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CNS Spectr. 2009;14(6):299-313
Faculty Affiliations and Disclosures
Dr. Weisler is Adjunct Professor of Psychiatry in the Department of Psychiatry at the University of North Carolina, Chapel Hill, and Adjunct Associate Professor of Psychiatry at Duke University, in Durham, North Carolina. Dr. Joyce is Principal Investigator at CNS Healthcare in Jacksonville, FL. Dr. McGill is Lead Principal Investigator at CNS Healthcare in Memphis, TN. Dr. Lazarus is Senior Director, Clinical Research at AstraZeneca Pharmaceuticals LP in Wilmington, DE. Mr. Szamosi is Principal Statistician at AstraZeneca in Södertälje, Sweden. Dr. Eriksson is Medical Science Director at AstraZeneca in Södertälje, Sweden.
Faculty Disclosures: Dr. Weisler is a consultant to Abbott, the Agency of Toxic Substances and Disease Registry/Centers for Disease Control and Prevention, AstraZeneca, Biovail, Bristol-Myers Squibb, Cephalon, Corcept, Eli Lilly, Forest, GlaxoSmithKline, Johnson & Johnson, Organon, Otsuka America Pharmaceutical, Pfizer, Pharmacia, Sanofi, Sanofi-Synthelabo, Shire, Solvay, Validus, and Wyeth; is on the speaker’s bureau of Abbott, AstraZeneca, Biovail, Bristol-Myers Squibb, Burroughs Wellcome, Cephalon, Ciba Geigy, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Johnson & Johnson, Novartis, Organon, Pfizer, Sanofi, Sanofi-Synthelabo, Shire, Solvay, Validus, and Wyeth; has received grant/research support from Abbott, AstraZeneca, Biovail, Bristol-Myers Squibb, Burroughs Wellcome, Cenerx, Cephalon, Ciba Geigy, CoMentis, Dainippon Sumitomo Pharma America, Eisai, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Johnson & Johnson, Lundbeck , McNeil Pharmaceuticals, Medicinova, Merck, National Institute of Mental Health, Neurochem, New River Pharmaceuticals, Novartis, Organon, Pfizer, Pharmacia, Repligen, Saegis, Sandoz, Sanofi, Sanofi-Synthelabo, Schwabe/Ingenix, Sepracor, Shire, Synaptic, Takeda, TAP, UCB Pharma, Vela, and Wyeth; and owns stock in Bristol-Myers Squibb, Cortex, Merck, and Pfizer. Dr. McGill has received honoraria from Indevus Pharmaceuticals. Dr. Lazarus, Mr. Szamosi, and Dr. Eriksson are employees of AstraZeneca.
Funding/Support: The study (Moonstone; D1448C00001) was funded by AstraZeneca. The study was registered at ClinicalTrials.gov (identifier number NCT00320268).
Acknowledgments: The authors would like to thank Jocelyn Woodcock, MPhil, from Complete Medical Communications, who provided medical writing support funded by AstraZeneca. The authors would also like to thank the investigators involved in the study: Dr. Mohammed Alam, Dr. Grant Belnap, Dr. Guy Brannon, Dr. John Carman, Dr. Harry Croft, Dr. Himasiri DeSilva, Dr. Bradley Diner, Dr. Michael Downing, Dr. Neil Dubin, Dr. Beal Essink, Dr. Donald Garcia, Dr. Steven Glass, Dr. Susanna Goldstein, Dr. Daniel Grosz, Dr. Mark Joyce, Dr. Arifulla Khan, Dr. Irving Kolin, Dr. Jelena Kunovac, Dr. Sidney Lerfald, Dr. Michael Levy, Dr. Arnold Licht, Dr. Adam Lowy, Dr. Azfar Malik, Dr. Laura McGill, Dr. Leslie Moldauer, Dr. Mahmoud Okasha, Dr. Nader Oskooilar, Dr. Angela Pinhiero, Dr. Robert Riesenberg, Dr. Leon Rosenberg, Dr. Dwight St. Clair, Dr. Jeffrey Simon, Dr. Ward Smith, Dr. Jerry Steiert, Dr. Nicholas Vatakis, Dr. Cherian Verghese, and Dr. Inna Yuryev-Golger.
Submitted for publication: November 25, 2008; Accepted for publication: May 11, 2009
Please direct all correspondence to: Dr. Richard Weisler, 700 Spring Forest, Suite 125, Raleigh, NC 27609; Tel: 919-872-5900, Fax: 919-878-0942; E-mail: rweisler@aol.com.
Abstract
Introduction: Once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy was evaluated in major depressive disorder (MDD).
Method: This was an 8-week (6-week randomized-phase; 2-week drug-discontinuation/tapering phase), double-blind, parallel-group, placebo-controlled study. The primary outcome measure was Montgomery-Åsberg Depression Rating Scale (MADRS) total score randomization-to-Week 6 change. Other assessments included the Hamilton Rating Scale for Depression, the Hamilton Rating Scale for Anxiety, and adverse events (AEs).
Results: 723 patients were randomized: 182, 178, 179, and 184 to quetiapine XR 50, 150, 300 mg/day, and placebo, respectively. At Week 6, significant reductions occurred in MADRS score with quetiapine XR 50 mg/day (–13.56; P<.05), 150 mg/day (–14.50; P<.01) and 300 mg/day (–14.18; P<.01) versus placebo (–11.07); at Day 4, reductions for quetiapine XR (titrated to 50 or 150 mg/day according to dose group) versus placebo (–2.9) were: –4.7 (P<.01), –5.2 (P<.001), and –5.1 (P<.001), respectively. At endpoint, MADRS response (≥50% reduction in score) was 42.7% (P<.01), 51.2% (P<.001), and 44.9% (P≤.001) for quetiapine XR 50, 150, and 300 mg/day, respectively; 30.3% for placebo. Overall, quetiapine XR 150 mg/day provided consistently more positive secondary efficacy results than 50 mg/day and 300 mg/day versus placebo. The most common AEs in quetiapine XR-treated patients were dry mouth, sedation, somnolence, headache, and dizziness.
Conclusion: In patients with MDD, quetiapine XR monotherapy (50/150/300 mg/day) is effective in reducing depressive symptoms, with improvement from Day 4 onwards. Safety and tolerability were consistent with the known profile of quetiapine.
INTRODUCTION
Major depressive disorder (MDD) is a disabling and sometimes chronic condition requiring effective treatment in order to relieve patients’ symptoms, restore their functionality, and reduce the risk of suicide. Although established treatments, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are available for MDD, ~50% to 60% of patients do not achieve full remission of symptoms following antidepressant therapy.1,2 Residual symptoms are associated with relapse3 and chronicity, as well as increased medical and psychiatric morbidity, mortality, and healthcare costs.4,5 Indeed, in the United States, hospitalizations due to depression and other affective disorders accounted for 54% of all hospitalizations for mental health conditions in 2006.6 Furthermore, existing pharmacotherapies for MDD may have a slow onset of symptom improvement; studies have shown that patients typically require 2–4 weeks before responding to antidepressants.7 Suicidality risk (a common problem in adults with MDD8) may increase in the initial treatment stage (<1 month) with antidepressants9 (especially in patients <25 years of age); this is possibly due to delayed response to treatment, since the rate of suicide ideation has been shown to reduce significantly following 3 weeks of antidepressant treatment.10 For patients with MDD, particularly those who do not adequately respond to existing therapies, there is a current need for additional treatment options that achieve a rapid and sustained improvement of depressive symptoms.11
The current impact of MDD on global health is significant,12 with unipolar depressive disorders predicted to be the second leading cause of disability-adjusted life years in 2030 (with HIV/AIDS predicted to be the leading cause).13 In addition, the economic burden of MDD is high, such that in the US, the total economic cost of MDD in 2000 was an estimated $83.1 billion ($106.2 billion adjusted for inflation).14
The atypical antipsychotic quetiapine improves the affective symptoms of schizophrenia.15 More recently, two double-blind, randomized, phase III, placebo-controlled studies demonstrated that quetiapine monotherapy was effective in the acute treatment of patients with bipolar I or II depression,16-18 and the efficacy of quetiapine monotherapy in bipolar depression has since been confirmed by two additional maintenance studies.19,20 Furthermore, in a maintenance treatment study in patients with bipolar I disorder, quetiapine monotherapy significantly reduced the risk of either a manic or mood event either as much or more effectively than lithium for mania, and more effectively than lithium for depression.21 In MDD, extended release quetiapine fumarate (quetiapine XR) was effective as adjunct to antidepressant therapy in two large, double-blind, placebo-controlled studies22,23 and in a small (n=58) study in patients with MDD, comorbid anxiety symptoms, and residual depressive symptoms.24
The quetiapine XR formulation provides a more gradual release of quetiapine than the immediate release (IR) formulation. At equivalent total daily doses, Tmax is longer with quetiapine XR dosed once daily than with quetiapine IR dosed twice daily (5 versus 2 hours, respectively). This, combined with gradual drug release, has been shown to produce a smoother pharmacokinetic profile, a delayed onset of sedation, and less overall sedation over the dose initiation period with quetiapine XR than with quetiapine IR.25,26 The current recommended dosing for quetiapine XR in schizophrenia and bipolar disorder is in the evening either without food or after a light meal.27
This study (Moonstone; D1448C00001) evaluated the efficacy and tolerability of once-daily quetiapine XR monotherapy in patients with MDD and is one of five large, short-term studies evaluating quetiapine XR monotherapy in this indication.28-31 An additional longer-term study evaluating the maintenance treatment of MDD found that quetiapine XR once-daily monotherapy significantly reduced the risk of relapse of depression.32 The primary hypothesis of the present study was that quetiapine XR 50 mg/day, 150 mg/day, and 300 mg/day would be more effective than placebo in reducing Montgomery-Åsberg Depression Rating Scale (MADRS) total score from randomization to Week 6.
Methods
Study Design
This was an 8-week (6-week randomized-phase, 2-week post-treatment drug-discontinuation phase), randomized, double-blind, parallel-group, placebo-controlled Phase III study conducted between April 28, 2006 and May 14, 2007 in 47 centers in the US (38 centers were able to provide data from enrolled patients). The study consisted of an enrollment period of ≤28 days, including a ≥7-day washout period for discontinuation of psychotropic medication. Eligible patients entered a 6-week double-blind, randomized-treatment phase and received fixed doses of study medication according to their randomization group (a computer-generated randomization schedule assigned patients to treatment groups in an equal ratio): quetiapine XR 50, 150, or 300 mg/day, or placebo. A 2-week post-treatment drug discontinuation/tapering phase followed (Figure 1). Treatment codes indicating the treatment for each randomized patient were available to the investigator(s) or pharmacists at the study center; the code was not to be broken except in medical emergencies. No treatment codes were broken prior to database lock in this study.
The study was performed in accordance with the Declaration of Helsinki and International Conference on Harmonization/Good Clinical Practice guidelines. The protocol was approved by Institutional Review Boards at each center. Written informed consent was obtained from all patients.
Patients
Outpatients (18–65 years of age) with a documented clinical diagnosis meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,33 criteria for single episode or recurrent MDD (296.2x or 296.3x) were eligible for inclusion in this study. Diagnosis was confirmed using the Mini-International Neuropsychiatric Interview.34
Patients were required to have a Hamilton Rating Scale for Depression (HAM-D) 17 item total score ≥22 and HAM-D item 1 (depressed mood) score ≥2 both at enrollment and randomization.
Exclusion criteria included: a DSM-IV Axis I disorder other than MDD within 6 months prior to enrollment; a DSM-IV Axis II disorder significantly impacting the patient’s current psychiatric status; duration of current MDD episode >12 months or <4 weeks from enrollment; history of inadequate response to adequate treatment (6 weeks) with ≥2 classes of antidepressants during current depressive episode; substance abuse/dependence within 6 months prior to enrollment; clinically significant medical illness, such as renal/hepatic impairment or coronary artery disease; conditions that may affect absorption/metabolism of study medication; suicide or homicide risk (in investigator’s opinion); HAM-D Item 3 score of ≥3; suicide attempt within past 6 months; clinically significant deviation from reference range in clinical laboratory results. Patients requiring psychotherapy (other than supportive psychotherapy) were excluded, unless psychotherapy had been ongoing for ≥3 months prior to randomization. Drugs that induce or inhibit hepatic metabolizing cytochrome P450 3A4 enzymes (for example, carbamazepine and fluvoxamine) were not permitted within 2 weeks prior to randomization. Additional medications not permitted prior to randomization included: antipsychotic, mood stabilizer, or antidepressant drugs (within 7 days); fluoxetine (within 28 days); monoamine oxidase inhibitors, anxiolytics, or hypnotics (within 14 days); or a depot antipsychotic injection (within 2 dosing intervals).
Treatment
Quetiapine XR was titrated to the daily target dose of 50 mg, 150 mg, or 300 mg as follows: 50 mg/day, Days 1–2; 150 mg/day, Days 3–4; and 300 mg/day, Day 5. Study medication was taken orally, once daily in the evening. The packaging of all treatments was identical and the placebo and active treatment tablets were identical in taste, smell, appearance, and number.
Other psychoactive medication usage was not permitted. Lorazepam (maximum 2 mg/day), zolpidem tartrate (10 mg), zaleplon (20mg), zopiclone (7.5 mg), and chloral hydrate (1 g) were permitted at bedtime for insomnia if treatment had been regular and commenced 28 days before enrollment. Anticholinergics for treatment of extrapyramidal symptoms (EPS) were allowed, but not for prophylactic treatment.
Efficacy Assessments
The primary efficacy outcome measure was the change from randomization to Week 6 in MADRS total score. Secondary efficacy outcome measures included: change from randomization in MADRS total score over time (Day 4, Weeks 1, 2, 4, and 6); MADRS response rates (≥50% reduction in total score from randomization) at Week 1 and Week 6; MADRS remission rate (total score ≤8) at Week 6 (post hoc analyses of MADRS score ≤10 and ≤12 at Week 6 were also conducted); change from randomization to Week 6 in HAM-D total and item 1 scores; change from randomization to Day 4 and Week 6 in Clinical Global Impression-Severity (CGI-S) score; proportion of patients with a Clinical Global Impression-Improvement (CGI-I) score of 1 (“very much improved”) or 2 (“much improved”) at Week 6; change from randomization to Week 6 in Hamilton Rating Scale for Anxiety (HAM-A) total score; change from randomization to Week 6 in Quality of Life, Enjoyment, and Satisfaction Questionnaire short-form (Q-LES-Q) percent maximum total score (Items 1-14), Item 15 (satisfaction with medication) and Item 16 (overall quality of life) scores; and change from randomization to Week 6 in Pittsburgh Sleep Quality Index (PSQI) global score.
To ensure consistency throughout the study, investigators and study personnel received central and standardized training approved by the sponsor. For the primary efficacy measure (MADRS) and the inclusion criteria (HAM-D), raters were approved and certified by the sponsor. To reduce scoring variability, it was recommended that, whenever possible, the same rater conduct all assessments for a given patient for a specific scale. The CGI was administered only by qualified physician raters.
Safety and Tolerability
Adverse events (AEs), including serious AEs, were reported throughout the study and coded using Medical Dictionary for Regulatory Activities (MedDRA) terms. All AEs and serious AEs, including any ongoing at study end or discontinuation, were followed-up until resolution or the investigator decided no further follow-up was necessary. Selected prespecified MedDRA terms were aggregated to assess AEs of special interest.
Clinical laboratory assessments and an electrocardiogram (ECG) were assessed at enrollment and Week 6. Body weight, height, waist circumference, vital signs, and concomitant medication were recorded. A physical examination was conducted at enrollment and all subsequent visits during the randomized phase. Barnes Akathisia Rating Scale (BARS) and Simpson-Angus Scale (SAS) scores (to evaluate EPS), and Changes in Sexual Functioning Questionnaire (CSFQ) scores were recorded at randomization and Weeks 4 and 6.
Treatment discontinuation signs and symptoms (TDSS) during the 2 week drug-discontinuation/tapering phase were measured using an 18-item TDSS scale (developed by AstraZeneca as a hybrid of the 17-item discontinuation scale developed by Michelson and colleagues35 and the 43 item Discontinuation Emergent Signs and Symptoms scale36). All patients who completed the randomized treatment period were asked to rate discontinuation symptoms using the TDSS scale. Baseline TDSS was collected at final randomized treatment period visit (Day 43) and patients completed the TDSS by telephone on post-treatment Days 1, 3, and 5 and at the study center on post-treatment Days 7 and 14. Patients were asked whether the symptom was “present” or “absent”. If a symptom was present on post-treatment Days 1, 3, 5, 7, and 14 and also on Day 43, the patient was asked if it was better, unchanged, or worse compared with baseline. The mean TDSS scores represent the mean number of items in the 18-item TDSS that showed worsening during the 2-week follow-up period.
Statistical Analyses
An analysis of covariance (ANCOVA) model with treatment and center as factors and baseline MADRS score as covariate was used for the analysis of change in MADRS total score from randomization to Week 6 (primary objective). The null hypotheses were that there were no differences between the three quetiapine XR treatments (50 mg, 150 mg, and 300 mg) and placebo in change in MADRS total score from randomization to Week 6. Each quetiapine XR group was compared with placebo. Missing data were estimated using the last observation carried forward (LOCF) principle.
To assess robustness of the primary analysis results, a mixed-model repeated measures (MMRM) analysis was performed on change from randomization in MADRS total score. The model included treatment, center, baseline MADRS total score, visit, and treatment-by-visit interaction as explanatory variables (treatment, visit, and treatment-by-visit interaction were fixed effects; center was a random effect). Robust variance estimates for fixed effects were used for testing treatment differences. Confidence levels and P-values displayed for robustness analyses were nominal with no adjustment for multiplicity. Robustness was also assessed by a per protocol (PP) analysis.
All statistical analyses were two-sided and with a significance level of 5%, (ie, a=.05). The primary analysis of MADRS total score and the analysis of Q-LES-Q percent maximum total score, for the comparison between quetiapine XR and placebo, reported adjusted P-values. All other secondary analyses reported nominal P-values. Where appropriate, model-based point estimates were presented together with their 95% confidence intervals.
Descriptive statistics only were provided for safety and tolerability assessments, which were based on observed case data.
The change in MADRS individual item scores over time was conducted post hoc using an ANCOVA; least squares means (LSM) change and corresponding P-values were reported.
Number needed to treat (NNT) was calculated using the formula37:
1
(proportion of quetiapine XR-treated patients with positive response) – (proportion of placebo-treated patients with positive response)
Adjustments for multiplicity were made for the comparisons of each quetiapine XR dose versus placebo for MADRS and Q-LES-Q using the tree-gatekeeping procedure.38
The populations employed were: modified intention-to-treat (MITT) (all patients assigned to randomized treatment who took study medication and who had a MADRS assessment at randomization and ≥1 valid MADRS assessment after randomization; the primary efficacy population); PP (a subset of the MITT population of patients who had no significant protocol violations or deviations affecting efficacy); and safety population (all randomized patients who received ≥1 dose of study medication).
Sample Size
The sample size calculation was conducted to ensure an overall 80% power in demonstrating improved efficacy for one of the quetiapine XR doses over placebo with regard to the primary outcome variable. Sample size was based on an expected 3.5 point difference from placebo and a standard deviation (SD) of 9 points for change in MADRS total score from baseline to Week 6. Based on a two-sided test at 2.5% significance (ie, a=.025) and a power of 90% for each of the two high doses, it was planned to randomize 166 patients for each of the four arms.
Results
Patient Population
A total of 723 patients were randomized to double-blind treatment; of these, 511 (70.7%) patients completed the 6-week randomized phase (Figure 2). Completion rates (randomized phase) were: 73.6%, quetiapine XR 50 mg/day; 69.1%, quetiapine XR 150 mg/day; 67.0%, quetiapine XR 300 mg/day; and 72.8%, placebo. Approximately 50% of patients completed the whole study (6-week randomized phase plus 2-week post-treatment drug-discontinuation phase).
The MITT population comprised 700 patients: 178, quetiapine XR 50 mg/day; 168, quetiapine XR 150 mg/day; 176, quetiapine XR 300 mg/day; and 178, placebo. The PP population comprised 651 patients (163, 154, 165, and 169, respectively) and the safety population comprised 717 patients (181, 176, 179, and 181, respectively).
Patients’ baseline demographic and clinical characteristics were similar across treatment groups (Table 1).
Sleep medication (including hypnotics and benzodiazepines) use at Week 1 was reported by 1.1%, 1.7%, 3.4%, and 0.6% of patients in the
quetiapine XR 50 mg/day, 150 mg/day, 300 mg/day, and placebo groups, respectively; these proportions remained consistent throughout the study.
Efficacy
There was a statistically significant change in the primary outcome measure (mean change in MADRS total score from randomization to Week 6) with quetiapine XR 50 mg/day (–13.56; P<.05 [adjusted P<.05]), 150 mg/day (–14.50; P<.001 [adjusted P<.01]), and 300 mg/day (–14.18; P<.01 [adjusted P<.01]) compared with placebo (–11.07) (Figure 3). At Day 4, quetiapine XR 50 mg/day (–4.91; P<.01), 150 mg/day (–5.43; P<.001), and 300 mg/day (–5.35; P<.001; dose titrated to 150 mg/day by Day 4) had statistically significantly reduced the mean MADRS total score compared with placebo (–3.27). The reduction in mean MADRS total score for all quetiapine XR groups compared with placebo was statistically significant at all time points (Figure 3).
PP population and MMRM analyses of the primary efficacy variable confirmed the primary analysis results (that used the MITT population).
At Week 1, response rates (≥50% reduction in MADRS total score from randomization) were 17.5% (P<.05), 11.3% (P=.413), and 18.0% (P≤.01) for the quetiapine XR 50, 150, and 300 mg/day groups, respectively, versus placebo (8.5%). At Week 6, response rates were 42.7% (P<.01), 51.2% (P<.001), and 44.9% (P≤.001) for quetiapine XR 50, 150, and 300 mg/day groups, respectively, and all were statistically significantly higher than placebo (30.3%).
The proportion of patients achieving remission (MADRS total score ≤8) at Week 6 was 25.8% (P=.081), 20.8% (P=.537), and 26.1% (P=.081) for quetiapine XR 50, 150, and 300 mg/day, respectively, compared with placebo (18.5%). Using definitions of remission of MADRS total score ≤10 or ≤12, remission rates at Week 6 for quetiapine XR 50, 150, 300 mg/day, and placebo were 29.2% (P=.071), 29.8% (P=.059), 30.7% (P<.05), and 21.3%, and 35.4% (P=.065), 40.5% (P<.01), 36.9% (P<.05), and 27.0%, respectively.
At Week 6, both quetiapine XR 150 and 300 mg/day had statistically significantly reduced HAM-D total and Item 1 (depressed mood) scores from randomization compared with placebo (Table 2). HAM-A total scores were statistically significantly reduced at Week 6 in all quetiapine XR groups compared with placebo.
At Day 4, improvement in CGI-S mean scores was statistically significant versus placebo in the quetiapine XR 300 mg/day group; however, these patients were receiving 150 mg/day at Day 4 as the target dose of 300 mg/day was not reached until Day 5. At Week 6, CGI-S mean scores had statistically significantly improved compared with placebo in all quetiapine XR groups.
At Week 6, a statistically significantly greater proportion of patients in the quetiapine XR 50, 150, and 300 mg/day groups had a CGI-I score of 1 or 2 (“very much” or “much” improved) compared with placebo.
There was no statistical difference between any quetiapine XR groups and placebo in change from randomization to Week 6 in Q-LES-Q percent maximum score (Table 2).
At Week 6, PSQI global score had improved from baseline in all groups: LSM change was –4.21 (P=.06), –3.91 (P=.248), and –4.25 (P=.053) for quetiapine XR 50, 150, and 300 mg/day, respectively, compared with placebo (–3.42).
All quetiapine XR groups demonstrated improvement in individual MADRS item scores at Day 4 and Week 6 (Figure 4). At Week 6,
quetiapine XR (50-300 mg/day) significantly improved 6 out of 10 MADRS items (apparent sadness, reported sadness, reduced sleep, inability to feel, pessimistic thoughts, and suicidal thoughts; P<.05) compared with placebo. For individual dose groups at Week 6 (Figure 4), significant improvements versus placebo were seen with quetiapine XR 50 mg/day for 2 of the 10 items (apparent sadness and reduced sleep), quetiapine XR 150 mg/day for 5 items (apparent sadness, reported sadness, reduced sleep, inability to feel, and pessimistic thoughts), and quetiapine XR 300 mg/day for 5 items (apparent sadness, reported sadness, inner tension, reduced sleep, and suicidal thoughts).
NNT values calculated using the Week 6 response data were: 8.1, 4.8, and 6.9 for quetiapine XR 50, 150, and 300 mg/day, respectively.
Safety and Tolerability
Adverse Events
Overall, the incidences of AEs were 79.6%, 85.2%, 88.3%, and 69.6% in the quetiapine XR 50, 150, and 300 mg/day, and placebo groups, respectively. The most common AEs (≥5% incidence) are reported in Table 3. There were no deaths during the study. Five serious AEs occurred; these were not considered to be related to study treatment: One (0.6%) in each quetiapine XR groups (pneumonia, fall, and acute cholecystitis in the 50, 150, and 300 mg/day groups, respectively) and two (1.1%) in the placebo group (suicide attempt and spontaneous abortion). The percentages of patients who withdrew due to an AE were 8.8%, 14.8%, 18.4%, and 7.7% in the quetiapine XR 50, 150, 300 mg/day, and placebo groups, respectively. The most common AEs leading to withdrawal (occurring in ≥3 patients in any treatment group) were sedation and somnolence in the quetiapine XR groups and depression in the placebo group (Table 4).
Sexual Dysfunction
AEs potentially related to sexual dysfunction (MedDRA terms: libido decreased, anorgasmia, erectile dysfunction, ejaculation delayed, dyspareunia, and vulvovaginal dryness) occurred in 1.7%, 1.1%, 2.2%, and 0.6% of patients receiving quetiapine XR 50, 150, 300 mg/day, and placebo, respectively.
Mean (SD) CSFQ total scores at baseline were 41.0 (10.2), 40.0 (10.7), 42.0 (9.5), and 40.7 (10.2) for quetiapine XR 50 mg/day, 150 mg/day, 300 mg/day, and placebo, respectively. At Week 6, there were slight improvements in CSFQ scores in all groups, with mean (SD) changes of: 2.1 (7.3), 2.5 (7.4), 1.7 (7.3), and 2.9 (8.1), respectively.
Assessments of EPS
The incidences of AEs potentially associated with EPS (MedDRA terms: tremor, akathisia, restlessness, hypokinesia and extrapyramidal disorders, involuntary muscle contractions, cogwheel rigidity, and psychomotor hyperactivity) were 3.3%, 5.7%, 5.0%, and 3.9% in the 50, 150, 300 mg/day quetiapine XR and placebo groups, respectively. At baseline, the mean BARS score was .1 in all groups. BARS scores had improved or were unchanged at Week 6 from baseline in 96.3%, 95.6%, 96.8%, and 95.6% of patients in the quetiapine XR 50, 150, 300 mg/day, and placebo groups, respectively. Mean SAS scores at baseline were .2, .3, .2, and .2, respectively. SAS scores had improved or were unchanged at Week 6 in 93.8%, 89.9%, 96.8%, and 90.5% of patients, respectively.
AEs Potentially Related to Somnolence
AEs potentially related to somnolence reported during the study were sedation, somnolence, sluggishness, and lethargy; these occurred at an incidence of 48.1%, 55.7%, 62.0%, and 18.8% in the quetiapine XR 50, 150, 300 mg/day, and placebo groups, respectively. Mean (SD) time to first onset of an AE potentially related to somnolence was: 3.2 (3.7) days for quetiapine XR and 8.6 (12.3) days for placebo; median (range): 2.0 (1-30) and 3.5 (1-58), respectively. Mean (SD) duration of AEs potentially related to somnolence was: 26.3 (16.7) days for quetiapine XR and 22.4 (17.1) days for placebo; median(range): 26 (1-56) and 17 (1-56), respectively.
Somnolence and sedation incidences are reported in Table 3; somnolence and sedation were generally mild to moderate in severity. The incidences of sluggishness were 2.2%, 1.7%, 3.9%, and 1.1%, and lethargy were 1.7%, 2.3%, 0.6%, and 0.6% for quetiapine XR 50, 150, 300 mg/day, and placebo, respectively.
Weight
Patients experienced a mean (SD) weight change during the study of +0.6 (1.8) kg, +0.9 (2.1) kg, and +1.0 (2.4) kg in the quetiapine XR 50 (n=178), 150 (n=168), and 300 mg/day (n=176) groups, respectively, and +0.6 (6.1) kg with placebo (n=178). Proportions of patients experiencing a ≥7% increase in weight were 0.6%, 3.6%, 4.5%, and 1.1% in the quetiapine XR 50, 150, 300 mg/day, and placebo groups, respectively.
Clinical Laboratory Assessments
Table 5 presents clinical laboratory data, including lipids and glucose, at treatment end (confirmed fasting safety population) and the proportion of patients with potentially clinically relevant shifts in these variables.
The proportion of patients who experienced a potentially clinically relevant elevation in fasting glucose at treatment end was 0.0%, 3.4%, 3.6%, and 1.6% for quetiapine XR 50, 150, and 300 mg/day, and placebo groups, respectively.
Vital Signs and ECG
There were no notable differences between patients treated with quetiapine XR and placebo in mean changes from baseline to treatment end in vital signs and ECG data. There was no indication of increased QTc interval in either treatment group.
Post-treatment Drug Discontinuation/Tapering Phase
The most common AEs that started during the drug discontinuation phase in the quetiapine XR groups were insomnia (5.2%), nausea (4.7%), headache (3.2%), and diarrhea (2.4%); these AEs occurred at an incidence of 3.9%, 1.1%, 1.7%, and 3.9%, respectively, in the placebo group. For placebo-treated patients, the most common AEs that started during the drug discontinuation phase were insomnia, headache, diarrhea, irritability (1.7%), and abnormal dreams (1.7%). Mean TDSS scores at post-treatment Day 7 were 3.2, 3.4, 3.5, and 2.9 for quetiapine XR 50, 150, and 300 mg/day, and placebo groups, respectively. In general, information about specific symptoms reported through the TDSS assessment confirmed data on AEs spontaneously reported during the discontinuation phase.
Discussion
This 8-week study demonstrates that quetiapine XR monotherapy (50, 150, and 300 mg/day) is effective in the treatment of patients with MDD, with symptom improvement seen as early as Day 4. This is the only study of quetiapine XR monotherapy in MDD to include a 50 mg/day dosage group and to conduct rating assessments at Day 4.
Mean MADRS total scores were statistically significantly reduced for all quetiapine XR doses compared with placebo at all timepoints. The results demonstrated that the effects of quetiapine XR on depressive symptoms were rapid and continued throughout the 6 weeks studied. The 300 mg/day group was titrated to just 150 mg/day on Day 4, showing that a lower dose (50 or 150 mg/day) may achieve initial depressive symptom improvement. The fast onset of antidepressant effect observed with quetiapine XR in some patients may be of clinical value.
The antidepressant effects of quetiapine XR were confirmed by a number of secondary efficacy parameters. Quetiapine XR was more effective than placebo in reducing a broad range of symptoms as indicated by reductions in HAM-D total and Item 1 scores, HAM-A total scores, and CGI-S total scores at Week 6. Also, more quetiapine XR-treated patients had “very much” or “much” improved CGI-I total scores than placebo-treated patients. At Day 4, CGI-S total scores were statistically significantly reduced in the 300 mg/day group compared with placebo, confirming early improvement in depressive symptoms with quetiapine XR. The results also show that the 150 mg/day group had more consistently positive results for secondary efficacy parameters than the other two dosages studied, although for the primary measure all doses were effective.
Improvements with quetiapine XR were greater than placebo in the majority of individual MADRS item scores at Day 4, however, differences were statistically significant only for Item 4 (reduced sleep; all 3 doses) and Item 3 (inner tension; 300 mg/day only). Disturbed sleep is a core symptom of depression and associations have been made between sleep disturbances and suicidality.39,40 The early improvement seen with quetiapine XR in the current study appeared to be mainly due to a beneficial effect on sleep. At Week 6, statistically significant changes for quetiapine XR versus placebo were seen for seven individual MADRS items (apparent sadness, reported sadness, inner tension, reduced sleep, inability to feel, pessimistic thoughts, and suicidal thoughts). This demonstrates that the antidepressant effect of quetiapine XR was broad and occurred independently of its effects on sleep. While it should be noted that the patients included in the current study were considered not at risk of suicide, the early and sustained improvement in sleep seen here may be clinically relevant for some patients.
Response rates reported here for quetiapine XR are slightly lower than those reported in a meta-analysis of studies of reboxetine (59%) and SSRIs (64%).41 However, NNT values (using Week 6 response data) show that quetiapine XR is an effective treatment, indicating that five to eight patients would need to be treated with quetiapine XR for one of them to achieve a clinical response.
Week 6 remission rates were higher with quetiapine XR than placebo (21–26% versus 19%), particularly when using the less conservative cut-offs of MADRS total score ≤10 (29–31% versus 21%) or ≤12 (35–41% versus 27%). Remission rates reported for other antidepressants reach a similar magnitude, for example, in the STAR*D study, which was 6 weeks longer in duration, an overall remission rate (using criterion equivalent to ≤7 on the HAM-D) of 37% was reported for first-line treatments for MDD at Week 12.42
Although many questions remain, the antidepressant effect of quetiapine may be explained by its interaction with the dopamine, serotonin, and norepinephrine neurotransmitter systems. Both quetiapine and norquetiapine (its major active human metabolite) have moderate to high affinity for dopamine D2 and serotonin 5HT2A receptors. In addition, norquetiapine is a potent inhibitor of the norepinephrine transporter (NET).43 A recent positron emission tomography study in healthy volunteers has also demonstrated high NET occupancy by norquetiapine at clinically relevant plasma levels.44
Overall, quetiapine XR was generally well tolerated in this study; the most common AEs with quetiapine XR were dry mouth, sedation, somnolence, headache, and dizziness. Based on the known safety and tolerability profile of quetiapine in other indications,27 no new safety findings for quetiapine were noted in this study.
Mean weight change was similar between groups. However, in the quetiapine XR groups the standard deviations were smaller (1.8–2.4 kg) than with placebo (6.1 kg), suggesting a greater variation in weight change (both loss and gain) in patients who received placebo. Relative to placebo, there was no weight gain for the 50 mg/day quetiapine XR group. Similarly, relative to placebo, there was no change in triglycerides or fasting glucose levels in the 50 mg/day quetiapine XR group. Additional assessments of quetiapine XR may be required to fully understand any longer-term effects on weight in patients with MDD and whether there is a dose-related weight change. It is important that, whatever treatment is prescribed, patients with MDD (consistent with other mood and anxiety disorders) are advised of the benefits of a balanced diet and the need for regular physical exercise that ideally raises the metabolic rate to 4–6 times normal, as mood and anxiety symptoms may be improved by physical activity.45 In addition, although a causal relationship with diabetes has not been established, patients who are at risk for developing diabetes are advised to have appropriate clinical monitoring. Similarly, patients with existing diabetes should be monitored for possible exacerbation.
In this study, time to first onset of an AE potentially related to somnolence was markedly shorter with quetiapine XR than placebo. On average, duration of AEs potentially related to somnolence was longer for quetiapine XR than placebo by approximately 4 days. This is not an unexpected occurrence with quetiapine XR.
Incidence of EPS-related AEs with quetiapine XR in this study was low and at treatment end, the majority of patients had experienced no change or an improvement in SAS and BARS scores (assessing parkinsonian and akathisia symptoms, respectively). EPS-related AEs are commonly associated with conventional antipsychotics. In general, EPS incidence is considerably lower with the atypical antipsychotics.46 EPS, in particular akathisia, have also been reported in patients treated with the SSRIs.47
AEs frequently associated with the SSRIs and SNRIs include nausea, insomnia, and sexual dysfunction. For example, in a series of 6-week clinical trials of paroxetine in MDD, nausea was the most common AE occurring in approximately 26% of paroxetine-treated patients versus 8% in placebo-treated patients.48 In a recent 8-week, placebo-controlled, double-blind study in patients with MDD the most common AEs were dry mouth and insomnia with bupropion XR and nausea, hyperhidrosis, fatigue, and insomnia with venlafaxine XR.49 Incidence of treatment-emergent sexual dysfunction has been reported to be higher with both escitalopram (49%) and duloxetine (33%) than placebo (17%) over the short term (8 weeks) in patients with MDD.50 Furthermore, remission of MDD symptoms was found to have a significant effect on patients’ sexual functioning.
The safety profile of quetiapine XR is different from these agents; low rates of nausea (7.7–8.9%, quetiapine XR versus 6.1%, placebo) were reported in this study and quetiapine XR improved sleep quality, as demonstrated by improvements in PSQI global scores. Moreover, quetiapine XR did not appear to have a marked effect on patients’ sexual functioning. The tolerability profile of quetiapine XR means that it may be a useful treatment option for patients with MDD who are experiencing nausea and vomiting, sleep problems, and/or sexual dysfunction with their existing therapy, although further evaluation over the longer term is warranted.
The strengths of the present study include the use of several clinician- and patient-rated assessment scales, allowing for a broad evaluation of efficacy, and its robust design (double-blind, randomized, placebo-controlled) that included assessments at Day 4, allowing data to be obtained during the early phase of treatment. The large population size is also a key study strength. Furthermore, measures to reduce inter-rater variability were implemented, thereby increasing confidence in data obtained.
Study limitations include the short treatment duration, since MDD is sometimes a chronic condition, and publication of data from a completed longer-term study are awaited. In addition, there was no active comparator; this limits the conclusions that may be drawn regarding the efficacy of quetiapine XR in MDD in comparison with specific antidepressant agents.
Conclusion
Once-daily quetiapine XR monotherapy at 50, 150, and 300 mg/day was effective in the treatment of patients with MDD, with improvements in depressive symptoms seen as early as Day 4. Overall, the tolerability and safety data reported in this study were consistent with the known safety and tolerability profile of quetiapine.
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