Efficacy and safety of flexibly dosed brexpiprazole for the adjunctive treatment of major depressive disorder: a randomized, active-referenced, placebo-controlled study

Figures & data

Figure 1. Study design: (A) Blinded study design (as provided in the protocol for the investigators). (B) Unblinded study design (as per IVRS/IWRS design). From the start of prospective treatment, patients visited the study center at weekly intervals for the first 4 weeks and then every 2 weeks for the remainder of the 18-week treatment period. Abbreviations. ADT, antidepressant treatment; CR, controlled-release; IVRS/IWRS, interactive voice/web response system; XR, extended-release.

Figure 2. Patient disposition. Abbreviations. ADT, antidepressant treatment; XR, extended-release.

Table 1. Baseline demographic and clinical characteristics, and assigned antidepressant treatment (randomized population).

Variable	ADT + placebo (n = 206)	ADT + brexpiprazole 2–3 mg (n = 197)	ADT + quetiapine XR 150–300 mg (n = 100)
Demographic characteristics
Age (years), mean (SD)^a	41.8 (11.7)	43.6 (11.5)	44.6 (11.6)
Body mass index (kg/m^2), mean (SD)^b	27.9 (6.9)	27.9 (5.9)	28.0 (7.3)
Female, n (%)	149 (72.3)	128 (65.0)	66 (66.0)
White, n (%)	186 (90.3)	178 (90.4)	90 (90.0)
Clinical characteristics
Duration of current episode (months), mean (SD)^a	11.7 (14.6)	12.3 (19.0)	14.3 (19.1)
Recurrent episode, n (%)	176 (85.4)	169 (85.8)	81 (81.0)
Number of lifetime episodes, mean (SD)	3.2 (2.0)	3.3 (2.6)	3.2 (3.2)
Number of prior ADT failures, n (%)^c
1	171 (83.0)	168 (85.3)	82 (82.0)
2	28 (13.6)	26 (13.2)	16 (16.0)
3	5 (2.4)	3 (1.5)	2 (2.0)
4	1 (0.5)	0 (0.0)	0 (0.0)
MADRS total score, mean (SD)^b	25.4 (5.2)	25.4 (5.1)	25.6 (5.5)
SDS mean score, mean (SD)^b	5.7 (1.9)	5.6 (1.7)	5.6 (2.0)
CGI-S score, mean (SD)^b	4.0 (0.6)	4.0 (0.6)	4.1 (0.6)
Assigned antidepressant treatment, n (%)^d
Escitalopram	38 (18.4)	47 (23.9)	17 (17.0)
Fluoxetine	25 (12.1)	35 (17.8)	13 (13.0)
Paroxetine CR	28 (13.6)	22 (11.2)	19 (19.0)
Sertraline	27 (13.1)	32 (16.2)	17 (17.0)
Duloxetine	47 (22.8)	38 (19.3)	18 (18.0)
Venlafaxine XR	41 (19.9)	23 (11.7)	16 (16.0)

^aAt the start of prospective treatment.

^bAt baseline (randomization).

^cData missing for one patient in the ADT + placebo group.

^dInvestigators were asked to distribute the ADTs evenly, and no more than two of every six patients at each center were to be assigned to the same ADT without approval by the medical monitor.

Abbreviations. ADT, antidepressant treatment; CGI-S, Clinical Global Impressions–Severity of illness; CR, controlled-release; MADRS, Montgomery–Åsberg Depression Rating Scale; SD, standard deviation; SDS, Sheehan Disability Scale; XR, extended-release.

Figure 3. Effects of brexpiprazole, placebo, and quetiapine XR as adjunct to antidepressant treatment on Montgomery–Åsberg Depression Rating Scale (MADRS) total score (efficacy population). *p < .05, **p < .01, ***p < .001 vs placebo. Baseline MADRS total scores: ADT + placebo = 25.4; ADT + brexpiprazole = 25.3; ADT + quetiapine XR = 25.6. Abbreviations. ADT, antidepressant treatment; LS, least squares; SE, standard error; XR, extended-release.

Table 2. Effects of brexpiprazole, placebo, and quetiapine XR as adjunct to antidepressant treatment on efficacy endpoints at week 6 (efficacy population).

Variable	ADT + placebo (n = 205)	ADT + brexpiprazole 2–3 mg (n = 191)			ADT + quetiapine XR 150–300 mg (n = 99)
	LS mean (SE) change from baseline	LS mean (SE) change from baseline	Difference from ADT + placebo		LS mean (SE) change from baseline	Difference from ADT + placebo
			LS mean (95% CI)	p-value		LS mean (95% CI)	p-value
MADRS total	−4.6 (0.4)	−6.0 (0.4)	−1.48 (−2.56, −0.39)	.0078^a	−4.9 (0.6)	−0.30 (−1.63, 1.04)	.66
SDS mean	−0.7 (0.1)	−1.0 (0.1)	−0.23 (−0.52, 0.07)	.13	−0.3 (0.2)	0.42 (0.06, 0.78)	.024^b
SDS work/studies	−0.7 (0.2) (n = 136)	−0.6 (0.2) (n = 125)	0.16 (−0.25, 0.56)	.45	−0.2 (0.2) (n = 67)	0.52 (0.03, 1.02)	.038^b
SDS social life	−0.7 (0.1)	−1.0 (0.1)	−0.34 (−0.66, −0.01)	.044^a	−0.3 (0.2)	0.43 (0.03, 0.84)	.035^b
SDS family life	−0.7 (0.1)	−1.0 (0.1)	−0.35 (−0.69, −0.01)	.042^a	−0.3 (0.2)	0.33 (−0.09, 0.75)	.12
CGI-S	−0.6 (0.1)	−0.7 (0.1)	−0.15 (−0.29, −0.01)	.035^a	−0.6 (0.1)	−0.05 (−0.22, 0.12)	.56
	n (%)	n (%)	Ratio (95% CI)		n (%)	Ratio (95% CI)
MADRS response^c	14 (6.8)	20 (10.5)	1.49 (0.78, 2.84)	.22	8 (8.1)	1.26 (0.53, 2.98)	.60
MADRS remission^d	9 (4.4)	13 (6.8)	1.52 (0.66, 3.49)	.33	2 (2.0)	0.51 (0.11, 2.46)	.39

^aActive treatment better than placebo (p < .05).

^bActive treatment worse than placebo (p < .05).

^cDefined as a ≥50% reduction from baseline in MADRS total score.

^dDefined as a MADRS total score ≤10 and ≥50% reduction from baseline. Ratio of response rate = ADT + brexpiprazole/ADT + placebo, or ADT + quetiapine XR/ADT + placebo.

Abbreviations. ADT, antidepressant treatment; CGI-S, Clinical Global Impressions−Severity of illness; CI, confidence interval; LS, least squares; MADRS, Montgomery−Åsberg Depression Rating Scale; SDS, Sheehan Disability Scale; SE, standard error; XR, extended-release.

Figure 4. Effects of brexpiprazole, placebo, and quetiapine XR as adjunct to antidepressant treatment on Sheehan Disability Scale (SDS) scores at week 6 (efficacy population). *p < .05 vs placebo, in favor of active treatment (considered nominal within the formal testing hierarchy). Baseline SDS mean scores: ADT + placebo = 5.7; ADT + brexpiprazole = 5.6; ADT + quetiapine XR = 5.6. Patient numbers for the work/studies item: ADT + placebo, n = 136; ADT + brexpiprazole, n = 125; ADT + quetiapine XR, n = 67. Abbreviations. ADT, antidepressant treatment; LS, least squares; SE, standard error; XR, extended-release.

Table 3. Treatment-emergent adverse events (TEAEs) from baseline of the randomized treatment phase (safety population).

	ADT + placebo (n = 206)	ADT + brexpiprazole 2–3 mg (n = 197)	ADT + quetiapine XR 150–300 mg (n = 100)
At least one TEAE	107 (51.9)	100 (50.8)	58 (58.0)
Discontinuation due to TEAE	1 (0.5)^a	2 (1.0)^b	4 (4.0)^c
TEAEs occurring in ≥5% of patients in any treatment group
Akathisia	4 (1.9)	12 (6.1)	3 (3.0)
Somnolence	2 (1.0)	11 (5.6)	18 (18.0)
Headache	10 (4.9)	11 (5.6)	1 (1.0)
Increased appetite	2 (1.0)	5 (2.5)	5 (5.0)
Dry mouth	1 (0.5)	2 (1.0)	6 (6.0)

^aDifferential white blood cell count abnormal.

^bAkathisia, restlessness.

^cMalignant melanoma, sedation, somnolence, breast engorgement.

Abbreviations. ADT, antidepressant treatment; XR, extended-release.

Table 4. Laboratory assessments (safety population).

Parameter	ADT + placebo	ADT + brexpiprazole 2–3 mg	ADT + quetiapine XR 150–300 mg
Glucose
Fasting serum glucose (mg/dL), mean change^a	−1.74 (n = 185)	−0.21 (n = 172)	−1.67 (n = 83)
Fasting serum glucose normal to high (<100 mg/dL to ≥126 mg/dL), % (n/N)^b	0.0 (0/132)	0.8 (1/123)	1.9 (1/54)
Fasting serum glucose impaired to high (≥100 and <126 mg/dL to ≥126 mg/dL), % (n/N)^b	2.1 (1/47)	8.9 (4/45)	0.0 (0/26)
HbA1c (%), mean change^a	0.04 (n = 199)	0.02 (n = 190)	0.01 (n = 94)
Lipids (fasting)
Total cholesterol (mg/dL), mean change^a	1.78 (n = 187)	1.97 (n = 175)	5.39 (n = 84)
HDL cholesterol (mg/dL), mean change^a	0.81 (n = 183)	−0.13 (n = 173)	−0.19 (n = 83)
LDL cholesterol (mg/dL), mean change^a	1.84 (n = 175)	−0.09 (n = 164)	4.94 (n = 81)
Triglycerides (mg/dL), mean change^a	−5.54 (n = 186)	12.86 (n = 175)	−3.46 (n = 84)
HDL cholesterol normal to low (≥40 mg/dL to <40 mg/dL), % (n/N)^b	3.1 (5/163)	7.0 (11/157)	4.1 (3/74)
LDL cholesterol normal to high (<100 mg/dL to ≥160 mg/dL), % (n/N)^b	0.0 (0/50)	0.0 (0/48)	4.3 (1/23)
Triglycerides normal to high (<150 mg/dL to ≥200 and <500 mg/dL), % (n/N)^b	5.8 (8/137)	9.2 (11/120)	3.3 (2/61)
Triglycerides normal/borderline to high (<200 mg/dL to ≥200 and <500 mg/dL), % (n/N)^b	8.2 (13/158)	15.8 (24/152)	6.9 (5/72)
Prolactin
Serum prolactin (ng/mL), female	(n = 147)	(n = 122)	(n = 66)
Mean change^a	0.42	1.09	−1.72
Median change^a	−0.08	0.04	0.11
Serum prolactin (ng/mL), male	(n = 56)	(n = 68)	(n = 33)
Mean change^a	−0.90	0.26	−1.45
Median change^a	−0.58	−0.26	0.22
Prolactin >2× ULN, % (n/N)^c
Female	0.0 (0/148)	0.8 (1/123)	1.5 (1/66)
Male	5.4 (3/56)	5.9 (4/68)	3.0 (1/33)
Prolactin >3× ULN, % (n/N)^c
Female	1.4 (2/148)	1.6 (2/123)	3.0 (2/66)
Male	0.0 (0/56)	1.5 (1/68)	0.0 (0/33)

^aFrom baseline to last evaluable value.

^bShift from baseline to any post-baseline visit.

^cAt any post-baseline visit (patients counted once, in the highest category that applies).

Abbreviations. ADT, antidepressant treatment; HDL, high-density lipoprotein; LDL, low-density lipoprotein; n/N, number of patients with potentially clinically relevant shift/total number of patients in category; ULN, upper limit of the normal range; XR, extended-release.