Quetiapine monotherapy for mania associated with bipolar disorder: combined analysis of two international, double-blind, randomised, placebo-controlled studies

OBJECTIVE: To evaluate the efficacy and safety of quetiapine monotherapy for mania in bipolar disorder by an a priori defined combined analysis of data from two placebo-controlled studies. METHOD: The intent-to-treat (ITT) populations from two studies of patients with DSM-IV bipolar I disorder, manic episode, randomised to 12 weeks of double-blind treatment with quetiapine (up to 800 mg/day) or placebo were combined. The primary efficacy endpoint was change in Young Mania Rating Scale (YMRS) score from baseline to Day 21. Secondary endpoints included change from baseline in YMRS to Day 84, YMRS response and remission rates and change from baseline to Days 21 and 84 in the Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impressions (CGI), Clinical Global Impressions-Bipolar (CGI-BP) and the Positive and Negative Syndrome Scale (PANSS). These endpoints were analysed as continuous variables, using an analysis of covariance (ANCOVA), with the baseline as covariate. In order to account for any difference in response between studies, the analyses were stratified by study as a fixed effect, and centre as a random effect. The Cochran-Mantel-Haenszel test was used to analyse binary variables. A chi square test was used to compare the frequency of adverse events between the treatment groups. RESULTS: The combined analysis included a total of 403 patients from two quetiapine monotherapy studies in patients with bipolar I disorder. A significant improvement in YMRS score was observed from Day 4 (p = 0.021) onward in the quetiapine group compared with placebo. The treatment advantage of quetiapine over placebo continued to increase to Day 21 (p < 0.001) and Day 84 (p < 0.001). Significantly more quetiapine-treated than placebo-treated patients achieved a response (p < 0.001). The average quetiapine dose in responders was approximately 600 mg daily. Of adverse events occurring in > or = 5% of patients, quetiapine-treated patients had a significantly greater incidence versus placebo of somnolence (16.3% vs. 4.0%), dry mouth (15.8% vs. 3%), weight gain (9.1% vs. 1.5%) and dizziness (6.7% vs. 2.5%). CONCLUSIONS: The data from this combined analysis support the results from the individual studies and indicate that quetiapine monotherapy is effective across a broad range of mood symptoms, fast-acting and well tolerated in the treatment of mania.     

Quetiapine monotherapy for mania associated with bipolar disorder: combined analysis of two international,double-blind,randomised, placebo-controlled studies

ABSTRACT

Objective: To evaluate the efficacy and safety of quetiapine monotherapy for mania in bipolar disorder by an a priori defined combined analysis of data from two placebo-controlled studies.

Method: The intent-to-treat (ITT) populations from two studies of patients with DSM-IV bipolar I disorder, manic episode, randomised to 12 weeks of double-blind treatment with quetiapine (up to 800?mg/day) or placebo were combined. The primary efficacy endpoint was change in Young Mania Rating Scale (YMRS) score from baseline to Day 21. Secondary endpoints included change from baseline in YMRS to Day 84, YMRS response and remission rates and change from baseline to Days 21 and 84 in the Montgomery–Asberg Depression Rating Scale (MADRS), Clinical Global Impressions (CGI), Clinical Global Impressions – Bipolar (CGI-BP) and the Positive and Negative Syndrome Scale (PANSS). These endpoints were analysed as continuous variables, using an analysis of covariance (ANCOVA), with the baseline as covariate. In order to account for any difference in response between studies, the analyses were stratified by study as a fixed effect, and centre as a random effect. The Cochran–Mantel–Haenszel test was used to analyse binary variables. A chi square test was used to compare the frequency of adverse events between the treatment groups.

Results: The combined analysis included a total of 403 patients from two quetiapine monotherapy studies in patients with bipolar I disorder. A significant improvement in YMRS score was observed from Day 4 (?p = 0.021) onward in the quetiapine group compared with placebo. The treatment advantage of quetiapine over placebo continued to increase to Day 21 (?p < 0.001) and Day 84 (?p < 0.001). Significantly more quetiapine-treated than placebo-treated patients achieved a response (?p < 0.001). The average quetiapine dose in responders was approximately 600?mg daily. Of adverse events occurring in ≥ 5% of patients, quetiapine-treated patients had a significantly greater incidence versus placebo of somnolence (16.3% vs. 4.0%), dry mouth (15.8% vs. 3%), weight gain (9.1% vs. 1.5%) and dizziness (6.7% vs. 2.5%).

Conclusions: The data from this combined analysis support the results from the individual studies and indicate that quetiapine monotherapy is effective across a broad range of mood symptoms, fast-acting and well tolerated in the treatment of mania.     

Efficacy of extended release quetiapine fumarate monotherapy in patients with major depressive disorder: a pooled analysis of two 6-week, double-blind, placebo-controlled studies

Prospectively planned pooled analysis evaluating the efficacy of quetiapine extended release (XR) monotherapy in major depressive disorder (MDD). Data were pooled from two 6-week, randomized, double-blind, placebo-controlled studies of quetiapine XR in outpatients with MDD. The primary endpoint was Montgomery-?sberg Depression Rating Scale (MADRS) total score change from randomization at week 6. Other evaluations were MADRS response/remission, Hamilton Rating Scale for Anxiety, and subgroup analyses. A total of 968 patients were randomized to quetiapine XR, 150 mg/day (n=315), 300 mg/day (n=323), or placebo (n=330). The mean MADRS total score reductions from randomization were significant at week 6 with quetiapine XR, 150 mg/day (-14.7; P<0.001) and 300 mg/day (-14.7; P<0.001) versus placebo (-11.1), with significant reductions versus placebo from week 1 onward. Response rates (week 6): 52.7% (P<0.001) quetiapine XR 150 mg/day and 49.5% (P<0.001) quetiapine XR 300 mg/day versus placebo (33.0%). MADRS remission (score≤8; week 6): 23.5% (P=0.208) quetiapine XR 150 mg/day and 28.8% (P<0.01) quetiapine XR 300 mg/day versus placebo (19.4%). Quetiapine XR (both doses) significantly improved eight of 10 MADRS items versus placebo at week 6. The therapeutic effect of quetiapine XR was neither limited to nor driven by factors such as sex, age, or severity of depression. In patients with MDD, quetiapine XR (150 and 300 mg/day) monotherapy reduced depressive symptoms, with significant improvements compared with placebo from week 1 onward.     

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

Objectives: This study aimed to demonstrate efficacy of once-daily extended release quetiapine fumarate (quetiapine XR) versus placebo in patients with acute schizophrenia. Methods: 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. Results: 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. Conclusions: 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.     

Efficacy and tolerability of extended release quetiapine fumarate monotherapy in the acute treatment of generalized anxiety disorder: a randomized, placebo controlled and active-controlled study

The main objective of this study was to evaluate efficacy and tolerability of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in generalized anxiety disorder (GAD). This was a 8 week randomized, 2-week follow-up, double-blind, placebo-controlled, and active-controlled study. Patients were randomized to quetiapine XR 150 (n=219) or 300 mg/day (n=207); escitalopram, 10 mg/day (n=213); or placebo (n=215). The primary endpoint was the change from randomization at week 8 in Hamilton Anxiety Rating (HAM-A) total score. Week 8 mean HAM-A total score was significantly reduced from randomization with quetiapine XR 150 mg/day (-13.9, P<0.001), 300 mg/day (-12.3, P<0.05) and escitalopram (-12.3, P<0.05) versus placebo (-10.7); significant improvements with quetiapine XR (150 and 300 mg/day) versus placebo (P<0.001) were also shown at day 4. At week 8, significant improvements versus placebo were observed in HAM-A psychic [quetiapine XR (both doses) and escitalopram] and somatic (quetiapine XR 150 mg/day and escitalopram) cluster scores and HAM-A response and remission rates (quetiapine XR 150 mg/day). Most common adverse events were dry mouth, somnolence and sedation (quetiapine XR), headache, and nausea (escitalopram). In patients with GAD, quetiapine XR (150 and 300 mg/day) demonstrated significant efficacy at week 8 with symptom improvement as early as day 4. We concluded that quetiapine XR safety and tolerability results were consistent with the known profile of quetiapine.     

A comparison of the effects of quetiapine ('seroquel') and haloperidol in schizophrenic patients with a history of and a demonstrated, partial response to conventional antipsychotic treatment. PRIZE Study Group

Quetiapine ('Seroquel') is a well-tolerated, novel, atypical antipsychotic with consistent efficacy in the treatment of schizophrenia. To date, no clinical studies have evaluated the effect of quetiapine in patients who only partially respond to conventional antipsychotics, yet this type of patient is most frequently seen by psychiatrists. Therefore, this international, multicentre, double-blind study was conducted to compare the efficacy and tolerability of 8 weeks' treatment of quetiapine 600 mg/day with haloperidol 20 mg/day in 288 patients who had a history of partial response to conventional antipsychotics and displayed a partial or no response to 1 month of fluphenazine (20 mg/day) treatment. Patients on quetiapine tended to have greater improvement than those on haloperidol in the primary efficacy measure, mean Positive and Negative Symptom Scale (PANSS) score, after 4 weeks' treatment (-9.05, -5.82, respectively, P = 0.061) and at study end (-11.50, -8.87, respectively, P = 0.234). Similarly, there was a trend towards patients on quetiapine demonstrating greater improvements in the secondary efficacy measures (Clinical Global Impression, PANSS subscale and Brief Psychiatric Rating Scale scores) [week 4 (baseline) to week 12 (end)], but the difference between treatments did not reach significance. Significantly more patients on quetiapine than on haloperidol showed a clinical response-patient response rates, defined as > 20% reduction in PANSS total score between weeks 4 and 12, were 52.2% for quetiapine and 38.0% for haloperidol (P = 0.043). Patients receiving quetiapine required less anticholinergic medication (P < 0.011), had greater reduction in extrapyramidal symptoms (EPS) (P = 0.005) and fewer treatment-emergent EPS-related adverse events compared to those on haloperidol (P < 0.001). Serum prolactin concentrations were elevated at the end of fluphenazine treatment in 73% of patients. Between weeks 4 and 12, elevated serum prolactin concentrations significantly decreased in quetiapine-treated patients compared to those receiving haloperidol (P < 0.001). At the end of quetiapine treatment, 83% of patients had normal prolactin levels while only 21% of patients receiving haloperidol were within the normal range. These results suggest that quetiapine may make a valuable contribution to the management of patients with a history of partial response to conventional antipsychotics.     

Quetiapine. A review of its use in the management of schizophrenia

Quetiapine (Seroquel), a dibenzothiazepine derivative, is an atypical antipsychotic with demonstrated efficacy in acute schizophrenia. In short-term, randomised, double-blind trials, it was usually more effective than placebo, and was generally effective against both positive and negative symptoms. Overall, quetiapine (up to 750 mg/day) was at least as effective as chlorpromazine (up to 750 mg/day) and had similar efficacy to haloperidol (up to 16 mg/day) in patients with acute schizophrenia in randomised, double-blind trials; it was at least as effective as haloperidol 20 mg/day in patients with schizophrenia unresponsive or partially responsive to previous antipsychotic treatment. Improvements in overall psychopathology and positive and negative symptoms with quetiapine (up to 800 mg/day) were similar to those with risperidone (up to 8 mg/day) or olanzapine (15 mg/day) [interim analysis]. Efficacy was maintained for at least 52 weeks in open-label follow-up studies in adult and elderly patients. Quetiapine improved cognitive function versus haloperidol, and depressive symptoms and hostility/aggression versus placebo. Quetiapine is well tolerated. It is associated with placebo-level incidence of extrapyramidal symptoms (EPS) across its entire dose range, appears to have a low risk for EPS in vulnerable patient groups (e.g. the elderly, adolescents or patients with organic brain disorders) and has a more favourable EPS profile than risperidone. Irrespective of dose, quetiapine, unlike risperidone and amisulpride, does not elevate plasma prolactin levels compared with placebo, and previously elevated levels may even normalise. Quetiapine appears to have minimal short-term effects on bodyweight and a favourable long-term bodyweight profile. Preliminary studies indicate that there is a high level of patient acceptability and satisfaction with quetiapine. In conclusion, quetiapine has shown efficacy against both positive and negative symptoms of schizophrenia, and has benefits in improving cognitive deficits, affective symptoms and aggression/hostility. The beneficial effects of quetiapine have been maintained for at least 52 weeks. Quetiapine was effective and well tolerated in hard-to-treat patients, and may be of particular use in these individuals. It is at least as effective as standard antipsychotics and appears to have similar efficacy to risperidone and olanzapine. The relative risk/benefit profile of quetiapine compared with other atypical antipsychotics requires further research in head-to-head trials, although quetiapine's relatively benign tolerability profile distinguishes it from other commonly used atypical agents, particularly with respect to bodyweight, EPS and plasma prolactin levels. Overall, quetiapine has an excellent risk/benefit profile and is a suitable first-line option for the treatment of schizophrenia.     

Efficacy and tolerability of quetiapine in patients with schizophrenia who switched from haloperidol, olanzapine or risperidone

A post hoc analysis of the SPECTRUM trial was carried out to evaluate whether the improvements in efficacy and tolerability gained on switching to quetiapine occurred consistently for patients previously treated with either: haloperidol (n = 43); olanzapine (n = 66); or risperidone (n = 55) monotherapy. Patients were initiated with quetiapine to 400 mg/day over 7 days, and then flexibly dosed (300-750 mg/day) for 11 weeks. The mean (SD) modal dose of quetiapine was 501 (138) mg/day in the haloperidol subgroup, 472 (147) mg/day in the olanzapine subgroup and 485 (141) mg/day in the risperidone subgroup at the study endpoint. Switching to quetiapine induced significant improvements from baseline in PANSS scores, with least square mean changes in total scores of -32.5, -15.4, and -18.5 for patients previously treated with haloperidol, olanzapine and risperidone, respectively, (all p < 0.001 vs baseline). Significant improvements were also noted in CDSS scores, particularly for patients clinically depressed at baseline (all p < 0.001 vs baseline). There were significant reductions in EPS on the SAS and BAS for all subgroups (all p < 0.001 vs baseline). Switching to quetiapine produced efficacy and tolerability benefits regardless of whether their previous antipsychotic was haloperidol, olanzapine or risperidone.     

Safety and efficacy of rapid dose administration of quetiapine in bipolar mania

In this open-label pilot study, 20 adult patients hospitalized for acute bipolar mania received oral quetiapine as a single evening dose of 200 mg on day 1, increased by 200 mg/day on days 2, 3, and 4 until 800 mg/day taken in 2 divided doses on day 4. From day 5 onward, patients received a flexible total dose of 400-800 mg/day until completion of 3 weeks of treatment. Safety and tolerability were assessed by adverse-event (AE)-related dropouts in week 1, incidence of AEs including EPS, changes in electrocardiogram, and vital signs. Efficacy was assessed using the YMRS, PANSS, and CGI scales. Nineteen of 20 patients (95%) completed the quetiapine rapid titration during week 1. Significant improvement was observed in YMRS, PANSS, and CGI Severity of Illness scores by day 5, and was maintained throughout the study. A reduction of > or = 50% in YMRS score was achieved by 75% of patients by day 7, and maintained to day 21. Overall, 20% of patients discontinued due to AEs. Agitation was the most common cause of AE-related study discontinuation. Thirty-five per cent of patients required dose adjustment due to AEs after rapid dose administration was completed. Most patients tolerated rapid titration of quetiapine to 800 mg/day by day 4 of therapy, with a significant improvement in manic symptoms by day 7 of treatment.     

An analysis of safety and tolerability data from controlled, comparative studies of quetiapine in patients with schizophrenia, focusing on extrapyramidal symptoms

AIM: This analysis evaluated the tolerability profile of quetiapine using data from all comparative controlled studies in patients with schizophrenia or related disorders in the AstraZeneca clinical trials database, focusing on extrapyramidal symptoms (EPS). METHODS: Adverse event (AE) data from randomised, double-blind, controlled studies in the AstraZeneca clinical trials database were pooled, allowing comparison of quetiapine (mean daily doses 357-496 mg/day) with placebo, haloperidol (10.4 mg/day), risperidone (5.5 mg/day) or chlorpromazine (552 mg/day). Incidence of EPS-related AEs in relation to quetiapine dose was also analysed using a subset of data from fixed-dose studies. RESULTS: Data from 4956 patients were analysed. Quetiapine was well tolerated, and did not increase EPS-related AEs when compared with placebo (9.6 vs. 10.6%, respectively). The incidence of EPS-related AEs with quetiapine was consistent across the dose range (4.2-13.2% vs. 11.1% with placebo). Patients receiving haloperidol, risperidone and chlorpromazine experienced significantly higher levels of EPS-related AEs than those on quetiapine. The most common quetiapine- associated AEs, with significantly higher incidence than placebo, were sedation, somnolence and orthostatic hypotension. CONCLUSION: Quetiapine is generally well tolerated in patients with schizophrenia or related disorders, with placebo-level EPS-related AEs. Quetiapine has a more favourable EPS profile than haloperidol, chlorpromazine or risperidone.     

Acute and continuation risperidone monotherapy in bipolar mania: a 3-week placebo-controlled trial followed by a 9-week double-blind trial of risperidone and haloperidol.

In a randomized, double-blind trial, patients with acute bipolar mania received 1-6 mg/day of risperidone, 2-12 mg/day of haloperidol, or placebo for 3 weeks, followed by double-blind risperidone or haloperidol for 9 weeks. Of 438 patients, 154 were randomized to risperidone, 144 to haloperidol, and 140 to placebo. The mean+/-S.D. modal doses were 4.2+/-1.7 mg/day of risperidone and 8.0+/-3.6 mg/day of haloperidol during the initial 3-week phase and 4.1+/-1.8 and 7.4+/-3.7 mg/day during the 12-week period. At week 3, mean Young Mania Rating Scale (YMRS) score reductions from baseline were significantly greater in patients receiving risperidone than placebo (p<0.001). Differences between risperidone and haloperidol on this efficacy measure were not significant. Further reductions in YMRS scores were seen in patients receiving risperidone or haloperidol during the subsequent 9 weeks. No unexpected adverse events were reported. Extrapyramidal disorder and hyperkinesias, the most commonly reported adverse events with antipsychotic use, occurred less frequently with risperidone than haloperidol. We conclude that risperidone monotherapy was an effective and well-tolerated treatment for bipolar mania and that efficacy was maintained over the long term.     

Number needed to treat and time to response/remission for quetiapine monotherapy efficacy in acute bipolar depression: evidence from a large, randomized, placebo-controlled study

The objectives of this analysis are to elucidate the clinical significance of antidepressant effects with quetiapine by evaluating number needed to treat as well as time to response and remission with quetiapine monotherapy in patients with acute bipolar depression. A post-hoc analysis was conducted of 542 patients with bipolar I or II disorder, (moderate to severe depression), randomized to 8 weeks of double-blind treatment with quetiapine 600 mg/day (n=180), quetiapine 300 mg/day (n=181), or placebo (n=181). Number needed to treat, time to response (> or =50% reduction from baseline in Montgomery-Asberg Depression Rating Scale total score) and time to remission (Montgomery-Asberg Depression Rating Scale total score < or =12) were evaluated. Response rates at week 8 were 58.2 and 57.6% for quetiapine 600 and 300 mg/day, respectively, and 36.1% for placebo (P<0.001). Remission rates were 52.9% for both quetiapine groups and 28.4% for placebo (P<0.001). The number needed to treat was five for both response and remission for quetiapine (600 and 300 mg/day) compared with placebo. Median time to response and remission were significantly shorter with quetiapine 600 and 300 mg/day than placebo. No between-group difference was found in the incidence of treatment-emergent mania or hypomania (quetiapine 600 mg/day: 2.2%, quetiapine 300 mg/day: 3.9, and placebo: 3.9%). In conclusion, quetiapine compared with placebo significantly reduces time to response and remission compared with placebo, and has a favorable number needed to treat.     

Extended release quetiapine fumarate (quetiapine XR) monotherapy as maintenance treatment for generalized anxiety disorder: a long-term, randomized, placebo-controlled trial

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.     

Extended Release Quetiapine Fumarate (Quetiapine XR) as Adjunct Therapy in Patients with Generalized Anxiety Disorder and a History of Inadequate Treatment Response: A Randomized,Double-Blind Study

Objective

To evaluate the efficacy and tolerability of adjunct extended release quetiapine fumarate (quetiapine XR) in patients with generalized anxiety disorder (GAD) and inadequate response to selective serotonin reuptake inhibitors/ serotonin norepinephrine reuptake inhibitors (SSRI/SNRIs).

Methods

11-week (1-week single-blind placebo run-in; 8-week randomized treatment; 2-week post-treatment period), double-blind, placebo-controlled study. Patients were randomized to quetiapine XR or placebo adjunct to SSRI/SNRI. 50 mg initial dose; 150 mg/day, Day 3; 300 mg/day, Weeks × and 4 if indicated (Clinical Global Impressions-Severity of Illness [CGI-S] ≥ 4; 150 mg/day tolerated). Primary endpoint: change from randomization to Week 8 in HAM-A total score. Secondary variables: Hamilton Rating Scale for Anxiety (HAM-A) psychic/somatic clusters, response and remission; and CGI-S.

Results

409 patients were randomized to quetiapine XR (n = 209) or placebo (n = 200); 41% and 55% of patients, respectively, had dose increases (300 mg/day). Week 8 mean change in HAM-A total score was not statistically significant for quetiapine XR (–10.74; p = 0.079) versus placebo (–9.61). Secondary variables were generally consistent with the primary analysis, except a significant reduction in HAM-A total score at Week 1 (–6.45, quetiapine XR versus –4.47, placebo; p < 0.001); significant improvements in HAM-A psychic cluster (p < 0.05) and CGI-S total (p < 0.05) scores at Week 8. Adverse events (.10% either group) were dry mouth, somnolence, sedation, headache, and dizziness.

Conclusions

In patients with GAD and inadequate response to SSRI/SNRI, adjunct quetiapine XR did not show a statistically significant effect for the primary endpoint at Week 8, although some secondary endpoints were statistically significant versus placebo. Quetiapine XR was generally well tolerated.     

Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study

This study compares the efficacy, safety, and tolerability of a partial dopamine agonist, aripiprazole, with placebo in the treatment of patients with bipolar I disorder experiencing an acute manic or mixed episode. In total, 272 hospitalized patients were randomized to aripiprazole 30 mg/day or placebo in this 3-week, double-blind, placebo-controlled trial. Dosing could be reduced to 15 mg/day for tolerability and, subsequently, increased to 30 mg/day based on clinical response. Primary efficacy measure was mean change from baseline to endpoint in Young Mania Rating Scale (YMRS) total score; response was defined as > or = 50% decrease from baseline YMRS score. Aripiprazole-treated patients demonstrated significantly greater improvement from baseline to endpoint in mean YMRS total scores compared with placebo-treated patients as early as Day 4 and sustained through Week 3. A significantly higher response rate was observed in aripiprazole-treated patients (53% vs. 32% at endpoint). Aripiprazole produced significantly greater improvements from baseline on other efficacy assessments compared with placebo, including Clinical Global Impression - Bipolar Version Severity and Improvement scores. The 30 mg/day dose was maintained by 85% of aripiprazole-treated patients. Incidence of discontinuations due to adverse events was similar for aripiprazole (8.8%) and placebo (7.5%). Aripiprazole treatment resulted in no significant difference from placebo in change in mean body weight and was not associated with elevated serum prolactin or QTc prolongation. In conclusion, aripiprazole demonstrated superior efficacy to placebo in the treatment of patients with bipolar I disorder presenting with acute manic or mixed episodes, and exhibited a favourable safety and tolerability profile.     

A randomized, double-blind study of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in patients with generalized anxiety disorder

This study evaluated once-daily, extended-release quetiapine fumarate (quetiapine XR) monotherapy in generalized anxiety disorder (GAD). This was a 10-week (8-week active treatment/2-week posttreatment drug-discontinuation/tapering phase), double-blind, randomized, placebo-controlled study (D1448C00009). Primary end point was change from randomization at week 8 in Hamilton Anxiety Rating Scale (HAM-A) total score. Overall, 951 patients with GAD were randomized (quetiapine XR: 50 mg/d, n = 234; 150 mg/d, n = 241; 300 mg/d, n = 241; placebo, n = 235). At week 8, HAM-A total scores significantly (P < 0.001) improved versus placebo (-11.10) with quetiapine XR 50 mg/d (-13.31) and 150 mg/d (-13.54), but not 300 mg/d (-11.87; P = 0.240). At week 1, HAM-A total scores significantly improved versus placebo (-5.94) with quetiapine XR 50 mg/d (-7.47; P < 0.01), 150 mg/d (-8.19; P < 0.001), and 300 mg/d (-7.23; P < 0.01). Versus placebo at week 8, quetiapine XR 50 and 150 mg/d significantly improved HAM-A psychic (P < 0.01 and P < 0.001, respectively) and somatic (P < 0.001; P < 0.01, respectively) cluster scores, HAM-A response (≥ 50% total score reduction; P < 0.05), and Clinical Global Impression-Improvement categorical changes (P < 0.05). For quetiapine XR 150 mg/d, significant (P < 0.05) improvements were seen for HAM-A remission (total score, ≤ 7) and Clinical Global Impression-Severity of Illness scores. For quetiapine XR 300 mg/d, improvements in these secondary variables were not significantly different versus placebo. Pittsburgh Sleep Quality Index global scores improved with all 3 doses (quetiapine: XR 50 mg/d, -4.07 [P < 0.05]; 150 mg/d, -4.38 [P < 0.05]; 300 mg/d, -3.97 [P < 0.05], versus -3.31 with placebo). Adverse events (>10% with quetiapine XR) were dry mouth, somnolence, sedation, dizziness, headache, and fatigue. Quetiapine XR (50/150 mg/d) monotherapy was effective at week 8 in patients with GAD; symptom improvement was seen at week 1 for all doses (50/150/300 mg/d). Safety and tolerability were consistent with the known profile of quetiapine.     

Quetiapine versus placebo in combination with lithium or divalproex for the treatment of bipolar mania

Quetiapine (QTP) combined with lithium (Li) or divalproex (DVP) for the treatment of mania was evaluated in 2 double-blind, placebo-controlled studies. Patients were randomized to 3 or 6 weeks of treatment with QTP plus Li/DVP or placebo (PBO) plus Li/DVP. Quetiapine was dosed up to 800 mg/d; Li was dosed to achieve serum concentrations of 0.7-1.0 mEq/L and DVP to 50-100 microg/mL. A total of 402 patients were randomized: 197 to QTP + Li/DVP and 205 to PBO + Li/DVP. The mean quetiapine dose in responders was 492 (+/-204) mg/d. Improvement in the Young Mania Rating Scale (YMRS) at day 21 in the QTP + Li/DVP group (-15.29) was statistically superior to the PBO + Li/DVP group (-12.19) (P < 0.05). A statistically significant difference in favor of quetiapine was observed within the first week (P < 0.05). Significantly more QTP + Li/DVP patients achieved a response (> or =50% decrease in the YMRS) at day 21 (QTP + Li/DVP, 55.7%; PBO + Li/DVP, 41.6%;P < 0.01). Improvements in Clinical Global Impression-Bipolar Severity of Illness scores by day 21 were also significantly greater in QTP + Li/DVP-treated patients (-1.59) versus PBO + Li/DVP (-1.19) (P < 0.01). Common adverse events (> or =5% and twice that in the PBO + Li/DVP group) in the QTP + Li/DVP group were somnolence, dry mouth, and asthenia. Quetiapine combined with Li/DVP was not associated with extrapyramidal symptoms (including akathisia) or emergent depression. More QTP + Li/DVP-treated patients completed the trial, and there was no difference in discontinuation rates due to adverse events between the two groups. Quetiapine, in combination with lithium or divalproex, is well tolerated and has superior efficacy to lithium or divalproex alone in the treatment of bipolar mania.     

Evaluation of the effect of paliperidone extended release and quetiapine on corrected QT intervals: a randomized, double-blind, placebo-controlled study

The effect of two atypical antipsychotics on QTc intervals (heart rate-corrected QT interval) was evaluated. Patients (N=109) with schizophrenia (79%) or schizoaffective disorder (21%) were randomly assigned in 2 : 2 : 1 ratio to paliperidone extended release (ER), quetiapine, or placebo. Doses of 12 and 18 mg/day of paliperidone ER were compared with quetiapine 800 mg/day. Least-squares mean change from baseline in population-specific linear-derived correction method from baseline to days 6-7 at individual tmax was 5.1 ms less [90% confidence interval: -9.2 to -0.9] with paliperidone ER 12 mg/day than with quetiapine 800 mg/day. On the basis of a prespecified 10-ms noninferiority margin, paliperidone ER was thus declared noninferior to quetiapine (primary analysis). Mean change in population-specific linear-derived correction method from baseline to days 11-12 at individual tmax was 2.3 ms less (90% confidence interval: -6.8 to 2.3) with paliperidone ER 18 mg/day than with quetiapine 800 mg/day. Treatment-emergent adverse events occurred in 36 (82%) patients treated with paliperidone ER, 41 (95%) patients treated with quetiapine, and 14 (64%) patients treated with placebo. No adverse events of a proarrhythmic nature were noted. The effect on the QTc interval in patients with schizophrenia or schizoaffective disorder was comparable between paliperidone ER 12 mg/day (maximum recommended dose), paliperidone ER 18 mg/day (supratherapeutic dose), and quetiapine 800 mg/day.     

Long-term functioning and sleep quality in patients with major depressive disorder treated with extended-release quetiapine fumarate

The aim of this study was to assess patients' functioning and sleep quality during extended-release quetiapine fumarate (quetiapine XR) maintenance treatment. A double-blind, randomized-withdrawal maintenance study of quetiapine XR monotherapy was carried out in patients with major depressive disorder. Following 4-8 weeks of open-label quetiapine XR and 12-18 weeks of open-label quetiapine XR stabilization (50, 150, or 300 mg/day), eligible patients were randomized to quetiapine XR (50, 150, or 300 mg/day) or placebo. Secondary variables of the Sheehan Disability Scale (SDS) and the Pittsburgh Sleep Quality Index (PSQI) were used to assess functioning and sleep quality and are reported here. Quetiapine XR significantly maintained functioning versus placebo. Changes in the least squares means (LSM) from randomization in the SDS total scores were as follows: -0.45, quetiapine XR (P<0.05), versus 0.44, placebo. Quetiapine XR significantly maintained SDS domains 'social life/leisure' (-0.19; P<0.05) and 'family life/home responsibilities' (-0.22; P<0.05) versus placebo (0.13 and 0.10, respectively). Quetiapine XR significantly maintained sleep quality (LSM change in PSQI total scores: 0.06, quetiapine XR vs. 1.35, placebo; P<0.001), with five of seven PSQI components being significant for quetiapine XR versus placebo. In conclusion, quetiapine XR (50-300 mg/day) monotherapy better maintains overall functioning and sleep quality than placebo in patients with major depressive disorder.     

Efficacy of quetiapine for the treatment of schizophrenia: a combined analysis of three placebo-controlled trials

OBJECTIVE: To determine the effectiveness of quetiapine (Seroquel) against specific aspects of schizophrenic symptomatology. RESEARCH DESIGN AND METHODS: Combined data from three placebo-controlled, double-blind, randomised trials that had previously demonstrated quetiapine's overall clinical effectiveness and tolerability were analysed. Efficacy assessments evaluated were the Clinical Global Impression (CGI) Severity of Illness score, Brief Psychiatric Rating Scale (BPRS) factors I-V, BPRS positive symptom cluster score and 18 individual BPRS items. The Simpson-Angus Scale (SAS), the Abnormal Involuntary Movements Scale (AIMS), changes in weight and prolactin concentrations and the recording of adverse events comprised the main tolerability measures. RESULTS: Efficacy assessments were available for a total of 426 quetiapine patients (mean age 36.9 years) with a DSM-IIIR diagnosis of schizophrenia; 502 patients were included in the tolerability analyses. The mean quetiapine dose was 300.5 mg/day with a mean maximum dose of 686.0 mg/day. Quetiapine was efficacious across a broad range of symptoms, including depression, anxiety and hostility. Significant improvements compared with placebo were noted for CGI Severity of Illness (p < 0.001) and in 14 of the 18 individual BPRS items (p < 0.001). Positive symptoms also improved (p < 0.01 at Week 2 and p < 0.001 from Week 3); greater improvements were observed in patients who received at least 400 mg/day quetiapine. Quetiapine was generally well tolerated: 4.0% of patients withdrew from treatment due to adverse events compared with 3.0% of placebo patients. Akathisia occurred in 2.0% and 2.5% of quetiapine and placebo patients, respectively. Similar decreases in prolactin levels for quetiapine (-10.0 microg/L) and placebo (-10.9 microg/L) were noted from baseline to end of treatment. Agitation and headache, the most common adverse events, were comparable in the quetiapine and placebo groups (agitation: 19.3% vs. 20.3%, respectively; headache: 19.1% vs. 17.3%, respectively). CONCLUSIONS: The results of this combined analysis confirm the individual findings of the three pivotal studies to demonstrate that quetiapine is effective across several domains of schizophrenia, improving positive, negative and depressive symptoms and reducing agitation, aggression and hostility. Similarly, the analysis reiterated the good tolerability profile of quetiapine, particularly in terms of its placebo-like effects on prolactin levels and incidence of extrapyramidal symptoms (EPS).