A pooled analysis of two randomised, placebo-controlled studies ofextended release quetiapine fumarate adjunctive to antidepressant therapyin patients with major depressive disorder
Michael Bauer a,⁎, Nizar El-Khalili b, Catherine Datto c, Johan Szamosi d, Hans Eriksson d
a Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01307 0 Dresden, Germanyb Alpine Clinic, Lafayette, IN, USAc AstraZeneca Pharmaceuticals, Wilmington, DE, USAd AstraZeneca R&D, Södertälje, Sweden
Article history:Received 24 September 2009Received in revised form 26 August 2010Accepted 26 August 2010Available online 29 September 2010
Background: Two positive studies evaluated adjunctive extended release quetiapine fumarate(quetiapine XR) in patients with major depressive disorder (MDD) showing inadequateresponse to antidepressant treatment. This preplanned, pooled analysis provides anopportunity for subgroup analyses investigating the influence of demographic and disease-related factors on observed responses. Additional post hoc analyses examined the efficacy ofquetiapine 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-dailyquetiapine XR 150 mg/day (n=309), 300 mg/day (n=307) or placebo (n=303) adjunctive toongoing antidepressant therapy. The primary endpoint was change from randomisation toWeek 6 in MADRS total score. Other assessments included MADRS response (≥50% decrease intotal 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 everyassessment including Week 6 (−14.5, −14.8, −12.0; pb0.001 each dose) and Week 1 (−7.8,−7.3,−5.1; pb0.001 each dose). For quetiapine XR 150 and 300 mg/day and placebo, respectivelyat Week 6: MADRS response 53.7% (p=0.063), 58.3% (pb0.01) and 46.2%; MADRS remission35.6% (pb0.01), 36.5% (pb0.001) and 24.1%. Quetiapine XR 150 and 300 mg/day significantlyimproved HAM-D, HAM-A, PSQI and CGI-S scores at Week 6 vs placebo. Quetiapine XRdemonstrated 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 inadequateresponse to antidepressant therapy, with improvement in depressive symptoms seen as early asWeek 1.
Major depressive disorder (MDD) leads to significantmorbidity 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 limitedtherapeutic options if patients have an inadequate responseto first-line antidepressant treatments. These are largelyrestricted to: (1) increasing the dose of the initial therapy;(2) switching to another first-line agent; or (3) adjunctivemedication. There is no conclusive evidence supportingdose escalation of standard antidepressant therapy inpatients experiencing an inadequate response to initialtreatment (Ruhé et al., 2006a). Furthermore, there is noclear evidence to support switching between classes ofantidepressants in patients with an inadequate responseto SSRIs (Ruhé et al., 2006b). Indeed, low rates of re-mission have been reported in patients with MDD followinga switch to a third antidepressant monotherapy followingtwo consecutive unsuccessful antidepressant trials (Favaet al., 2006).
Failing to achieve disease remission severely impairspatient functioning and increases the risk of relapse(McIntyre and O'Donovan, 2004). Commonly used anti-depressants, such as selective serotonin reuptake inhibitors(SSRIs) and serotonin–norepinephrine reuptake inhibitors(SNRIs), do not produce full remission of symptoms in a largeproportion of patients (Rush et al., 2003). In addition, it cantake several weeks before the onset of symptom relief andpatient reports of tolerability issues with SSRIs and SNRIs,such as sexual dysfunction, are common (Hansen et al., 2005;Nemeroff, 2007). Furthermore, treatment resistance withSSRIs and SNRIs is reported in approximately one-third andone-half of patients, respectively, who fail to respond to
standard antidepressant therapy of sufficient dose andduration (Fava and Davidson, 1996).
Among the drug classes that have been investigated asadjuncts to standard antidepressant therapy, the atypicalantipsychotics have also shown clinically relevant efficacy inpatients with MDD (Berman et al., 2007; Mahmoud et al.,2007; Thase et al., 2007).
Quetiapine has demonstrated an antidepressant effectacross a range of psychiatric disorders. In addition to studiesinvestigating the effectiveness of quetiapine as an adjunctivetreatment in patientswithMDD (Doree et al., 2007;Mattinglyet al., 2006; McIntyre et al., 2007; Yargic et al., 2004), there isalso good evidence to support the antidepressant effect ofquetiapine 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 aonce-daily formulation that has demonstrated efficacy both asmonotherapy 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 patientswithMDD (Bauer et al.,2009; El-Khalili et al., 2010).
The mode of action of quetiapine has not been fullyelucidated. Although questions remain, the recent character-isation of the major active human metabolite norquetiapine(N-desalkylquetiapine) has provided new mechanistic expla-nations for the antidepressant effects seen in clinical trials(Jensen et al., 2008). Both quetiapine and norquetiapine havemoderate-to-high affinity for serotonin 5-HT2A and dopamineD2 receptors; however, norquetiapine is also a potent inhibitorof the norepinephrine transporter (NET) (Goldstein et al., 2008;Jensen et al., 2008). The clinical relevance of these findings hasbeen 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-establishedmechanism of action for many antidepressants (e.g. tricyclics,monoamine oxidase inhibitors and SNRIs). This action has notbeen shown by other atypical antipsychotics at clinicallyrelevant doses and is believed to contribute to the antidepres-sant effect of quetiapine XR (Goldstein et al., 2007).
Previous reports from two 6-week trials of quetiapine XRas adjunct to antidepressant monotherapy in patients withMDD and an inadequate response to ongoing antidepressanttreatment (Bauer et al., 2009; El-Khalili et al., 2010) describedsimilar safety and tolerability findings; however, differenceswere observed in their primary and secondary efficacyoutcomes. We present results from a prospectively plannedanalysis of pooled data with a larger sample size that enablesfurther evaluation of efficacy outcomes. In addition, thepooled analysis provides an opportunity for subgroupanalyses investigating the influence of demographic anddisease-related factors in explaining observed responses. Posthoc analyses also examined the efficacy of quetiapine XRagainst specific symptoms of depression including sleep.
2. Methods
2.1. Study designs
Full details of themethodology employed in the two studiespresented 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-controlledPhase III studies (D1448C00006 [Pearl] and D1448C00007[Onyx]). One US study was conducted at 56 centres betweenApril 2006 and July 2007. The second international study wasconducted at 87 centres in Australia, Canada, Europe and SouthAfrica between May 2006 and April 2007.
Both studies consisted of an enrolment/washout period ofup to 14 days (for the discontinuation of all prohibitedmedications), a 6-week randomised treatment period and inthe 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 Commit-tee approval was obtained at each study centre. In accordancewith the Declaration of Helsinki, International Conference ofHarmonization, Good Clinical Practice guidelines and applica-ble regulatory requirements were adhered to.
2.2. Patients
In brief, outpatients (age 18–65 years) with a Diagnosticand Statistical Manual of Mental Disorders, Fourth Edition(DSM-IV) diagnosis ofMDD (single episode 296.2x or recurrent296.3x; confirmed by the Mini-International NeuropsychiatricInterview), Hamilton Depression Rating Scale (HAM-D) totalscore≥20 and a HAM-D Item 1 (depressed mood) score≥2 atenrolment and randomisation were eligible for inclusion inthese studies.
Patients were required to have an inadequate responseduring their current depressive episode to one of several pre-specified antidepressants (amitriptyline, bupropion, citalo-pram, duloxetine, escitalopram, fluoxetine, paroxetine, ser-traline or venlafaxine). An inadequate response was defined
as continuing depressive symptoms despite≥6 weeks oftherapy at an adequate dose (minimum effective doseaccording to the product label and including at least onedose increase as permitted by the label).
Key exclusion criteria included: anyDSM-IVAxis I disorderother than MDD within 6 months prior to enrolment; anyDSM-IV Axis II disorder significantly impacting the patient'scurrent psychiatric status; and duration of current MDDepisode N12 months or b4 weeks from enrolment.
2.3. Treatment
Patients were randomised (in a 1:1:1 ratio) to receive6 weeks of double-blind treatment with quetiapine XR150 mg/day, quetiapine XR 300 mg/day or a placebo asadjunct to their ongoing antidepressant therapy. Patientsreceived quetiapine XR tablets and/or placebo tablets oncedaily in the evening with or without food.
Titration of quetiapine XR to target dose was 50 mg/day onDays 1–2, 150 mg/day on Days 3–4 and 300 mg/day on Day 5.Ongoing antidepressant treatmentwasmaintained at the samedose throughout the studies.
2.4. Efficacy evaluations
The primary endpoint for both trials was the change fromrandomisation to Week 6 in the Montgomery–ÅsbergDepression Rating Scale (MADRS) total score (Montgomeryand Åsberg, 1979).
Secondary efficacy evaluations included change in MADRStotal score from randomisation at each assessment (Weeks 1, 2,4 and 6); change from randomisation atWeek 1 and atWeek 6in MADRS individual item scores; MADRS response (≥50%reduction from randomisation in MADRS total score) atWeeks1 and 6; MADRS remission (MADRS total score≤8) atWeek 6.Additional remission cut-offs (MADRS total scores of ≤10 and≤12),more commonly used in clinical trials, were defined posthoc. Further secondary efficacy evaluations included subgroupanalyses of pooled primary variable data for severity ofdepression at randomisation, age, gender and class of anti-depressants (SSRI or SNRI) (a post hoc analysis was alsoconducted for patients with or without somnolence orsedation); change from randomisation inHAM-DandHamiltonAnxiety Rating scale (HAM-A) total scores (Hamilton, 1959) atWeek 1 andWeek 6; change from randomisation toWeek 6 inHAM-D sleep disturbance factor, Clinical Global Impression-Severity of Illness (CGI-S) score (National Institutes of MentalHealth, 1970), Pittsburgh Sleep Quality Index (PSQI) globalscore (Buysse et al., 1989) and Quality of Life Enjoyment andSatisfaction Questionnaire (Q-LES-Q) % maximum total score(Endicott et al., 1993).
2.5. Safety and tolerability
Adverse events (AEs) and withdrawals due to AEs weredocumented throughout the studies. Serious AEs (SAEs) wererecorded for up to 30 days after the last dose of studymedication. AEs were followed-up until resolution or untilthe investigator decided it was unnecessary. Physical exami-nation, laboratory measurements, and electrocardiogram(ECG) were conducted at enrolment andWeek 6. Bodyweight,
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vital signs and concomitant medication were recorded atenrolment and all subsequent visits.
2.6. Statistical analyses
Primary and secondary efficacy analyses of pooled datawere performed on the modified intent-to-treat (MITT)analysis set, which included all enrolled patients who tookstudy medication and had a valid randomisation MADRS totalscore and at least 1 valid post-randomisation MADRS totalscore.
For the primary endpoint, pooled analyses across thestudies were performed by the use of the last observationcarried forward (LOCF) approach, including an analysis ofcovariance (ANCOVA) model with the study as an additionalfixed effect in themodel. Hence, a random effect of centrewasnested within the fixed effect for the study. Least squaresmeans (LSM) for all pairwise differences between quetiapineXR and placebowere calculated alongwith the associated 95%confidence intervals (CIs). Point estimates of change fromrandomisation for each treatment group are also presentedtogether with corresponding 95% CIs. A non-parametricWilcoxon test was used to test the robustness of the primarypooled analysis (ANCOVAmodel) of changes from baseline inindividual MADRS items. As part of the post hoc analyses, thenumber needed to treat (NNT) for MADRS responders wasalso calculated (NNT=100/[% responders with quetiapineXR-% responders with placebo]). Independence of treatmenteffects on sleep and the primary endpoint were investigatedusing ANCOVAmodels that tested for treatment effects on (a)MADRS total score usingMADRS Item 4 (reduced sleep) scoreas a covariate, and (b) a modified MADRS total score (MADRSItem 4 score omitted).
Analysis of change from randomisation to Week 6 (LOCF)for secondary endpoints (HAM-A andHAM-D total scores, PSQIglobal score and CGI-S score) was used to compare the efficacyof quetiapine XRwith a placebo. These variableswere analysedin the same way as the primary endpoint with the respectivebaseline score as the covariate. A logistic regressionmodelwiththe treatment and study as factor and randomisation values asthe covariate was used to analyse the effect of each quetiapineXR group vs placebo with respect to MADRS response andremission. The confidence levels and p-values presented arenominal with no adjustment for multiplicity issues.
3. Results
3.1. Patient population
Across the two studies, a total of 939 patients wererandomised to receive quetiapine XR 150 mg/day (n=315),quetiapine XR 300 mg/day (n=313) or placebo (n=311) asadjuncts to ongoing antidepressant therapy. Of the patientswho were randomised, 767 (83.5%) completed 6 weeks oftreatment (Fig. 1).
Overall, 20 patients were excluded from the MITT popula-tion resulting in a total MITT population of 919 patients. Thereasons for exclusion were similar across treatment groups,with most of the exclusions being due to patients having novalid 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 demographicand clinical characteristics at randomisation and medicationused at any time during randomised treatment (Table 1).Across the two studies, 61.9%, 27.1%, 9.5% and 1.5% of patientswere receiving an SSRI, an SNRI, bupropion and amitriptyline,respectively, prior to study entry.
3.2. Efficacy
3.2.1. Primary endpointLSM 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, thanwith placebo (−14.5,−14.8 and −12.0, respectively; pb0.001 for each dose). Thisstatistically significant changewas apparent as early asWeek 1with quetiapine XR 150 mg/day and 300 mg/day, comparedwith placebo (−7.8,−7.3 and−5.1, respectively; pb0.001 foreach dose). Both doses of quetiapine XR were associated withsignificantly greater improvements in MADRS total score thanplacebo at each subsequent assessment (Fig. 2).
3.2.2. MADRS secondary endpointsConsistent improvements in individualMADRS itemswere
seen during the studies with significant improvementobserved as early as Week 1 with both doses of quetiapineXR. At Week 1, quetiapine XR 150 mg/day significantlyimproved 6 of 10 items and quetiapine XR 300 mg/day 4 of10 items, compared with placebo (Fig. 3a). Significantreductions compared with placebo were observed in 4 of 10MADRS individual item scores with quetiapine XR 150 mg/day and in 7 of 10 items with quetiapine XR 300 mg/day atWeek 6 (Fig. 3b). At Week 6, quetiapine XR 150 mg/daysignificantly improved the following items: apparent sadness,inner tension, reduced sleep and inability to feel. At Week 6,quetiapine XR 300 mg/day significantly improved apparentsadness, reported sadness, inner tension, reduced sleep,inability to feel and pessimistic thoughts and suicidalthoughts. Analysis of MADRS individual item data using thenon-parametric Wilcoxon test confirmed findings from theprimary analysis with quetiapine XR-treated patients achiev-ing significant improvements vs placebo across multipleitems.
3.2.3. ResponseMADRS response (≥50% decrease in total score) rates at
Week 1 were 18.6% (pb0.01, compared with placebo), 17.5%(pb0.05, comparedwith placebo) and 10.8% for quetiapine XR150 mg/day, quetiapine XR 300 mg/day and placebo, respec-tively. At Week 6, response rates were 53.7% (p=0.063),58.3% (pb0.01) and 46.2%, respectively (Fig. 4a). Using theWeek 6 MADRS response data, the NNT values for quetiapineXR 150 and 300 mg/day were 14.2 and 8.3, respectively.
3.2.4. RemissionRemission (MADRS total score ≤8) rates at Week 6 were
35.6% (pb0.01) and 36.5% (pb0.001) in the quetiapine XR150 mg/day and 300 mg/day groups, respectively vs placebo(24.1%) (Fig. 4b). Using more common definitions ofremission (MADRS total score ≤10 and ≤12), higher rates
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.
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of remission were observed at Week 6 in the quetiapine XR150 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 analysesThe 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 fromrandomisation atWeek 6 by class of adjunctive antidepressantshowedsignificantly greater improvementswithquetiapineXR150 and 300 mg/day, compared with placebo as adjunct toSSRIs (−14.8,−14.7 and−12.7, respectively; pb0.05, for eachdose) and SNRIs (−14.8, −15.1 and −10.8, respectively;pb0.01, for each dose).
Analysis of the primary endpoint using MADRS Item 4(reduced sleep) score as a covariate showed thattreatment with quetiapine XR 150mg/day and 300 mg/dayled to significant improvements from randomisation inMADRS
total score at Week 6 (−14.6 [pb0.001] and−15.0 [pb0.001],respectively) comparedwith placebo (−12.1). Thisfindingwasconfirmed in an analysis of a modified version of the primaryendpoint (change from randomisation to Week 6 in themodified MADRS total score (MADRS Item 4 score omitted):−12.2 (pb0.05) and −12.8 (pb0.01) vs −10.8 in thequetiapine XR 150mg/day, 300 mg/day and placebo groups,respectively.
An additional analysis of patients with and withoutsomnolence (as determined by an AE associatedwith a sedativeeffect)was undertaken. It should be noted that as these patientsrepresent subpopulations theywerenot inherently randomised.AtWeek 6, quetiapine XR (dose groups combined) significantlyimproved MADRS total score in patients reporting sedation/somnolence (n=250), compared with placebo (n=303)(−14.9 and −12.0, respectively; pb0.001). In patients notreporting sedation/somnolence (n=366) mean change inMADRS score was also significantly improved, compared withplacebo (−14.4 and−12.0, respectively; pb0.001).
Table 1Patient demographics, baseline study characteristics and medications received during randomised treatment (pooled MITT population).
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 RatingScale; CGI-S, Clinical Global Impression — Severity of Illness; PSQI, Pittsburgh Sleep Quality Index.
a n=308
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3.2.6. Other secondary endpointsSignificant improvements in HAM-D and HAM-A total
scores, CGI-S score and PSQI global score were seen atWeek 6with quetiapine XR 150 mg and 300 mg, compared with
Fig. 2. Change in MADRS total score from randomisation at Weeks 1, 2, 4 and6 (pooled MITT population; LOCF). XR, extended release; LSM, least squaresmeans; MADRS, Montgomery-Åsberg Depression Rating Scale; MITTmodified intent-to-treat; LOCF, last observation carried forward.
,
placebo (Table 2). However, no significant improvement wasseen in Q-LES-Q % maximum total score with either dose ofquetiapine XR at Week 6, compared with placebo (Table 2).
3.3. Safety and tolerability
3.3.1. AEsIn the pooled safety population, AEs were experienced
by 73.3%, 80.8% and 60.2% of patients in the quetiapine XR150 mg/day, 300 mg/day and placebo groups, respectively. Themost common AEs (≥5% of patients in any group) experiencedduring the two studies are presented in Table 3. Most AEs weremild 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 studiesdue to AEs was higher in quetiapine XR-treated patients(150 mg/day, 8.9%; 300 mg/day, 15.4%), comparedwithplacebo(1.9%). In the quetiapine XR groups, the most common AEsleading 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%).
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 andtremor. The incidences of AEs potentially related to EPS were
Fig. 4. MADRS a) responders at Weeks 1 and 6 and b) remitters at Week 6(pooled MITT population; LOCF). XR, extended release; MADRS, Montgom-ery-Åsberg Depression Rating Scale; MITT, modified intent-to-treat; LOCF,last observation carried forward.
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3.8%, 6.4% and4.2%of patients in thequetiapineXR150 mg/day,300 mg/day and placebo groups, respectively.
3.3.3. SuicidalityThe 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, ofthe patientswithMADRS Item 10 (suicidal thoughts) score b4at randomisation, the incidences of scores≥4 atWeek 6 were0.6% (quetiapine XR 150 mg/day), 1.0% (quetiapine XR300 mg/day) and 2.6% (placebo).
Two patients (both from Study D1448C00007) had discon-tinued treatment due to AEs potentially related to suicid-ality (quetiapine XR 150 mg/day, n=1; placebo, n=1). Thequetiapine-treated patient had an AE of suicidal ideation onDay 20 of treatment of severe intensity that was consideredto be neither serious nor related to study treatment. The
placebo-treated patient had an AE of suicide attempt on Day 2of treatment that was of severe intensity, was considered tobe serious, and was not considered to be related to studytreatment.
3.3.4. WeightMean (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% ofpatients at any visit in the pooled safety population,respectively.
4. Discussion
This pooled analysis of two large, placebo-controlled,randomised studies shows adjunct quetiapine XR (150 mg/dayand 300 mg/day) to be significantlymore effective than placeboat improving a broad range of symptoms associated with MDD,with improvement seen as early as Week 1. This finding isconsistent with that of the individual studies and supports theuse of quetiapine XR as adjunct therapy in patients with MDDwho have experienced suboptimal response to antidepressanttherapy. By pooling these studies the larger sample size enabledsubgroup analyses to be conducted to investigate demographicand disease-related factors. These analyses demonstrated thatimprovement in depressive symptoms with quetiapine XR wasneither limited nor driven by severity of depression, adjunctiveantidepressant, gender or age.
Quetiapine XR (150 and 300 mg/day) adjunct therapy,significantly improved depressive symptoms as assessed bychange inMADRS total score atWeek6andat every assessmentfrom Week 1, compared with placebo. MADRS response rateswere significantly greater at Week 6 with quetiapine XR300 mg/day but not 150 mg/day compared with placebo. AtWeek 1, both doses of quetiapine XR were associated withsignificantly great MADRS response rates than placebo. Theresults of the current analysis confirm thoseof the internationalstudy included in this pooled analysis in which adjunctivequetiapine XR therapy (150 and 300 mg/day) significantlyreducedMADRS total score throughout the 6 weeks of the trial(Bauer et al., 2009). However, in the US study, no significantdifference in MADRS total score was seen between quetiapineXR 150 mg/day and placebo from Week 4. A potential reasonfor this difference between the two studies is variation indisease history between the two patient populations. Forexample, in the US study, a higher percentage of patients hadrecurrent MDD and patients also had a greater number ofprevious lifetime depressed episodes (El-Khalili et al., 2010).
The response rates seen in this pooled analysis atWeek6arecomparable with the rate reported in a meta-analysis of10 studies (6–12 weeks duration) investigating the use ofatypical antipsychotics as adjuncts to antidepressant therapy inpatients with treatment-resistant depression (57.2%) (Papa-kostas et al., 2007). Furthermore, NNT values confirm theefficacy of quetiapine XR, with between 8.3 and 14.2 patientsneeding to be treated for one to achieve a clinical response.
Theefficacyof quetiapineXR inpatientswithMDD is furthersupported by the significantly greater remission rates observedcompared with placebo. Significant rates of remission vs
Table 2Change in MADRS total score by severity of depression, gender and age and change from randomisation at Week 6 in secondary efficacy endpoints (pooled MITTpopulation, LOCF).
LSM change at Week 6 −1.91 −2.95*** −2.82***Difference (95% CI) vs placebo −1.03 (−1.32,−0.75) −0.90 (−1.19,−0.62)
HAM-A total scoreLSM change at Week 6 −7.33 −8.90** −9.13***Difference (95% CI) vs placebo −1.57 (−2.57,−0.57) −1.80 (−2.81,−0.80)
CGI-S scoreLSM change at Week 6 −1.25 −1.61*** −1.58***Difference (95% CI) vs placebo −0.36 (−0.56,−0.16) −0.34 (−0.54,−0.14)
PSQI global scoreLSM change at Week 6 −3.00 −4.91*** −4.82***Difference (95% CI) vs placebo −1.91 (−2.50,−1.32) −1.82 (−2.41,−1.22)
Q-LES-Q % maximum total scoreLSM change at Week 6 11.96 12.71 12.39Difference (95% CI) vs placebo 0.75 (−1.65, 3.15) 0.43 (−1.98, 2.84)
*pb0.05; **pb0.01; ***pb0.001 vs placebo.MADRS, Montgomery–Åsberg Depression Rating Scale; MITT, modified intent-to-treat; LOCF, last observation carried forward; XR, extended release; LSM, leastsquares 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.
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placebo were seen in this pooled analysis and the remissionrates observed at Week 6, using the usual definition of MADRStotal score ≤10 or ≤12, are similar to those reported inthe meta-analysis of 10 similar studies (47.4%) describedpreviously (Papakostas et al., 2007).
In this pooled analysis, significant improvement in theHAM-A total score was seen at Week 6 with both doses ofquetiapine XR. This is important because patients with MDDcommonly present with anxiety symptoms. Although thepatients included in this pooled analysis did not the meetcriteria for a comorbid anxiety disorder, quetiapine XR showedimprovement in anxiety symptoms.
A subgroup analysis showed significant improvement indepressive symptoms, as measured by change inMADRS totalscore, with adjunctive quetiapine XR, irrespective of the classof concomitant antidepressant (SSRIs or SNRIs). As SSRIs arethe current first-line recommendation for MDD (AmericanPsychiatric Association, 2000; National Institute of Health
and Clinical Excellence, 2009) adjunctive treatments mustimprove efficacy in combination. This finding highlights thepotential clinical importance of quetiapine XR as an adjuncttherapy for patients whose disease is inadequately controlledby standard antidepressant therapy.
Depression has been shown to have a detrimental effecton many aspects of sleep, including extended time to sleepinitiation and poor sleep quality (Slaughter, 2006). Indeed,according to DSM-IV criteria, insomnia is a core symptom ofdepression and is one of the most common presentingsymptoms (Baldwin and Papakostas, 2006). The earlyimprovement seen with quetiapine XR in the current studymay appear to be in part due to a beneficial effect on sleepsince among the individual MADRS items, the greatestmagnitude of improvement at Weeks 1 and 6 was observedin Item 4 (reduced sleep). Quetiapine XR was also associatedwith significant improvement in PSQI global score, MADRSItem 4 (reduced sleep) and HAM-D sleep disturbance factor
Table 3Most common AEs (≥5%) occurring in any group during the study (pooled safety population).
AE, adverse event; XR, extended release.a Patients with multiple events of an AE are counted only once in that term.
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scores at Week 6. However, it is of interest to note that theresults from the post hoc analysis to determine whethertreatment effects on sleep were independent of effects on theprimary endpoint relationship between sleep and efficacyshowed a significant overall improvement in MADRS totalscore at Week 6. This demonstrates the broad effects ofquetiapine XR across a range of symptoms of depressionwhich occur independently of its effect on sleep. Beyondimprovements in sleep quetiapine XR also improved otherMADRS items at Week 1.
Significant improvements in MADRS total score were seenin patients, irrespective of whether or not they experienced anAE potentially related to somnolence, suggesting that anyconcomitant sedative effects do not interfere with theantidepressant effect of quetiapine XR. This observation furthersupports our finding that quetiapine XR antidepressantproperties are independent of treatment effects on the coresymptom of reduced sleep in patients with MDD.
The results of the present pooled analysis show that, overall,adjunctive quetiapine XR was generally well tolerated, withan AE profile consistent with that documented for acutequetiapine XR use in other psychiatric illnesses, such asschizophrenia, bipolar mania and bipolar depression (Cutleret al., 2008; Kahn et al., 2007; Suppes et al., 2008). Thepercentages of patients who experienced an AE and whowithdrew due to an AE were higher with quetiapine XR thanwith placebo, however, the number of SAEs was similar acrossthe treatment groups. Somnolence and sedation were morecommonwith quetiapine XR than with placebo, a finding that isconsistent with the recommendation to dose quetiapine XR inthe evening in patients with bipolar depression in order tominimise the impact of sedation/somnolence during theday (Seroquel XR (quetiapine fumarate) Extended-ReleaseTablets — US prescribing information, 2010). For patients withMDD it is recommended that quetiapine XR is taken inthe evening without food or a light meal (approximately300 cal), with a recommended dose range of 15–300 mg/daystarting 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 healthysubjects has demonstrated a delayed onset of sedation andless overall sedation over the dose-initiation period withquetiapine XR than with quetiapine immediate release (Datto
et al., 2009). Furthermore, food intake has minimal effects onquetiapine absorption (DeVane and Nemeroff, 2001) with thebioavailability of quetiapinebeingonlymarginally affectedby theadministration with food (maximum concentration and areaunder the curve increased by 25% and 15%, respectively)(Seroquel® (quetiapine fumarate) tablets — US prescribinginformation, 2010).
Increases from baseline in bodyweight were seenwith bothdoses of quetiapine XR. The proportion of patients whoexperienced weight gain ≥7% was greater with both doses ofquetiapine XR than with placebo. These changes in weight areconsistent with observations in monotherapy studies from thequetiapine 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 shouldconsider the potential for such effects before initiating anytreatment in a patientwithMDDand for atypical antipsychoticsappropriate clinical monitoring of hyperglycaemia, lipids andweight is recommended. There is potential variation betweenthe tolerability profiles of atypical antipsychotics evaluated forthe adjunctive treatment of MDD. In a study demonstrating theefficacy of aripiprazole in combination with standard anti-depressant therapy (Berman et al., 2007), the incidence of AEsassociated with EPS in patients who received aripiprazole was27.5% (placebo 9.7%). In the present analysis the incidencesof AEs associated with EPS in the quetiapine XR 150 and300 mg/day groups were 3.8% and 6.4%, respectively (placebo,4.2%). The variation in tolerability profiles between the atypicalantipsychotics has been demonstrated in patients with schizo-phrenia (Lieberman et al., 2005); however, no direct compar-isons in patients with MDD have been conducted and aretherefore required.
Strengths of the present analysis include the large, multi-national patient population, providing increased statisticalpower to enable investigation of treatment differencesbetween specific subsets of patients. Limitations of thestudies included in this pooled analysis include fixed dosing,which is not reflective of clinical practice, and the lack of anactive comparator, which limits the comparison of quetiapineXR with other potential treatments for MDD. Furthermore,due to the short duration of this study interpretation of thesefindings is only applicable to acute therapy. However, theefficacy, safety and tolerability of quetiapine XR in the
29M. Bauer et al. / Journal of Affective Disorders 127 (2010) 19–30
maintenance treatment of patients with MDD have beenreported (Liebowitz et al., 2010).
In summary, this pooled analysis of two randomised,placebo-controlled studies demonstrates that adjunctive que-tiapine XR (150 and 300 mg/day) is effective and generallywelltolerated in patients with MDD who have an inadequateresponse to ongoing antidepressant treatment, with symptomimprovement seen as early as Week 1.
Role of funding sourceFunding for the initial studies was provided by AstraZeneca; AstraZeneca
was involved in the development of the study design and in the analysis andinterpretation of data; AstraZeneca provided funding for the writing of thismanuscript.
Conflict of interestDr Bauer has received grant/research support from The Stanley Medical
Research Institute, NARSAD, Eli Lilly and AstraZeneca. He is a consultant forAstraZeneca, Eli Lilly Deutschland, Servier, Lundbeck, Janssen-Cilag, Bristol-Myers Squibb and Otsuka. Dr Bauer has received speaker honoraria fromAstraZeneca, Eli Lilly, GlaxoSmithKline, Pfizer, Bristol-Myers Squibb andOtsuka.
Nizar El-Khalili has received research grants from AstraZeneca, Eli Lilly,GlaxoSmithKline, Pfizer, and Sanofi-Aventis, and has participated in advisoryboards for Eli Lilly and speakers bureaus for AstraZeneca, Eli Lilly and Sanofi-Aventis.
Catherine Datto, Johan Szamosi and Hans Eriksson are employees ofAstraZeneca.
Acknowledgements
These studies (D1448C00006 [Pearl] and D1448C00007[Onyx]) were funded by AstraZeneca. We thank Dr AlexMitchell from Complete Medical Communications, whoprovided 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), EliasSarkis (Gainsville, Florida), Anita Kablinger (Shreveport,Louisiana), James Kocsis (New York, New York), JelenaKunovac (Oceanside, California), Charles Morin (Braintree,Massachusetts), Amy Mulroy (San Antonio, Texas), VeroniqueSebastian (Oklahoma City, Oklahoma), Ismail Sendi (Clinton,Michigan), Phebe Tucker (Oklahoma City, Oklahoma), RobertBuynak (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), JeroldKreisman (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), RamanathGopalan (Arlington, Virginia), Riaz Baber (Naperville, Illinois),Bijan Bastani (Beechwood, Ohio), Elly Lee (Irvine, California),Robert Hudrick (Cherry Hill, New Jersey), Deborah Bergen
(Wichita, Kansas), Susanna Goldstein (New York, New York),Robert Riesenberg (Atlanta, Georgia), Fares Arguello (Salt LakeCity,Utah),DavidKrefetz (Clementon,New Jersey), StevenEisen(Philadelphia, Pennsylvania), Mohammed Alam (Oak Brook,Illinois) and Arifulla Khan (Bellevue, Washington).
Study 7 (Opal): ThomasGeorge,Michael Theodoros, JayashriKulkarni, Peter Farnbach, Bernhard Baune (Australia); EricConstant, 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); MarketaZemanova, Tibor Miklos, Yvona Hendrychova, Alena Railova,Michaela Klabusayova, Marek Perez, Silvia Musilova, MarcelaBolkova Janikova, Zdenek Solle (Czech Republic); Antti Ahokas,Anna Savela, Raili Kansanen, Riitta Jokinen, Jukka Penttinen,Juhani Aer (Finland); Joël Gailledreau, Eric Neuman, FrédéricChapelle, Christian Gaussares, Mocrane Abbar, ChristianGeraud, Francis Gheysen, Paule Khalifa, Nicole Parant, JeanAudet, Bertrand Baranovsky, Bernard Vanier (France); MatthiasRothermundt, Michael Bauer, Albert Diefenbacher, HansGutzmann, Volker Schumann, Thomas Messer, Franz-MarkusLeweke, Günther Schumann, Eugen Schlegel (Germany); EspenAnker, Dag Oulie, Kjetil Høye, Shaheen Asghar, TorbjørnTvedten, Sverre Tønseth (Norway); Jolanta Rabe-Jablońska,Mieczyslaw Janiszewski, Jolanta Ferszka, Jerzy Samochowiec,Andrzej Kokoszka, Wlodzimierz Chrzanowski, Dariusz Juszczak,Krzysztof Klinke (Poland);MirelaManea, Elena Gherman,MariaLadea, Cristian Marinescu (Romania); Lynette Nel, HermanPretorius, ChristiaanVerster,Mahomed Salduker (SouthAfrica);Curt Rolleri, Per Ekdahl, Konrad Rosman, KurtWahlstedt, GöranBjörling, Eija Maahr and Anna Loewenstein (Sweden).
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