Extended Release Quetiapine Research Articles

P02-14 - Effects of once-daily adjunct quetiapine XR on sleep disturbance in patients with mdd: a pooled analysis from two acute studies

IntroductionDisrupted sleep is common in depression.ObjectivesInvestigate effects of adjunct extended release quetiapine fumarate (QTP-XR) on sleep disturbance and quality in patients with MDD and inadequate response to antidepressant (AD) therapy.MethodsData were pooled from two (D1448C00006/D1448C00007) 6-week, double-blind, randomised, placebo (placebo+AD)-controlled studies of adjunct QTP-XR (15 0 mg/day and 300 mg/day). Primary endpoint: MADRS total score change versus placebo+AD. Secondary endpoints (post hoc): change from randomisation in MADRS item 4 (reduced sleep), HAM-D items 4, 5 and 6 (early-, middle- and late-insomnia), sleep disturbance factor (HAM-D items 4+5+6) and sleep quality (PSQI global score). MADRS total score change in patients with baseline HAM-D sleep disturbance factor score > = 4 or < 4 (high and low sleep disturbance, respectively) was evaluated.Results919 patients received adjunct QTP-XR: 150 mg/day (n = 309), 300 mg/day (n = 307), placebo+AD (n = 303). At Week 6, adjunct QTP-XR (both doses) reduced MADRS item 4, HAM-D sleep disturbance factor, HAM-D items 4, 5 and 6 and PSQI global scores from baseline versus placebo+AD (p < 0.001). In patients with baseline HAM-D>=4 (n = 226, 215 and 210, respectively) adjunct QTP-XR (both doses) improved (p< 0.01) MADRS total score versus placebo+AD from Week 1 onward. In patients with baseline HAM-D< 4 (n = 83, 92, 93, respectively) adjunct QTP-XR (both doses) improved (not statistically significantly) MADRS total score versus placebo+AD at Week 6.ConclusionsAdjunct QTP-XR significantly restored sleep and improved sleep quality in patients with MDD and inadequate response to AD. Significant improvement in depressive symptoms was demonstrated with adjunct QTP-XR in patients with MDD and high baseline sleep disturbance. AstraZeneca funded.

P03-242 - Efficacy and tolerability of quetiapine XR 400/600/800mg/day in acute schizophrenia: a post-hoc analysis of data from two pooled randomised studies

IntroductionData from two, identically designed, placebo-controlled, randomised, double-blind clinical trials (D1444C00132+D1444C00133) for once-daily extended-release quetiapine fumarate (QTP-XR) were pooled and analysed.ObjectiveEvaluate dose response, efficacy and safety for QTP-XR in schizophrenia.MethodsPost-hoc analysis of data from patients receiving QTP-XR 400, 600, 800 mg/day or placebo. Endpoints: least squares means (LSM) change from baseline to Day 42 in PANSS total and positive and negative subscale scores. No corrections for multiplicity were performed. Adverse events (AEs) were recorded.Results914 patients were included; PANSS scores were assessed in the MITT population (n = 889). LSM change from baseline in PANSS total score diverged significantly from placebo at: Day 14 for QTP-XR 800 mg/day (-15.3 vs -12.1 for placebo; p = 0.018); Day 21 for 600 mg/day (-17.3 vs -14.2; p = 0.039); Day 42 for 400 mg/day (-19.2 vs -15.4; p = 0.033).Jonckheere-Terpstra analysis of change in PANSS total score at Day 42 showed a significant QTP-XR dose response (p = 0.0196; p < 0.001 with placebo). PANSS positive scores diverged by Day 21 for both QTP-XR 800 (-5.7 vs -4.8; p = 0.049) and 600 mg/day (-5.8 vs -4.8; p = 0.046). PANSS negative scores diverged by Day 21 (-4.0 vs -3.2; p = 0.040) and 42 (-4.8 vs -3.6; p = 0.009) for QTP-XR 800 and 600 mg/day, respectively. AEs occurred in 59.4%, 66.5%, 62.1% and 56.2% of patients in the QTP-XR 800, 600, 400 mg/day and placebo groups, respectively. Most common AEs were somnolence, dry mouth, sedation, insomnia, dizziness, headache, constipation and nausea.ConclusionsQTP-XR was generally well tolerated and demonstrated efficacy that increased with dose in schizophrenia.Financial support: AstraZeneca.

P03-246 - Extended-release quetiapine fumarate (quetiapine XR) versus risperidone in the treatment of depressive symptoms in schizophrenic or schizoaffective patients

IntroductionDepressive symptoms are associated with poor outcomes, increased risk of relapse and high suicide rates in patients with schizophrenia and schizoaffective disorder (1, 2).ObjectiveAssess the efficacy of quetiapine XR (QTP-XR) versus risperidone on depressive symptoms in schizophrenia and schizoaffective disorder.MethodsA randomised, open-label, parallel-group, flexible-dose study (NCT00640562).Primary endpointLSM change from baseline to Week 12 in Calgary Depression Scale for Schizophrenia (CDSS) (3) score. Secondary endpoints: change in HAM-D and PANSS scores, and adverse events (AEs). No scorrection for multiplicity was done for the secondary endpoints.Results216 patients received QTP-XR (n = 109; 400–800 mg/day) or risperidone (n = 107; 4–6 mg/day). From baseline, QTP-XR significantly reduced CDSS, HAM-D and PANSS negative total scores compared with risperidone (QTP-XR vs risperidone: -7.31 versus -5.53, p = 0.0107; -14.68 versus -11.53, p = 0.0005; -8.23 versus -5.45, p = 0.0008, respectively). No major differences in AEs were observed between QTP-XR and risperidone. Four serious AEs were experienced with QTP-XR and 5 with risperidone. Two patients receiving QTP-XR died (unrelated to study drug). Prolactin levels were significantly reduced from baseline with QTP-XR versus risperidone (-9.15 ng/mL and +22.18 ng/mL respectively; p < 0.0001). No important differences were seen in other laboratory parameters.ConclusionsIn this study, QTP-XR was superior to risperidone at reducing depressive symptoms in schizophrenia or schizoaffective disorder according to CDSS, HAM-D and PANSS negative scores.

Extended release quetiapine fumarate (quetiapine XR) monotherapy as maintenance treatment for generalized anxiety disorder

The objective of this study was to evaluate the efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) as maintenance monotherapy for patients with generalized anxiety disorder (GAD). Time-to-event (anxiety symptom recurrence; maximum 52 weeks) multicenter, randomized-withdrawal, parallel-group, double-blind, placebo-controlled study of quetiapine XR (50-300 mg/day) following open-label run-in (4-8 weeks) and open-label stabilization (≥ 12 weeks). Primary variable: time from randomization to anxiety event. Secondary variables included: Hamilton Anxiety Rating Scale (HAM-A) total, HAM-A psychic/somatic anxiety factors, Clinical Global Impression-Severity of Illness (CGI-S), and Quality of Life, Enjoyment and Satisfaction Questionnaire (Q-LES-Q) scores; adverse events (AE) reporting. Four hundred and thirty-two patients, stabilized on quetiapine XR, were randomized to continue quetiapine XR (N=216) or switch to placebo (N=216). Risk of anxiety symptom recurrence was significantly reduced by 81% for quetiapine XR versus placebo: hazard ratio=0.19 (95% confidence interval 0.12-0.31; P<0.001). Fewer patients receiving quetiapine XR (N=22, 10.2%) than placebo (N=84, 38.9%) experienced anxiety symptom recurrence. Significant differences were observed between quetiapine XR and placebo in: HAM-A total, psychic/somatic, CGI-S (all P<0.001) and Q-LES-Q (P<0.05) scores. AEs (>10%) during open-label treatment were dry mouth, sedation, somnolence, dizziness, fatigue, and constipation. During randomized treatment, the most common AEs for quetiapine XR were headache and nasopharyngitis. Quetiapine XR monotherapy reduced the risk of anxiety symptom recurrence in patients with GAD stabilized on quetiapine XR, with tolerability results consistent with the known profile of quetiapine.

The management of schizophrenia: focus on extended-release quetiapine fumarate

Effective management of schizophrenia remains a significant clinical challenge. While antipsychotic medications have proven efficacy in this disease, there remains an opportunity to further improve symptom control and long-term relapse prevention. Also, a number of factors, including tolerability and complex dosing regimens, can result in nonadherence to medication. Quetiapine is an atypical antipsychotic with proven efficacy and an established tolerability profile in schizophrenia. The once-daily extended-release formulation (quetiapine XR) offers a simplified dosing regimen and titration schedule. Short-term clinical studies have shown that quetiapine XR (400–800 mg/d) is efficacious in the acute treatment of schizophrenia, while a long-term study has shown that quetiapine XR was significantly more effective than placebo at preventing relapse. Furthermore, an investigation in which stable patients switched from the immediate-release formulation (quetiapine IR) to quetiapine XR showed that quetiapine XR is generally well tolerated and has no loss of efficacy compared with quetiapine IR. In patients who experienced insufficient efficacy or poor tolerability on their previous antipsychotic, switching to quetiapine XR significantly improved efficacy compared with the previous treatment. In conclusion, quetiapine XR is an effective and generally well tolerated treatment for schizophrenia. Furthermore, once-daily dosing may improve patient adherence, which may impact positively on patient outcomes.

A Pilot, 8-Week, Placebo Lead-In Trial of Quetiapine Extended Release for Depression in Midlife Women

Perimenopausal and early postmenopausal women have shown an increased risk for developing depression (new onset or recurrent); concomitant vasomotor and other menopause-related complaints significantly affect quality of life and overall functioning. This study examined the effects of quetiapine extended release (XR) in midlife women with major depressive disorder who also reported significant menopause-related symptoms. Forty eligible women with major depressive disorder entered a 2-week, placebo lead-in phase, followed by an 8-week open trial with quetiapine XR, flexible dose, 150-300 mg/d. The primary outcome measure (depressive symptoms) was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) scores. Other measures included menopause symptoms (Greene Climacteric Scale total scores and subscores) and the impact of hot flashes on functioning (Hot Flash-Related Daily Interference Scale). Weight, cholesterol, triglycerides, and glucose levels were monitored. Data from 24 subjects (modified intent-to-treat, last observation carried forward; quetiapine XR mean dose, 191 [SD, 55] mg/d) showed improvement in depressive and menopause-related symptoms, that is, reduction in MADRS, GCS, and Hot Flash-Related Daily Interference Scale scores (P < 0.01 for all comparisons). Seventeen subjects were considered responders (>50% reduction in MADRS scores); 15 achieved remission (MADRS<10). Main adverse effects included drowsiness and dry mouth. Based on these preliminary results, quetiapine XR should be further examined in larger, controlled trials for the management of depressed, symptomatic midlife women.

Leucopenia due to quetiapine abuse and combination with olanzapine: a case report

Leucopenia due to quetiapine abuse and combination with olanzapine: a case report Quetiapine is an atypical antipsychotic that can be abused. Olanzapine is an another atypical antipsychotic that is similar to quetiapine in chemical structure and cases of leucopenia after olanzapine use have rarely been presented in the literature. In this report, we presented a case of high dose quetiapine abuse and olanzapine combination treatment leading to leucopenia. Blood levels returned to normal levels in a short period of time both by passing to extended release quetiapine and decreasing the daily dosage.

Efficacy and tolerability of extended release quetiapine fumarate monotherapy as maintenance treatment of major depressive disorder: a randomized, placebo-controlled trial

evaluate the efficacy (time to recurrence of depressive symptoms) of once daily extended release quetiapine fumarate (quetiapine XR) as maintenance monotherapy treatment to prevent relapse for major depressive disorder (MDD). Time-to-event (maximum 52 weeks), double-blind, multicenter, randomized withdrawal, placebo-controlled study of quetiapine XR (50-300 mg/day) comprising four treatment phases: enrollment (up to 28 days), open-label run-in (4-8 weeks), open-label stabilization (12-18 weeks), and randomization (up to 52 weeks). Seven hundred and seventy-six patients stabilized on quetiapine XR were eligible for randomization (Montgomery-Åsberg Depression Rating Scale [MADRS] score ≤12 and Clinical Global Impression-Severity of Illness [CGI-S] score ≤3); 391 received quetiapine XR and 385 received placebo (same dose as last open-label visit). Primary endpoint: time to recurrence of depressive event from randomization. Secondary outcomes included changes from randomization in MADRS total, CGI-S, Pittsburgh Sleep Quality Index (PSQI) global, and Hamilton Anxiety Rating Scale (HAM-A) total scores. Adverse events were recorded throughout. Risk of recurrence of depressive event was significantly (P<.001) reduced by 66% (HR=.34; 95% CI: .25, .46) in patients randomized to continue with quetiapine XR versus patients randomized to switch to placebo. During the randomized phase, quetiapine XR maintained improvements in secondary outcomes (P<.001 for all): MADRS (0.15 versus 2.03), CGI-S (-0.03 versus 0.23); PSQI global (0.06 versus 1.35), and HAM-A total score (0.20 versus 1.58), respectively. The most common AEs (>10% any group) during the randomized period were headache and insomnia. Quetiapine XR maintenance therapy significantly reduced the risk of a depressive event in patients with MDD stabilized on quetiapine XR, with a safety and tolerability profile consistent with the known profile of quetiapine.

Efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) monotherapy in major depressive disorder: A placebo-controlled, randomized study

Background Evaluate the efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) once-daily monotherapy for patients with major depressive disorder (MDD). Methods In this 10-week, (8-week active treatment phase and 2-week drug-discontinuation/tapering phase), multicenter, parallel-group, placebo-controlled, double-blind, randomized, Phase III study (D1448C00003: Opal), patients initially received quetiapine XR 150 mg/day or placebo. At Week 2, inadequate responders (< 20% reduction in MADRS total score) were up-titrated to 300 mg/day quetiapine XR or matching placebo for the final 6 weeks. Primary endpoint: change from randomization to Week 8 in MADRS total score. Secondary endpoints included: MADRS response (≥ 50% reduction in total score from randomization) and changes from randomization to Week 8 in HAM-D and CGI-S. Results 310 patients were randomized. At Week 8, quetiapine XR significantly reduced mean MADRS total score versus placebo (−16.49 vs −13.10, respectively; p < 0.01). Mean MADRS score was significantly reduced by quetiapine XR versus placebo at Week 1 ( p < 0.05). MADRS response rates were significantly greater at Week 8 for quetiapine XR versus placebo (61.9% vs 48.0%, respectively; p < 0.05). Significant changes in HAM-D total score and CGI-S were seen at Week 8 for quetiapine XR versus placebo. Withdrawal rates due to AEs were 9.9% and 2.6% for quetiapine XR and placebo, respectively. Common AEs (> 10% any group during the randomized phase) for quetiapine XR and placebo, respectively were dry mouth (32.9% and 6.5%), sedation (21.7% and 1.9%), somnolence (20.4% and 5.2%), and headache (10.5% and 10.3%). Limitations The study was not designed to compare quetiapine XR 150 mg/day and 300 mg/day; it was intended to reflect dose titration that might occur in clinical practice. Conclusions Quetiapine XR monotherapy is effective in patients with MDD, with symptom improvement seen as early as Week 1, and tolerability results consistent with the known profile of quetiapine.

P.2.a.034 Impact of methodology on the efficacy of extended release quetiapine fumarate in major depressive disorder

P.2.a.034 Impact of methodology on the efficacy of extended release quetiapine fumarate in major depressive disorder

Adjunctive Aripiprazole, Olanzapine, or Quetiapine for Major Depressive Disorder: An Analysis of Number Needed to Treat, Number Needed to Harm, and Likelihood to be Helped or Harmed

Objective: To describe the efficacy and safety of adjunctive aripiprazole, olanzapine, and quetiapine for major depressive disorder. Data sources: Published registration study reports, supplemented by clinical trial synopses as disclosed by manufacturers and product labeling. Study selection: All available reports of studies were identified. Data extraction: Descriptions of the principal results and calculation of number needed to treat (NNT) for response and remission and number needed to harm (NNH) for relevant dichotomous adverse outcomes were extracted. Likelihood to be helped or harmed (LHH) was subsequently calculated. Data synthesis: Three registration studies of adjunctive aripiprazole, 5 for olanzapine-fluoxetine combination, and 2 for quetiapine extended-release reveal NNT for response and remission to range from 7 to 14 and 7 to 13, respectively, for adjunctive antipsychotic versus antidepressant monotherapy, depending on the antipsychotic and/or dose. Adverse event profiles for the 3 different adjunctive antipsychotics are more diverse, with adjunctive aripiprazole more strongly associated with akathisia (NNH, 6), adjunctive olanzapine with weight gain (NNH, 3), and adjunctive quetiapine with somnolence (NNH, 5 for 300 mg/d and NNH, 6 for 150 mg/d). Conclusions: Number needed to treat and NNH can be used to quantify efficacy and tolerability outcomes and help place various therapeutic options into clinical perspective. Likelihood to be helped or harmed can illustrate to the clinician and the patient the trade-offs between obtaining potential benefits versus harms. In the case of the adjunctive second-generation antipsychotics approved for treating major depressive disorder, these trade-offs vary greatly among the choices available and require careful, individualized, patient-centered clinical decision making.

High-dose loading with extended release quetiapine

Extended release quetiapine fumarate (quetiapine XR) was initiated at the recommended maximum dose 800 mg and maintained at the same dose in five patients with schizophrenia. Although the loadings of quetiapine XR were well tolerated in four patients in these five cases, one patient with a history of cerebral infarction developed serious side-effects, notably bladder distention and dizziness. This case series indicates that loading with maximum dose quetiapine XR may be tolerable and used safely in most schizophrenia patients with no other concurrent disease such as brain infarction.

Long-term symptomatic remission of schizophrenia with once-daily extended release quetiapine fumarate: post-hoc analysis of data from a randomized withdrawal, placebo-controlled study

Despite available effective medications, many patients with schizophrenia do not become completely symptom free. We report analyses of data from a randomized, double-blind, placebo-controlled relapse prevention study of extended release quetiapine fumarate (quetiapine XR) using Remission in Schizophrenia Working Group criteria for symptomatic remission. During 16-week open-label stabilization, patients with stable schizophrenia were switched from their current antipsychotic to quetiapine XR (400, 600 or 800 mg/day flexibly dosed). One hundred and ninety-seven patients were randomized to either quetiapine XR or placebo (planned for 1 year or until relapse). The study was terminated early because the planned interim analysis showed quetiapine XR to be statistically superior to placebo in the primary outcome variable (time to schizophrenia relapse). One hundred and eighty of 195 (92.3%) patients with an available Positive and Negative Syndrome Scale assessment met symptomatic remission criteria at randomization (following 16 weeks' quetiapine XR). The risk of losing symptomatic remission was statistically significantly higher with placebo versus quetiapine XR: hazard ratio 0.39 (95% confidence interval: 0.19-0.81, P=0.009), that is, 61% risk reduction for quetiapine XR-treated versus placebo-treated patients. At 6 months postrandomization, the probability that patients would be in remission was 76% for quetiapine XR and 52% for placebo. Once-daily quetiapine XR was effective in preserving symptomatic remission in the longer-term treatment of patients with schizophrenia.

Safety and tolerability of once‐daily extended release quetiapine fumarate in acute schizophrenia: pooled data from randomised, double‐blind, placebo‐controlled studies

Extended release quetiapine fumarate (quetiapine XR) is a new formulation that allows once-daily dosing and a titration regimen that is simpler than that of immediate release quetiapine (quetiapine IR) and may potentially increase patients' adherence to their prescribed medication. The tolerability of quetiapine XR was examined in an analysis of pooled data from three Phase III, double-blind, placebo-controlled, randomised studies with quetiapine IR as a reference treatment. The overall incidence of adverse events (AEs) was similar for quetiapine XR (69.5%) and quetiapine IR (72.5%). Most AEs were mild to moderate in severity and in line with those observed with quetiapine IR. The more rapid dose titration of quetiapine XR did not produce any new safety concerns and was as well tolerated as the regimen for quetiapine IR. The results of this pooled analysis show that quetiapine XR administered once daily is generally as well tolerated as quetiapine IR given twice daily. These data, together with the simpler dose-titration of quetiapine XR that allowed therapeutically effective doses to be reached by Day 2, suggest that this formulation potentially may improve adherence in patients with schizophrenia.

Assuring That Double-Blind Is Blind

Assuring That Double-Blind Is Blind

Extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in major depressive disorder (MDD) in patients with an inadequate response to ongoing antidepressant treatment: a multicentre, randomized, double-blind, placebo-controlled study

This study evaluated once-daily extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in patients with major depressive disorder (MDD) with inadequate response to ongoing antidepressant treatment. In this 8-wk (6-wk active treatment/2-wk post-treatment drug-discontinuation/follow-up), multicentre, double-blind, placebo-controlled, Phase III study, 446 patients were randomized to quetiapine XR 150 mg/d, 300 mg/d, or placebo adjunct to ongoing antidepressant treatment. The primary endpoint was the change from randomization to week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score. At week 6, MADRS total scores significantly improved with quetiapine XR 300 mg/d vs. placebo (-14.7 vs. -11.7, p<0.01). Quetiapine XR 300 mg/d showed significant improvements vs. placebo for: MADRS total score from week 1 onwards; MADRS response [(> or = 50% total score reduction) 58.9% vs. 46.2%, p<0.05] and remission [(total score < or = 8) 42.5% vs. 24.5%, p<0.01] rates; Hamilton Depression Rating Scale (HAMD) (-13.53 vs. -10.80, p<0.01) and Clinical Global Impression-Severity of illness (CGI-S) change (-1.52 vs. -1.23, p<0.05) at week 6. For quetiapine XR 150 mg/d, improvements were not significantly different vs. placebo, except for MADRS (weeks 1 and 2) and HAMD (week 6) total scores. Withdrawal rates due to adverse events (AEs) were: quetiapine XR 150 mg/d 11.5%, 300 mg/d 19.5%, and placebo 0.7%. The most common AEs (>10%) with quetiapine XR were dry mouth, somnolence, sedation, dizziness, constipation, nausea, insomnia, headache, and fatigue. In this study, quetiapine XR 300 mg/d as adjunctive therapy in patients with MDD with an inadequate response to ongoing antidepressant treatment was effective at week 6. However, the difference from placebo for quetiapine XR 150 mg/d at week 6 was not statistically significant. Both doses studied (150 and 300 mg/d) were effective at week 1 and generally well tolerated.

Role of extended release quetiapine in the management of bipolar disorders

Atypical antipsychotics have become a widely utilized component of the bipolar disorder treatment armamentarium, with approximately 45% of bipolar patients prescribed atypicals. Over the last decade all atypical drugs except for clozapine have received a Food and Drug Administration (FDA) bipolar indication. In October 2008, the FDA approved quetiapine XR monotherapy for the treatment of acute depressive episodes of bipolar disorder and acute manic or mixed episodes in bipolar I disorder based on two placebo-control trials. Quetiapine was also approved as adjunct therapy with lithium and divalproex for the treatment of acute manic or mixed episodes as well as maintenance of bipolar I disorder. In contrast to immediate release quetiapine which may require a twice-daily regimen, the XR formulation is intended for once-daily administration. This drug profile of quetiapine XR will address chemistry, pharmacodynamics, pharmacokinetics, metabolism, safety and tolerability and clinical trials in bipolar disorder.

P01-79 - Pet-measured occupancy of the D2 receptor: a comparison of quetiapine fumarate immediate-and extended-release formulations in healthy subjects

ObjectivesDeveloped as an antipsychotic, quetiapine displays moderate, transient occupancy of dopamine D2 receptors. Characterization of norquetiapine indicates this major human metabolite potently inhibits the norepinephrine transporter and binds to D2 receptors with affinity similar to quetiapine. Clinical pharmacology studies indicate pharmacodynamic differences between the immediate-release (IR) and the recently developed extended-release (XR) quetiapine formulation. The objectives of this study were to further investigate the pharmacokinetics of these formulations, and to relate D2-receptor occupancy to quetiapine and norquetiapine exposures.MethodsEleven healthy male volunteers, aged 20-45 years, underwent PET using the radioligand [11C]raclopride. After baseline measurements, quetiapine XR was administered once-daily for 8 days, with titration to 300 mg on Days 5-8. Quetiapine IR was administered at 300 mg daily on Days 9-12. PET measurements were repeated after the last doses of XR and IR at predicted times of Cmax. D2-receptor occupancy was calculated using a reference tissue model. Concomitant pharmacokinetic measurements were performed.ResultsFor quetiapine XR, mean D2-receptor occupancy at Cmax was 32% (SD ±11%; n=11). For quetiapine IR, mean D2-receptor occupancy at Cmax was 47% (SD ±9%; n=10). Quetiapine XR produced lower peak D2 occupancy than quetiapine IR in all subjects.ConclusionsPharmacokinetic differences between quetiapine XR and IR formulations translate to different profiles of brain receptor occupancy. Quetiapine XR was associated with lower peak D2-receptor occupancy than quetiapine IR at corresponding doses. This observation may provide important mechanistic underpinnings for emerging clinical data comparing the 2 quetiapine formulations.Supported by funding from AstraZeneca Pharmaceuticals LP.

PW01-03 - Evaluation of the effects of quetiapine XR monotherapy on sleep disturbance in patients with MDD

ObjectivesEvaluate the effects of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy on sleep disturbance in patients with major depressive disorder (MDD).MethodsPooled data from four 6- or 8-week placebo-controlled quetiapine XR (50-300mg/day, administered in the evening) monotherapy studies (D1448C00001, D1448C00002, D1448C00003, D1448C00004) were analysed. Primary endpoint: change from randomisation in Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Post-hoc analyses assessed changes in: MADRS item 4 (reduced sleep); Hamilton Rating Scale for Depression (HAM-D) items 4 (insomnia-early), 5 (insomnia-middle) and 6 (insomnia-late) and sleep disturbance factor (items 4+5+6); Pittsburgh Sleep Quality Index (PSQI) total and item scores. MADRS total score change was analysed for patients experiencing high (baseline HAM-D sleep disturbance factor score &gt;=4) and low (baseline HAM-D sleep disturbance factor score &lt; 4) sleep disturbance.ResultsIn total, 2,116 patients were randomised. At last assessment, quetiapine XR (all doses combined) significantly (p&lt; 0.001) reduced MADRS item 4, HAM-D sleep disturbance factor and items 4, 5 and 6 and PSQI total scores from baseline versus placebo. Quetiapine XR significantly (p&lt; 0.001) improved MADRS total score from baseline versus placebo at all time points in patients experiencing high sleep disturbance (n=865, quetiapine XR; n=514, placebo). Quetiapine XR improved MADRS total score versus placebo in patients with low sleep disturbance (n=252, quetiapine; n=121, placebo): difference significant at Weeks 2(p&lt; 0.001), 4(p&lt; 0.05) and 6(p&lt; 0.05).ConclusionsQuetiapine XR monotherapy improved symptoms of sleep disturbance in MDD and was effective against depressive symptoms in patients experiencing high and low sleep disturbance levels. AstraZeneca funded.

PW01-25 - Extended release quetiapine fumarate (quetiapine XR) in patients with MDD: results from 8 placebo-controlled studies

ObjectivesTo evaluate once-daily extended release quetiapine fumarate (quetiapine XR) as monotherapy (50, 150 and 300mg/day) (acute and maintenance treatment) or adjunct treatment (150 and 300mg/day) in patients with MDD.MethodsEight (7 acute, 1 maintenance) placebo-controlled studies were analysed. Primary endpoints: change from randomisation in Montgomery-Åsberg Depression Rating Scale (MADRS) scores (acute); time from randomisation to depressed event (maintenance). Statistical analyses: ANCOVA for difference between quetiapine XR and placebo in LSM change in MADRS total score from randomisation to study end (LOCF; acute); hazard ratio (HR) for time to recurrence of a depressed event (maintenance).ResultsFigure 1 shows treatment differences (95% CIs) for primary efficacy variable for the seven acute studies. Four monotherapy studies (D1448C00001, D1448C00002, D1448C00003, D1448C00014) were significant in favour of quetiapine XR; Study D1448C00004 (monotherapy) was not. Studies D1448C00006 and D1448C00007 were significant in favour of adjunct quetiapine XR. Time from randomisation to depressed event (Study D1448C00005) significantly increased with quetiapine XR; HR (95% CI): 0.34(0.25, 0.46); p&lt; 0.001; number of depressed events: 55, quetiapine XR; 132, placebo. Safety findings were consistent with the known tolerability profile of quetiapine.ConclusionsQuetiapine XR consistently demonstrated antidepressant efficacy, with 6/7 acute studies positive in favour of quetiapine XR (monotherapy or adjunct). Quetiapine XR maintenance therapy significantly reduced risk of a depressed event, demonstrating relapse prevention. AstraZeneca funded