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

Journal of Affective Disorders 127 (2010) 19–30

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Journal of Affective Disorders j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / j a d

Review

A pooled analysis of two randomised, placebo-controlled studies of extended release quetiapine fumarate adjunctive to antidepressant therapy in patients with major depressive disorder Michael Bauer a,⁎, Nizar El-Khalili b, Catherine Datto c, Johan Szamosi d, Hans Eriksson d a b c d

Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01307 0 Dresden, Germany Alpine Clinic, Lafayette, IN, USA AstraZeneca Pharmaceuticals, Wilmington, DE, USA AstraZeneca R&D, Södertälje, Sweden

a r t i c l e

i n f o

Article history: Received 24 September 2009 Received in revised form 26 August 2010 Accepted 26 August 2010 Available online 29 September 2010 Keywords: Extended release Quetiapine Adjunctive Major depressive disorder

a b s t r a c t 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 diseaserelated 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 quetiapine XR 150 mg/day (n = 309), 300 mg/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 300 mg/day) reduced MADRS total scores vs placebo at every assessment including Week 6 (−14.5, −14.8, −12.0; p b 0.001 each dose) and Week 1 (−7.8, −7.3,−5.1; p b 0.001 each dose). For quetiapine XR 150 and 300 mg/day and placebo, respectively at Week 6: MADRS response 53.7% (p = 0.063), 58.3% (p b 0.01) and 46.2%; MADRS remission 35.6% (p b 0.01), 36.5% (p b 0.001) and 24.1%. Quetiapine XR 150 and 300 mg/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. © 2010 Elsevier B.V. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

⁎ Corresponding author. Tel.: + 49 351 458 2772; fax: +49 351 458 4324. E-mail address: [email protected] (M. Bauer). 0165-0327/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2010.08.032

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2.1. Study designs . . . . . . . . . . . . . 2.2. Patients . . . . . . . . . . . . . . . 2.3. Treatment . . . . . . . . . . . . . . 2.4. Efficacy evaluations . . . . . . . . . . 2.5. Safety and tolerability . . . . . . . . . 2.6. Statistical analyses . . . . . . . . . . . 3. Results . . . . . . . . . . . . . . . . . . . 3.1. Patient population . . . . . . . . . . 3.2. Efficacy . . . . . . . . . . . . . . . . 3.2.1. Primary endpoint . . . . . . . 3.2.2. MADRS secondary endpoints . . 3.2.3. Response . . . . . . . . . . . 3.2.4. Remission . . . . . . . . . . 3.2.5. Subgroup analyses . . . . . . 3.2.6. Other secondary endpoints . . 3.3. Safety and tolerability . . . . . . . . . 3.3.1. AEs . . . . . . . . . . . . . 3.3.2. Extrapyramidal symptoms (EPS) 3.3.3. Suicidality . . . . . . . . . . 3.3.4. Weight . . . . . . . . . . . . 4. Discussion . . . . . . . . . . . . . . . . . . Role of funding source . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . .

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1. Introduction Major depressive disorder (MDD) leads to significant morbidity and is highly prevalent in the global population, affecting more than 16% of adults at some point in their life (Kessler et al., 2003). Physicians currently have limited therapeutic options if patients have an inadequate response to first-line antidepressant treatments. These are largely restricted to: (1) increasing the dose of the initial therapy; (2) switching to another first-line agent; or (3) adjunctive medication. There is no conclusive evidence supporting dose escalation of standard antidepressant therapy in patients experiencing an inadequate response to initial treatment (Ruhé et al., 2006a). Furthermore, there is no clear evidence to support switching between classes of antidepressants in patients with an inadequate response to SSRIs (Ruhé et al., 2006b). Indeed, low rates of remission have been reported in patients with MDD following a switch to a third antidepressant monotherapy following two consecutive unsuccessful antidepressant trials (Fava et al., 2006). Failing to achieve disease remission severely impairs patient functioning and increases the risk of relapse (McIntyre and O'Donovan, 2004). Commonly used antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs), do not produce full remission of symptoms in a large proportion of patients (Rush et al., 2003). In addition, it can take several weeks before the onset of symptom relief and patient reports of tolerability issues with SSRIs and SNRIs, such as sexual dysfunction, are common (Hansen et al., 2005; Nemeroff, 2007). Furthermore, treatment resistance with SSRIs and SNRIs is reported in approximately one-third and one-half of patients, respectively, who fail to respond to

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standard antidepressant therapy of sufficient dose and duration (Fava and Davidson, 1996). Among the drug classes that have been investigated as adjuncts to standard antidepressant therapy, the atypical antipsychotics have also shown clinically relevant efficacy in patients with MDD (Berman et al., 2007; Mahmoud et al., 2007; Thase et al., 2007). Quetiapine has demonstrated an antidepressant effect across a range of psychiatric disorders. In addition to studies investigating the effectiveness of quetiapine as an adjunctive treatment in patients with MDD (Doree et al., 2007; Mattingly et al., 2006; McIntyre et al., 2007; Yargic et al., 2004), there is also good evidence to support the antidepressant effect of quetiapine in patients with schizophrenia (Buckley, 2004) and bipolar depression (Calabrese et al., 2005; McElroy et al., 2008; Thase et al., 2006; Young et al., 2008). Extended release quetiapine fumarate (quetiapine XR) is a once-daily formulation that has demonstrated efficacy both as monotherapy in the short and long term (Bortnick et al., 2010; Cutler et al., 2009; Liebowitz et al., 2010; Weisler et al., 2009) and as acute adjunct therapy in patients with MDD (Bauer et al., 2009; El-Khalili et al., 2010). The mode of action of quetiapine has not been fully elucidated. Although questions remain, the recent characterisation of the major active human metabolite norquetiapine (N-desalkylquetiapine) has provided new mechanistic explanations for the antidepressant effects seen in clinical trials (Jensen et al., 2008). Both quetiapine and norquetiapine have moderate-to-high affinity for serotonin 5-HT2A and dopamine D2 receptors; however, norquetiapine is also a potent inhibitor of the norepinephrine transporter (NET) (Goldstein et al., 2008; Jensen et al., 2008). The clinical relevance of these findings has been supported by positron emission tomography (PET) imaging of NET occupancy in quetiapine-treated subjects

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(Nyberg et al., 2008). NET inhibition is a well-established mechanism of action for many antidepressants (e.g. tricyclics, monoamine oxidase inhibitors and SNRIs). This action has not been shown by other atypical antipsychotics at clinically relevant doses and is believed to contribute to the antidepressant effect of quetiapine XR (Goldstein et al., 2007). Previous reports from two 6-week trials of quetiapine XR as adjunct to antidepressant monotherapy in patients with MDD and an inadequate response to ongoing antidepressant treatment (Bauer et al., 2009; El-Khalili et al., 2010) described similar safety and tolerability findings; however, differences were observed in their primary and secondary efficacy outcomes. We present results from a prospectively planned analysis of pooled data with a larger sample size that enables further evaluation of efficacy outcomes. In addition, the pooled analysis provides an opportunity for subgroup analyses investigating the influence of demographic and disease-related factors in explaining observed responses. Post hoc analyses also examined the efficacy of quetiapine XR against specific symptoms of depression including sleep.

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as continuing depressive symptoms despite ≥ 6 weeks of therapy at an adequate dose (minimum effective dose according to the product label and including at least one dose increase as permitted by the label). Key exclusion criteria included: any DSM-IV Axis I disorder other than MDD within 6 months prior to enrolment; any DSM-IV Axis II disorder significantly impacting the patient's current psychiatric status; and duration of current MDD episode N12 months or b4 weeks from enrolment. 2.3. Treatment

2. Methods

Patients were randomised (in a 1:1:1 ratio) to receive 6 weeks of double-blind treatment with quetiapine XR 150 mg/day, quetiapine XR 300 mg/day or a placebo as adjunct to their ongoing antidepressant therapy. Patients received quetiapine XR tablets and/or placebo tablets once daily in the evening with or without food. Titration of quetiapine XR to target dose was 50 mg/day on Days 1–2, 150 mg/day on Days 3–4 and 300 mg/day on Day 5. Ongoing antidepressant treatment was maintained at the same dose throughout the studies.

2.1. Study designs

2.4. Efficacy evaluations

Full details of the methodology employed in the two studies presented here have been reported previously (Bauer et al., 2009; El-Khalili et al., 2010). In brief, these were multicentre, double-blind, randomised, parallel-group, placebo-controlled Phase III studies (D1448C00006 [Pearl] and D1448C00007 [Onyx]). One US study was conducted at 56 centres between April 2006 and July 2007. The second international study was conducted at 87 centres in Australia, Canada, Europe and South Africa between May 2006 and April 2007. Both studies consisted of an enrolment/washout period of up to 14 days (for the discontinuation of all prohibited medications), a 6-week randomised treatment period and in the US study, a 2-week drug-discontinuation/follow-up period. Following randomisation, study visits occurred at Weeks 1, 2, 4 and 6. Institutional Review Board or Independent Ethics Committee approval was obtained at each study centre. In accordance with the Declaration of Helsinki, International Conference of Harmonization, Good Clinical Practice guidelines and applicable regulatory requirements were adhered to.

The primary endpoint for both trials was the change from randomisation to Week 6 in the Montgomery–Åsberg Depression Rating Scale (MADRS) total score (Montgomery and Åsberg, 1979). Secondary efficacy evaluations included change in MADRS total score from randomisation at each assessment (Weeks 1, 2, 4 and 6); change from randomisation at Week 1 and at Week 6 in MADRS individual item scores; MADRS response (≥50% reduction from randomisation in MADRS total score) at Weeks 1 and 6; MADRS remission (MADRS total score ≤8) at Week 6. Additional remission cut-offs (MADRS total scores of ≤10 and ≤12), more commonly used in clinical trials, were defined post hoc. Further secondary efficacy evaluations included subgroup analyses of pooled primary variable data for severity of depression at randomisation, age, gender and class of antidepressants (SSRI or SNRI) (a post hoc analysis was also conducted for patients with or without somnolence or sedation); change from randomisation in HAM-D and Hamilton Anxiety Rating scale (HAM-A) total scores (Hamilton, 1959) at Week 1 and Week 6; change from randomisation to Week 6 in HAM-D sleep disturbance factor, Clinical Global ImpressionSeverity of Illness (CGI-S) score (National Institutes of Mental Health, 1970), Pittsburgh Sleep Quality Index (PSQI) global score (Buysse et al., 1989) and Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) % maximum total score (Endicott et al., 1993).

2.2. Patients In brief, outpatients (age 18–65 years) with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis of MDD (single episode 296.2x or recurrent 296.3x; confirmed by the Mini-International Neuropsychiatric Interview), Hamilton Depression Rating Scale (HAM-D) total score≥ 20 and a HAM-D Item 1 (depressed mood) score ≥ 2 at enrolment and randomisation were eligible for inclusion in these studies. Patients were required to have an inadequate response during their current depressive episode to one of several prespecified antidepressants (amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline or venlafaxine). An inadequate response was defined

2.5. Safety and tolerability Adverse events (AEs) and withdrawals due to AEs were documented throughout the studies. Serious AEs (SAEs) were recorded for up to 30 days after the last dose of study medication. AEs were followed-up until resolution or until the investigator decided it was unnecessary. Physical examination, laboratory measurements, and electrocardiogram (ECG) were conducted at enrolment and Week 6. Body weight,

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vital signs and concomitant medication were recorded at enrolment and all subsequent visits. 2.6. Statistical analyses Primary and secondary efficacy analyses of pooled data were performed on the modified intent-to-treat (MITT) analysis set, which included all enrolled patients who took study medication and had a valid randomisation MADRS total score and at least 1 valid post-randomisation MADRS total score. For the primary endpoint, pooled analyses across the studies were performed by the use of the last observation carried forward (LOCF) approach, including an analysis of covariance (ANCOVA) model with the study as an additional fixed effect in the model. Hence, a random effect of centre was nested within the fixed effect for the study. Least squares means (LSM) for all pairwise differences between quetiapine XR and placebo were calculated along with the associated 95% confidence intervals (CIs). Point estimates of change from randomisation for each treatment group are also presented together with corresponding 95% CIs. A non-parametric Wilcoxon test was used to test the robustness of the primary pooled analysis (ANCOVA model) of changes from baseline in individual MADRS items. As part of the post hoc analyses, the number needed to treat (NNT) for MADRS responders was also calculated (NNT = 100/[% responders with quetiapine XR-% responders with placebo]). Independence of treatment effects on sleep and the primary endpoint were investigated using ANCOVA models that tested for treatment effects on (a) MADRS total score using MADRS Item 4 (reduced sleep) score as a covariate, and (b) a modified MADRS total score (MADRS Item 4 score omitted). Analysis of change from randomisation to Week 6 (LOCF) for secondary endpoints (HAM-A and HAM-D total scores, PSQI global score and CGI-S score) was used to compare the efficacy of quetiapine XR with a placebo. These variables were analysed in the same way as the primary endpoint with the respective baseline score as the covariate. A logistic regression model with the treatment and study as factor and randomisation values as the covariate was used to analyse the effect of each quetiapine XR group vs placebo with respect to MADRS response and remission. The confidence levels and p-values presented are nominal with no adjustment for multiplicity issues. 3. Results 3.1. Patient population Across the two studies, a total of 939 patients were randomised to receive quetiapine XR 150 mg/day (n = 315), quetiapine XR 300 mg/day (n = 313) or placebo (n = 311) as adjuncts to ongoing antidepressant therapy. Of the patients who were randomised, 767 (83.5%) completed 6 weeks of treatment (Fig. 1). Overall, 20 patients were excluded from the MITT population resulting in a total MITT population of 919 patients. The reasons for exclusion were similar across treatment groups, with most of the exclusions being due to patients having no valid MADRS assessment. Three patients were excluded from

the pooled safety population for not taking any study drug (n = 936). The groups were well matched in terms of demographic and clinical characteristics at randomisation and medication used at any time during randomised treatment (Table 1). Across the two studies, 61.9%, 27.1%, 9.5% and 1.5% of patients were receiving an SSRI, an SNRI, bupropion and amitriptyline, respectively, prior to study entry. 3.2. Efficacy 3.2.1. Primary endpoint LSM change in MADRS total score from randomisation to Week 6 was significantly greater with quetiapine XR 150 mg/ day and quetiapine XR 300 mg/day, than with placebo (−14.5, −14.8 and −12.0, respectively; p b 0.001 for each dose). This statistically significant change was apparent as early as Week 1 with quetiapine XR 150 mg/day and 300 mg/day, compared with placebo (−7.8, −7.3 and −5.1, respectively; p b 0.001 for each dose). Both doses of quetiapine XR were associated with significantly greater improvements in MADRS total score than placebo at each subsequent assessment (Fig. 2). 3.2.2. MADRS secondary endpoints Consistent improvements in individual MADRS items were seen during the studies with significant improvement observed as early as Week 1 with both doses of quetiapine XR. At Week 1, quetiapine XR 150 mg/day significantly improved 6 of 10 items and quetiapine XR 300 mg/day 4 of 10 items, compared with placebo (Fig. 3a). Significant reductions compared with placebo were observed in 4 of 10 MADRS individual item scores with quetiapine XR 150 mg/ day and in 7 of 10 items with quetiapine XR 300 mg/day at Week 6 (Fig. 3b). At Week 6, quetiapine XR 150 mg/day significantly improved the following items: apparent sadness, inner tension, reduced sleep and inability to feel. At Week 6, quetiapine XR 300 mg/day significantly improved apparent sadness, reported sadness, inner tension, reduced sleep, inability to feel and pessimistic thoughts and suicidal thoughts. Analysis of MADRS individual item data using the non-parametric Wilcoxon test confirmed findings from the primary analysis with quetiapine XR-treated patients achieving significant improvements vs placebo across multiple items. 3.2.3. Response MADRS response (≥50% decrease in total score) rates at Week 1 were 18.6% (p b 0.01, compared with placebo), 17.5% (p b 0.05, compared with placebo) and 10.8% for quetiapine XR 150 mg/day, quetiapine XR 300 mg/day and placebo, respectively. At Week 6, response rates were 53.7% (p = 0.063), 58.3% (p b 0.01) and 46.2%, respectively (Fig. 4a). Using the Week 6 MADRS response data, the NNT values for quetiapine XR 150 and 300 mg/day were 14.2 and 8.3, respectively. 3.2.4. Remission Remission (MADRS total score ≤8) rates at Week 6 were 35.6% (p b 0.01) and 36.5% (p b 0.001) in the quetiapine XR 150 mg/day and 300 mg/day groups, respectively vs placebo (24.1%) (Fig. 4b). Using more common definitions of remission (MADRS total score ≤10 and ≤12), higher rates

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Fig. 1. Disposition of patients at each stage of two studies evaluating quetiapine XR as adjunct to ongoing antidepressant therapy for the treatment of MDD. MITT, modified intent-to-treat; XR, extended release; AE, adverse event; MDD, major depressive disorder.

of remission were observed at Week 6 in the quetiapine XR 150 mg/day and 300 mg/day groups compared with placebo (≤10: 41.8%, 46.3% and 32.0%, respectively; ≤12: 49.8%, 53.1% and 40.3%, respectively) (Fig. 4b). 3.2.5. Subgroup analyses The results of subgroup analyses of the primary variable by severity of depression, age and gender are shown in Table 2. Analysis of the change in mean MADRS total scores from randomisation at Week 6 by class of adjunctive antidepressant showed significantly greater improvements with quetiapine XR 150 and 300 mg/day, compared with placebo as adjunct to SSRIs (−14.8, −14.7 and −12.7, respectively; p b 0.05, for each dose) and SNRIs (−14.8, −15.1 and −10.8, respectively; p b 0.01, for each dose). Analysis of the primary endpoint using MADRS Item 4 (reduced sleep) score as a covariate showed that treatment with quetiapine XR 150 mg/day and 300 mg/day led to significant improvements from randomisation in MADRS

total score at Week 6 (−14.6 [p b 0.001] and −15.0 [p b 0.001], respectively) compared with placebo (−12.1). This finding was confirmed in an analysis of a modified version of the primary endpoint (change from randomisation to Week 6 in the modified MADRS total score (MADRS Item 4 score omitted): − 12.2 (p b 0.05) and − 12.8 (p b 0.01) vs − 10.8 in the quetiapine XR 150 mg/day, 300 mg/day and placebo groups, respectively. An additional analysis of patients with and without somnolence (as determined by an AE associated with a sedative effect) was undertaken. It should be noted that as these patients represent subpopulations they were not inherently randomised. At Week 6, quetiapine XR (dose groups combined) significantly improved MADRS total score in patients reporting sedation/ somnolence (n = 250), compared with placebo (n = 303) (−14.9 and −12.0, respectively; p b 0.001). In patients not reporting sedation/somnolence (n = 366) mean change in MADRS score was also significantly improved, compared with placebo (−14.4 and −12.0, respectively; p b 0.001).

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Table 1 Patient demographics, baseline study characteristics and medications received during randomised treatment (pooled MITT population).

Gender, n (%) Male Female Age (years) Mean (SD) Range Ethnicity, n (%) White Black Asian Other Weight (kg) Mean (SD) DSM-IV diagnosis of MDD, n (%): Single episode (296.2x) Recurrent (296.3x) Mean (SD) number of depressive episodes in past year Mean (SD) scores MADRS total HAM-D total HAM-A total CGI-S PSQI total Anticholinergic usage, % patients Sleep medication usage, % patients

Placebo + antidepressant (n = 303)

Quetiapine XR 150 mg/day + antidepressant (n = 309)

Quetiapine XR 300 mg/day + antidepressant (n = 307)

101 (33.3) 202 (66.7)

85 (27.5) 224 (72.5)

91 (29.6) 216 (70.4)

45.4 (10.6) 20 to 65

45.9 (10.5) 20 to 65

45.0 (11.2) 18 to 65

285 (94.1) 16 (5.3) 1 (0.3) 1 (0.3)

293 (94.8) 10 (3.2) 1 (0.3) 5 (1.6)

289 (94.1) 13 (4.2) 1 (0.3) 4 (1.3)

80.9 (20.8)

81.4 a (20.8)

80.9 (19.3)

41 (13.5) 262 (86.5) 1.4 (2.6)

40 (12.9) 269 (87.1) 1.6 (2.9)

43 (14.0) 264 (86.0) 1.4 (3.5)

27.9 (5.6) 24.3 (3.2) 19.1 (5.9) 4.5 (0.7) 11.8 (3.7) 1.7 14.9

27.9 (5.4) 24.3 (3.2) 19.4 (6.3) 4.5 (0.7) 12.3 (3.9) 1.3 23.5

28.0 (5.3) 24.4 (3.1) 19.9 (5.9) 4.6 (0.7) 12.1 (4.0) 2.3 17.3

MITT, modified intent-to-treat; XR, extended release; SD, standard deviation; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; MDD, major depressive disorder; MADRS, Montgomery–Åsberg Depression Rating Scale; HAM-D, Hamilton Depression Rating Scale; HAM-A, Hamilton Anxiety Rating Scale; CGI-S, Clinical Global Impression — Severity of Illness; PSQI, Pittsburgh Sleep Quality Index. a n = 308

3.2.6. Other secondary endpoints Significant improvements in HAM-D and HAM-A total scores, CGI-S score and PSQI global score were seen at Week 6 with quetiapine XR 150 mg and 300 mg, compared with

placebo (Table 2). However, no significant improvement was seen in Q-LES-Q % maximum total score with either dose of quetiapine XR at Week 6, compared with placebo (Table 2). 3.3. Safety and tolerability 3.3.1. AEs In the pooled safety population, AEs were experienced by 73.3%, 80.8% and 60.2% of patients in the quetiapine XR 150 mg/day, 300 mg/day and placebo groups, respectively. The most common AEs (≥5% of patients in any group) experienced during the two studies are presented in Table 3. Most AEs were mild to moderate in severity. SAEs were reported by 1.0%, 1.0% and 1.3% of patients in the quetiapine XR 150 mg/day, 300 mg/day and placebo groups, respectively. The percentage of patients who withdrew from the studies due to AEs was higher in quetiapine XR-treated patients (150 mg/day, 8.9%; 300 mg/day, 15.4%), compared with placebo (1.9%). In the quetiapine XR groups, the most common AEs leading to withdrawal were somnolence (150 mg/day, 2.9%; 300 mg/day, 3.2%) and sedation (150 mg/day, 1.9%; 300 mg/day, 4.8%).

Fig. 2. Change in MADRS total score from randomisation at Weeks 1, 2, 4 and 6 (pooled MITT population; LOCF). XR, extended release; LSM, least squares means; MADRS, Montgomery-Åsberg Depression Rating Scale; MITT, modified intent-to-treat; LOCF, last observation carried forward.

3.3.2. Extrapyramidal symptoms (EPS) AEs categorised as being potentially related to EPS included the following Medical Dictionary for Regulatory Activities (MedDRA) preferred terms: akathisia, cogwheel rigidity, drooling, dyskinesia, extrapyramidal disorder, hypertonia, hypokinesia, psychomotor hyperactivity, restlessness and tremor. The incidences of AEs potentially related to EPS were

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Fig. 3. Change in individual MADRS items from randomisation to a) Week 1 and b) Week 6 (pooled MITT population; LOCF). XR, extended release; LSM, least squares means; MADRS, Montgomery-Åsberg Depression Rating Scale; MITT, modified intent-to-treat; LOCF, last observation carried forward.

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placebo-treated patient had an AE of suicide attempt on Day 2 of treatment that was of severe intensity, was considered to be serious, and was not considered to be related to study treatment. 3.3.4. Weight Mean (SD) changes from randomisation in body weight to end of treatment (Week 6) were +0.9 (2.2), +1.3 (2.3) and + 0.2 (2.5) kg in the quetiapine XR 150 mg/day, quetiapine XR 300 mg/day and placebo groups, respectively. Weight gain ≥7% was experienced by 3.2%, 7.2% and 1.7% of patients at any visit in the pooled safety population, respectively. 4. Discussion

Fig. 4. MADRS a) responders at Weeks 1 and 6 and b) remitters at Week 6 (pooled MITT population; LOCF). XR, extended release; MADRS, Montgomery-Åsberg Depression Rating Scale; MITT, modified intent-to-treat; LOCF, last observation carried forward.

3.8%, 6.4% and 4.2% of patients in the quetiapine XR 150 mg/day, 300 mg/day and placebo groups, respectively. 3.3.3. Suicidality The incidences of AEs potentially related to suicidality (MedDRA terms: suicidal ideation and suicide attempt) were 1.0%, 0.0% and 0.6% in the quetiapine XR 150 mg/day, 300 mg/day and placebo groups, respectively. In addition, of the patients with MADRS Item 10 (suicidal thoughts) score b4 at randomisation, the incidences of scores ≥4 at Week 6 were 0.6% (quetiapine XR 150 mg/day), 1.0% (quetiapine XR 300 mg/day) and 2.6% (placebo). Two patients (both from Study D1448C00007) had discontinued treatment due to AEs potentially related to suicidality (quetiapine XR 150 mg/day, n = 1; placebo, n = 1). The quetiapine-treated patient had an AE of suicidal ideation on Day 20 of treatment of severe intensity that was considered to be neither serious nor related to study treatment. The

This pooled analysis of two large, placebo-controlled, randomised studies shows adjunct quetiapine XR (150 mg/day and 300 mg/day) to be significantly more effective than placebo at improving a broad range of symptoms associated with MDD, with improvement seen as early as Week 1. This finding is consistent with that of the individual studies and supports the use of quetiapine XR as adjunct therapy in patients with MDD who have experienced suboptimal response to antidepressant therapy. By pooling these studies the larger sample size enabled subgroup analyses to be conducted to investigate demographic and disease-related factors. These analyses demonstrated that improvement in depressive symptoms with quetiapine XR was neither limited nor driven by severity of depression, adjunctive antidepressant, gender or age. Quetiapine XR (150 and 300 mg/day) adjunct therapy, significantly improved depressive symptoms as assessed by change in MADRS total score at Week 6 and at every assessment from Week 1, compared with placebo. MADRS response rates were significantly greater at Week 6 with quetiapine XR 300 mg/day but not 150 mg/day compared with placebo. At Week 1, both doses of quetiapine XR were associated with significantly great MADRS response rates than placebo. The results of the current analysis confirm those of the international study included in this pooled analysis in which adjunctive quetiapine XR therapy (150 and 300 mg/day) significantly reduced MADRS total score throughout the 6 weeks of the trial (Bauer et al., 2009). However, in the US study, no significant difference in MADRS total score was seen between quetiapine XR 150 mg/day and placebo from Week 4. A potential reason for this difference between the two studies is variation in disease history between the two patient populations. For example, in the US study, a higher percentage of patients had recurrent MDD and patients also had a greater number of previous lifetime depressed episodes (El-Khalili et al., 2010). The response rates seen in this pooled analysis at Week 6 are comparable with the rate reported in a meta-analysis of 10 studies (6–12 weeks duration) investigating the use of atypical antipsychotics as adjuncts to antidepressant therapy in patients with treatment-resistant depression (57.2%) (Papakostas et al., 2007). Furthermore, NNT values confirm the efficacy of quetiapine XR, with between 8.3 and 14.2 patients needing to be treated for one to achieve a clinical response. The efficacy of quetiapine XR in patients with MDD is further supported by the significantly greater remission rates observed compared with placebo. Significant rates of remission vs

M. Bauer et al. / Journal of Affective Disorders 127 (2010) 19–30

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Table 2 Change in MADRS total score by severity of depression, gender and age and change from randomisation at Week 6 in secondary efficacy endpoints (pooled MITT population, LOCF).

MADRS total score LSM change at Week 6 Difference (95% CI) vs placebo MADRS total score subgroup analyses Severity of depression Baseline HAM-D b 28, n (%) MADRS LSM change at Week 6 Baseline HAM-D ≥ 28, n (%) MADRS LSM change at Week 6 Gender Male, n (%) MADRS LSM change at Week 6 Female, n (%) MADRS LSM change at Week 6 Age Age group 18–39 years, n (%) MADRS LSM change at Week 6 Age group 40–65 years, n (%) MADRS LSM change at Week 6 HAM-D total score LSM change at Week 6 Difference (95% CI) vs placebo HAM-D sleep disturbance factor LSM change at Week 6 Difference (95% CI) vs placebo HAM-A total score LSM change at Week 6 Difference (95% CI) vs placebo CGI-S score LSM change at Week 6 Difference (95% CI) vs placebo PSQI global score LSM change at Week 6 Difference (95% CI) vs placebo Q-LES-Q % maximum total score LSM change at Week 6 Difference (95% CI) vs placebo

Placebo + antidepressant (n = 303)

Quetiapine XR 150 mg/day + antidepressant (n = 309)

Quetiapine XR 300 mg/day + antidepressant (n = 307)

− 11.96

− 14.47 − 2.50*** (− 3.88,−1.13)

−14.82 −2.85*** (− 4.23,−1.47)

251 (82.8) −11.56 52 (17.2) − 14.93

257 (83.2) −13.91** 52 (16.8) − 17.75

256 (83.4) − 14.34*** 51 (16.6) − 17.92

101 (33.3) − 11.51 202 (66.7) −12.44

85 (27.5) − 14.50* 224 (72.5) − 14.58*

91 (29.6) − 14.64* 216 (70.4) − 15.07**

85 − 11.82 218 − 12.23

77 − 13.60 232 −14.88**

92 − 14.53* 215 − 15.13***

−10.95

− 13.26 − 2.31*** (−3.48,−1.14)

− 13.52 − 2.57*** (−3.74,−1.40)

− 1.91

−2.95*** −1.03 (− 1.32,−0.75)

− 2.82*** − 0.90 (− 1.19,−0.62)

− 7.33

−8.90** −1.57 (− 2.57,−0.57)

− 9.13*** − 1.80 (− 2.81,−0.80)

− 1.25

−1.61*** −0.36 (− 0.56,−0.16)

− 1.58*** − 0.34 (− 0.54,−0.14)

− 3.00

−4.91*** −1.91 (− 2.50,−1.32)

− 4.82*** − 1.82 (− 2.41,−1.22)

11.96

12.71 0.75 (− 1.65, 3.15)

12.39 0.43 (− 1.98, 2.84)

*p b 0.05; **p b 0.01; ***p b 0.001 vs placebo. MADRS, Montgomery–Åsberg Depression Rating Scale; MITT, modified intent-to-treat; LOCF, last observation carried forward; XR, extended release; LSM, least squares means; CI, confidence interval; HAM-D, Hamilton Depression Rating Scale; HAM-A, Hamilton Anxiety Rating Scale; CGI-S, Clinical Global Impression — Severity of Illness; PSQI, Pittsburgh Sleep Quality Index; Q-LES-Q %, Quality of Life Enjoyment and Satisfaction Questionnaire.

placebo were seen in this pooled analysis and the remission rates observed at Week 6, using the usual definition of MADRS total score ≤10 or ≤12, are similar to those reported in the meta-analysis of 10 similar studies (47.4%) described previously (Papakostas et al., 2007). In this pooled analysis, significant improvement in the HAM-A total score was seen at Week 6 with both doses of quetiapine XR. This is important because patients with MDD commonly present with anxiety symptoms. Although the patients included in this pooled analysis did not the meet criteria for a comorbid anxiety disorder, quetiapine XR showed improvement in anxiety symptoms. A subgroup analysis showed significant improvement in depressive symptoms, as measured by change in MADRS total score, with adjunctive quetiapine XR, irrespective of the class of concomitant antidepressant (SSRIs or SNRIs). As SSRIs are the current first-line recommendation for MDD (American Psychiatric Association, 2000; National Institute of Health

and Clinical Excellence, 2009) adjunctive treatments must improve efficacy in combination. This finding highlights the potential clinical importance of quetiapine XR as an adjunct therapy for patients whose disease is inadequately controlled by standard antidepressant therapy. Depression has been shown to have a detrimental effect on many aspects of sleep, including extended time to sleep initiation and poor sleep quality (Slaughter, 2006). Indeed, according to DSM-IV criteria, insomnia is a core symptom of depression and is one of the most common presenting symptoms (Baldwin and Papakostas, 2006). The early improvement seen with quetiapine XR in the current study may appear to be in part due to a beneficial effect on sleep since among the individual MADRS items, the greatest magnitude of improvement at Weeks 1 and 6 was observed in Item 4 (reduced sleep). Quetiapine XR was also associated with significant improvement in PSQI global score, MADRS Item 4 (reduced sleep) and HAM-D sleep disturbance factor

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Table 3 Most common AEs (≥5%) occurring in any group during the study (pooled safety population). AE a, n (%)

Placebo + antidepressant (n = 309)

Quetiapine XR 150 mg/day + antidepressant (n = 315)

Quetiapine XR 300 mg/day + antidepressant (n = 312)

Dry mouth Somnolence Sedation Dizziness Fatigue Constipation Headache Nausea Weight increased Insomnia

24 (7.8) 11 (3.6) 13 (4.2) 20 (6.5) 12 (3.9) 11 (3.6) 36 (11.7) 22 (7.1) 1 (0.3) 17 (5.5)

86 (27.3) 71 (22.5) 41 (13.0) 36 (11.4) 45 (14.3) 18 (5.7) 36 (11.4) 22 (7.0) 10 (3.2) 19 (6.0)

124 (39.7) 81 (26.0) 54 (17.3) 36 (11.5) 34 (10.9) 33 (10.6) 24 (7.7) 24 (7.7) 16 (5.1) 14 (4.5)

AE, adverse event; XR, extended release. a Patients with multiple events of an AE are counted only once in that term.

scores at Week 6. However, it is of interest to note that the results from the post hoc analysis to determine whether treatment effects on sleep were independent of effects on the primary endpoint relationship between sleep and efficacy showed a significant overall improvement in MADRS total score at Week 6. This demonstrates the broad effects of quetiapine XR across a range of symptoms of depression which occur independently of its effect on sleep. Beyond improvements in sleep quetiapine XR also improved other MADRS items at Week 1. Significant improvements in MADRS total score were seen in patients, irrespective of whether or not they experienced an AE potentially related to somnolence, suggesting that any concomitant sedative effects do not interfere with the antidepressant effect of quetiapine XR. This observation further supports our finding that quetiapine XR antidepressant properties are independent of treatment effects on the core symptom of reduced sleep in patients with MDD. The results of the present pooled analysis show that, overall, adjunctive quetiapine XR was generally well tolerated, with an AE profile consistent with that documented for acute quetiapine XR use in other psychiatric illnesses, such as schizophrenia, bipolar mania and bipolar depression (Cutler et al., 2008; Kahn et al., 2007; Suppes et al., 2008). The percentages of patients who experienced an AE and who withdrew due to an AE were higher with quetiapine XR than with placebo, however, the number of SAEs was similar across the treatment groups. Somnolence and sedation were more common with quetiapine XR than with placebo, a finding that is consistent with the recommendation to dose quetiapine XR in the evening in patients with bipolar depression in order to minimise the impact of sedation/somnolence during the day (Seroquel XR (quetiapine fumarate) Extended-Release Tablets — US prescribing information, 2010). For patients with MDD it is recommended that quetiapine XR is taken in the evening without food or a light meal (approximately 300 cal), with a recommended dose range of 15–300 mg/day starting at 50 mg/day and increasing to 150 mg/day on Day 3 (Seroquel XR (quetiapine fumarate) Extended-Release Tablets — US prescribing information, 2010). Recent research in healthy subjects has demonstrated a delayed onset of sedation and less overall sedation over the dose-initiation period with quetiapine XR than with quetiapine immediate release (Datto

et al., 2009). Furthermore, food intake has minimal effects on quetiapine absorption (DeVane and Nemeroff, 2001) with the bioavailability of quetiapine being only marginally affected by the administration with food (maximum concentration and area under the curve increased by 25% and 15%, respectively) (Seroquel® (quetiapine fumarate) tablets — US prescribing information, 2010). Increases from baseline in body weight were seen with both doses of quetiapine XR. The proportion of patients who experienced weight gain ≥7% was greater with both doses of quetiapine XR than with placebo. These changes in weight are consistent with observations in monotherapy studies from the quetiapine XR clinical programme in patients with MDD (Bortnick et al., 2010; Cutler et al., 2009; Earley et al., 2008; Liebowitz et al., 2010; Weisler et al., 2009). Physicians should consider the potential for such effects before initiating any treatment in a patient with MDD and for atypical antipsychotics appropriate clinical monitoring of hyperglycaemia, lipids and weight is recommended. There is potential variation between the tolerability profiles of atypical antipsychotics evaluated for the adjunctive treatment of MDD. In a study demonstrating the efficacy of aripiprazole in combination with standard antidepressant therapy (Berman et al., 2007), the incidence of AEs associated with EPS in patients who received aripiprazole was 27.5% (placebo 9.7%). In the present analysis the incidences of AEs associated with EPS in the quetiapine XR 150 and 300 mg/day groups were 3.8% and 6.4%, respectively (placebo, 4.2%). The variation in tolerability profiles between the atypical antipsychotics has been demonstrated in patients with schizophrenia (Lieberman et al., 2005); however, no direct comparisons in patients with MDD have been conducted and are therefore required. Strengths of the present analysis include the large, multinational patient population, providing increased statistical power to enable investigation of treatment differences between specific subsets of patients. Limitations of the studies included in this pooled analysis include fixed dosing, which is not reflective of clinical practice, and the lack of an active comparator, which limits the comparison of quetiapine XR with other potential treatments for MDD. Furthermore, due to the short duration of this study interpretation of these findings is only applicable to acute therapy. However, the efficacy, safety and tolerability of quetiapine XR in the

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maintenance treatment of patients with MDD have been reported (Liebowitz et al., 2010). In summary, this pooled analysis of two randomised, placebo-controlled studies demonstrates that adjunctive quetiapine XR (150 and 300 mg/day) is effective and generally well tolerated in patients with MDD who have an inadequate response to ongoing antidepressant treatment, with symptom improvement seen as early as Week 1. Role of funding source Funding for the initial studies was provided by AstraZeneca; AstraZeneca was involved in the development of the study design and in the analysis and interpretation of data; AstraZeneca provided funding for the writing of this manuscript. Conflict of interest Dr Bauer has received grant/research support from The Stanley Medical Research Institute, NARSAD, Eli Lilly and AstraZeneca. He is a consultant for AstraZeneca, Eli Lilly Deutschland, Servier, Lundbeck, Janssen-Cilag, BristolMyers Squibb and Otsuka. Dr Bauer has received speaker honoraria from AstraZeneca, Eli Lilly, GlaxoSmithKline, Pfizer, Bristol-Myers Squibb and Otsuka. Nizar El-Khalili has received research grants from AstraZeneca, Eli Lilly, GlaxoSmithKline, Pfizer, and Sanofi-Aventis, and has participated in advisory boards for Eli Lilly and speakers bureaus for AstraZeneca, Eli Lilly and SanofiAventis. Catherine Datto, Johan Szamosi and Hans Eriksson are employees of AstraZeneca.

Acknowledgements These studies (D1448C00006 [Pearl] and D1448C00007 [Onyx]) were funded by AstraZeneca. We thank Dr Alex Mitchell from Complete Medical Communications, who provided medical writing support funded by AstraZeneca. The following investigators were involved in the studies: Study 6 (Pearl): Amit Anand (Indianapolis, Indiana), Sarah Atkinson (Rochester, New York), Michael Banov, (Roswell, Georgia), Benny Barnhart (Wichita Falls, Texas), Brian Bortnick (Atlanta, Georgia), Ronald Brenner (Cedarhurst, New York), Edward Cherlin (El Centro, California), Adnan Dahdul (Springfield, Massachusetts), Nizar El-Khalili (Lafayette, Indiana), Prakash Ettigi (Richmond, Virginia), Miguel Flores (Hialeah, Florida), Richard Jackson (Royal Oaks, Michigan), Elias Sarkis (Gainsville, Florida), Anita Kablinger (Shreveport, Louisiana), James Kocsis (New York, New York), Jelena Kunovac (Oceanside, California), Charles Morin (Braintree, Massachusetts), Amy Mulroy (San Antonio, Texas), Veronique Sebastian (Oklahoma City, Oklahoma), Ismail Sendi (Clinton, Michigan), Phebe Tucker (Oklahoma City, Oklahoma), Robert Buynak (Valparaiso, Indiana), Carlos Danger (Miami, Florida), Kettlie Daniels (Toledo, Ohio), Robert Earle (Friendswood, Texas), Sanjay Gupta (Olean, New York), Gregory Mattingly (St Charles, Missouri), Haydn Thomas (Prairie Village, Kansas), Ethan Kass (Coral Springs, Florida), James Whalen (Lincoln, Rhode Island), Jeffrey Ross (Hoffman Estates, Illinois), Jerold Kreisman (St Louis, Missouri), Barbara Harris (Phoenix, Arizona), Joseph Ripperger (Norman, Oklahoma), Michael Levy (Staten Island, New York), Lora McGill (Memphis, Tennessee), John Joyce (Jacksonville, Florida), Charles Bailey (Orlando, Florida), Charles Meredith (San Diego, California), Ramanath Gopalan (Arlington, Virginia), Riaz Baber (Naperville, Illinois), Bijan Bastani (Beechwood, Ohio), Elly Lee (Irvine, California), Robert Hudrick (Cherry Hill, New Jersey), Deborah Bergen

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(Wichita, Kansas), Susanna Goldstein (New York, New York), Robert Riesenberg (Atlanta, Georgia), Fares Arguello (Salt Lake City, Utah), David Krefetz (Clementon, New Jersey), Steven Eisen (Philadelphia, Pennsylvania), Mohammed Alam (Oak Brook, Illinois) and Arifulla Khan (Bellevue, Washington). Study 7 (Opal): Thomas George, Michael Theodoros, Jayashri Kulkarni, Peter Farnbach, Bernhard Baune (Australia); Eric Constant, Kurt Audenaert, William Pitchot, Joseph Lejeune, Serge Seghers, Stefaan Geerts, Antonio Gazziano, Bart Leroy, Firmin Janssen (Belgium); Dennis O'Keefe, Brian Ramjattan, John Li, Jeannette Janzen, Lew Pliamm, (Canada); Marketa Zemanova, Tibor Miklos, Yvona Hendrychova, Alena Railova, Michaela Klabusayova, Marek Perez, Silvia Musilova, Marcela Bolkova Janikova, Zdenek Solle (Czech Republic); Antti Ahokas, Anna Savela, Raili Kansanen, Riitta Jokinen, Jukka Penttinen, Juhani Aer (Finland); Joël Gailledreau, Eric Neuman, Frédéric Chapelle, Christian Gaussares, Mocrane Abbar, Christian Geraud, Francis Gheysen, Paule Khalifa, Nicole Parant, Jean Audet, Bertrand Baranovsky, Bernard Vanier (France); Matthias Rothermundt, Michael Bauer, Albert Diefenbacher, Hans Gutzmann, Volker Schumann, Thomas Messer, Franz-Markus Leweke, Günther Schumann, Eugen Schlegel (Germany); Espen Anker, Dag Oulie, Kjetil Høye, Shaheen Asghar, Torbjørn Tvedten, Sverre Tønseth (Norway); Jolanta Rabe-Jablońska, Mieczyslaw Janiszewski, Jolanta Ferszka, Jerzy Samochowiec, Andrzej Kokoszka, Wlodzimierz Chrzanowski, Dariusz Juszczak, Krzysztof Klinke (Poland); Mirela Manea, Elena Gherman, Maria Ladea, Cristian Marinescu (Romania); Lynette Nel, Herman Pretorius, Christiaan Verster, Mahomed Salduker (South Africa); Curt Rolleri, Per Ekdahl, Konrad Rosman, Kurt Wahlstedt, Göran Björling, Eija Maahr and Anna Loewenstein (Sweden).

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