Efficacy, acceptability, and safety of adjunctive aripiprazole in treatment-resistant depression: a meta-analysis of randomized controlled trials

Figures & data

Figure 1 Eligibility of studies for inclusion in meta-analysis.

Table 1 Baseline characteristics of patients in the trials included in the meta-analysis

Study	Country	Treatment regimen	Patients (n)	Male/female	Age (y)	Duration of current episode (m)
Fava et al^Citation29	USA	Adjunctive aripiprazole 2 mg/day	56	19/56	45.36±10.35	NR
		Placebo	169	61/169	45.06±11.34	NR
Berman et al^Citation30	USA	Adjunctive aripiprazole 2–20 mg/day	177	39/138	45.1±10.6	18.8 (2.1–433.1)
		Placebo	172	55/117	45.6±11.3	17.2 (1.6–236.5)
Lin et al^Citation31	China	Adjunctive aripiprazole 2.5 mg/day	21	17/4	35.86±11.61	NR
		Placebo	20	16/4	35.15±10.03	NR
Berman et al^Citation32	USA	Adjunctive aripiprazole 2–15 mg/day	182	70/112	46.5±10.6	38.6±59
		Placebo	176	63/113	44.2±10.9	43.6±53.8
Marcus et al^Citation33	USA	Adjunctive aripiprazole 2–20 mg/day	191	65/126	44.6±11.0	43.7±68.0
		Placebo	190	62/128	44.4±10.7	48.5±88.8
Lenze et al^Citation34	USA	Adjunctive aripiprazole 10 mg/day	91	52/39	66.4	27.5
		Placebo	90	51/39	65.7	24.3
Schüle et al^Citation35	Germany	15 mg/day aripiprazole +45 mg/day mirtazapine	20	9/11	44.7±12.58	NR
		45 mg/day mirtazapine	20	4/16	50.30±15.63	NR
Kamijima et al^Citation36	Japan	Adjunctive aripiprazole 3–15 mg/day	194	101/93	38.1±9.6	17.5±26.1
		Adjunctive aripiprazole 3 mg/day	197	124/73	39.2±9.1	15.7±21.6
		Placebo	195	115/80	38.7±9.2	15.6±16.4

Note: Data presented as n; mean ± SD; or mean (range).

Abbreviations: m, months; NR, not reported; SD, standard deviation; y, years.

Figure 2 Risk of bias summary.

Table 2 GRADE evidence profile

Quality assessment							No of patients		Effect		Quality*	Importance
Studies (n)	Design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations			Relative (95% CI)	Absolute
Remission rate
8	Randomized trials	Seriousa	No serious inconsistency	No serious indirectness	No serious imprecision	Strong associationb	388/1,302 (29.8%)	232/1,284 (18.1%)	RR 1.64 (1.42 to 1.89)	116 more per 1,000 (from 76 more to 161 more)	⊕⊕⊕⊕ High	Critical
								15.9%		102 more per 1,000 (from 67 more to 142 more)
Response rate
7	Randomized trials	Seriousa	No serious inconsistency	No serious indirectness	No serious imprecision	Strong associationb	522/1,211 (43.1%)	374/1,194 (31.3%)	RR 1.45 (1.13 to 1.87)	141 more per 1,000 (from 41 more to 273 more)	⊕⊕⊕⊕ High	Critical
								23.9%		108 more per 1,000 (from 31 more to 208 more)
Change from baseline in MADRS score (better indicated by lower values)
6	Randomized trials	No serious risk of bias	No serious inconsistency	No serious indirectness	No serious imprecision	None	1,076	1,069	–	WMD −2.83 lower (−2.92 higher to −2.73 lower)	⊕⊕⊕⊕ High	Critical
Change from baseline in CGI-S score (better indicated by lower values)
6	Randomized trials	No serious risk of bias	No serious inconsistency	No serious indirectness	No serious imprecision	None	953	805	–	WMD −0.36 lower (−0.46 higher to −0.26 lower)	⊕⊕⊕⊕ High	Important
Change from baseline in CGI-I score (better indicated by lower values)
6	Randomized trials	No serious risk of bias	No serious inconsistency	No serious indirectness	No serious imprecision	None	953	805	–	WMD −0.45 lower (−0.50 higher to −0.40 lower)	⊕⊕⊕⊕ High	Important
Change from baseline in HAM-D17 score (better indicated by lower values)
6	Randomized trials	Seriousa	No serious inconsistency	No serious indirectness	No serious imprecision	None	437	435	–	WMD −1.70 lower (−2.18 higher to −1.22 lower)	⊕⊕⊕O Moderate	Important
Changes from baseline in SDS score (better indicated by lower values)
6	Randomized trials	Seriousa	No serious inconsistency	No serious indirectness	No serious imprecision	None	437	435	–	WMD −0.50 lower (−0.54 higher to −0.46 lower)	⊕⊕⊕O Moderate	Important
Changes from baseline in IDS-SR score (better indicated by lower values)
6	Randomized trials	Seriousa	No serious inconsistency	No serious indirectness	No serious imprecision	None	437	435	–	WMD −1.57 lower (−1.81 higher to −1.32 lower)	⊕⊕⊕O Moderate	Important
Discontinuations due to adverse events
6	Randomized trials	No serious risk of bias	No serious inconsistency	No serious indirectness	No serious imprecision	None	39/1,044 (3.7%)	18/1,029 (1.7%)	RR 2.12 (1.23 to 3.67)	20 more per 1,000 (from 4 more to 47 more)	⊕⊕⊕⊕ High	Important
								1.03%		12 more per 1,000 (from 2 more to 28 more)
Adverse events
8	Randomized trials	Seriousa	No serious inconsistency	No serious indirectness	No serious imprecision	Strong associationc	672/989 (67.9%)	588/1,097 (53.6%) 60.0%	RR 1.24 (1.17 to 1.33)	129 more per 1,000 (from 91 more to 177 more) 144 more per 1,000 (from 102 more to 198 more)	⊕⊕⊕⊕ High	Important

Notes:

a One study was classified as being at high risk of bias.

b A total of 2,210 patients were enrolled.

c A total of 2,260 patients were enrolled.

* The number of crossed circle symbols indicate quality: 4= high quality, 3= moderate quality, and ≤2 = low quality.

Abbreviations: CGI-I, Clinical Global Impression-improvement; CGI-S, Clinical Global Impression-severity; GRADE, grading of recommendations assessment, development, and evaluation; HAM-D17, 17-Item Hamilton Rating Scale for Depression; IDS-SR, inventory of depressive symptomatology self-report scale; MADRS, Montgomery–Asberg Depression Rating Scale; RR, risk ratio; SDS, Sheehan disability scale; WMD, weight mean difference.

Figure 3 Forest plot showing the effect of adjunctive aripiprazole on remission rate.

Abbreviations: CI, confidence interval; RR, risk ratio.

Figure 4 Forest plot showing the effect of adjunctive aripiprazole on response rate.

Note: Weights are from random effects analysis.
Abbreviations: CI, confidence interval; RR, risk ratio.

Figure 5 Forest plot showing the effect of adjunctive aripiprazole on change from baseline in MADRS score.

Abbreviations: CI, confidence interval; MADRS, Montgomery–Asberg Depression Rating Scale; WMD, weight mean difference.

Figure 6 Forest plot showing the effect of adjunctive aripiprazole on changes from baseline in CGI-I and CGI-S scores.

Note: Weights are from random effects analysis.
Abbreviations: CGI-I, Clinical Global Impression-improvement; CGI-S, Clinical Global Impression-severity; CI, confidence interval; WMD, weight mean difference.

Table 3 Summary of the RRs with 95% CIs of adverse events

Adverse events	RR (95% CI)	P-value
Constipation	2.33 (1.21 to 4.49)	0.011
Diarrhea	0.81 (0.49 to 1.35)	0.416
Dry mouth	0.93 (0.25 to 3.49)	0.912
Nausea	0.91 (0.60 to 1.39)	0.659
Fatigue	1.68 (1.04 to 2.70)	0.033
Akathisia	4.47 (1.77 to 11.28)	0.002
Headache	0.81 (0.56 to 1.18)	0.280
Somnolence	1.86 (0.64 to 5.43)	0.256
Insomnia	2.19 (1.35 to 3.54)	0.001
Dizziness	1.45 (0.50 to 4.20)	0.492
Restlessness	4.51 (2.36 to 8.63)	<0.001
Blurred vision	4.05 (1.68 to 9.75)	0.002
Tremor	2.49 (0.99 to 6.28)	0.054

Abbreviations: CI, confidence interval; RR, risk ratio.

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