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

doi:10.1016/j.clinthera.2009.03.002

Clinical Therapeutics

Volume 31, Issue 3, March 2009, Pages 492-502

https://doi.org/10.1016/j.clinthera.2009.03.002 Get rights and content

Abstract

Objectives: The primary study objective was to assess the time course and intensity of sedation after administration of immediate-release (IR) and extended-release (XR) quetiapine fumarate in healthy subjects during dose initiation. The tolerability of the 2 formulations was also evaluated.

Methods: This was a randomized, double-blind, double-dummy, 2-period crossover study in healthy adult (age 18–50 years) subjects. It employed the dose-initiation schedule used in studies of the 2 quetiapine formulations in patients with bipolar depression: 50 mg on day 1, 100 mg on day 2, 200 mg on day 3, and 300 mg on days 4 and 5. Doses were administered in the morning. The primary end point was the level of sedation 1 hour after dosing on day 1, as rated by subjects using a visual analog scale (VAS) ranging from 0 = alert to 100 = drowsy. Secondary VAS end points included sedation over a 14-hour period on day 1, and on days 2 through 5. Blood was drawn on day 5 of both periods for determination of plasma drug concentrations by a liquid chromatography method with tandem mass-spectrometric detection. Adverse events (AEs) were recorded throughout the study.

Results: Sixty-three subjects were enrolled in the study, comprising the safety population. The perprotocol population consisted of 58 subjects (79.0% male, 21.0% female; 67.2% black, 24.1% white; mean age, 31.8 years; mean weight, 80.7 kg). One hour after dosing on day 1, sedation was significantly greater with quetiapine IR than with quetiapine XR (mean VAS score, 33.2 vs 11.3, respectively; P < 0.001). There were no significant differences in sedation between formulations at 7 hours after dosing (64.5 and 53.6), 8 hours after dosing (46.9 and 50.8), or 14 hours after dosing (both, 12.7). On day 1, numerically more subjects had a VAS score>75 (substantial sedation) 1 hour after dosing in the quetiapine IR group than in the quetiapine XR group (14 vs 4 subjects). On day 5, the mean (95% CI) quetiapine C_max for the IR and XR formulations was 689.19 (605.83–784.02) and 381.70 (341.40–426.76) ng/mL; the mean was AUC_0–11 was 2835.89 (2517.92–3194.02) and 2515.21 (2281.76-–2772.55) ng · h/mL; and the median T_max was 2.0 and 5.0 hours. The incidence of any AEs was 21.7% with quetiapine IR and 9.8% with quetiapine XR.

Conclusion: In these healthy subjects, quetiapine XR was associated with a lower intensity of self-reported sedation compared with quetiapine IR. ClinicalTrials.gov Identifier: NCT00702676; Astra Zenecaclinicaltrials.com Identifier: D1443C00033.

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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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Citation 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.
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.
Effectiveness of different dosing regimens of risperidone and olanzapine in schizophrenia
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The objective of this study was to evaluate the effectiveness and impact of once- versus twice-daily dosing of risperidone and olanzapine on clinical outcomes in patients with schizophrenia. Data from phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study were used. Patients with schizophrenia were randomly allocated to treatment with risperidone and olanzapine, and were also randomly assigned to once-daily (N=173 and 169, respectively) or twice-daily (N=168 and 167, respectively) dosing and followed for up to 18 months. Discontinuation rate and time to discontinuation were used as primary outcome measures to compare the two groups. The following outcome measures were also analyzed: efficacy, safety, medication adherence, adverse events, and concomitant psychotropic medications. No significant differences in discontinuation rates and time to discontinuation were observed between the once- and twice-daily dosing groups (P>0.05) in patients receiving risperidone or olanzapine. The once-daily dosing group demonstrated significantly lower mean daily doses of risperidone and olanzapine across phase 1, and lower rates of hospitalization for exacerbation of schizophrenia, sleepiness, and orthostatic faintness in patients receiving olanzapine (P<0.05) compared to the twice-daily dosing group. No significant differences were found in any other outcome measures between the two dosing groups. In conclusion, effectiveness and efficacy outcomes between once- and twice-daily dosing for risperidone and olanzapine were not significantly different. However, in view of the lower mean dose and better side effect profile, it is advisable to adhere to a once-daily dosing regimen, especially in the case of olanzapine.
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)
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Citation Excerpt :
Both formulations have a demonstrated efficacy and established tolerability profile (Peuskens, 2011) and have been shown to improve cognitive function in patients with schizophrenia (predominantly outpatients) (Kivircik Akdede et al., 2005) and in hospitalised patients with an acute schizophrenic episode (Riedel et al., 2010). However, previous studies have shown that quetiapine XR shows less daytime sedation than quetiapine IR in the first few hours post-dose, when given at a starting dose of 50 mg in the morning in healthy volunteers and patients with bipolar depression, though later time points (8–14 h post-dose) showed no treatment differences in sedation (Datto et al., 2009; Riesenberg et al., 2012). In addition, the time to maximal concentration for quetiapine IR has been reported as 2.0 h, which would account for the time frames observed in previous studies and is the time point used in the present study (Datto et al., 2009).
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.
Effect of quetiapine XR on depressive symptoms and sleep quality compared with lithium in patients with bipolar depression
2014, Journal of Affective Disorders
Bipolar depression is one of the most serious psychiatric conditions. In addition, sleep disturbance in bipolar disorder is common, and therapeutic agents restoring sleep disturbances in bipolar disorder patients will be clinically beneficial. In the current study, we compared the effect of quetiapine XR with lithium on depressive symptoms and sleep in bipolar depression patients during 8 weeks of trial.
An open-label, randomized comparison of sleep-activity and depressive symptoms between 8-week quetiapine XR monotherapy and lithium monotherapy for bipolar depression was conducted. Each assessment consisted of HDRS-17, Clinical Global Impression-severity (CGI-S), and self-reported Pittsburgh Sleep Quality Index (PSQI). Actigraphy-measured sleep parameters were assessed.
A total of 42 patients (35.7±10.9 years; gender: male 15, female 27) with bipolar depression were screened out. Out of 42 patients, six patients were excluded before randomization. After randomization, seven patients were withdrawn. Twenty-nine patients with more than two visits after randomization (lithium group: 17, quetiapine XR group: 12, mean age: 36.1±10.4, gender: male 13, female 16) were included in the final analysis. In both groups, Hamilton Depression Rating Scale (HDRS) scores were significantly decreased at weeks 1, 2, 4, 6, and 8 compared with baseline. Remission rate (HDRS≤7) in the quetiapine XR was significantly higher than that of the lithium group. In the quetiapine XR group, PSQI scores at weeks 1, 2, 4, 6, and 8 was significantly decreased compared with baseline. Sleep efficiency at weeks 6 and 8 was significantly increased. WASO at week 8 was significantly decreased.
First, the present study was conducted with the relatively small number of study subjects. Second, bias could have affected the study results due to its open-label design. Third, study subjects were made up of high proportion of bipolar II disorder patients.
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Clinical Therapeutics

Abstract

References (28)

Pharmacokinetic profiles of extended release quetiapine fumarate compared with quetiapine immediate release

Prog Neuropsychopharmacol Biol Psychiatry

Disability and its treatment in bipolar disorder patients

Bipolar Disord

Acute treatment of mania: An update on new medications

Curr Psychiatry Rep

New approaches in managing bipolar depression

J Clin Psychiatry

Bipolar depression: Trial-based insights to guide patient care

Dialogues Clin Neurosci

Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: Update 2007

Bipolar Disord

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

Seroquel (quetiapine fumarate) [US prescribing information]

A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression

Am J Psychiatry

Efficacy of quetiapine monotherapy in bipolar I and II depression: A double-blind, placebocontrolled study (the BOLDER II study) [published correction appears in J Clin Psychopharmacol. 2007;27: 51]

J Clin Psychopharmacol

Efficacy of quetiapine monotherapy for the treatment of depressive episodes in bipolar I disorder: A post hoc analysis of combined results from 2 double-blind, randomized, placebo-controlled studies

J Clin Psychiatry

A double-blind, placebo-controlled study with acute and continuation phase of quetiapine and paroxetine in adults with bipolar depression (EMBOLDEN II)

Bipolar Disord

A double-blind, placebocontrolled study with acute and continuation phase of quetiapine and lithium in adults with bipolar depression (EMBOLDEN I)

Int J Neuropsychopharmacol

Cited by (58)

Factors associated with increased risk of lurasidone-induced somnolence: Two case-control studies based on one bioequivalence trial in healthy volunteers

Change in daytime sleepiness and cognitive function in a 6-month, double-blind study of lurasidone and quetiapine XR in patients with schizophrenia

Effectiveness of different dosing regimens of risperidone and olanzapine in schizophrenia

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)

Effect of quetiapine XR on depressive symptoms and sleep quality compared with lithium in patients with bipolar depression

Clozapine administered once versus twice daily: Does it make a difference?