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 RESEARCH ARTICLE

Extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in patients with generalized anxiety disorder and a history of inadequate treatment response: A randomized, double-blind study

Arifulla Khan, MD

Northwest Clinical Research Center, Bellevue, Washington, USA; Duke University School of Medicine, Department of Psychiatry and Behavioral Sciences, Durham, North Carolina, USA

Sarah Atkinson, MD

Finger Lakes Clinical Research, Rochester, New York, USA

Irina Mezhebovsky, MD

Boston Clinical Trials, Inc., Boston, Massachusetts, USA

Fahua She, MS

AstraZeneca Pharmaceuticals, Wilmington, Delaware, USA

Todd Leathers, MBA

AstraZeneca Pharmaceuticals, Wilmington, Delaware, USA

Sanjeev Pathak, MD

AstraZeneca Pharmaceuticals, Wilmington, Delaware, USA

BACKGROUND: For many patients with generalized anxiety disorder (GAD), first-line treatment does not lead to remission. This study investigated the efficacy and tolerability of adjunctive extended-release quetiapine fumarate (quetiapine XR) in patients with GAD and an inadequate response to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).

METHODS: Patients were randomized to quetiapine XR or placebo adjunctive to SSRI/SNRIs in an 11-week study. The primary endpoint was change from randomization to week 8 in Hamilton Anxiety Rating Scale (HAM-A) total score. Secondary variables were HAM-A psychic/somatic clusters, response, and remission, and Clinical Global Impression–Severity of Illness (CGI-S) score.

RESULTS: A total of 409 patients received quetiapine XR (n=209) or placebo (n=200). The week 8 mean change in HAM-A total score was not statistically significant for quetiapine XR (–10.74; P=.079) vs placebo (–9.61). Secondary variables were generally consistent with the primary analysis, except for a significant reduction in HAM-A total score (week 1) and significant improvements in HAM-A psychic cluster and CGI-S total scores (week 8). Adverse events included dry mouth, somnolence, sedation, headache, and dizziness.

CONCLUSIONS: In patients with GAD and an inadequate response to SSRI/SNRIs, adjunctive quetiapine XR did not show a statistically significant effect for the primary endpoint at week 8, although some secondary endpoints were statistically significant vs placebo. Quetiapine XR was generally well tolerated.

KEYWORDS: clinical trial, phase 3, anxiety disorders, sustained-release preparations, antipsychotics, treatment efficacy

ANNALS OF CLINICAL PSYCHIATRY 2014;26(1):3-18

  INTRODUCTION

Generalized anxiety disorder (GAD) is a chronic condition with low recovery rates and a high likelihood of recurrence. For example, the 12-year Harvard-Brown Anxiety Research Project predicted probabilities for recovery and recurrence of GAD of 0.58 and 0.45, respectively.1 Patients with GAD experience impaired functioning, decreased work productivity, and increased healthcare utilization.2,3

Published guidelines recommend selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) as first-line treatment for GAD.4-7 In clinical studies, remission rates of 33% to 39% have been reported with paroxetine8 and 43% with venlafaxine XR.9 The World Federation of Societies of Biological Psychiatry also includes pregabalin as a first-line option.5 However, for many patients with GAD, initial pharmacotherapy does not lead to remission,2 and the concept of “refractory” or “treatment-resistant” GAD has emerged. As yet, a uniform definition of treatment-resistant GAD is lacking, although failure to achieve remission following treatment with an adequate antidepressant dose for an appropriate length of time has been used to define treatment resistance in clinical trials.10,11 Benzodiazepines may be used for short-term (2 to 4 weeks) therapy,4,7 second-line treatment,6 or treatment-resistant cases.5 Other strategies for treatment-resistant GAD include tricyclic antidepressants or adjunctive therapy with an atypical antipsychotic.5

The efficacy and tolerability of once-daily extended-release quetiapine fumarate (quetiapine XR) have been evaluated in GAD; 3 acute monotherapy studies in adults12-14 and 1 in geriatric patients15 demonstrated that quetiapine XR was effective at significantly reducing anxiety symptoms compared with placebo. Also, in a long-term (up to 52 weeks) monotherapy maintenance study in patients stabilized on quetiapine XR, improvement in anxiety symptoms was maintained, and the risk of recurrence of anxiety was significantly reduced with quetiapine XR compared with placebo.16 In all 5 studies the overall tolerability and safety results among quetiapine XR–treated patients were consistent with the known profile of quetiapine.17,18 Currently, quetiapine XR is not approved for treatment of GAD in the United States or Europe.

This study evaluated the efficacy and tolerability of quetiapine XR as an adjunct to SSRI/SNRI therapy in patients with GAD with a history of partial or no (inadequate) response to SSRI/SNRI treatment either as monotherapy or in combination with a benzodiazepine.

  METHODS

Study design

This was an 11-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled study (D1441L00016, Palladium; NCT00534599). Eligible patients entered a 1-week single-blind placebo run-in period, followed by an 8-week randomized active-treatment phase and a 2-week posttreatment period (FIGURE 1).

The study was approved by the institutional review board or independent ethics committee for each site and performed in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Guideline for Good Clinical Practice, and applicable regulatory requirements. After completely describing the study to the patients, written informed consent was obtained.

FIGURE 1: Study design
aEnrollment was a maximum of 28 days prior to placebo run-in period.
bDose increase in patients who continued to have a CGI-S score ≥4 and who were able to tolerate the 150 mg/d dose.
CGI-S: Clinical Global Impression–Severity of illness; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor.

Patients

Male or female outpatients (age 18 to 65) with a DSM-IV19 diagnosis of GAD as assessed by the Mini International Neuropsychiatric Interview20 were eligible for inclusion in the study. Patients were required to have a Hamilton Rating Scale for Anxiety (HAM-A)21 total score ≥20, with item 1 (anxious mood) and item 2 (tension) scores ≥2 at enrollment, placebo run-in, and randomization, and a Clinical Global Impression–Severity of Illness (CGI-S)22 score ≥4 at enrollment and randomization. During the current episode of anxiety, patients were required to have a history of partial or no (inadequate) response to duloxetine, escitalopram, paroxetine, or venlafaxine XR. Partial or no (inadequate) response was defined as continuing symptoms following ≥8 weeks of therapy prior to enrollment at adequate doses (minimum effective dose according to the FDA-approved label and including ≥1 dose increase as permitted by the label).

Exclusion criteria included the following: any DSM-IV Axis I disorder other than GAD within 6 months prior to enrollment; presence or history of schizophrenia or other psychotic disorder using DSM-IV criteria; any DSM-IV Axis II disorder likely to interfere with the patient’s participation in the study; depressive symptoms (Montgomery-Åsberg Depression Rating Scale [MADRS] total score >16 at enrollment or randomization); current serious suicidal or homicidal risk, MADRS item 10 score ≥4, or a suicide attempt during the 6 months prior to enrollment; substance or alcohol abuse within 6 months prior to enrollment; evidence of clinically relevant disease; and clinically significant deviation from the reference range in clinical laboratory results. Patients could not have received an antipsychotic, antidepressant (except those listed above), or benzodiazepine (unless ongoing at a stable dose for ≥4 weeks prior to enrollment) within 7 days of randomization; mood stabilizers or monoamine oxidase inhibitors within 14 days prior to randomization; or fluoxetine within 28 days. Patients could continue to receive psychotherapy if it had been ongoing for ≥3 months prior to randomization.

Treatment

Following placebo run-in, patients were randomized (1:1 ratio using a computer-based system to generate the randomization list) to quetiapine XR + SSRI/SNRI or placebo + SSRI/SNRI for 8 weeks. Placebo tablets were identical to quetiapine XR 50 mg or 300 mg tablets in size, color, smell, and taste, and the packaging was identical. Quetiapine XR or placebo was administered orally, once daily in the evening.

Quetiapine XR was initiated at a dose of 50 mg/d, with the dose increased to 150 mg/d on day 3. At weeks 3 or 4, a mandatory dose increase to 300 mg/d was made in patients with a CGI-S score ≥4 who tolerated the 150 mg/d dose. No dose increases were permitted after week 4. Patients unable to tolerate the higher dose returned to 150 mg/d at any time at the investigator’s discretion. Patients continued to receive the same SSRI or SNRI at the same dose as at enrollment throughout the study.

Adherence

Treatment adherence was assessed at each visit based on returned tablet count, defined as a ≥70% to ≤120% consumption of doses. Patients repeatedly or severely nonadherent were discontinued at the investigator’s discretion.

Concomitant treatment

Chloral hydrate (1 g), zaleplon (20 mg), zolpidem tartrate (10 mg), or zopiclone (7.5 mg) were permitted twice weekly for insomnia up to day 14 (except before study assessments). Other psychoactive medication was not permitted. Anticholinergics for extrapyramidal symptoms (EPS) were permitted except for prophylactic use.

Efficacy evaluations

The primary efficacy endpoint was change from randomization to week 8 in HAM-A total score.

Secondary endpoints included: change in HAM-A total score from randomization to week 1; change from randomization in HAM-A psychic and somatic cluster scores at weeks 1 and 8; HAM-A response (≥50% decrease in HAM-A total score from randomization) rate at weeks 1 and 8; HAM-A remission (HAM-A total score ≤7) rate at week 8; change from randomization in CGI-S total score at weeks 1 and week 8; and proportion of patients with a CGI-Improvement (CGI-I) score of 1 (“very much improved”) or 2 (“much improved”) at week 8.

HAM-A and CGI-S scores were assessed at enrollment, randomization (day 1), and weeks 1 to 4, 6, and 8. HAM-A scores were also determined at the start of placebo run-in. CGI-I scores were determined at weeks 1 to 4, 6, and 8. Standardized training was provided to ensure interrater reliability for the HAM-A, CGI-S, and CGI-I scales. To reduce scoring variability, the same rater conducted all assessments for a given patient for a specific scale whenever possible.

Health-related quality of life

The 16-item Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q)23 was administered at randomization and at weeks 2, 4, and 8. Each item was scored on a scale of 1 (very poor) to 5 (very good) for overall satisfaction. The total score was the sum of the scores for items 1 to 14. The percentage of the maximum possible score (Q-LES-Q percent maximum total score) was calculated by subtracting 14 from the total score, dividing by 56, then multiplying by 100.23 The change from randomization at week 8 in Q-LES-Q percent maximum total score (items 1 to 14), item 15 (satisfaction with medication), and item 16 (overall life satisfaction) were recorded.

Safety and tolerability evaluations

The incidence and severity of adverse events (AEs), and AEs leading to withdrawal were recorded throughout the study. Serious AEs (SAEs) were recorded until 30 days after the last dose of study medication. All AEs and SAEs were followed until resolution or until the investigator decided no further follow-up was necessary.

All AEs of suicidality (suicide attempts, ideation, completed suicide, and suicidal behavior) were monitored during the study. The number of patients with either a MADRS Item 10 score ≥4 or an AE associated with suicidality was assessed. An analysis of suicidality using a classification system similar to that established by Columbia University24 was also conducted; incidences of suicidal behavior/ideation (Columbia codes 1, 2, 3, 4) and possible suicidal behavior/ideation (Columbia codes 5, 6, 9) were evaluated.

A physical examination and electrocardiogram (ECG) were conducted at enrollment and week 8. Laboratory measurements were performed at enrollment and at weeks 4 and 8. Vital signs and body weight were recorded at enrollment and all subsequent visits. Simpson-Angus Scale (SAS)25 and Barnes Akathisia Scale (BAS)26 total scores were assessed at randomization and weeks 2, 4, 6, and 8. MADRS scores (evaluating depressive symptoms) were assessed at enrollment, randomization, and at weeks 4 and 8.

During the posttreatment period, a modified 18-item treatment discontinuation signs and symptoms (TDSS) scale was used. This scale was a hybrid of the 43-item discontinuation emergent signs and symptoms scale27 and the 17-item discontinuation scale28 and included additional AEs of vomiting, nausea, and trouble sleeping, insomnia. Patients completing the randomized phase rated discontinuation symptoms using the TDSS scale via a telephone-based interactive voice response system at week 8 (TDSS baseline) and posttreatment days 1, 3, 5, 7, and 14.

Statistical analysis

To provide 90% power, the target sample size was 191 evaluable patients per group based on a treatment difference of 2.5 points between quetiapine XR and placebo, and a standard deviation (SD) of 7.5 for the mean change from randomization in HAM-A total score at week 8.

Efficacy analyses used the modified intention-to-treat (MITT) population (randomized patients who received study drug, and had randomization and ≥1 postrandomization HAM-A total score). The per-protocol (PP) population was a subset of the MITT population who had no significant protocol violations or deviations that would potentially affect efficacy. The safety population included all patients who received ≥1 dose of study medication. The TDSS population included patients who completed 8 weeks of treatment and had a week 8 and ≥1 other TDSS score.

The last observation carried forward (LOCF) approach was used for imputation of missing data. Statistical tests were 2-sided with an alpha level of significance of .05 (α=.05), unless otherwise specified. Secondary analyses reported nominal 5% levels of significance. No confirmatory analyses were made for secondary variables other than Q-LES-Q percent maximum total score.

For the primary efficacy endpoint, an analysis of covariance (ANCOVA) model was used, with HAM-A total score at randomization as a covariate, treatment as a fixed effect, and center as a random effect. To control the overall type I error rate at .05,29 a sequential stepwise procedure was used, starting with the primary efficacy variable followed by the Q-LES-Q percent maximum score; both nominal and adjusted P values were presented. A similar ANCOVA model was used for other continuous variables. Logistic regression (with score at randomization as covariate and treatment included as a fixed effect) was used to compare quetiapine XR with placebo for categorical variables including HAM-A response, HAM-A remission, and CGI-I.

To assess the robustness of the primary analysis, a mixed-effects model repeated measures (MMRM) analysis was performed on the change from randomization over time in HAM-A total score (observed cases [OCs]); treatment, visit, and treatment-by-visit interactions were included as fixed effects, center was included as a random effect, and baseline HAM-A total score was adjusted as a covariate. A robustness analysis for the primary efficacy variable using an ANCOVA model on the PP analysis population also was performed.

A subgroup analysis of change from randomization in HAM-A total score according to final prescribed quetiapine XR dose (150 mg/d or 300 mg/d) and an ANCOVA including final prescribed dose group were performed. Similarly, an ANCOVA of the primary efficacy variable by sex, age group (18 to 39, 40 to 65), baseline body mass index (BMI), and baseline severity subgroup of severe (HAM-A total score at baseline ≥29) vs nonsevere (HAM-A total score at baseline <29) was conducted.

Number needed to treat (NNT) was calculated using the formula 1/([proportion of quetiapine XR–treated patients with positive response] – [proportion of placebo-treated patients with positive response]).30

Descriptive statistics were provided for tolerability variables and TDSS total scores. In addition, for the assessment of suicidal ideation/behavior (Columbia Classification codes 1, 2, 3, 4), a log binomial regression analysis was performed to estimate the relative risk ratio and 95% CI (treatment was included as a fixed effect) for quetiapine XR vs placebo.

  RESULTS

Patient population

The first patient was enrolled on August 31, 2007, and the last patient completed the study on September 2, 2008. Of the 607 patients recruited from 54 centers in the United States, 409 were randomized to quetiapine XR + SSRI/SNRI (n=209) or placebo + SSRI/SNRI (n=200); no randomized patients were excluded from the safety population (FIGURE 2). The MITT population comprised 402 patients (7 patients were excluded due to missing/invalid randomization or postrandomization HAM-A scores): quetiapine XR + SSRI/SNRI (n=204) or placebo + SSRI/SNRI (n=198). The PP population comprised 181 and 177 patients, and the TDSS population comprised 141 and 159 patients in the quetiapine XR + SSRI/SNRI and placebo + SSRI/SNRI groups, respectively. A total of 320/409 (78.2%) patients completed the study: 152/209 quetiapine XR–treated and 168/200 placebo-treated patients. In the quetiapine XR + SSRI/SNRI group, the most common reason for withdrawal was an AE (n=25); in the placebo + SSRI/SNRI group, the most common reason for withdrawal was “lost to follow-up” (n=14) (FIGURE 2).

Treatment groups were generally well matched with respect to demographic and clinical characteristics at randomization and the SSRI or SNRI used (TABLE 1). The mean dose at randomization and the duration of treatment prior to randomization of the combination therapies are shown in TABLE 1.

FIGURE 2: Patient disposition
aCompleted the randomized treatment period and the 2-week posttreatment period.
bSubset of MITT population that includes only patients who completed 8 weeks of treatment and entered the posttreatment period.
GAD: generalized anxiety disorder; MITT: modified intention-to-treat; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; TDSS: treatment discontinuation signs and symptoms.


TABLE 1

Patient demographics and clinical characteristics at randomization (MITT population)

  Quetiapine XR + SSRI/SNRI (n=204) Placebo + SSRI/SNRI (n=198)   Quetiapine XR + SSRI/SNRI (n=204) Placebo + SSRI/SNRI (n=198)
Sex, n (%) Rating scale scores, mean (SD)
  Male 58 (28.4%) 48 (24.2%)   HAM-A total 24.5 (3.9) 24.6 (3.7)
  Female 146 (71.6%) 150 (75.8%)   HAM-A psychic cluster 13.7 (2.4) 14.0 (2.4)
Age, years   HAM-A somatic cluster 10.8 (2.9) 10.7 (2.6)
  Mean (SD) 44.6 (12.1) 44.2 (10.9)   CGI-S total 4.3 (0.6) 4.3 (0.5)
Ethnicity, n (%)   Q-LES-Q % maximum total 53.2 (15.8) 53.6 (14.6)
  White 181 (88.7%) 177 (89.4%)   Q-LES-Q item 15 3.2 (0.8) 3.2 (0.9)
  Black 18 (8.8%) 18 (9.1%)   Q-LES-Q item 16 3.1 (0.9) 3.1 (0.8)
  Asian 3 (1.5%) 2 (1.0%)   MADRS totala 11.7 (2.8) 11.6 (2.9)
  Other 2 (1.0%) 1 (0.5%) Combination therapy used, n (%)a
Weight, kg   SSRI
    Escitalopram
      Mean dose (mg/d)b
      Treatment duration (days)c
    Paroxetine
      Mean dose (mg/d)b
      Treatment duration (days) c

99 (48.5%)
19.3
148.5
53 (26.0%)
38.0
131.7

89 (44.9%)
20.8
173.8
55 (27.8%)
36.8
97.7
  Mean (SD) 81.8 (20.7) 80.7 (22.6)
Body mass index, kg/m2
  Mean (SD) 29.5 (6.5) 29.5 (8.1)
Time since first diagnosis of GAD, years
  Mean (SD) 8.2 (9.2) 8.3 (9.4)   SNRI
    Duloxetine
      Mean doseb
      Treatment duration (days)c
    Venlafaxine
      Mean doseb
      Treatment duration (days) c

17 (8.3%)
76.7
162.4
36 (17.6%)
151.3
138.4

16 (8.1%)
73.4
126.1
38 (19.2%)
155.9
286.6
Time since onset of anxiety symptoms, years
  Mean (SD) 15.8 (13.0) 15.0 (12.7)
Time since first treated for anxiety, years
  Mean (SD) 7.8 (8.4) 8.5 (9.4)
aAll patients in the MITT population received an SSRI/SNRI; one patient received escitalopram and venlafaxine prior to and at randomization.
bMean daily dose at randomization.
cDuration of treatment prior to randomization.
CGI-S: Clinical Global Impression–Severity of Illness; GAD: generalized anxiety disorder; HAM-A: Hamilton Rating Scale for Anxiety; MADRS: Montgomery-Åsberg Depression Rating Scale; MITT: modified intention-to-treat; Q-LES-Q; Quality of Life Enjoyment and Satisfaction Questionnaire; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor.
Study treatment

The mean (SD) dose of adjunctive agent (quetiapine XR or placebo) was 174.3 (49.0) mg/d and 190.3 (49.6) mg/d for quetiapine XR–treated and placebo-treated patients, respectively. In total, 86/209 (41.1%) quetiapine XR–treated and 110/200 (55.0%) placebo-treated patients received a maximum dose of 300 mg/d; 4 quetiapine XR–treated and 3 placebo-treated patients received a maximum dose of 50 mg/d.

In the MITT population, 95.1% and 95.5% of patients in the quetiapine XR + SSRI/SNRI and placebo + SSRI/SNRI groups, respectively, were treatment adherent.

Concomitant medication

At week 1, concomitant sleep medication was used by 10.0% and 12.5% of patients in the quetiapine XR and placebo + SSRI/SNRI groups, respectively; this level of use remained consistent throughout the randomized period. Benzodiazepines were used by 10.4% of quetiapine XR–treated patients and 12.0% of placebo-treated patients at the end of the randomized period.

During the randomized period, anticholinergic medication use was low in both groups: 0.5% to 1.2%, quetiapine XR + SSRI/SNRI, and 1.5% to 1.7%, placebo + SSRI/SNRI.

Efficacy

Primary efficacy endpoint. At week 8, quetiapine XR + SSRI/SNRI (–10.74; P=.079; adjusted P=.079) did not demonstrate a statistically significant reduction from randomization in least squares means (LSM) HAM-A total score compared with placebo + SSRI/SNRI (–9.61) (FIGURE 3A).

The PP population analysis of the primary efficacy variable confirmed the results of the primary analysis in the MITT population. MMRM analysis (OCs, MITT population) results were also similar to the primary efficacy analysis results.

Secondary endpoints. At week 1, quetiapine XR + SSRI/SNRI significantly reduced mean HAM-A total scores compared with placebo + SSRI/SNRI: LSM changes from randomization were –6.45 vs –4.47 (95% CI, –2.88 to –1.09; P < .001; FIGURE 3A). FIGURE 3B shows the MMRM analysis of mean change in HAM-A total score from randomization at each time point. A significant reduction in HAM-A total score was seen with quetiapine XR + SSRI/SNRI at week 1 (–6.43; P < .001) and week 6 (–11.13; P < .05) compared with placebo + SSRI/SNRI (–4.45, –9.69, respectively), but not at the other time points. The effect of explanatory variables—including final prescribed dose, baseline severity subgroup severe vs nonsevere (HAM-A ≥29 vs HAM-A <29), sex, age, and baseline BMI subgroups—was investigated with respect to the primary outcome variable (TABLE 2). With the adjustment of each of these effects, at week 8 quetiapine XR + SSRI/SNRI did not demonstrate a statistically significant difference from placebo in HAM-A total score change from randomization. Quetiapine XR + SSRI/SNRI significantly reduced HAM-A psychic cluster scores at week 1 (–3.70; P < .001) and week 8 (–6.09; P < .05) compared with placebo + SSRI/SNRI (–2.46 at week 1 and –5.21 at week 8) (FIGURE 4). Significant reductions were also seen in the HAM-A somatic cluster scores at week 1 for quetiapine XR + SSRI/SNRI (–2.74; P < .01) compared with placebo + SSRI/SNRI (–2.00), but not at week 8 (–4.63 vs –4.38; P = .421) (FIGURE 4).

In addition, quetiapine XR + SSRI/SNRI significantly reduced CGI-S total scores from randomization at week 1 (–0.56; P < .001) and week 8 (–1.36; P < .05) compared with placebo + SSRI/SNRI (–0.35 and –1.13, respectively).

Figure 3: LSM change in HAM-A total score from randomization
aP < .001 vs placebo.
bP = .079.
SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor.

Figure 3: LSM change in HAM-A total score from randomization
aP < .001 vs placebo.
bP < .05.
HAM-A: Hamilton Rating Scale for Anxiety; LOCF: last observation carried forward; LSM: least squares means; MITT: modified intention-to-treat; MMRM: mixed-effects model repeated measures; OCs: observed cases; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor.

Figure 4: LSM change from randomization in HAM-A psychic and somatic cluster scores (LOCF, MITT population)
aP < .01 vs placebo.
bP < .05.
cP < .01.
dP = .421.
HAM-A: Hamilton Rating Scale for Anxiety; LOCF: last observation carried forward; LSM: least squares means; MITT: modified intention-to-treat; SNRI: serotonin-norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor.


TABLE 2

Results for change from randomization for secondary efficacy endpoints (MITT population, LOCF)

  Quetiapine XR + SSRI/SNRI (n=204) Placebo + SSRI/SNRI (n=198)
HAM-A total
Week 1 LSM change
LSM difference (95% CI) vs placebo
P value
–6.45
–1.99 (–2.88 to –1.09)
<.001
–4.47
Week 8 LSM change
LSM difference (95% CI) vs placebo
P value
–10.74
–1.13 (2.39 to 0.13)
.079
–9.61
HAM-A adjusted by final prescribed dose
Week 8 LSM change
LSM difference (95% CI) vs placebo
P value
–10.06
–0.50 (–1.73 to 0.73)
.425
–9.56
HAM-A adjusted by baseline disease severity
Week 8 LSM change
LSM difference (95% CI) vs placebo
P value
–11.36
–1.13 (–2.39 to 0.13)
.278
–10.23
HAM-A adjusted by sex
Week 8 LSM change
LSM difference (95% CI) vs placebo
P value
–11.06
–1.07 (–2.33 to 0.18)
.059
–9.99
HAM-A adjusted by age
Week 8 LSM change
LSM difference (95% CI) vs placebo
P value
–10.89
–1.14 (–2.40 to 0.12)
.157
–9.75
HAM-A adjusted by baseline BMI
Week 8 LSM change
LSM difference (95% CI) vs placebo
P value
–11.63
–1.16 (–2.43 to 0.11)
.521
–10.47
HAM-A psychic clustera
Week 8 LSM change
LSM difference (95% CI) vs placebo
P value
–6.09
–0.88 (–1.66 to –0.09)
<.05
–5.21
HAM-A somatic clusterb
Week 8 LSM change
LSM difference (95% CI) vs placebo
P value
–4.63
–0.25 (–0.87 to 0.37)
.421
–4.38
HAM-A response, n (%)
Week 1
Odds ratio (95% CI) vs placebo
P value
33 (16.9)
1.55 (0.87 to 2.78)
.138
22 (11.5)
Week 8
Odds ratio (95% CI) vs placebo
P value
84 (41.2)
1.22 (0.81 to 1.82)
.342
72 (36.4)
HAM-A remission (HAM-A total score ≤8), n (%)
Week 8
Odds ratio (95% CI) vs placebo
P value
48 (23.5)
1.47 (0.89 to 2.42)
.134
34 (17.2)
CGI-S total score
Week 1 LSM change
LSM difference (95% CI) vs placebo
P value
–0.56
–0.21 (–0.33 to –0.09)
<.001
–0.35
Week 8 LSM change
LSM difference (95% CI) vs placebo
P value
–1.36
–0.23 (–0.42 to –0.03)
<.05
–1.13
CGI-I score
Patients “very much” or “much” improved at Week 8, %
Odds ratio (95% CI) vs placebo
P value
55.9%
1.33 (0.90 to 1.97)
.158
49.0%
Q-LES-Q % maximum total score
Week 8 LSM change
LSM difference (95% CI) vs placebo
P value
7.33
0.90 (–1.79 to 3.59)
.512
6.43
Q-LES-Q item 15 scorec
Week 8 LSM change 0.3 0.4
Q-LES-Q item 16 scorec
Week 8 LSM change 0.3 0.2
aVariables were not assessed statistically.
bThe HAM-A psychic cluster comprised the following items: anxious mood, tension, fears, insomnia, intellectual difficulties, depressed mood, and behavior at interview.
cThe HAM-A somatic cluster comprised the following items: somatic muscular, somatic sensory, cardiovascular system, respiratory system, gastrointestinal system, genitourinary system, and autonomic system.
BMI: body mass index; CGI-S: Clinical Global Impression–Severity of Illness; HAM-A: Hamilton Rating Scale for Anxiety; LSM: least squares means; MITT: modified intention-to-treat; Q-LES-Q: Quality of Life Enjoyment and Satisfaction Questionnaire.

For other secondary endpoints relating to the HAM-A and CGI-I scales, there were no statistically significant differences between treatment groups in change from randomization to week 8 (TABLE 2).

The NNT value calculated using the end of treatment response data for quetiapine XR was 20.8.

Health-related quality of life. There was no statistically significant difference between treatment groups in change from randomization to week 8 in Q-LES-Q percent maximum total score (TABLE 2). In addition, the magnitude of improvement (randomization to week 8) in Q-LES-Q item 15 and item 16 scores was similar in the 2 groups (TABLE 2).

Safety and tolerability

Adverse events. The overall incidence of AEs was 73.7% and 60.0% in the quetiapine XR + SSRI/SNRI and placebo + SSRI/SNRI groups, respectively. The most common AEs (>5% in either group) are reported in TABLE 3. The percentages of patients with an AE considered to be treatment-related were 62.2% and 36.0% in the quetiapine XR + SSRI/SNRI and placebo + SSRI/SNRI groups, respectively. No deaths or SAEs occurred during the study.


TABLE 3

Most common adverse events (occurring at an incidence of >5% in either group) during the study (safety population)

  Quetiapine XR + SSRI/SNRI (n=209) Placebo + SSRI/SNRI (n=200)
Adverse event, n (%)a
Dry mouth 49 (23.4%) 16 (8.0%)
Somnolence 47 (22.5%) 24 (12.0%)
Sedation 26 (12.4%) 5 (2.5%)
Headache 24 (11.5%) 21 (10.5%)
Dizziness 22 (10.5%) 9 (4.5%)
Fatigue 20 (9.6%) 8 (4.0%)
Insomnia 15 (7.2%) 3 (1.5%)
Constipation 13 (6.2%) 8 (4.0%)
Nausea 12 (5.7%) 12 (6.0%)
Nasopharyngitis 7 (3.3%) 17 (8.5%)
aMedDRA preferred term.

No AEs potentially related to suicidality were reported and no incidences of suicidal behavior/ideation (Columbia Classification codes 1, 2, 3, 4) were reported in either treatment group. The incidence of possible suicidal behavior/ideation (Columbia Classification codes 5, 6, 9) was 1.4% and 1.5% with quetiapine XR + SSRI/SNRI and placebo + SSRI/SNRI, respectively. The relative risk (95% CI) for suicidal behavior/ideation and possible suicidal behavior/ideation for quetiapine XR + SSRI/SNRI vs placebo + SSRI/SNRI treatment was .96 (95% CI, 0.195 to 4.686).

AEs potentially related to somnolence (MedDRA preferred terms: lethargy, sedation, sluggishness, and somnolence) were reported by 35.9% and 14.5% of patients in the quetiapine XR + SSRI/SNRI and placebo + SSRI/SNRI groups, respectively. The majority of AEs associated with somnolence were mild to moderate in intensity, and the median time to onset of these AEs was 3 days with quetiapine XR + SSRI/SNRI and 10 days with placebo + SSRI/SNRI.

The incidences of AEs potentially related to EPS (MedDRA preferred terms: akathisia, psychomotor hyperactivity, restlessness, and tremor) were 3.8% and 2.0% in the quetiapine XR + SSRI/SNRI and placebo + SSRI/SNRI groups, respectively. All of the EPS-related AEs were mild to moderate in severity. At treatment end, the majority of patients in both groups experienced either “no change” or “improvement” in SAS (88.8%, quetiapine XR + SSRI/SNRI; 93.3%, placebo + SSRI/SNRI) and BAS (95.1%, quetiapine XR + SSRI/SNRI; 96.4%, placebo + SSRI/SNRI) total scores from randomization.

AEs potentially related to sexual dysfunction (MedDRA preferred terms: libido decreased and ejaculation delayed) were reported by 2.9% of patients in the quetiapine XR + SSRI/SNRI group and no patients in the placebo + SSRI/SNRI group.

The percentage of patients who discontinued the study (from start of study treatment to last dose) due to an AE was 11.0% (n=23) for quetiapine XR + SSRI/SNRI and 2.0% (n=4) for placebo + SSRI/SNRI. One patient randomized to the quetiapine XR group discontinued treatment due to an AE in the placebo run-in period and one patient discontinued after the treatment period. The most common AEs leading to discontinuation were sedation (n=11, quetiapine XR + SSRI/SNRI; n=0, placebo + SSRI/SNRI) and somnolence (n=6, quetiapine XR + SSRI/SNRI; n=0, placebo + SSRI/SNRI).

The mean change from randomization in MADRS total score was –2.8 and –1.8 at week 4, and –3.4 and –2.5 at week 8 with quetiapine XR + SSRI/SNRI and placebo + SSRI/SNRI, respectively.

No clinically relevant differences between groups were seen in mean change from randomization to week 8 for vital signs, ECG, or hematology data. There was no indication of increased QTc interval in either group.

TABLE 4 presents changes in body weight, glucose and lipid data and the proportions of patients with clinically relevant shifts from normal in these parameters from randomization to treatment end in the fasting status confirmed safety population. More patients in the placebo group experienced a clinically relevant shift (elevation) from randomization to treatment end in plasma glucose levels (3.0%) compared with the quetiapine XR group (1.7%). Conversely, more patients in the quetiapine XR + SSRI/SNRI group (16.8%) experienced a clinically relevant shift (elevation) from randomization to treatment end in triglyceride levels than in the placebo + SSRI/SNRI group (10.3%).

Mean change in body weight at treatment end was +1.0 kg in the quetiapine XR + SSRI/SNRI group, and +0.3 kg in the placebo + SSRI/SNRI group; 4.3% and 1.0% of patients, respectively, experienced a ≥7% increase in body weight (TABLE 4).


TABLE 4

Changes in glucose and lipid data and body weight and the proportions of patients with clinically relevant shifts from normal in these parameters from randomization to treatment end (safety population)

Parametera Quetiapine XR + SSRI/SNRI (n=209) Placebo + SSRI/SNRI (n=200)
Glucose (mg/dL)b
Randomization
Change
Patients with a clinically relevant shift in fasting glucose (≥126 mg/dL), n (%)
90.65 (10.0)
0.38 (16.75) (n=146)
3 (1.7%) (n=173)
93.18 (15.40)
1.7 (16.54) (n=135)
5 (3.0%) (n=164)
Total cholesterol (mg/dL)b
Randomization
Change
Patients with a clinically relevant shift in fasting total cholesterol (≥240 mg/dL), n (%)
206.67 (43.22)
–1.65 (27.46) (n=144)
11 (8.6%) (n=128)
203.05 (46.83)
–6.83 (27.48) (n=124)
4 (3.5%) (n=114)
HDL-cholesterol (mg/dL)b
Randomization
Change
Patients with a clinically relevant shift in fasting HDL- cholesterol (≤40 mg/dL), n (%)
52.64 (13.86)
–1.61 (9.87) (n=144)
15 (11.6%) (n=114)
55.07 (14.88)
0.45 (8.12) (n=124)
12 (10.1%) (n=107)
LDL-cholesterol (mg/dL)b
Randomization
Change
Patients with a clinically relevant shift in fasting LDL- cholesterol (≥160 mg/dL), n (%)
124.76 (38.03)
–2.27 (24.81) (n=144)
7 (5.1%) (n=136)
122.23 (39.05)
–6.76 (22.79) (n=124)
2 (1.7%) (n=117)
Triglycerides (mg/dL)b
Randomization
Change
Patients with a clinically relevant shift in fasting triglycerides (≥200 mg/dL), n (%)
147.53 (84.47)
13.60 (71.58) (n=144)
20 (16.8%) (n=119)
128.83 (73.80)
–2.03 (68.18) (n=124)
12 (10.3%) (n=117)
Prolactin (ng/mL)
Randomization
Change
8.65 (6.18)
1.19 (9.91) (n=187)
8.29 (6.67)
1.58 (11.59) (n=179)
Weight, kg
Randomization
Change
Patients with a clinically relevant shift in weight (≥7% increase), n (%)
81.9 (20.6)
1.0 (2.3) (n=207)
9 (4.3%)
80.6 (22.6)
0.3 (2.3) (n=199)
2 (1.0%)
aNumbers of patients include only those who were assessed. Values shown as mean (SD) unless otherwise indicated.
bFasting status was determined based on a documented patient report that the last meal was ≥8 hours before the blood sample was taken for randomization and postrandomization laboratory measurements. However, not all samples could be confirmed as fasted despite there being an 8-hour interval since the last meal, as patients could have had caloric intake.
HDL: high-density lipoprotein; LDL: low-density lipoprotein.

Posttreatment period. The most common (>2%) AEs reported during the 2-week posttreatment period were insomnia (4.8%) and nausea (2.4%) in the quetiapine XR + SSRI/SNRI group; these AEs were reported during the posttreatment period by 0% and 1.0% of patients in the placebo + SSRI/SNRI groups, respectively.

Mean (SD) TDSS total scores at day 7 and 14 of the posttreatment period were 6.0 (4.2) and 5.8 (4.4) in the quetiapine XR + SSRI/SNRI group and 5.5 (4.0) and 5.6 (4.2) in the placebo + SSRI/SNRI group, respectively.

  DISCUSSION

This study evaluated the efficacy and tolerability of quetiapine XR as an adjunct to SSRI/SNRI therapy in patients with GAD who demonstrated partial or no (inadequate) response to SSRI/SNRI treatment (alone or in combination with a benzodiazepine). A patient population comprising both partial or no (inadequate) responders was selected for inclusion in this study since there is debate regarding the definition of treatment resistance in GAD.31

In the current study, the primary efficacy variable did not show statistical separation for quetiapine XR compared with placebo. This contrasts with the findings of previous studies conducted with quetiapine XR monotherapy in patients with GAD (not specified as being treatment-resistant GAD) that found quetiapine XR to be effective in reducing anxiety symptoms when compared with placebo.12-16

Failure of active treatment to separate from placebo is not unusual; around half (51.8%) of the clinical studies evaluating antidepressant and anxiolytic drugs do not show statistical superiority to placebo.32 High placebo response often is a major contributory factor, although other possibilities include: inclusion/exclusion criteria; high attrition rates; outcome measure sensitivity; unreliable rating scales; misdiagnosis; severity of illness; and study design.33,34

The single-blind, placebo run-in period included in the current study was designed to reduce the effects of any potential placebo response. However, the magnitude of change in HAM-A total score seen here for the placebo group (–9.61) was unexpectedly high when compared with those seen in other placebo-controlled adjunct studies. For example, in a 5-week study in patients with GAD who continued to experience symptoms despite previous therapy, the mean changes in HAM-A total scores were –9.8 and –6.2 with adjunctive risperidone and placebo plus antidepressant, respectively.35 In this study, adjunctive risperidone was associated with significant improvements in anxiety symptoms, with greater reductions in HAM-A total score (P=.034) and HAM-A psychic anxiety factor score (P=.047) compared with placebo. No significant differences were observed for other outcome measures, but greater improvements were seen with risperidone vs placebo. The authors concluded that, at low doses, risperidone may be efficacious in the management of symptomatic GAD patients.35

The changes in HAM-A total score in the current study with adjunctive quetiapine XR are lower than those reported in previous short-term studies (10-week studies with an 8-week active treatment period) of quetiapine XR monotherapy (from –13.5 to –16.0 in the 150 mg/d groups).12-14 Patients in the current study had already received treatment (SSRI/SNRI) for their anxiety; therefore, it might be expected that on study entry some improvement in symptoms would have already occurred. However, baseline HAM-A scores in the present study (24.5, quetiapine XR; 24.6, placebo) were similar to those in 2 previous studies of quetiapine XR monotherapy in GAD: Studies D1448C00009 (24.5, quetiapine XR 150 mg/d; 24.9, placebo)13 and D1448C00010 (25.0, quetiapine XR 150 mg/d; 25.3, placebo),14 whereas baseline HAM-A scores reported in Study D1448C00011 (26.6, quetiapine XR 150 mg/d; 27.3, placebo)12 were higher than those seen here. In addition, patients in the current study had on average been experiencing anxiety symptoms for a longer duration (15 to 16 years) than in Study D1448C00009 (13 to 15 years), Study D1448C00010 (13 to 15 years), and Study D1448C00011 (11 to 12 years). It has been suggested that duration of neuropsychological disease may be associated with treatment resistance; if this is the case, the patients enrolled in this study may be representative of a more treatment-resistant patient population.

The patients in the current study had an inadequate response to prior treatment and so, compared with treatment-naïve or -responsive patients, may have a reduced capacity for symptom improvement, and any benefits experienced by these patients may not be captured by HAM-A score change.

Because the baseline characteristics of the 2 treatment groups were well matched, it is not unexpected that the findings of the analysis of the primary efficacy variable by baseline severity (severe vs nonsevere), sex, age, and baseline BMI were similar to those of the primary analysis. The MMRM analysis of change in HAM-A total score also failed to reach statistical significance for quetiapine XR compared with placebo at week 8; however, a significant difference from placebo was found at weeks 1 and 6. The analysis using change from randomization in HAM-A total score according to final prescribed quetiapine XR dose (150 mg/d or 300 mg/d) at week 8 also found no statistically significant difference between quetiapine XR and placebo.

The discontinuation rate in the present study (22%) was comparable with that seen in other studies: approximate discontinuation rates of 35%, 29%, and 23% were reported in quetiapine XR studies D1448C00009, D1448C00010, and D1448C00011, respectively,12-14 and approximately 23% of patients discontinued in a study of adjunctive risperidone.35 High attrition does not explain the lack of statistical separation from placebo for the primary efficacy variable. Likewise, failure to statistically separate cannot be explained by treatment adherence, as this was similar in the 2 groups. It is important to note that in the current study, benzodiazepine use was slightly lower in the quetiapine XR group (10.4%) than in the placebo group (12.0%). Benzodiazepines have been shown to improve psychic and somatic symptoms of anxiety,36 and so concomitant benzodiazepine use may have been an important factor in the symptom improvement seen for some patients receiving placebo in the current study. Concomitant benzodiazepine use was specifically excluded in the aforementioned quetiapine XR monotherapy studies.12-14

At week 8, significant reductions in CGI-S total score were seen with quetiapine XR compared with placebo. Significant differences between quetiapine XR and placebo at time points other than week 8 were seen for several secondary outcome variables. For example, at week 1, significant differences between quetiapine XR and placebo were seen for HAM-A total, HAM-A psychic and somatic cluster scores, and CGI-S total score. Significant separation from placebo with quetiapine XR at week 1 but not week 8 cannot be easily explained. One possible explanation is that placebo-treated patients may have taken benzodiazepines because of a lack of symptom improvement. However, benzodiazepine use remained relatively constant over the 8-week randomized period. Moreover, the adjunctive quetiapine XR group approached a significant level of separation from placebo at week 8, although statistical significance was not reached. While the ability to predict outcomes based on an early response to treatment (weeks 1 or 2) would be advantageous to clinicians in determining the likelihood of a positive outcome to treatment, such early response should be monitored since, as demonstrated by this study, other factors may influence outcomes.

The NNT value reported here (20.8) for quetiapine XR may be explained by the comparatively low response rate for quetiapine XR (41.2%) vs placebo (36.4%) compared with response rates reported for quetiapine XR monotherapy (55% to 71%) in other GAD clinical trials.12-14

At week 8, significant reductions in the HAM-A psychic cluster score were seen with quetiapine XR compared with placebo. The anxiolytic effect of quetiapine XR may be translated through the psychic cluster items (anxious mood, tension, fears, insomnia, intellectual difficulties, depressed mood, and behavior at interview). Quetiapine XR has demonstrated a beneficial effect on sleep in patients with GAD12-14 and major depressive disorder (MDD),37-41 and has improved cognitive function in patients with schizophrenia.42

Quetiapine XR (at doses of 50, 150, and 300 mg/d) previously has demonstrated efficacy in treating depressive symptoms in patients with MDD, as monotherapy38,39,41,43 and as adjunctive treatment.37,40 Also, in the current study, quetiapine XR reduced symptoms of depression assessed by the MADRS. The broad spectrum of efficacy demonstrated by quetiapine XR against symptoms of anxiety and depression may be explained by its mechanism of action. Quetiapine and norquetiapine (the major active metabolite of quetiapine) have moderate to high affinity for serotonin 5-HT2A and dopamine D2 receptors; norquetiapine is also a potent inhibitor of the norepinephrine transporter (NET).44,45 NET inhibition has not been demonstrated by other atypical antipsychotics at clinically relevant doses; however, it is a property shared by a number of traditional antidepressants, such as SNRIs,46 and is believed to contribute to the therapeutic effect of quetiapine.45

In this study, the overall tolerability and safety results in quetiapine XR–treated patients were consistent with the known profile of quetiapine.12-16,37-39,41,43,47-49 Patients received concomitant SSRI/SNRI therapy and were permitted to receive benzodiazepines; therefore, safety/tolerability data reported here may be due to the effects of several agents. The clinical laboratory data reported here for quetiapine XR + SSRI/SNRI are consistent with those from acute studies of quetiapine XR monotherapy in adult patients with GAD.12-14

This was the first randomized, placebo-controlled study to evaluate the efficacy of quetiapine XR as an adjunct to antidepressants for the treatment of GAD in patients with an inadequate response to SSRI/SNRI treatment in a large patient population. Study limitations include the lack of an active comparator and the use of inclusion criteria relating to disease status (HAM-A and CGI-S scores) that were similar to those in acute studies of quetiapine XR monotherapy, despite the fact that this study assessed quetiapine XR as adjunctive therapy. More restrictive exclusion criteria could have been used to better determine the potential effect of adjunctive quetiapine XR, for example, exclusion of patients who had anxiety for >10 years, and concomitant benzodiazepine use. In addition, the HAM-A may have been an insensitive measure in this patient population, where little improvement in symptoms could be expected in the context of prior treatment failure.

  CONCLUSIONS

In this study, statistical separation from placebo with adjunctive quetiapine XR was not achieved in patients with GAD and an inadequate response to previous therapy for the primary efficacy variable. Statistical separation was achieved for some secondary variables, including change in HAM-A psychic cluster scores and CGI-S total scores at weeks 1 and 8. Quetiapine XR was generally well tolerated and its safety profile was consistent with the known profile of quetiapine. Further studies to evaluate the efficacy of adjunctive quetiapine XR in patients with GAD and an inadequate response to previous treatment should take into consideration the methodological difficulties that may be encountered.

ACKNOWLEDGMENTS: Clinicaltrials.gov identifier number: NCT00534599. This study (Palladium, D1441L00016) was funded by AstraZeneca Pharmaceuticals. The authors thank Jocelyn Woodcock, MPhil, from Complete Medical Communications, who provided medical writing support funded by AstraZeneca.

The following investigators were involved in the study: Donald Anderson, Redlands, CA; Emelina Arocha, Coral Gables, FL; Sarah Atkinson, Rochester, NY; Padmini Atri, Richmond, VA; Benny Barnhart, Wichita Falls, TX; Jason Baron, Houston, TX; Michael Biunno, New Orleans, LA; Brian Bortnick, Atlanta, GA; Ronald Brenner, Cedarhurst, NY; Robert Buynak, Merrillville, IL; Mario Cuervo, Miami, FL; Andrew Cutler, Brandenton, FL; Jeffrey Danziger, Maitland, FL; Michael Downing, Dallas, TX; Bernadette D’Souza, Dayton, OH; Nazir El-Khalili, Lafayette, IN; Beal Esink, Portland, OR; Gary Gerard, Toledo, OH; Jerome Goldstein, San Francisco, CA; Michael Greenbaum, Libertyville, IL; Daniel Grosz, Encino, CA; Daniel Gruener, Philadelphia, PA; Paras Harshawat, Terre Haute, IN; Howard Hassman, Clementon, NJ; Mark Hernandez, Hialeah, FL; John Heussy, New York, NY; Alexander Horwitz, Salem, OR; John Joyce, Jacksonville, FL; Arifulla Khan, Bellevue, WA; Jelena Kunovac, Oceanside, CA; Michael Levy, Staten Island, NY; H. Edward Logue, Birmingham, AL; Antonio Lourenco, Miami, FL; Paul Markovitz, Fresno, CA; Joshua McDavid, Seattle, WA; Lora McGill, Memphis, TN; Charles Merideth, San Diego, CA; Irina Mezhebovsky, Boston, MA; Janice Miller, West Palm Beach, FL; Amy Mulroy, San Antonio, TX; Dennis Munjack, Burbank, CA; John Murphy, Beverly Hills, CA; Duong Nguyen, Little Rock, AR; Brett Plyler, Chicago, IL; Jorge Porras, San Diego, CA; Robert Riesenberg, Atlanta, GA; Leon Rosenberg, Cherry Hill, NJ; Norman Rosenthal, Rockville, MD; Richard Saini, Orlando, FL; Angelo Sambunaris, Atlanta, GA; Veronique Sebastian, Oklahoma City, OK; Andrew Sedillo, Owensboro, KY; Scott Segal, North Miami, FL; Thomas Shiovitz, Sherman Oaks, CA; Mary Stedman, Tampa, FL; Haydn Thomas, Prairie Village, KS; John Tran, Spokane, WA; Aggy Vallanat, Fresh Meadows, NY; Reinaldo Verson, Columbus, GA; Inna Yuryev-Golger, Brooklyn, NY.

DISCLOSURES: Dr. Khan is Medical Director of the Northwest Clinical Research Center (NWCRC) and has been a Principal Investigator for more than 340 clinical trials sponsored by more than 65 pharmaceutical companies and 30 clinical research organizations. He has not been compensated for consulting or speaking on behalf of these companies, nor does he own stock in any of these or other pharmaceutical companies. Dr. Khan is not compensated for this role as author of medical manuscripts. NWCRC enrolled 17 patients in the trial of quetiapine XR for generalized anxiety disorder. In 2009 Dr. Khan founded Columbia Northwest Pharmaceuticals, LLC, and is Medical Director of the company. Columbia Northwest Pharmaceuticals owns intellectual property rights for potential therapies for central nervous system disorders and other medical conditions. Dr. Atkinson receives grant/research support from AstraZeneca, Eli Lilly and Company, Forest Pharmaceuticals, Lundbeck, Merck, Naurex, Otsuka, Pfizer, Sunovion, Takeda, and Targacept; and is a consultant to Eli Lilly and Company. Dr. Mezhebovsky reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products. Ms. She, Mr. Leathers, and Dr. Pathak are employees of AstraZeneca.

    REFERENCES

  1. Bruce SE, Yonkers KA, Otto MW, et al. Influence of psychiatric comorbidity on recovery and recurrence in generalized anxiety disorder, social phobia, and panic disorder: a 12-year prospective study. Am J Psychiatry. 2005;162:1179–1187.
  2. Pollack MH. Refractory generalized anxiety disorder. J Clin Psychiatry. 2009;70(suppl 2):32–38.
  3. Wittchen HU. Generalized anxiety disorder: prevalence burden, and cost to society. Depress Anxiety. 2002;16:162–171.
  4. Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2005;19:567–596.
  5. Bandelow B, Zohar J, Hollander E, et al; WFSBP Task Force on Treatment Guidelines for Anxiety. Obsessive-Compulsive and Post-Traumatic Stress Disorders. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety obsessive-compulsive and post-traumatic stress disorders – first revision. World J Biol Psychiatry. 2008;9:248–312.
  6.  Canadian Psychiatric Association. Management of anxiety disorders. Can J Psychiatry. 2006;51(8 suppl 2):1S–93S.
  7.  NICE guidelines. Anxiety: management of anxiety (panic disorder, with or without agoraphobia, and generalised anxiety disorder) in adults in primary, secondary and community care. http://www.nice.org.uk/CG022NICEguidelines. Accessed April 1,2010.
  8. Rickels K, Rynn M, Iyengar M, et al. Remission of generalized anxiety disorder: a review of the paroxetine clinical trials database. J Clin Psychiatry. 2006;67:41–47.
  9. Montgomery SA, Sheehan DV, Meoni P, et al. Characterization of the longitudinal course of improvement in generalized anxiety disorder during long-term treatment with venlafaxine XR. J Psychiatr Res. 2002;36:209–217.
  10. Katzman MA, Vermani M, Jacobs L, et al. Quetiapine as an adjunctive pharmacotherapy for the treatment of non-remitting generalized anxiety disorder: a flexible-dose, open-label pilot trial. J Anxiety Disord. 2008;22:1480–1486.
  11. Lohoff FW, Etemad B, Mandos LA, et al. Ziprasidone treatment of refractory generalized anxiety disorder: a placebo-controlled, double-blind study. J Clin Psychopharmacol. 2010;30:185–189.
  12. Bandelow B, Chouinard G, Bobes J, et al. Extended-release quetiapine fumarate (quetiapine XR): a once-daily monotherapy effective in generalized anxiety disorder. Data from a randomized, double-blind, placebo- and active-controlled study. Int J Neuropsychopharmacol. 2010;13:305–320.
  13. Khan A, Joyce M, Atkinson S, et al. A randomized, double-blind study of once-daily extended release quetiapine fumarate (quetiapine XR) monotherapy in patients with generalized anxiety disorder. J Clin Psychopharmacol. 2011;31:418–428.
  14. Merideth C, Cutler AJ, She F, et al. Efficacy and tolerability of extended release quetiapine fumarate monotherapy in the acute treatment of generalized anxiety disorder: a randomized, placebo-controlled and active-controlled study. Int Clin Psychopharmacol. 2012;27:40–54.
  15. Mezhebovsky I, Magi K, She F, et al. Double-blind, randomized study of extended release quetiapine fumarate (quetiapine XR) monotherapy in older patients with generalized anxiety disorder. Int J Geriatr Psychiatry. 2013;28:615–625.
  16. Katzman MA, Brawman-Mintzer O, Reyes EB, et al. Extended release quetiapine fumarate (quetiapine XR) monotherapy as maintenance treatment for generalized anxiety disorder: a long-term, randomized, placebo-controlled trial. Int Clin Psychopharmacol. 2011;26:11–24.
  17.  AstraZeneca. Seroquel XR: summary of product characteristics (Ireland). http://www.medicines.ie/medicine/13032/SPC/Seroquel+XR+50mg%2c+150mg%2c+200mg%2c+300mg%2c+400mg+prolonged-release+tablets. Updated August 30, 2013. Accessed September 6, 2013.
  18.  Wilmington DE: AstraZeneca; 2013.
  19.  Diagnostic and statistical manual of mental disorders, 4th edition. Washington, DC: American Psychiatric Association; 1994.
  20. Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(suppl 20):22–33.
  21. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32:50–55.
  22. Guy W. Clinical Global Impressions. In: ECDEU Assessment Manual for Psychopharmacology. Washington DC: US Department of Health, Education and Welfare; 1976;218–222.
  23. Endicott J, Nee J, Harrison W, et al. Quality of Life Enjoyment and Satisfaction Questionnaire: a new measure. Psychopharmacol Bull. 1993;29:321–326.
  24. Posner K, Oquendo MA, Gould M, et al. Columbia Classification Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA’s pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 2007;164:1035–1043.
  25. Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl. 1970;212:11–19.
  26. Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry. 1989;154:672–676.
  27. Rosenbaum JF, Fava M, Hoog SL, et al. Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biol Psychiatry. 1998;44:77–87.
  28. Michelson D, Fava M, Amsterdam J, et al. Interruption of selective serotonin reuptake inhibitor treatment. Double-blind, placebo-controlled trial. Br J Psychiatry. 2000;176:363–368.
  29. Hommel G. A stagewise rejective multiple test procedure based on a modified Bonferroni test. Biometrika. 1988;75:383–386.
  30. Pinson L, Gray GE. Psychopharmacology: number needed to treat: an underused measure of treatment effect. Psychiatr Serv. 2003;54:145–146154.
  31. Rynn MA, Brawman-Mintzer O. Generalized anxiety disorder: acute and chronic treatment. CNS Spectr. 2004;9:716–723.
  32. Khan A, Khan S, Brown WA. Are placebo controls necessary to test new antidepressants and anxiolytics? Int J Neuropsychopharmacol. 2002;5:193–197.
  33. Fava M, Evins AE, Dorer DJ, et al. The problem of the placebo response in clinical trials for psychiatric disorders: culprits, possible remedies, and a novel study design approach. Psychother Psychosom. 2003;72:115–127.
  34. Katz MM, Halbreich UM, Bowden CL, et al. Enhancing the technology of clinical trials and the trials model to evaluate newly developed, targeted antidepressants. Neuropsychopharmacology. 2002;27:319–328.
  35. Brawman-Mintzer O, Knapp RG, Nietert PJ. Adjunctive risperidone in generalized anxiety disorder: a double-blind placebo-controlled study. J Clin Psychiatry. 2005;66:1321–1325.
  36. Lydiard RB, Rickels K, Herman B, et al. Comparative efficacy of pregabalin and benzodiazepines in treating the psychic and somatic symptoms of generalized anxiety disorder. Int J Neuropsychopharmacol. 2010;13:229–241.
  37. Bauer M, Pretorius HW, Constant EL, et al. Extended-release quetiapine as adjunct to an antidepressant in patients with major depressive disorder: results of a randomized, placebo-controlled, double-blind study. J Clin Psychiatry. 2009;70:540–549.
  38. Bortnick B, El-Khalili N, Banov M, et al. Efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) monotherapy in major depressive disorder: a placebo-controlled, randomized study. J Affect Disord. 2011;128:83–94.
  39. Cutler AJ, Montgomery SA, Feifel D, et al. Extended release quetiapine fumarate monotherapy in major depressive disorder: a placebo- and duloxetine- controlled study. J Clin Psychiatry. 2009;70:526–539.
  40. El-Khalili N, Joyce M, Atkinson S, et al. Extended-release quetiapine fumarate (quetiapine XR) as adjunctive therapy in major depressive disorder (MDD) in patients with an inadequate response to ongoing antidepressant treatment: a multicentre, randomized, double-blind, placebo-controlled study. Int J Neuropsychopharmacol. 2010;13:917–932.
  41. Weisler R, Joyce M, McGill L, et al. Extended release quetiapine fumarate monotherapy for major depressive disorder: results of a double-blind, randomized, placebo-controlled study. CNS Spectr. 2009;14:299–313.
  42. Purdon SE, Malla A, Labelle A, et al. Neuropsychological change in patients with schizophrenia after treatment with quetiapine or haloperidol. J Psychiatry Neurosci. 2001;26:137–149.
  43. Liebowitz M, Lam RW, Lepola U, et al. Efficacy and tolerability of extended release quetiapine fumarate monotherapy as maintenance treatment of major depressive disorder: a randomized, placebo-controlled trial. Depress Anxiety. 2010;27:964–976.
  44. Nyberg S, Widzowski D. Translational pharmacology of quetiapine and norquetiapine: preclinical findings support multifunctional psychotropic properties. Eur Psychiatry. 2010;25(suppl 1):1446.
  45. Jensen NH, Rodriguiz RM, Caron MG, et al. N-desalkylquetiapine, a potent norepinephrine reuptake inhibitor and partial 5-HT(1A) agonist, as a putative mediator of quetiapine’s antidepressant activity. Neuropsychopharmacology. 2008;33:2303–2312.
  46. Owens MJ, Krulewicz S, Simon JS, et al. Estimates of serotonin and norepinephrine transporter inhibition in depressed patients treated with paroxetine or venlafaxine. Neuropsychopharmacology. 2008;33:3201–3212.
  47. Arvanitis LA, Miller BG. Multiple fixed doses of “Seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The Seroquel Trial 13 Study Group. Biol Psychiatry. 1997;42:233–246.
  48. Kahn RS, Schulz SC, Palazov VD, et al. Efficacy and tolerability of once-daily extended release quetiapine fumarate in acute schizophrenia: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2007;68:832–842.
  49. Timdahl K, Carlsson A, Stening G. An analysis of safety and tolerability data from controlled comparative studies of quetiapine in patients with schizophrenia, focusing on extrapyramidal symptoms. Hum Psychopharmacol. 2007;22:315–325.

CORRESPONDENCE: Arifulla Khan, MD Department of Psychiatry and Behavioral Sciences Duke Medical Hospital Northwest Clinical Research Center 1951 152nd Place NE, Suite 200 Bellevue, WA 98007 USA E-MAIL: akhan@nwcrc.net