extended release quetiapine fumarate monotherapy for major depressive disorder: results of a double-blind, randomized, placebo-controlled study
CNS Spectr
(2009)
M. Sanford et al.
Quetiapine: a review of its use in the management of bipolar depression
CNS Drugs
(2012)

M. Nord et al.

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

Int J Neuropsychopharmacol

(2011)

Once-daily Seroquel XR (quetiapine fumarate) extended-release tablets [US prescribing information]

Declaration of Helsinki

BMJ

(1996)

International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use

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Somnolence is a common adverse effect of antipsychotic drugs used to treat psychotic disorders. It causes problems in many areas of life, such as gainful employment, driving, childcare, and social interactions. Somnolence is a major problem for a relatively new antipsychotic drug, lurasidone, whose dose-effect relationship remains unclear. Based on data from a bioequivalence study of two 40 mg lurasidone hydrochloride tablets, we designed two case-control studies to explore the correlation between somnolence and exposure to lurasidone and determine the factors associated with lurasidone-induced somnolence. In the first case-control study, lurasidone was administered to healthy volunteers; 30 experienced somnolence (as pre-defined) but 29 did not. Moreover, plasma concentration at 1 h was significantly associated with somnolence (OR = 1.124; p = 0.001). In the second case-control study, 48 volunteers administered lurasidone were classified into somnolence and no-somnolence groups based on different time-related criteria. We observed a positive association between plasma concentration at 0.75 h and somnolence (OR = 1.024; p = 0.002). Receiver operating characteristic analysis revealed that a plasma lurasidone concentration >21.65 ng/mL 1 h after administration strongly predicted somnolence. Our findings in healthy volunteers need to be further validated in patients in clinical settings to determine the optimal dose and duration of lurasidone administration.
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We investigated the comparative efficacy and tolerability of pharmacological treatment strategies for the treatment of acute bipolar depression.
A systematic review and network meta-analysis was conducted by searching eight registries for published and unpublished, double-blind, randomized controlled trials of pharmacotherapies for the acute treatment of bipolar depression.
PRISMA guidelines were used for abstracting data, while the Cochrane Risk of Bias Tool was used to assess data quality. Data extraction was done independently by two reviewers, with discrepancies resolved by consensus. Data were pooled using a random-effects model.
Primary outcomes were efficacy (response and remission rate) and acceptability (completion of treatment and dropouts due to adverse events). Summary odds ratios (ORs) were estimated using pairwise and network meta-analysis with random effects.
Identified citations (4,404) included 50 trials comprising 11,448 participants. Escitalopram, phenelzine, moclobemide, carbamazepine, sertraline, lithium, paroxetine, aripiprazole, gabapentin and ziprasidone appear to be ineffective as compared to placebo in treatment of bipolar depression. Divalproex, olanzapine/fluoxetine, olanzapine, quetiapine, cariprazine, and lamotrigine, appear to be effective as compared to placebo in treatment of bipolar depression according to the network meta-analysis. Aripiprazole showed higher discontinuation rates versus placebo due to the appearance of any adverse event. Quetiapine was better than placebo at reducing treatment-emergent affective switches. For Bipolar I Disorder, cariprazine, fluoxetine, imipramine, lamotrigine, lurasidone, olanzapine-fluoxetine, and olanzapine were significantly better than placebo at response, while fluoxetine, imipramine, cariprazine, lurasidone, olanzapine-fluoxetine, and olanzapine were significantly better than placebo at remission.
These results could serve evidence-based practice and inform patients, physicians, guideline developers, and policymakers on the relative benefits of the different antidepressants, antipsychotics, and mood-stabilizing agents for the treatment of bipolar depression.
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Patients with bipolar disorder (BD) do not always achieve full remission between episodes. Subthreshold symptoms (depressive, manic or mixed) represent a major cause of relapse and disability in these patients. Immediate release (IR) and extended release (XR) formulations of quetiapine are both indicated for short and long-term treatment of BD. The aim of this study was to evaluate the efficacy of quetiapine XR vs placebo in subthreshold symptomatology when added to previous mood stabilizer treatment. A pilot phase IIIB, multicentre, prospective, placebo controlled, randomized, double blinded study of 12 weeks follow-up was performed (NCT01197846). Patients were randomized to quetiapine XR 300 mg or placebo once daily. The primary outcome was the mean change between quetiapine XR and placebo from baseline to study endpoint (week 6) in the Montgomery-Åsberg Depression Rating Scale (MADRS). Quetiapine XR 300 mg (n=16) significantly improved depressive subthreshold symptoms compared with placebo (n=16) after 6 weeks (P=0.021). Early response (reduction of at least the 20% of the MADRS total score) and remission rate (reduction in MADRS total score <8 and YMRS<8) did not show differences between groups. Quetiapine XR did not show superiority vs placebo when evaluating subthreshold manic symptoms, instead it was superior when evaluating functioning (GAF score) in BD type I patients (P=0.005). The most common adverse events were somnolence (9.1%), increased appetite, dry mouth and dizziness (6.8%). Quetiapine XR 300 mg once daily was significantly more effective than placebo in depressive subthreshold symptoms. Adverse events were consistent with the known side effects of quetiapine.
Change in daytime sleepiness and cognitive function in a 6-month, double-blind study of lurasidone and quetiapine XR in patients with schizophrenia
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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.
Daytime sleepiness is a commonly reported adverse effect associated with psychotropic agents that may impair cognitive performance and functioning. The objective of this post-hoc analysis was to evaluate the long-term effects of lurasidone and quetiapine XR on daytime sleepiness and neurocognitive performance during a 6-month, double-blind continuation study, in subjects who completed an initial 6-week, randomized, placebo-controlled trial comparing these agents. Daytime sleepiness, cognitive performance, and health-related quality of life were assessed with the Epworth Sleepiness Scale (ESS), CogState computerized battery, and the Quality of Well-Being (QWB-SA) Scale, respectively. Treatment with flexible-dose lurasidone 40–160 mg/d, administered once daily in the evening, was associated with significantly reduced daytime sleepiness compared with flexibly dosed quetiapine XR 200–800 mg/d (p = 0.03, effect size = 0.36) at week 32 (month 6 of the continuation study endpoint). Incidence of markedly high sleepiness (ESS > 10) was significantly higher in the quetiapine XR (200–800 mg/d) group compared with the lurasidone (40–160 mg/day) group at both months 3 and 6 visits (p < 0.05). Lurasidone (40–160 mg/d) significantly improved neurocognitive performance compared to quetiapine XR (200–800 mg/d) before (effect size = 0.49) and after adjustment (effect size = 0.45) for sleepiness effect (p = 0.008 and 0.010, respectively). Increased daytime sleepiness was significantly associated with reduced neurocognitive performance (p = 0.019) and quality of well-being (p = 0.05). Our findings suggest that clinicians should actively monitor patients for the presence of daytime sleepiness due in part to its potential impact on neurocognitive performance and well-being.
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 Research
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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.
To assess daytime cognitive performance, sedation and treatment satisfaction in patients with schizophrenia receiving quetiapine extended release (XR) versus quetiapine immediate release (IR).
Phase IV prospective, double-blind, crossover study (NCT01213836). Patients (N = 66) with stable schizophrenia, treated with XR or IR before study start, were randomised (1:1) to treatment with XR followed by IR, or IR followed by XR, at the dose received before enrolment (400–750 mg). After 10–16 days on formulation 1, patients switched to formulation 2. Assessments from three post-dose visits (≥ 5 days following treatment on each formulation) were analysed. Cognitive performance was measured by CogState Cognition testing. Sedation, treatment satisfaction and safety were also assessed.
65 patients received treatment (69.2% male; mean age 37.8 years). Daytime cognitive functioning was similar for both groups; adjusted mean difference in Attentional Composite Score in XR and IR patients was 0.005 (p = 0.907). Patients receiving XR were less sedated than those receiving IR, (Bond–Lader visual analogue scale score, mean [SD]: 23.5 [19.0] vs 28.6 [21.4]); estimated overall treatment difference: 5.2 (95% CI: 2.3, 8.2; p < 0.0009). Patients receiving XR reported feeling less sedated than those on IR (Stanford Sleepiness Scale, mean [SD]: 2.4 [0.9] vs 2.6 [1.0]); estimated overall treatment difference: 0.28 (95% CI: 0.12, 0.43; p < 0.0008). Patients reported improved overall treatment satisfaction (p = 0.0417) and milder side effects (p = 0.0035) with XR. Safety profile was similar in both groups.
Daytime cognitive performance was similar for both groups. XR was associated with less daytime sedation and improved patient satisfaction than IR.

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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

abstract

Background

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Patients and Methods

Study Patients

Discussion

Conclusions

Conflicts of Interest

Acknowledgments

Prog Neuropsychopharmacol Biol Psychiatry

J Affect Disord

J Affect Disord

Clin Ther

Clin Ther

Biol Psychiatry

Efficacy and tolerability of once-daily extended release quetiapine fumarate in acute schizophrenia: a randomized, double-blind, placebo-controlled study

J Clin Psychiatry

Extended-release quetiapine fumarate (quetiapine XR): a once-daily monotherapy effective in generalized anxiety disorder: data from a randomized, double-blind, placebo- and active-controlled study

Int J Neuropsychopharmacol

Extended release quetiapine fumarate monotherapy for major depressive disorder: results of a double-blind, randomized, placebo-controlled study

CNS Spectr

Quetiapine: a review of its use in the management of bipolar depression

CNS Drugs

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

Int J Neuropsychopharmacol

Once-daily Seroquel XR (quetiapine fumarate) extended-release tablets [US prescribing information]

Declaration of Helsinki

BMJ

International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use

Pharmacokinetic, bioavailability, & bioequivalence
Original research
Self-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