Willie Earley

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 quetiapine in children and adolescents with mania associated with bipolar i disorder: A 3-week, double-blind, placebo-controlled trial

OBJECTIVE To evaluate the efficacy and safety of quetiapine monotherapy in children and adolescents with mania associated with bipolar I disorder. METHOD Patients aged 10 to 17 years, with a DSM-IV-TR diagnosis of a manic episode associated with bipolar I disorder and Young Mania Rating Scale (YMRS) total score ≥ 20 were randomized to 3 weeks of quetiapine (400 or 600 mg/d) or placebo. The primary efficacy measure was change in YMRS total score. The study was conducted at 34 centers in the United States between August 2004 and July 2006. RESULTS The intent-to-treat population included 277 patients. Least squares mean change in YMRS score from baseline to end point by mixed-model, repeated-measures analysis was -14.25, -15.60, and -9.04 for quetiapine 400 mg/d, quetiapine 600 mg/d, and placebo, respectively (P < .001, each quetiapine dose vs placebo). Significant improvement in YMRS score versus placebo was first observed at day 4 (P = .015) with quetiapine 400 mg/d and day 7 (P < .001) with quetiapine 600 mg/d. Mean changes in body weight at day 21 (observed cases) were 1.7 kg for both quetiapine doses and 0.4 kg for placebo. Numerically larger mean increases in total cholesterol, low-density lipoprotein cholesterol, and triglycerides were observed with quetiapine than placebo. Adverse events associated with quetiapine were mostly mild to moderate in intensity. CONCLUSIONS In this 3-week study, quetiapine was significantly more effective than placebo in improving manic symptoms in youth with mania associated with bipolar disorder. Treatment was generally well tolerated and adverse events were broadly consistent with the known profile of quetiapine in adults with bipolar disorder. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00090311.

Efficacy and safety of quetiapine in adolescents with schizophrenia investigated in a 6-week, double-blind, placebo-controlled trial.

OBJECTIVE The purpose of this study was to evaluate the efficacy and safety of acute quetiapine monotherapy in adolescents with schizophrenia. METHODS Patients ages 13-17 years with an American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) diagnosis of schizophrenia and a Positive and Negative Syndrome Scale (PANSS) total score ≥60 were randomized to 6 weeks of quetiapine (400 or 800 mg/day) or placebo treatment. The primary efficacy measure was change in PANSS total score from baseline to day 42. Safety endpoints included adverse events and assessments of clinical chemistry values, suicidality, and extrapyramidal symptoms. RESULTS The intent-to-treat population included 220 patients. Least-squares mean change in PANSS total score from baseline to endpoint was -27.31 with quetiapine 400 mg/day, -28.44 with quetiapine 800 mg/day, and -19.15 with placebo (p=0.043 and 0.009 for quetiapine 400 and 800 mg/day, respectively, vs. placebo; mixed-model, repeated-measures analysis). Several secondary efficacy outcomes, including Clinical Global Impressions-Improvement score, supported the primary outcome measure in demonstrating significantly greater improvement in quetiapine groups than in the placebo group. Mean changes in body weight at day 42 were 2.2 kg and 1.8 kg for quetiapine 400 and 800 mg/day, respectively, and -0.4 kg for placebo. Mean changes in certain clinical chemistry parameters, including total cholesterol and triglycerides, were numerically greater in the quetiapine groups than in the placebo group. Adverse events associated with quetiapine were mostly mild to moderate in intensity and were consistent with its known profile in adults with schizophrenia. CONCLUSIONS In this 6-week study of adolescent patients, quetiapine at doses of 400 and 800 mg/day provided significant improvements in symptoms associated with schizophrenia in adolescent patients, including the primary efficacy measure of PANSS total score change. Quetiapine was generally well tolerated with a profile broadly similar to that reported in adult and adolescent populations. CLINICAL TRIAL REGISTRATION INFORMATION Quetiapine Fumarate (SEROQUEL(™)) Compared to Placebo in the Treatment of Adolescent Patients With Schizophrenia (ANCHOR 112). Available at: http://www.clinicaltrials.gov/ct2/show/NCT00090324?term=quetiapine+112&rank=1.

An 8-Week Randomized, Double-Blind, Placebo-Controlled Evaluation of the Safety and Efficacy of Cariprazine in Patients With Bipolar I Depression

OBJECTIVE The authors evaluated the efficacy, safety, and tolerability of cariprazine, an atypical antipsychotic candidate, in adult patients with acute bipolar I depression. METHOD This was an 8-week multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study in adult patients with bipolar I disorder experiencing a current major depressive episode. Patients were randomly assigned (1:1:1:1) to receive placebo or cariprazine at 0.75, 1.5, or 3.0 mg/day. The primary and secondary efficacy parameters were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impressions severity subscale (CGI-S), respectively, analyzed using a mixed-effects model for repeated measures on the modified intent-to-treat population. RESULTS The intent-to-treat population comprised 571 patients (141 in the placebo group and 140, 145, and 145 in the cariprazine 0.75-, 1.5-, and 3.0-mg/day groups). Cariprazine at 1.5 mg/day showed significantly greater improvement on MADRS total score change from baseline to week 6 compared with placebo; the least squares mean difference was -4.0 (95% CI=-6.3, -1.6; significant after adjustment for multiple comparisons). Cariprazine at 3.0 mg/day showed greater MADRS score reduction than placebo (-2.5, 95% CI=-4.9, -0.1; not significant when adjusted for multiple comparisons). The 0.75 mg/day dosage was similar to placebo. A similar pattern for significance was observed on the CGI-S (1.5 mg/day: least squares mean difference=-0.4, 95% CI=-0.6, -0.1; 3.0 mg/day: -0.3, 95% CI=-0.5, -0.0). The most common adverse events (≥10%) in cariprazine-treated patients were akathisia and insomnia; weight gain was slightly higher with cariprazine than with placebo. CONCLUSIONS Cariprazine at 1.5 mg/day demonstrated consistent efficacy compared with placebo across outcomes and was generally well tolerated, suggesting efficacy for the treatment of bipolar I depression.

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-Åsberg 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.

Efficacy and safety of extended-release quetiapine fumarate in youth with bipolar depression: an 8 week, double-blind, placebo-controlled trial.

OBJECTIVE Quetiapine is an atypical antipsychotic with demonstrated efficacy in the treatment of adolescent schizophrenia and pediatric bipolar mania. Large, placebo-controlled studies of interventions in pediatric bipolar depression are lacking. The current study investigated the efficacy and safety of quetiapine extended-release (XR) in patients 10-17 years of age, with acute bipolar depression. METHODS This multicenter, double-blind, randomized, placebo-controlled study investigated quetiapine XR (dose range, 150-300 mg/day) in pediatric outpatients with an American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) diagnosis of bipolar I or bipolar II disorder (current or most recent episode depressed) treated for up to 8 weeks (ClinicalTrials.gov identifier: NCT00811473). The primary study outcome was mean change in Childrens Depression Rating Scale-Revised (CDRS-R) total score. Secondary efficacy outcomes included CDRS-R-based response and remission rates. RESULTS Of 193 patients randomized to treatment, 144 patients completed the study (75.3% of quetiapine XR group [n=70]; 74.0% of placebo group [n=74]). Least squares mean changes in CDRS-R total score at week 8 were: -29.6 (SE, 1.65) with quetiapine XR and -27.3 (SE, 1.60) with placebo, a between-treatment group difference of -2.29 (SE, 1.99; 95% CI, -6.22, 1.65; p=0.25; mixed-model for repeated measures analysis). Rates of response and remission did not differ significantly between treatment groups. The safety profile of quetiapine XR was broadly consistent with the profile reported previously in adult studies of quetiapine XR and pediatric studies of quetiapine immediate-release (IR). Potentially clinically significant elevations in clinical chemistry values included triglycerides (9.3%, quetiapine XR; 1.4%, placebo group) and thyroid stimulating hormone (4.7%, quetiapine XR; 0%, placebo group). An adverse event potentially related to diabetes mellitus occurred in 3.3% of the quetiapine XR versus no adverse events in the placebo group. CONCLUSIONS Quetiapine XR did not demonstrate efficacy relative to placebo in this 8 week study of pediatric bipolar depression. Quetiapine XR was generally safe and well tolerated.

Efficacy and safety of adjunctive cariprazine in inadequate responders to antidepressants: a randomized, double-blind, placebo-controlled study in adult patients with major depressive disorder.

BACKGROUND Cariprazine is an atypical antipsychotic currently under investigation as adjunctive therapy in patients with major depressive disorder (MDD) who have inadequate response to standard antidepressant therapy. METHOD A randomized, double-blind, placebo-controlled, flexible-dose study was conducted from December 2011 to December 2013 in adults who met DSM-IV-TR criteria for MDD and had an inadequate antidepressant response. Eligible patients were randomized to 8-week adjunctive treatment with placebo (n = 269), cariprazine 1-2 mg/d (n = 274), or cariprazine 2-4.5 mg/d (n = 276). The primary efficacy parameter was change from baseline to week 8 in Montgomery-Asberg Depression Rating Scale (MADRS) total score; P values were adjusted for multiple comparisons. Safety assessments included adverse events, clinical laboratory tests, vital signs, electrocardiograms (ECGs), and suicidality. RESULTS Compared with placebo, reduction in MADRS total score at week 8 was significantly greater with adjunctive cariprazine 2-4.5 mg/d (least squares mean difference [LSMD] = -2.2; adjusted P = .0114), but not with cariprazine 1-2 mg/d (LSMD = -0.9; adjusted P = .2404). Significant LSMDs for MADRS total score change were detected at all earlier study visits (weeks 2, 4, 6) in the 2- to 4.5-mg/d group and at weeks 2 and 4 in the 1- to 2-mg/d group (all P values < .05). Treatment-emergent adverse events reported in ≥ 10% of patients in either cariprazine dosage group were akathisia (22.3%), insomnia (13.6%), and nausea (12.8%) (all in 2- to 4.5-mg/d group). Mean changes in metabolic parameters, vital signs, and ECG parameters were generally similar between groups. No suicide-related adverse events were reported. DISCUSSION These results show that adjunctive cariprazine 2-4.5 mg/d was effective and generally well tolerated in adults with MDD who had inadequate responses to standard antidepressants. Further clinical studies to confirm these results are warranted. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01469377.

Pharmacokinetic profile of the extended-release formulation of quetiapine fumarate (quetiapine XR): clinical implications.

Abstract Objectives: A series of studies were conducted to guide the development and characterise the pharmacokinetics of extended-release quetiapine fumarate (quetiapine XR), a once-daily formulation to control the release of the drug. Methods: Data from these studies are described and discussed herein. Results: Once-daily quetiapine XR produced a similar area under the plasma concentration–time curve (AUC), minimum plasma concentration (Cmin) and a slightly lower maximum plasma concentration (Cmax) than the equivalent dose of immediate-release quetiapine (quetiapine IR) given twice daily. In a crossover, head-to-head study, total daily exposure, measured by AUC at steady state, was less variable with quetiapine XR versus quetiapine IR (percent coefficient of variation 39.2% versus 51.2%, respectively). Compared with fasting, a high-fat meal increased the AUC and Cmax for quetiapine XR, whereas a light meal had no significant effect on these parameters. Quetiapine XR exhibits a less pronounced D2 receptor occupancy peak and receptor occupancy levels remain higher for longer compared with quetiapine IR. Quetiapine XR was generally well tolerated with a safety profile similar to quetiapine IR, although the intensity of sedation in the first hours of treatment was significantly lower (p < 0.01) with quetiapine XR versus IR. Conclusion: At steady state, quetiapine XR provided a similar AUC and Cmin and a slightly lower Cmax relative to an equivalent dose of quetiapine IR administered twice daily. Quetiapine XR exhibited linear pharmacokinetics in the dose range tested and no food effect was observed with a light meal. Once-daily dosing and simpler dose titration makes using quetiapine XR convenient for clinicians and patients. Quetiapine XR has predictable pharmacokinetics and was generally well tolerated, with significantly lower intensity of sedation after the first hours of administration compared with quetiapine IR. With once-daily quetiapine XR, the impact of daytime sedation may be mitigated by evening dosing.

A randomized, double-blind study of the efficacy and tolerability of extended-release quetiapine fumarate (quetiapine XR) monotherapy in patients with major depressive disorder.

Objectives To evaluate the efficacy and tolerability of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in patients with major depressive disorder (MDD). Patients and methods This was a 10-week (8-week active treatment/2-week post-treatment) randomized, double-blind, placebo- and active-controlled study (D1448C00004). Patients received quetiapine XR 150 mg/day, escitalopram 10 mg/day, or placebo; patients with an inadequate response (<20% improvement in Montgomery–Åsberg Depression Rating Scale [MADRS] total score) at week two received double-dose treatment. The primary end point was week eight change from randomization in MADRS total score. Secondary end points included MADRS response (≥50% improvement) and remission (score ≤8); Hamilton Rating Scale for Depression total and item 1; Hamilton Rating Scale for Anxiety total, psychic, and somatic; Clinical Global Impressions – Severity of Illness total; Pittsburgh Sleep Quality Index (PSQI) global; and Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form percentage maximum total scores. Tolerability was assessed throughout. Results A total of 471 patients was randomized. No significant improvements in MADRS total score were observed at week eight (last observation carried forward) with either active treatment (quetiapine XR, −17.21 [P=0.174]; escitalopram, −16.73 [P=0.346]) versus placebo (−15.61). There were no significant differences in secondary end points versus placebo, with the exception of week-eight change in PSQI global score (quetiapine XR, −4.96 [P<0.01] versus placebo, −3.37). Mixed-model repeated-measures analysis of observed-case data suggested that the primary analysis may not be robust. Most commonly reported adverse events included dry mouth, somnolence, and dizziness for quetiapine XR, and headache and nausea for escitalopram. Conclusion In this study, neither quetiapine XR (150/300 mg/day) nor escitalopram (10/20 mg/day) showed significant separation from placebo. Both compounds have been shown previously to be effective in the treatment of MDD; possible reasons for this failed study are discussed. Quetiapine XR was generally well tolerated, with a profile similar to that reported previously.

Extended release quetiapine fumarate as adjunct to antidepressant therapy in patients with major depressive disorder: pooled analyses of data in patients with anxious depression versus low levels of anxiety at baseline.

Abstract Objectives. To evaluate quetiapine XR in patients with anxious depression, as defined by HAM-A total and HAM-D anxiety/somatisation factor scores. Methods. Post hoc analyses of pooled data from two 6-week, double-blind, randomised, placebo-controlled studies of adjunctive quetiapine XR (150 or 300 mg/day) in patients with MDD and inadequate response to antidepressants. Patients were stratified in a primary analysis using HAM-A (HAM-A total score at baseline ≥ 20 [“high”] or < 20 [“low”]) and a secondary analysis using HAM-D (anxious depression defined as HAM-D anxiety/somatisation factor score ≥ 7). Outcomes included change in MADRS total score. Results. In patients with high anxiety levels (HAM-A total score ≥ 20), reductions in MADRS total score were –15.20 (P = 0.122) and –15.92 (P < 0.05) for quetiapine XR 150 and 300 mg/day, respectively, vs. placebo (–13.49). In patients with low levels of anxiety (HAM-A total score < 20), both quetiapine XR doses (P < 0.001) improved MADRS total scores vs. placebo. In the secondary analysis, quetiapine XR 150 (P < 0.01) and 300 mg/day (P < 0.001) improved MADRS total score vs. placebo in patients with HAM-D anxiety/somatisation factor score ≥ 7. Conclusions. Adjunct quetiapine XR demonstrates efficacy in patients with anxious and non-anxious depression, assessed using HAM-A total score, and anxious depression assessed using HAM-D anxiety/somatisation factor score.