Hans Eriksson

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.

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

INTRODUCTION Once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy was evaluated in major depressive disorder (MDD). METHOD This was an 8-week (6-week randomized-phase; 2-week drug-discontinuation/tapering phase), double-blind, parallel-group, placebo-controlled study. The primary outcome measure was Montgomery-Asberg Depression Rating Scale (MADRS) total score randomization-to-Week 6 change. Other assessments included the Hamilton Rating Scale for Depression, the Hamilton Rating Scale for Anxiety, and adverse events (AEs). RESULTS 723 patients were randomized: 182, 178, 179, and 184 to quetiapine XR 50, 150, 300 mg/day, and placebo, respectively. At Week 6, significant reductions occurred in MADRS score with quetiapine XR 50 mg/day (-13.56; P<.05), 150 mg/day (-14.50; P<.01) and 300 mg/day (-14.18; P<.01) versus placebo (-11.07); at Day 4, reductions for quetiapine XR (titrated to 50 or 150 mg/day according to dose group) versus placebo (-2.9) were: -4.7 (P<.01), -5.2 (P<.001), and -5.1 (P<.001), respectively. At endpoint, MADRS response (>or=50% reduction in score) was 42.7% (P<.01), 51.2% (P<.001), and 44.9% (P<or= .001) for quetiapine XR 50, 150, and 300 mg/day, respectively; 30.3% for placebo. Overall, quetiapine XR 150 mg/day provided consistently more positive secondary efficacy results than 50 mg/day and 300 mg/day versus placebo. The most common AEs in quetiapine XR-treated patients were dry mouth, sedation, somnolence, headache, and dizziness. CONCLUSION In patients with MDD, quetiapine XR monotherapy (50/150/300 mg/day) is effective in reducing depressive symptoms, with improvement from Day 4 onwards. Safety and tolerability were consistent with the known profile of quetiapine.

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

The efficacy and tolerability of extended-release quetiapine fumarate (quetiapine XR) once-daily monotherapy in generalized anxiety disorder (GAD) was assessed. This multicentre, double-blind, randomized, placebo- and active-controlled, phase III trial consisted of a 1- to 4-wk enrolment/wash-out period and a 10-wk (8-wk active treatment, 2-wk post-treatment drug-discontinuation) study period; 873 patients were randomized to 50 mg or 150 mg quetiapine XR, 20 mg paroxetine, or placebo. Primary endpoint was change from randomization at week 8 in Hamilton Rating Scale for Anxiety (HAMA) total score. At week 8, all active agents produced significant improvements in HAMA total and psychic subscale scores vs. placebo; HAMA somatic subscale scores were significantly reduced only by 150 mg quetiapine XR. Significant separation from placebo (-2.90) in HAMA total score was observed at day 4 for 50 mg quetiapine XR (-4.43, p<0.001) and 150 mg quetiapine XR (-3.86, p<0.05), but not for paroxetine (-2.69). Remission (HAMA total score 7) rates at week 8 were significantly higher for 150 mg quetiapine XR (42.6%, p<0.01) and paroxetine (38.8%, p<0.05) vs. placebo (27.2%). The most common adverse events (AEs) were dry mouth, somnolence, fatigue, dizziness, and headache, for quetiapine XR, and nausea, headache, dizziness for paroxetine. A lower proportion of patients reported sexual dysfunction with quetiapine XR [0.9% (50 mg), 1.8% (150 mg)] than with placebo (2.3%) or paroxetine (7.4%). The incidence of AEs potentially related to extrapyramidal symptoms was: quetiapine XR: 50 mg, 6.8%, 150 mg, 5.0%; placebo, 1.8%; and paroxetine, 8.4%. Once-daily quetiapine XR is an effective and generally well-tolerated treatment for patients with GAD, with symptom improvement seen as early as day 4.

A pooled analysis of two randomised, placebo-controlled studies of extended release quetiapine fumarate adjunctive to antidepressant therapy in patients with major depressive disorder

BACKGROUND Two positive studies evaluated adjunctive extended release quetiapine fumarate (quetiapine XR) in patients with major depressive disorder (MDD) showing inadequate response to antidepressant treatment. This preplanned, pooled analysis provides an opportunity for subgroup analyses investigating the influence of demographic and disease-related factors on observed responses. Additional post hoc analyses examined the efficacy of quetiapine XR against specific depressive symptoms including sleep. METHODS Data were analysed from two 6-week, multicentre, double-blind, randomised, placebo-controlled studies, prospectively designed to be pooled. Patients received once-daily quetiapineXR 150mg/day (n=309), 300mg/day (n=307) or placebo (n=303) adjunctive to ongoing antidepressant therapy. The primary endpoint was change from randomisation to Week 6 in MADRS total score. Other assessments included MADRS response (≥50% decrease in total score) and remission (total score≤8), change from randomisation in HAM-D, HAM-A, PSQI global and CGI-S scores. RESULTS Quetiapine XR (150 and 300mg/day) reduced MADRS total scores vs placebo at every assessment including Week 6 (-14.5, -14.8, -12.0; p<0.001 each dose) and Week 1 (-7.8,-7.3,-5.1; p<0.001 each dose). For quetiapineXR 150 and 300mg/day and placebo, respectively at Week 6: MADRS response 53.7% (p=0.063), 58.3% (p<0.01) and 46.2%; MADRS remission 35.6% (p<0.01), 36.5% (p<0.001) and 24.1%. QuetiapineXR 150 and 300mg/day significantly improved HAM-D, HAM-A, PSQI and CGI-S scores at Week 6 vs placebo. Quetiapine XR demonstrated broad efficacy, independent of factors including concomitant antidepressant. LIMITATIONS Fixed dosing; lack of active comparator. CONCLUSIONS Adjunctive quetiapine XR is effective in patients with MDD and an inadequate response to antidepressant therapy, with improvement in depressive symptoms seen as early as Week 1.

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.

Efficacy and Safety of Adjunctive Brexpiprazole 2 mg in Major Depressive Disorder: A Phase 3, Randomized, Placebo-Controlled Study in Patients With Inadequate Response to Antidepressants

OBJECTIVE To assess the efficacy, tolerability, and safety of brexpiprazole as adjunctive therapy to antidepressant treatments (ADTs) in adults with major depressive disorder (as defined by DSM-IV-TR criteria) and inadequate response to ADTs. METHOD Patients with historical inadequate response to 1-3 ADTs were enrolled. All patients entered a prospective 8-week phase on physician-determined, open-label ADT. Those with inadequate response were randomized to ADT + brexpiprazole 2 mg/d or ADT + placebo for 6 weeks. The study was conducted between July 2011 and May 2013. The primary efficacy end point was change from baseline to week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score. The key secondary end point was change from baseline to week 6 in Sheehan Disability Scale (SDS) mean score. The efficacy population comprised all patients who had ≥ 1 dose of study drug in the double-blind phase and both baseline and ≥ 1 postrandomization MADRS scores. The efficacy population per final protocol included patients from the efficacy population who met amended randomization criteria of inadequate response throughout prospective treatment. RESULTS Brexpiprazole (n = 175) reduced mean MADRS total score versus placebo (n = 178) at week 6 in the efficacy population per final protocol (-8.36 vs -5.15, P = .0002). Brexpiprazole improved SDS mean score versus placebo (-1.35 vs -0.89, P = .0349). The most common treatment-related adverse events were weight gain (brexpiprazole, 8.0%; placebo, 3.1%) and akathisia (7.4% vs 1.0%). CONCLUSIONS Adjunctive brexpiprazole therapy demonstrated efficacy and was well tolerated in patients with major depressive disorder and inadequate response to ADTs. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01360645.

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.

Adjunctive Brexpiprazole 1 and 3 mg for Patients With Major Depressive Disorder Following Inadequate Response to Antidepressants: A Phase 3, Randomized, Double-Blind Study

OBJECTIVE To evaluate efficacy, safety, and tolerability of brexpiprazole adjunctive to antidepressant treatments (ADTs) in patients with major depressive disorder (as defined by DSM-IV-TR criteria) with inadequate response to ADTs. METHOD Patients still depressed despite 1-3 prior ADTs followed by 8 weeks of prospective physician-determined, open-label ADT were randomized (1:1:1) to double-blind brexpiprazole 3 mg/d, brexpiprazole 1 mg/d, or placebo for 6 weeks. The primary efficacy end point was change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline to week 6. The key secondary efficacy end point was change in Sheehan Disability Scale mean score. The Hochberg procedure corrected for multiplicity. The efficacy population comprised all patients who had ≥ 1 dose of study drug with baseline and ≥ 1 postrandomization MADRS scores; the efficacy population per final protocol consisted of efficacy population patients meeting amended criteria for inadequate response throughout the 8-week prospective ADT. The study was conducted between June 2011 and September 2013. RESULTS In the efficacy population per final protocol, brexpiprazole 3 mg (n = 213) showed a greater improvement in MADRS total score versus placebo (n = 203; -8.29 vs -6.33; P = .0079), whereas brexpiprazole 1 mg did not (n = 211; -7.64 vs -6.33; P = .0737). The brexpiprazole groups showed comparable improvement in SDS mean score versus placebo (least squares [LS] mean difference: [1 mg] -0.49, P = .0158; [3 mg] -0.48, P = .0191). The most frequent adverse events were akathisia (4.4%, 13.5%, 2.3%), headache (9.3%, 6.1%, 7.7%), and weight increase (6.6%, 5.7%, 0.9%) in brexpiprazole 1-mg, 3-mg, and placebo groups, respectively. Mean changes from baseline in Abnormal Involuntary Movement Scale (LS mean difference = 0.08, P = .0141) and Barnes Akathisia Rating Scale (LS mean difference = 0.17, P = .0001) total scores were significantly greater with brexpiprazole 3 mg versus placebo. CONCLUSIONS Brexpiprazole 3 mg demonstrated efficacy versus placebo in the efficacy population per final protocol. Both doses of brexpiprazole were well tolerated. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01360632.

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.

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.

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.