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) 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, MD 1 ; Zachary J. Cain, PharmD 2 ; Tanya J. Fabian, PharmD, PhD 3 ; Linda M. Rollin, PhD 4 ; Robert A. Forbes, PhD 5 ; Robert M. Berman, MD 4 ; Ross A. Baker, PhD 2 ; Daniel E. Casey, MD 6 ; Kimberly Laubmeier, PhD 2 ; Sabrina Vogel Marler, MS 4 ; Jean-Yves Loze, MD, MSc 7 1 Bristol-Myers Squibb, Rome, Italy; 2 Bristol-Myers Squibb, Plainsboro, NJ, USA; 3 Western Psychiatric Institute and Clinic, Pittsburgh, PA, USA; 4 Bristol-Myers Squibb, Wallingford, CT, USA; 5 Otsuka Pharmaceutical Development and Commercialization Inc., Princeton, NJ, USA; 6 Oregon Health & Science University, Portland, OR, USA; 7 Otsuka Pharmaceutical, Paris, France Abstract Introduction: Patients with major depressive disorder (MDD) experience different levels of treatment response as well as varying degrees of functional impairment. Objectives: To evaluate: 1) the level of response achieved after 6 weeks of therapy, as assessed by changes in Montgomery–Åsberg Rating Depression Scale (MADRS) Total score, in patients receiving adjunctive aripiprazole therapy, and 2) the effect of adjunctive aripiprazole therapy on patient functioning. Methods: Data were pooled from three similar, randomised, double-blind, placebo- controlled trials with aripiprazole in MDD. Quartile response categories were defined 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 (Cochran–Mantel–Haenszel 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 significantly 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 significantly 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. Adjunctive Placebo Adjunctive Aripiprazole p-value N Mean Change N 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 significantly improved overall functioning, and the social and family life domains of functioning. Introduction • Approximately 80% of people with major depressive disorder (MDD) report some level of functional impairment and 27% report serious difficulties in work and home life 1 • Depressive symptoms often result in social isolation, marital problems and impaired occupational functioning, thereby underscoring the need for assessment of functional status 2 • To assess the onset of treatment efficacy, it is important to determine a priori how efficacy is going to be defined and measured 3 • A common criterion for response to antidepressant therapy (ADT) is a ≥50% reduction in severity scale scores from baseline 3 • 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 significantly 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 efficacy of adjunctive aripiprazole to ADT compared with adjunctive placebo 5–7 • Response was evaluated as quartile reductions in Montgomery–Åsberg 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 • 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 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) 5–7 • Quartile response categories were defined 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 Cochran–Mantel–Haenszel test • 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 responsibilities 4 – Each item is scored on a severity scale of 0–10, with 0–3 indicating not at all to mildly impaired, 4–6 moderately impaired, and 7–10 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 (0–3), moderate (4–6), or severe (7–10) functional impairment • 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 European Psychiatric Association, 19th European Congress of Psychiatry, 12–15 March, 2011, Vienna, Austria. Supported by funding from Bristol-Myers Squibb and Otsuka Pharmaceutical Co. Ltd. Patients and methods Figure 1. Study design • 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 Number of patients (%) Placebo Aripiprazole* Randomised and completed Phase B 540 550 Discontinued treatment 69 (12.8) 81 (14.7) Lack of efficacy 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) Completed Phase C 471 (87.2) 469 (85.3) *Two patients were randomised to aripiprazole in error Table 2. Baseline demographics, pooled randomised sample Placebo n=540 Aripiprazole n=552 Mean age, years (SD) 44.7 (10.9) 45.4 (10.8) Gender, % female 66.5 68.5 Race, n (%) White 483 (89.4) 486 (88.0) Black/African American 42 (7.8) 43 (7.8) Asian 6 (1.1) 9 (1.6) American Indian/Alaska Native 2 (0.4) 2 (0.4) Native Hawaiian/Other Pacific Islander 0 3 (0.5) Other 7 (1.3) 9 (1.6) Median duration of current episode, months (range) 18.8 (1.6–678.8) 18.8 (1.7–474.1) Previous ADT trials in current episode, n (%) 0 5 (0.9) 3 (0.5) 1 363 (67.3) 385 (69.9) 2 142 (26.3) 132 (24.0) 3 27 (5.0) 30 (5.4) ≥4 2 (0.4) 1 (0.2) Recurrent episode (%) 79.8 82.1 ADT = antidepressant therapy; SD = standard deviation • Adjunctive aripiprazole treatment was associated with a significantly 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 significantly greater proportion of patients achieving a minimal response compared with adjunctive aripiprazole (59.6% vs 38.7%, p<0.001) Figure 2. MADRS responder quartile analysis Results • Overall, 81% of patients in the randomised population reported experiencing moderate-to-severe functional impairments at baseline (Week 8) according to mean SDS scores • Adjunctive aripiprazole treatment produced significant improvements in mean SDS score and in social and family life domains of the SDS compared with adjunctive placebo (p<0.001) (Figure 3) • There was no statistically significant difference between adjunctive aripiprazole and adjunctive placebo in mean change from baseline to endpoint for the work/ school domain of the SDS scale Figure 3. Mean change in Sheehan Disability Scale Mean score and item scores, pooled efficacy sample (LOCF) • Akathisia (22.7%) and restlessness (12.4%) were the most common treatment- emergent 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 Placebo+ADT (n=538) n (%) Aripiprazole+ADT (n=547) n (%) Akathisia 22 (4.1) 124 (22.7) Restlessness 12 (2.2) 68 (12.4) Fatigue 23 (4.3) 47 (8.6) Insomnia 17 (3.2) 45 (8.2) Blurred vision 8 (1.5) 34 (6.2) Somnolence 14 (2.6) 32 (5.9) ADT = antidepressant therapy 1. Pratt LA, et al. National Center for Health Statistics, 2008. 2. Sheehan KH, et al. Int Clin Psychopharmacol. 2008;23:70–83. 3. Gelenberg AJ, et al. J Clin Psychiatry. 2000;61:712–21. 4. Trivedi M, et al. Int Clin Psychopharmacol. 2009;24:133–8. 5. Berman RM, et al. J Clin Psychiatry. 2007;68:843–53. 6. Marcus RN, et al. J Clin Psychopharmacol. 2008;28:156–65. 7. Berman R, et al. CNS Spectrums. 2009;14:197–206. References Conclusions • Pooled data from three similarly designed studies of patients with an inadequate response to ADT showed that adjunctive aripiprazole significantly 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 • Adjunctive aripiprazole significantly improved mean SDS total score and social and family life domain scores compared with adjunctive placebo • Although previous studies did not show a correlation between efficacy (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 • Further research is needed to assess how: – Different levels of symptomatic improvement correspond to changes in the severity of functional impairment – Improvements in symptoms correspond to functional improvements over time – 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 Phase A Screening phase Phase B Prospective treatment phase Non-Responders Phase C Randomised, double-blind treatment phase Responders: Phase B+ (Not randomised) Week 0 8 14 Screening (7–28 days) Assigned ADT* + single-blind placebo (8 weeks) Aripiprazole + ADT (6 weeks) Single-blind placebo + ADT (6 weeks) Placebo + ADT (6 weeks) ADT = antidepressant therapy; CR = controlled release; XR = extended release; *Investigator choice 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 *p<0.05, ***p<0.001, p-values are for aripiprazole vs. placebo comparisons ADT = antidepressant therapy; ARI = aripiprazole; MADRS = Montgomery–Åsberg Depression Rating Scale; PBO = placebo Response Quartiles on MADRS: minimal (≤25%), partial (>25% to <50%), moderate ( ≥50% to <75%), robust (≥75%) 0 60 50 40 30 20 10 70 Percent of patients PBO+ADT (n=525) 59.6 *** 38.7 ARI+ADT (n=540) Moderate response Partial response Minimal response Robust response * 23.9 17.9 15.0 *** 23.1 *** 14.3 7.4 ADT = antidepressant therapy; ARI aripiprazole; LOCF = last observation carried forward; PBO = placebo –1.6 ***p<0.001 vs placebo –0.2 –0.4 –0.6 –0.8 –1.0 –1.2 –1.4 0 Mean change from baseline PBO+ADT 4.8 4.8 ARI+ADT Family life Social life Work/school Baseline score: Mean score 5.7 5.8 5.7 5.6 5.4 5.5 n=392 n=384 n=508 n=494 n=494 n=508 n=507 n=492 –0.6 –0.8 –1.4 *** –0.7 –0.7 –1.4 *** –1.2 *** –0.7 Results 7711672_vienna_posters2.indd 1 07/03/2011 10:47
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)
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
1Bristol-Myers Squibb, Rome, Italy; 2Bristol-Myers Squibb,
Plainsboro, NJ, USA; 3Western Psychiatric Institute and Clinic,
Pittsburgh, PA, USA; 4Bristol-Myers Squibb, Wallingford, CT, USA;
5Otsuka Pharmaceutical Development and Commercialization Inc.,
Princeton, NJ, USA; 6Oregon Health & Science University,
Portland, OR, USA; 7Otsuka Pharmaceutical, Paris, France
AbstractIntroduction: Patients with major depressive disorder
(MDD) experience different levels of treatment response as well as
varying degrees of functional impairment.
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.
Methods: Data were pooled from three similar, randomised,
double-blind, placebo-controlled trials with aripiprazole in MDD.
Quartile response categories were de ned by reduction (%) in MADRS
after 6 weeks of treatment: minimal response (25%), partial
response (>25% to
