Functioning outcomes with adjunctive treatments for major depressive disorder: a systematic review of randomized placebo-controlled studies

Figures & data

Figure 1 Flow diagram of published articles examined for inclusion in a systematic review.

Abbreviations: ADT, antidepressant treatment; MDD, major depressive disorder; OFC, olanzapine–fluoxetine combination.

Table 1 Characteristics of included studies

Reference (ClinicalTrials.gov identifier)	Adjunctive treatment	Adjunctive treatment duration	Randomized patients	Inadequate response to (current episode)	Inadequate response definition		Primary efficacy measure	Setting	Source of funding
					Historical ADTa	Prospective/ongoing ADTb
Berman et al, 2007^Citation29 (NCT00095823)	Aripiprazole 2–20 mg	6 weeks	362	1–3 historical ADTs + 1 prospective SSRI/SNRI	<50% improved on ATRQ	<50% reduction in HAM-D17 total score from start of prospective treatment to week 8; HAM-D17 total score ≥14 and CGI-I score ≥3 at week 8	MADRS total	24 outpatient sites in the US	Bristol-Myers Squibb and Otsuka
Marcus et al, 2008^Citation30 (NCT00095758)	Aripiprazole 2–20 mg	6 weeks	381	1–3 historical ADTs + 1 prospective SSRI/SNRI	<50% improved on ATRQ	<50% reduction in HAM-D17 total score from start of prospective treatment to week 8; HAM-D17 total score ≥14 and CGI-I score ≥3 at week 8	MADRS total	36 outpatient sites in the US	Bristol-Myers Squibb and Otsuka
Berman et al, 2009^Citation31 (NCT00105196)	Aripiprazole 2–20 mg	6 weeks	349	1–3 historical ADTs + 1 prospective SSRI/SNRI	<50% improved on ATRQ	<50% reduction in HAM-D17 total score from start of prospective treatment to week 8; HAM-D17 total score ≥14 at week 8; CGI-I score ≥3 at weeks 6 and 8	MADRS total	36 outpatient sites in the US	Bristol-Myers Squibb and Otsuka
Kamijima et al, 2013^Citation32 (NCT00876343)	Aripiprazole 3 mg/3–15 mg	6 weeks	586	1–3 historical ADTs + 1 prospective ADT	Not specified	<50% reduction in HAM-D17 total score from start of prospective treatment to week 8; HAM-D17 total score ≥14 and CGI-I score ≥3 at week 8c	MADRS total	169 sites in Japan	Otsuka
Quiroz et al, 2016^Citation33 (NCT01437657)	Basimglurant MR 0.5 mg/1.5 mg	6 weeks	333	1–3 historical ADTs (1 ongoing SSRI/SNRI)	Investigator judgment	MADRS total score ≥25 and CGI-S score ≥4 at screeningd	MADRS total	59 outpatient sites in Chile, Europe, Japan, Mexico, and the US	Hoffmann-La Roche
Thase et al, 2015^Citation34 (NCT01360645)	Brexpiprazole 2 mg	6 weeks	379	1–3 historical ADTs + 1 prospective SSRI/SNRI	<50% improved on ATRQ	<50% reduction in HAM-D17 total score from start of prospective treatment to week 8; HAM-D17 total score ≥14 at week 8; <50% reduction in MADRS total score from start of prospective treatment to weeks 2, 4, 6, and 8; CGI-I score ≥3 at weeks 2, 4, 6, and 8e	MADRS total	59 outpatient sites in Canada, Europe, and the US	Otsuka and Lundbeck
Thase et al, 2015^Citation35 (NCT01360632)	Brexpiprazole 1 mg/3 mg	6 weeks	677	1–3 historical ADTs + 1 prospective SSRI/SNRI	<50% improved on ATRQ	<50% reduction in HAM-D17 total score from start of prospective treatment to week 8; HAM-D17 total score ≥14 at week 8; <50% reduction in MADRS total score from start of prospective treatment to weeks 2, 4, 6, and 8; CGI-I score ≥3 at weeks 2, 4, 6, and 8e	MADRS total	92 outpatient sites in Canada, Europe, Russia, and the US	Otsuka and Lundbeck
Fava et al, 2016^Citation36 (NCT01500200)	Buprenorphine + samidorphan 2 mg + 2 mg/8 mg + 8 mg	Stage 1: 5 weeks; stage 2: 5 weeksf	142	1–2 historical ADTs (1 ongoing)	<50% improved on ATRQ	For entry into stage 2f: <50% reduction in HAM-D17 total score from start of stage 1 to week 5; HAM-D17 total score ≥14 at week 5	HAM-D17 total	31 sites in the US	Alkermes
Durgam et al, 2016^Citation37 (NCT01469377)	Cariprazine 1–2 mg/2–4.5 mg	8 weeks	819	1–2 historical ADTs (1 ongoing)	Not specified	ATHF resistance rating ≥3 with global confidence ≥3 at screeninge	MADRS total	76 outpatient sites in Europe and the US	Forest Laboratories (Allergan) and Gedeon Richter
Fava et al, 2015^Citation38 (NCT01098240)	CP-601,927 2–4 mg	6 weeks	162	1–3 historical ADTs + 1 prospective SSRI	<50% improved on ATRQ	<50% reduction in HAM-D17 total score from start of prospective treatment to week 8; HAM-D17 total score ≥16 at week 8	MADRS total	25 outpatient sites in the US	Pfizer
Vieta et al, 2014^Citation39 (NCT01157078, NCT01180400)	Dexmecamylamine 2–8 mg (2 studies)	8 weeks	319, 295	0–1 historical ADTs + 1 prospective SSRI/SNRI	Not specified	<50% reduction in HAM-D17 total score from start of prospective treatment to week 8; HAM-D17 total score ≥16 and CGI-S score ≥4 at week 8	MADRS total	70 outpatient sites in India and the US; 80 outpatient sites in Europe	AstraZeneca and Targacept
Möller et al, 2015^Citation40 (NCT01153347, NCT01197508)	Dexmecamylamine 0.2 mg/1 mg/2 mg/4 mg/8 mg (across 2 studies)	8 weeks	641, 696	0–1 historical ADTs + 1 prospective SSRI/SNRI	Not specified	<50% reduction in HAM-D17 total score from start of prospective treatment to week 8; HAM-D17 total score ≥16 and CGI-S score ≥4 at week 8	MADRS total	114 outpatient sites in India and the US; 132 outpatient sites in Europe, South Africa, and South America	AstraZeneca and Targacept
Tummala et al, 2015^Citation41 (NCT01152554)	Dexmecamylamine 2–8 mg	52 weeks	813 (769 de novog)	0–1 historical ADTs + 1 prospective SSRI/SNRI	Not specified	De novo patientsg: HAM-D17 total score ≥10 and CGI-S score ≥3 at week 6 of prospective treatment	Not applicable (safety)	115 outpatient sites in the US	AstraZeneca
Ball et al, 2014^Citation42 (NCT00840034)	Edivoxetine 6–18 mg	8 weeks	227	1 ongoing SSRI	Not applicable	Investigator judgment at screening; <25% reduction in QIDS-SR16 score from start of adjunctive placebo phase to week 2	MADRS total	25 outpatient sites in the US	Eli Lilly and Company
Ball et al, 2016^Citation43 (NCT01173601, NCT01187407, NCT01185340)	Edivoxetine 6 mg/12 mg/12–18 mg/18 mg (across 3 studies)	8 weeks	701, 689, 449	1 ongoing SSRI	Not applicable	Investigator judgment at screening and start of adjunctive placebo phase; <25% reduction in MADRS total score from start of adjunctive placebo phase to week 3; MADRS total score ≥14 at week 3	MADRS total	Multiple outpatient sites in Australia, Europe, Japan, Russia, South Africa, and the US	Eli Lilly and Company
Barbee et al, 2011^Citation44 (NCT00901407)	Lamotrigine 100–400 mg	10 weeks	96	≥1 historical ADT + 1 prospective paroxetine/paroxetine CR	Not specified	HAM-D17 total score ≥15 at week 8 of prospective treatment	MADRS total	19 sites in the US	GlaxoSmithKline
Sanacora et al, 2017^Citation45 (NCT01482221)	Lanicemine 50 mg/100 mg (IV regimen)	12 weeks (primary analysis at week 6)	302	≥1 historical ADT (1 ongoing)	Investigator judgment	Investigator judgment	MADRS total	49 outpatient sites in Chile, Europe, South Africa, and the US	AstraZeneca
Richards et al, 2016^Citation46 (NCT01436149, NCT01436162)	Lisdexamfetamine dimesylate 20–70 mg (2 studies)	8 weeks	404, 426	0–2 historical ADTs + 1 prospective SSRI/SNRI	Not specified	<50% reduction in MADRS total score from start of prospective treatment to week 8; MADRS total score ≥18 at week 8	MADRS total	76 sites in Canada, Europe, Mexico and the US; 94 sites in Europe, South Africa, and the US	Shire
Thase et al, 2007^Citation47 (NCT00035321)	Olanzapine 6–18 mg (as OFC; 2 studies pooled)	8 weeks	605 (pooled)	1 historical ADT + 1 prospective fluoxetine	Investigator judgment	<25% reduction in HAM-D17 total score from start of prospective treatment to week 8; HAM-D17 total score ≥18 at week 8; ≤15% reduction in HAM-D17 total score from week 7 to week 8	MADRS total	Multiple outpatient sites in Canada and the US	Eli Lilly and Company
Mahmoud et al, 2007^Citation48 (NCT00095134)	Risperidone 1–2 mg	6 weeks	274	1 ongoing ADT	Not applicable	CGI-S score ≥4 and CDS score ≥20 at week 4 of prospective phase	HAM-D17 total	75 outpatient sites in the US	Ortho-McNeil-Janssen

Notes:

a “Historical” describes an ADT that was discontinued prior to study enrollment.

b “Prospective” describes an ADT that was initiated during the study, whereas “ongoing” describes an ADT that was initiated prior to study enrollment and was continued during the study.

c The manuscript states that any one of these criteria is sufficient; however, by comparison with the other aripiprazole studies, we assume this is an error.

d In addition, where available, a patient-rated MADRS total score ≥23 at screening, with a permitted discrepancy of ≤7 points versus the clinician-rated MADRS total score.

e Revised criteria following a protocol amendment.

f Two-stage study design: 1) patients were randomized to placebo or active treatment; 2) placebo non-responders in stage 1 were re-randomized to placebo or active treatment.

g Study also rolled-over a small number of patients from two acute studies (NCT01157078 and NCT01153347).

Abbreviations: ADT, antidepressant treatment; ATHF, Antidepressant Treatment History Form; ATRQ, Massachusetts General Hospital Antidepressant Treatment Response Questionnaire; CDS, Carroll Depression Scale; CGI-I/S, Clinical Global Impressions – Improvement/Severity of illness; CR, controlled release; HAM-D₁₇, 17-item Hamilton Depression Rating Scale; IV, intravenous; MADRS, Montgomery–Åsberg Depression Rating Scale; MR, modified release; OFC, olanzapine–fluoxetine combination; QIDS-SR₁₆, 16-item Quick Inventory of Depressive Symptomatology (Self-Report); SNRI, serotonin–norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

Table 2 Change from baseline to endpoint in self-rated functioning scale scores (for the population who received ≥1 dose of randomized treatment and had ≥1 post-baseline efficacy evaluation)

Reference	Treatment arm	SDS summary score					SDS work/studies		SDS social life		SDS family life
		Baseline		Change to endpoint			Change to endpoint		Change to endpoint		Change to endpoint
		n	Mean (SD)	n	Mean (SE)	p-value versus placebo	Mean (SE)	p-value versus placebo	Mean (SE)	p-value versus placebo	Mean (SE)	p-value versus placebo
Aripiprazole		SDS mean
Berman et al, 200729	Placebo	164	5.4 (0.2)a	164	−0.7 (0.2)		−0.7 (0.3)b		−0.8 (0.2)		−0.5 (0.2)
	2–20 mg	167	5.7 (0.2)a	167	−1.1 (0.2)	0.055	−0.7 (0.2)c	0.98	−1.4(0.2)	0.030	−1.1 (0.2)	0.017
Marcus et al, 2008^Citation30	Placebo	168	5.4 (0.2)a	168	−0.7 (0.2)		−0.4 (0.2)d		−0.6 (0.2)e		−1.0 (0.2)e
	2–20 mg	180	5.1 (0.2)a	180	−1.3 (0.2)	0.012	−0.5 (0.2)f	0.62	−1.4 (0.2)g	0.002	−1.8 (0.2)g	0.002
Berman et al, 2009^Citation31	Placebo	160	5.9 (0.2)a	160	−0.8 (0.2)		−0.7 (0.3)h		−0.7 (0.2)		−0.8 (0.2)
	2–20 mg	160	5.7 (0.2)a	160	−1.2 (0.2)	0.075	−0.8 (0.3)i	0.79	−1.2 (0.2)	0.052	−1.4 (0.2)	0.037
Kamijima et al, 2013^Citation32	Placebo	195	5.3 (0.1)a	193	−0.5 (0.1)		−0.4 (0.1)		−0.6 (0.1)		−0.3 (0.1)
	3 mg	197	5.0 (0.1)a	197	−1.0 (0.1)	0.001	−0.9 (0.1)	0.003	−1.1 (0.1)	0.003	−0.9 (0.1)	0.003
	3–15 mg	194	5.0 (0.1)a	193	−1.0 (0.1)	<0.001	−1.0 (0.1)	<0.001	−1.2 (0.1)	<0.001	−0.9 (0.1)	0.003
Basimglurant MR		SDS sum of items 2 and 3
Quiroz et al, 2016^Citation33	Placebo	109j	13.2 (3.7)	109	−5.1 (0.6)
	0.5 mg	112j	13.8 (4.0)	112	−5.1 (0.6)	0.94
	1.5 mg	111j	13.5 (3.6)	111	−6.4 (0.6)	0.09
Brexpiprazole		SDS mean
Thase et al, 2015^Citation34	Placebo	191j	6.3 (2.1)	178	−0.9 (0.2)		−1.0 (0.2)		−1.0 (0.2)		−0.7 (0.2)
	2 mg	188j	6.0 (2.0)	175	−1.4 (0.2)	0.035	−1.1 (0.2)	0.61	−1.6 (0.2)	0.022	−1.3 (0.2)	0.011
Thase et al, 2015^Citation35	Placebo	221k	5.6 (1.9)	203	−0.8 (0.2)		−0.7 (0.2)		−0.9 (0.2)		−0.8 (0.2)
	1 mg	226k	5.9 (2.0)	211	−1.3 (0.2)	0.016	−1.1 (0.2)	0.082	−1.3 (0.2)	0.035	−1.3 (0.2)	0.019
	3 mg	230k	5.7 (2.2)	213	−1.3 (0.2)	0.019	−0.9 (0.2)	0.30	−1.4 (0.2)	0.028	−1.4 (0.2)	0.0077
Buprenorphine + samidorphan
Fava et al, 2016^Citation36	Placebo
	2 mg + 2 mg					NS
	8 mg + 8 mg					NS
Cariprazine		SDS total
Durgam et al, 2016^Citation37	Placebo	264	18.5 (4.7)	264	−6.6 (0.5)						−2.3
	1–2 mg	273	18.7 (4.7)	273	−7.7 (0.5)	0.24		NS		NS		NS
	2–4.5 mg	271	18.8 (4.8)	271	−8.0 (0.5)	0.11		NS		NS	−2.9	0.014
CP-601, 927		SDS total
Fava et al, 2015^Citation38	Placebo	85	18.5 (5.3)	85	−5.7 (8.2)l
	2–4 mg	77	19.0 (5.9)	77	−6.6 (8.0)l	NS		NS		NS		NS
Dexmecamylamine		SDS total
Vieta et al, 2014^Citation35	Placebo			151	−5.5 (0.7)		−1.7 (0.2)m		−1.9 (0.2)		−2.0 (0.3)
	2–8 mg			143	−6.1 (0.7)	0.42	−2.0 (0.2)n	0.21	−1.9 (0.2)	0.93	−2.1 (0.3)	0.76
	Placebo			142	−5.8 (0.5)		−1.8 (0.2)o		−1.9 (0.2)		−2.0 (0.2)
	2–8 mg			138	−5.8 (0.5)	0.96	−2.2 (0.3)p	0.20	−2.0 (0.2)	0.76	−1.9 (0.2)	0.62
Möller et al, 2015^Citation40	Placebo			153	−4.9 (0.6)		−1.7 (0.2)q		−1.9 (0.2)		−1.6 (0.2)
	1 mg			152	−5.5 (0.6)	0.42	−1.7 (0.2)r	0.95	−1.9 (0.2)	0.92	−1.9 (0.2)	0.21
	4 mg			148	−5.5 (0.6)	0.49	−1.8 (0.2)s	0.87	−1.9 (0.2)	0.97	−1.8 (0.2)	0.34
	8 mg			149	−4.5 (0.7)	0.60	−1.7 (0.2)t	0.79	−1.6(0.2)	0.24	−1.6 (0.2)	0.97
	Placebo			172	−7.1 (0.6)		−2.1 (0.2)u		−2.4 (0.2)		−2.3 (0.2)
	0.2 mg			171	−6.1 (0.6)	0.18	−2.0 (0.2)v	0.91	−2.1 (0.2)	0.25	−2.0 (0.2)	0.17
	2 mg			168	−6.3 (0.6)	0.33	−1.8 (0.2)w	0.45	−2.2 (0.2)	0.50	−2.1 (0.2)	0.40
	8 mg			163	−6.2 (0.6)	0.27	−1.9 (0.2)x	0.66	−2.2 (0.2)	0.44	−2.0 (0.2)	0.20
Tummala et al, 2015^Citation41	Placebo			70	−7.4 (7.5)l
	2–8 mg			185	−7.0 (7.9)l
Edivoxetine		SDS totaly
Ball et al, 2014^Citation42	Placebo	71k	19.2 (6.8)	68	−2.6		−0.4		−1.0		−1.0
	6–18 mg	67k	17.9 (6.9)	63	−6.0	0.039	−1.9	0.10	−2.1	0.046	−1.9	0.11
Ball et al, 2016^Citation43	Placebo	P: 690k	P: 18.1 (6.1)	240	−4.5 (0.4)
	12 mg	E: 1,149k	E: 18.2 (5.8)	231	−5.4 (0.4)	NS
	18 mg	(pooled)	(pooled)	230	−5.3 (0.4)	NS
	Placebo			231	−4.3 (0.4)
	6 mg			226	−6.3 (0.4)	≤0.05
	12–18 mg			232	−5.3 (0.4)	NS
	Placebo			219	−4.4 (0.5)
	12–18 mg			230	−4.5 (0.5)	NS
Lamotrigine
Barbee et al, 2011^Citation44	Placebo
	100–400 mg					NS
Lanicemine (IV regimen)		SDS total
Sanacoraet al, 2017^Citation45	Placebo			97	−6.9 (1.0)
	50 mg			101	−7.1 (1.0)	0.89
	100 mg			100	−6.9 (1.0)	0.99
Lisdexamfetamine dimesylate		SDS total
Richardset al, 20I6^Citation46	Placebo	198	15.6 (5.7)	164	−4.3 (−5.3, −3.3)z
	20–70 mg	198	15.9 (6.0)	162	−4.7 (−5.6, −3.7)z	0.58		NS		NS		NS
	Placebo	213	16.8 (5.8)	189	−4.3 (−5.2, −3.4)z
	20–70 mg	209	16.8 (5.3)	180	−4.9 (−5.8, −4.0)z	0.35		NS		NS		NS
Olanzapine (as OFC; 2 studies pooled)
Thase et al, 2007^Citation47	Fluoxetine			203					−1.1 (2.6)l		−1.2 (2.6)l
	6–18 mg			198				0.46	−1.6 (2.8)l	0.027	−1.7 (2.7)l	0.047
Risperidone		SDS total
Mahmoud et al, 2007^Citation48	Placebo	113	20.2 (0.6)a	101	−3.9		−0.8		−1.5		−1.4
	1–2 mg	110	19.9 (0.6)a	100	−7.6	<0.001	−1.7	0.12	−2.9	<0.001	−2.5	<0.001
Pandina et al, 2009^Citation28

Notes: Highlighted cells indicate p≤0.05 versus placebo.

a SE.

b n=130.

c n=127.

d n=136.

e n=170.

f n=142.

g n=181.

h n=126.

i n=115.

j For the population who received ≥1 dose of randomized treatment

k For the randomized population.

l SD.

m n=134.

n n=124.

o n=120.

p n=115.

q n=137.

r n=132.

s n=123.

t n=134.

u n=137.

v n=141.

w n=140.

x n=126.

y If the work/studies item was missing, the mean of the other two items was imputed to calculate the total score.

z 95% CI.

Abbreviations: E, edivoxetine; IV, intravenous; MR, modified release; NS, not statistically significant (and p-value not reported); OFC, olanzapine–fluoxetine combination; P, placebo; SDS, Sheehan Disability Scale.

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