Effect of adjunctive aripiprazole in achieving various

levels of response and on domains of functioning in MDD:

A pooled analysis (CN138-139; CN138-163; CN138-165)
Rossella Gismondi, MD1; Zachary J. Cain, PharmD2; Tanya J. Fabian, PharmD, PhD3; Linda M. Rollin, PhD4; Robert A. Forbes, PhD5;
Robert M. Berman, MD4; Ross A. Baker, PhD2; Daniel E. Casey, MD6; Kimberly Laubmeier, PhD2; Sabrina Vogel Marler, MS4; Jean-Yves Loze, MD, MSc7
Bristol-Myers Squibb, Rome, Italy; 2Bristol-Myers Squibb, Plainsboro, NJ, USA; 3Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA; 4Bristol-Myers Squibb, Wallingford, CT, USA;
5
Otsuka Pharmaceutical Development and Commercialization Inc., Princeton, NJ, USA; 6Oregon Health & Science University, Portland, OR, USA; 7Otsuka Pharmaceutical, Paris, France

Abstract

Patients and methods

Results

Introduction: Patients with major depressive disorder (MDD) experience different

levels of treatment response as well as varying degrees of functional impairment.

Figure 1. Study design

Overall, 81% of patients in the randomised population reported experiencing

moderate-to-severe functional impairments at baseline (Week 8) according to
mean SDS scores

Phase A
Screening phase

Objectives: To evaluate: 1) the level of response achieved after 6 weeks of therapy,

as assessed by changes in Montgomerysberg Rating Depression Scale (MADRS)
Total score, in patients receiving adjunctive aripiprazole therapy, and 2) the effect of
adjunctive aripiprazole therapy on patient functioning.

Adjunctive Placebo

Adjunctive Aripiprazole
p-value

Mean Change

Mean Change

Mean Score

492

0.7

507

1.2

<0.001

Social Domain

494

0.7

508

1.4

<0.001

Family Domain

494

0.7

508

1.4

<0.001

Work/School Domain

392

0.6

384

0.8

0.337

Conclusions: Most inadequate responders who continued on placebo were minimal

responders (60%). In contrast, 60% of aripiprazole patients rapidly achieved partial,
moderate or robust response status. Adjunctive aripiprazole therapy also signicantly
improved overall functioning, and the social and family life domains of functioning.

Phase B
Prospective treatment phase

Assigned ADT* +
single-blind
placebo (8 weeks)

Screening
(728 days)

Depressive symptoms often result in social isolation, marital problems and impaired
occupational functioning, thereby underscoring the need for assessment of functional
status2
To assess the onset of treatment efcacy, it is important to determine a priori how
efcacy is going to be dened and measured3
A common criterion for response to antidepressant therapy (ADT) is a 50% reduction
in severity scale scores from baseline3
In studies of patients treated with adjunctive aripiprazole to ADT for the treatment of
MDD, Sheehan Disability Scale (SDS) total and item scores were improved signicantly
more in patients in remission versus those with a response but without remission
(p<0.02) as well as non-response (p<0.001)4
The current post-hoc analysis is based on data from three similar 6-week, double-blind,
placebo-controlled MDD trials assessing the efcacy of adjunctive aripiprazole to ADT
compared with adjunctive placebo57
Response was evaluated as quartile reductions in Montgomerysberg Depression
Rating Scale (MADRS) Total score as minimal (25%), partial (>25% to <50%),
moderate (50% to <75%) and robust response (75%)
Mean changes from baseline to endpoint in functional impairment were assessed by
changes in domain scores in the SDS

Objective

Patients and methods

Pooled data were analysed from three methodologically similar, randomised,
double-blind, placebo-controlled trials of aripiprazole for the treatment of MDD
(Figure1)57

Changes from baseline to endpoint in mean SDS scores and domain scores, as
well as mean changes in MADRS Total score by study week, were compared
using analysis of covariance between patients randomised to receive adjunctive
aripiprazole or adjunctive placebo

Work/school
4.8

4.8

n=392 n=384

Social life

Family life

Mean score

5.8

5.7

5.5

5.7

n=494 n=508

5.6

n=494 n=508

5.4

n=492 n=507

0.4

87.2% of patients receiving adjunctive placebo and 85.3% receiving adjunctive

aripiprazole completed the randomised phase (Table 1)
The most common reasons for discontinuation in patients receiving adjunctive
aripiprazole were adverse event (4.4%) and withdrawal of consent (2.5%)
Baseline demographic characteristics were similar between patients receiving
adjunctive aripiprazole and adjunctive placebo (Table 2)
Table 1. Patient disposition, randomized sample

0.6

0.6
0.7

0.8

0.7

0.7

0.8
1.0
1.2

1.2
***

Number of patients (%)

Placebo

Aripiprazole*

540

550

69 (12.8)

81 (14.7)

Lack of efcacy

8 (1.5)

8 (1.5)

Adverse event

9 (1.7)

24 (4.4)

Subject withdrew consent

20 (3.7)

14 (2.5)

Lost to follow-up

13 (2.4)

13 (2.4)

Poor/non-compliance

7 (1.3)

7 (1.3)

Subject no longer meets study criteria

9 (1.7)

13 (2.4)

Other

3 (0.6)

2 (0.4)

471 (87.2)

469 (85.3)

Completed Phase C
*Two patients were randomised to aripiprazole in error

Table 2. Baseline demographics, pooled randomised sample

Mean age, years (SD)

Gender, % female

Placebo
n=540

Aripiprazole
n=552

44.7 (10.9)

45.4 (10.8)

66.5

68.5

1.4
PBO+ADT
1.6

ARI+ADT

White

1.4
***

1.4
***

***p<0.001 vs placebo
ADT = antidepressant therapy; ARI aripiprazole; LOCF = last observation carried forward; PBO = placebo

Akathisia (22.7%) and restlessness (12.4%) were the most common treatmentemergent adverse events (TEAEs) in the adjunctive aripiprazole group (Table 3)
Overall, 4.4% of patients randomised to adjunctive aripiprazole and 1.7% of
patients randomised to adjunctive placebo discontinued the study due to an
adverse event
The most common TEAEs leading to discontinuation in the adjunctive
aripiprazole group were akathisia (1.3%) and fatigue (0.7%)
Table 3. Treatment-emergent adverse events (>5% and twice the rate of
placebo), pooled safety sample

Race, n (%)

Placebo+ADT
(n=538)
n (%)

Aripiprazole+ADT
(n=547)
n (%)

483 (89.4)

486 (88.0)

Black/African American

42 (7.8)

43 (7.8)

Asian

6 (1.1)

9 (1.6)

Akathisia

22 (4.1)

124 (22.7)

American Indian/Alaska Native

2 (0.4)

2 (0.4)

Restlessness

12 (2.2)

68 (12.4)

3 (0.5)

Fatigue

23 (4.3)

47 (8.6)

7 (1.3)

9 (1.6)

Insomnia

17 (3.2)

45 (8.2)

18.8 (1.6678.8)

18.8 (1.7474.1)

Blurred vision

8 (1.5)

34 (6.2)

Somnolence

14 (2.6)

32 (5.9)

Native Hawaiian/Other Pacic Islander

Other
Median duration of current episode, months (range)
Previous ADT trials in current episode, n (%)
0

5 (0.9)

3 (0.5)

363 (67.3)

385 (69.9)

142 (26.3)

132 (24.0)

27 (5.0)

30 (5.4)

2 (0.4)

1 (0.2)

79.8

82.1

ADT = antidepressant therapy; SD = standard deviation

Adjunctive aripiprazole treatment was associated with a signicantly greater

proportion of patients achieving a partial response (23.9% vs 17.9%, p=0.017),
moderate response (23.1% vs 15.0%, p<0.001) and robust response (14.3%
vs 7.4%, p<0.001) compared with adjunctive placebo (Figure 2)
Conversely, adjunctive placebo treatment was associated with a signicantly
greater proportion of patients achieving a minimal response compared with
adjunctive aripiprazole (59.6% vs 38.7%, p<0.001)

59.6

PBO+ADT (n=525)
ARI+ADT (n=540)

Pooled data from three similarly designed studies of patients with an inadequate
response to ADT showed that adjunctive aripiprazole signicantly increased
the number of patients with partial, moderate or robust responses compared to
adjunctive placebo
Patients who failed to achieve an adequate response with ADT monotherapy
experienced marked overall functional impairment, particularly in social and family
relationships

Further research is needed to assess how:

Different levels of symptomatic improvement correspond to changes in the
severity of functional impairment

50

40

Conclusions

Although previous studies did not show a correlation between efcacy (as
assessed by the Hamilton Rating Scale for Depression scores) and functioning,4
those studies did not assess how varying levels of response correlate with
functional improvements

70

60

ADT = antidepressant therapy

Adjunctive aripiprazole signicantly improved mean SDS total score and social and
family life domain scores compared with adjunctive placebo

Figure 2. MADRS responder quartile analysis

Improvements in symptoms correspond to functional improvements over time

***
38.7

Pronounced responses, both in terms of symptomatic burden and functional

capacity, are necessary for patients to return to pre-morbid status; this also
warrants continued research

30

*
23.9

20

***
23.1

17.9

***
14.3

15.0
10

7.4

References
1. Pratt LA, et al. National Center for Health Statistics, 2008.
2. Sheehan KH, et al. Int Clin Psychopharmacol. 2008;23:7083.

0
Minimal
response

Partial
response

Moderate
response

Robust
response

*p<0.05, ***p<0.001, p-values are for aripiprazole vs. placebo comparisons

ADT = antidepressant therapy; ARI = aripiprazole; MADRS = Montgomerysberg Depression Rating Scale; PBO = placebo
Response Quartiles on MADRS: minimal (25%), partial (>25% to <50%), moderate ( 50% to <75%), robust (75%)

European Psychiatric Association, 19th European Congress of Psychiatry, 1215 March, 2011, Vienna, Austria.

7711672_vienna_posters2.indd 1

Results

Percent of patients

Patient functioning was assessed from baseline to endpoint using the SDS scale,
which assesses functional impairment in three domains: social life, family life, and
work/school responsibilities4
Each item is scored on a severity scale of 010, with 03 indicating not at all to
mildly impaired, 46 moderately impaired, and 710 markedly to extremely
impaired
Mean SDS scores were calculated as an average of the three individual items
(two items for patients not currently working or enrolled in school)
Mean and individual domain SDS scores were retrospectively categorised
at baseline and endpoint as mild (03), moderate (46), or severe (710)
functional impairment

14

Baseline
score:

0.2

Quartile response categories were dened based on percent reduction in MADRS

Total score from baseline to endpoint:
Minimal response (25%)
Partial response (>25% to <50%)
Moderate response (50% to <75%)
Robust response (75%)
The proportion of adjunctive placebo-treated versus adjunctive aripiprazole-treated
patients achieving a response was compared for each quartile response category
using the CochranMantelHaenszel test

Single-blind placebo + ADT

(6 weeks)

ADT = antidepressant therapy; CR = controlled release; XR = extended release; *Investigator choice

Recurrent episode (%)

To evaluate in patients receiving adjunctive aripiprazole for the treatment of MDD:

(a) the level of response achieved after 6 weeks of therapy, as assessed by
changes in MADRS Total score; and (b) the effect of adjunctive aripiprazole on
patient functioning

Figure 3. Mean change in Sheehan Disability Scale Mean score and item
scores, pooled efcacy sample (LOCF)

Discontinued treatment

Approximately 80% of people with major depressive disorder (MDD) report some level
of functional impairment and 27% report serious difculties in work and home life1

Responders: Phase B+
(Not randomised)

Escitalopram 10 or 20 mg/day
Fluoxetine 20 or 40 mg/day
Paroxetine CR 37.5 or 50 mg/day
Sertraline 100 or 150 mg/day
Venlafaxine XR 150 or 225 mg/day

Week

There was no statistically signicant difference between adjunctive aripiprazole

and adjunctive placebo in mean change from baseline to endpoint for the work/
school domain of the SDS scale

Placebo + ADT
(6 weeks)

Randomised and completed Phase B

Introduction

Adjunctive aripiprazole treatment produced signicant improvements in mean SDS

score and in social and family life domains of the SDS compared with adjunctive
placebo (p<0.001) (Figure 3)

Aripiprazole + ADT
(6 weeks)

Methods: Data were pooled from three similar, randomised, double-blind, placebocontrolled trials with aripiprazole in MDD. Quartile response categories were dened
by reduction (%) in MADRS after 6 weeks of treatment: minimal response (25%),
partial response (>25% to <50%), moderate response (50% to <75%) and robust
response (75%). The proportion of adjunctive placebo vs. adjunctive aripiprazole
patients achieving a response was compared (CochranMantelHaenszel test)
for each category. Functionality was assessed using mean changes in Sheehan
Disability Scale (SDS) scores. Changes in scores were compared (ANCOVA)
between adjunctive aripiprazole and adjunctive placebo patients.
Results: Adjunctive aripiprazole treatment had signicantly more patients (%)
compared with placebo, achieving partial (23.9% vs 17.9%, p=0.017), moderate
(23.1% vs 15.0%, p<0.001) and robust responses (14.3% vs 7.4%, p<0.001).
Adjunctive aripiprazole therapy resulted in signicantly less patients (%) achieving
minimal response compared with placebo (38.7% vs 59.6%, p<0.001). Mean
changes in SDS mean and domain scores are shown in the table below.

Non-Responders
Phase C
Randomised, double-blind
treatment phase

Mean change from baseline

3. Gelenberg AJ, et al. J Clin Psychiatry. 2000;61:71221.

4. Trivedi M, et al. Int Clin Psychopharmacol. 2009;24:1338.
5. Berman RM, et al. J Clin Psychiatry. 2007;68:84353.
6. Marcus RN, et al. J Clin Psychopharmacol. 2008;28:15665.
7. Berman R, et al. CNS Spectrums. 2009;14:197206.

Supported by funding from Bristol-Myers Squibb and Otsuka Pharmaceutical Co. Ltd.

07/03/2011 10:47