# Abstract

 

## Background Despite being present in up to 1% of the population, few controlled trials have examined the efficacy of treatments for bipolar II depression. Pooled data are presented from four placebo-controlled studies (BOLDER I [5077US/0049] and II [D1447C00135]; EMBOLDEN I [D1447C00001] and II [D1447C00134]) that evaluated the efficacy of quetiapine monotherapy for depressive episodes in patients with bipolar II disorder. 

## Methods All studies included an 8-week, double-blind treatment phase in which patients were randomly assigned to treatment with quetiapine 300 mg/day, quetiapine 600 mg/day, or placebo. Outcome measures included the change from baseline in MADRS total score at week 8, effect sizes, and MADRS response and remission rates. 

## Results and discussion Improvements in mean MADRS total scores from baseline to week 8 were significantly greater with quetiapine 300 and 600 mg/day (−15.58 \[*n* = 283\] and −14.88 \[*n* = 289\]; *p* \< 0.001) compared with placebo (−11.61 \[*n* = 204\]). The MADRS effect sizes were 0.44 for quetiapine 300 mg/day and 0.47 for 600 mg/day (*p* \< 0.001 vs placebo). Significantly higher proportions of patients receiving quetiapine, at both doses, than placebo-treated patients achieved response and remission at week 8 (*p* \< 0.01). Common adverse events associated with quetiapine (both doses) included dry mouth, somnolence, sedation, dizziness, and headache. Rates of mania and hypomania were similar for quetiapine and placebo. Quetiapine monotherapy demonstrated significant efficacy compared with placebo and was generally well tolerated in the treatment of bipolar II depression. # Results Patient disposition is shown in Figure [1](#). A total of 776 (35.2%) patients with bipolar II depression were included in the ITT population (283, 289, and 204 patients received quetiapine 300 mg/day, quetiapine 600 mg/day, or placebo, respectively). The safety population comprised 819 patients with bipolar II depression (298, 307, and 214 patients received quetiapine 300 mg/day, quetiapine 600 mg/day, or placebo, respectively), representing 35.4% of the total pooled safety population of patients with bipolar I or II depression from the four studies (*N* = 2,314). <figure> <p><img src="" /></p> <figcaption><strong>Patient disposition.</strong></figcaption> </figure> At baseline, the demographic and clinical characteristics were similar among treatment groups (Table [1](#)). The baseline symptom severity scores indicated a patient population with moderate to severe depression without mania symptoms. ::::table-wrap

::: caption
**Baseline demographic and clinical characteristics (safety
population)**
:::

```
                                 Quetiapine 300 mg/day ( ***n***  = 298)   Quetiapine 600 mg/day ( ***n***  = 307)   Placebo (***n*** = 214)
```

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Gender,%\
Male 36.9 39.7 37.4
Female 63.1 60.3 62.6
Age, mean (years) 38.4 39.4 37.7
Weight, mean (kg) 79.7 80.1 78.9
BMI, mean 28.0 28.0 27.8
Symptom rating, mean total score\
MADRS 27.8 27.5 28.0
HAM-D 24.2 24.0 24.2
YMRS 4.5 4.5 5.0
HAM-A 19.2 18.6 19.1:::: 

## Primary efficacy outcome: Montgomery-Åsberg depression rating scale total score Among patients with bipolar II disorder, treatment with quetiapine resulted in significantly greater improvements in depression symptoms compared with placebo, as measured by mean change in MADRS total score from baseline to week 8 (mean [SE] −15.58 [0.62] and −14.88 [0.62] for quetiapine 300 and 600 mg/day, respectively, vs−11.61 [0.70] for placebo; LOCF; *p* \< 0.001, both doses). Significant separation from placebo was observed from week 1 for both doses of quetiapine and was maintained through week 8 (Figure [2](#)). Effect sizes, based on MADRS scores, were moderate for both quetiapine 300 and 600 mg/day (MMRM: 0.44 and 0.47, respectively, *p* \< 0.001 vs placebo; Figure [3](#)). The effect sizes in the bipolar I population in the four trials were 0.58 for quetiapine 300 mg/day and 0.64 for quetiapine 600 mg/day (Figure [3](#)). <figure> <p><img src="" /></p> <figcaption><strong>Mean change from baseline to week 8 in MADRS total score (ITT population; LOCF).</strong></figcaption> </figure> <figure> <p><img src="" /></p> <figcaption><strong>Effect sizes of quetiapine 300 and 600 mg/day in patients with bipolar I or bipolar II disorder.</strong></figcaption> </figure> Patients with bipolar II disorder stratified by a rapid- (≥4 mood episodes per year) or nonrapid-cycling course also demonstrated significant improvements in MADRS total score at week 8. Among patients without a rapid-cycling course, MADRS total score improved significantly by a mean (SE) of 15.18 (0.67) and 14.25 (0.66) with quetiapine 300 and 600 mg/day compared with 11.58 (0.75) points for placebo (*p* \< 0.001 and *p* = 0.005 for quetiapine 300 and 600 mg/day, respectively) at week 8. Significant symptomatic improvements at week 8 were also observed in patients with rapid cycling: 16.80 (1.63) and 16.92 (1.71) for quetiapine 300 and 600 mg/day versus 11.12 (1.95) for placebo (*p* = 0.011 and *p* = 0.012, respectively). In the exploratory analysis of the relationship between MADRS total score at baseline and end of treatment, there was an indication that the difference between placebo and both quetiapine doses at end of treatment increased as baseline score increased (Table [2](#); Figure [4](#)). However, given the *post hoc* and exploratory nature of this analysis where the studies were not designed for this purpose, no formal inference can be made. ::::table-wrap
::: caption
**Relationship between MADRS total score at baseline and of treatment
(ITT) (ANCOVA with baseline score as covariate and treatment as fixed
effect)**
:::

Treatment Dependent variable Fixed factor Estimate Degrees of freedom ***t*** value ***p*** value

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Quetiapine 300 mg/day MADRS at end of treatment Intercept −0.242 281 −0.11 0.9119
MADRS at baseline 0.445 281 5.86 \<0.0001
Quetiapine 600 mg/day MADRS at end of treatment Intercept 1.127 287 0.53 0.5998
MADRS at baseline 0.423 287 5.59 \<0.0001
Placebo MADRS at end of treatment Intercept −4.302 202 −1.26 0.2086
MADRS at baseline 0.741 202 6.23 \<0.0001:::: <figure> <p><img src="" /></p> <figcaption><strong>Relationship between MADRS total score at baseline and of treatment (ITT).</strong></figcaption> </figure> 

## Secondary efficacy outcomes 

### MADRS item analyses Following 8 weeks of treatment, quetiapine at doses of 300 and 600 mg/day was associated with significant improvements in the majority of the individual MADRS items when compared with placebo (*p* \< 0.05 vs placebo, Figure [5](#)), with the exceptions of apparent sadness for quetiapine 300 mg/day, and concentration difficulties and lassitude for 600 mg/day. From week 4 onward, there were significantly greater improvements in MADRS Item 10 (suicidal thoughts) scores with both doses of quetiapine (*p* \< 0.05 vs placebo). <figure> <p><img src="" /></p> <figcaption><strong>Difference in mean change from baseline in MADRS individual item scores at week 8 (ITT population; LOCF).</strong></figcaption> </figure> 

### MADRS response and remission By week 8, significantly higher proportions of patients treated with quetiapine 300 and 600 mg/day had achieved response and remission when compared with placebo. Among quetiapine-treated patients, 64.7% (300 mg/day) and 62.6% (600 mg/day) were classified as responders at week 8 compared with 49.0% of placebo-treated patients (*p* \< 0.001 and *p* \< 0.01 for 300 and 600 mg/day, respectively; ITT, LOCF). When compared with placebo (46.1%), significantly more quetiapine-treated patients met remission criteria at week 8 (65.0% and 61.9%, respectively; *p* \< 0.001 vs placebo; ITT, LOCF). At week 8, NNT for response and remission were 6 and 5 for quetiapine 300 mg/day and 7 and 6 for quetiapine 600 mg/day, respectively. 

### Hamilton rating scale for depression total score Patients who were treated with quetiapine 300 and 600 mg/day demonstrated significantly greater improvements in HAM-D total score from week 1 through week 8 compared with placebo (*p* \< 0.001; ITT, LOCF). At week 8, HAM-D total scores improved by a mean (SE) of 14.00 (0.49) and 13.57 (0.49) points for quetiapine 300 and 600 mg/day, respectively, versus 10.88 (0.55) for placebo (*p* \< 0.001). 

### Hamilton rating scale for anxiety total score Following quetiapine treatment, patients demonstrated significant improvements in symptoms of anxiety, as measured by mean change from baseline in HAM-A total score at week 8 (*p* \< 0.05 both doses vs placebo; Figure [6](#)). Significant improvements in HAM-A total score with quetiapine 300 and 600 mg/day versus placebo were observed from week 1 onward (−9.62 \[*p* \< 0.001\] and −8.89 \[*p* \< 0.05\] vs −7.34 at week 8, respectively; ITT, LOCF). <figure> <p><img src="" /></p> <figcaption><strong>Mean change from baseline to week 8 in HAM-A total score (ITT population; LOCF).</strong></figcaption> </figure> 

### Safety Overall rates of adverse events in the pooled safety population were 73.8%, 74.3%, and 67.8% for the quetiapine 300 mg/day, 600 mg/day, and placebo arms, respectively. As shown in Table [3](#), common adverse events associated with quetiapine 300 and 600 mg/day included dry mouth, somnolence, sedation, and dizziness. Adverse events potentially related to extrapyramidal symptoms were observed in 12.4%, 8.8%, and 6.1% of the quetiapine 300 mg/day, quetiapine 600 mg/day, and placebo groups, respectively. Rates of treatment-emergent mania/hypomania during acute treatment were similar among the treatment groups: 1.3%, 3.3%, and 2.3% for quetiapine 300 mg/day, 600 mg/day, and placebo arms, respectively. Rates of discontinuation because of adverse events were 12.1% for quetiapine 300 mg/day, 17.9% for quetiapine 600 mg/day, and 5.1% for placebo. Changes from baseline in weight and laboratory parameters during acute treatment are presented in Table [4](#). Although average weight gain was only about 1 kg greater in the two groups receiving quetiapine, the proportions of patients in both arms gaining at least 7% body weight was higher in both quetiapine arms (Table [4](#)). ::::table-wrap
::: caption
**Common adverse events (≥5**% **of patients in any group; safety
population)**
:::

Adverse event, ***N*** (%) Quetiapine 300 mg/day (***n*** = 298) Quetiapine 600 mg/day (***n*** = 307) Placebo (***n*** = 214)

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Dry mouth 94 (31.5) 90 (29.3) 21 (9.8)
Somnolence 65 (21.8) 60 (19.5) 18 (8.4)
Sedation 60 (20.1) 59 (19.2) 12 (5.6)
Dizziness 39 (13.1) 48 (15.6) 12 (5.6)
Headache 27 (9.1) 37 (12.1) 40 (18.7)
Fatigue 26 (8.7) 30 (9.8) 14 (6.5)
Constipation 24 (8.1) 24 (7.8) 9 (4.2)
Nausea 23 (7.7) 22 (7.2) 21 (9.8)
Diarrhea 12 (4.0) 8 (2.6) 17 (7.9)
Insomnia 8 (2.7) 2 (0.7) 14 (6.5)
Upper respiratory tract infection 7 (2.3) 7 (2.3) 11 (5.1):::: ::::table-wrap
::: caption
**Weight, glucose, and lipid data (all samples; safety population)**
:::

Mean change from randomization (SD)^a^ Quetiapine 300 mg/day (***n*** = 298) Quetiapine 600 mg/day (***n*** = 307) Placebo (***n*** = 214)

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Total cholesterol (mg/dL) −2.3 (2.1) 0.8 (2.0) −3.5 (2.5)
LDL cholesterol (mg/dL) −5.3 (1.7) −0.3 (1.7) −4.4 (1.9)
HDL cholesterol (mg/dL) −0.5 (0.6) −1.6 (0.6) −1.0 (0.7)
Triglycerides (mg/dL) 21.4 (5.9) 14.2 (4.9) 9.0 (7.4)
Glucose (mg/dL) 3.3 (1.0) 2.8 (0.9) 1.8 (1.1)
Insulin (pmol/L) 31.0 (8.4) 24.2 (6.1) 12.5 (8.5)
Mean weight change, kg (SE) 1.0 (0.19) 1.1 (0.23) 0.0 (0.17)
Weight change ≥7%, *n* (%) 17 (6.5) 24 (9.7) 4 (2.2)

^a^Mean change from randomization to continuation phase to the end of
treatment.::::


Extracted trial result:
Outcome: improvement of disorder (continuous)
Intervention: quetiapine 300 mg/day
Comparator: placebo
Intervention group size: 283
Intervention mean: -15.58
Intervention standard deviation: 10.43
Comparator group size: 204
Comparator mean: -11.61
Comparator standard deviation: 10.12
Notes: Back calculated SD from SE.