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

Abstract

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.

Keywords: Phase III; antidepressive agents (pharmacological action); antipsychotic agents; clinical trial; sustained-release preparations; treatment efficacy.

Figures

Figure 1

Patient disposition. Notes:aPatients who failed to meet the criterion of adequate response (≥20% reduction in MADRS total score after 2 weeks of treatment) were up-titrated to double the initial randomized dose for the remaining 6 weeks of randomized treatment. Abbreviations: MADRS, Montgomery–Åsberg Depression Rating Scale; MDD, major depressive disorder.

Figure 2

(A and B) Change from randomization to week eight in MADRS total score. (A) LOCF approach; (B) MMRM analysis of observed-case data (MITT population). Notes: *P<0.05; **P<0.01; ***P<0.001 versus placebo. Abbreviations: LOCF, last observation carried forward; LSM, least-squares mean; MADRS, Montgomery–Åsberg Depression Rating Scale; MITT, modified intent-to-treat; MMRM, mixed-model repeated measures.

Figure 3

Change in MADRS total score over time in patients with an adequate and inadequate responsea,b at week two (LOCF; MITT population). Notes:aInadequate response defined as <20% reduction in MADRS total score from randomization to week two; bpatients with an inadequate response at week two had their dose doubled (quetiapine XR 300 mg/day; escitalopram 20 mg/day). Abbreviations: LOCF, last observation carried forward; MADRS, Montgomery–Åsberg Depression Rating Scale; MITT, modified intent-to-treat.

Figure 4

Change in individual MADRS item scores from randomization to week 8 (MITT population; LOCF). Note: ***P<0.001 versus placebo. Abbreviations: LOCF, last observation carried forward; LSM, least-squares means; MADRS, Montgomery–Åsberg Depression Rating Scale; MITT, modified intent-to-treat.