Table 2. Results: Outcomes Across Subgroup Analyses.

Resultsa	Primary outcomeb		Secondary outcomes
	SMD (95% CI)	τ	OR (95% CI)c		Continuous change from baseline, SMD (95% CI)	OR (95% CI)d
			Remission	Response		Dropouts	Dropouts due to AE
Whole sample	0.31 (0.19 to 0.44) [38 studies]	0.296	1.52 (1.20 to 1.92) [25 studies]	1.40 (1.15 to 1.69) [30 studies]	0.38 (0.22 to 0.54) [28 studies]	0.99 (0.86 to 1.14) [30 studies]	1.17 (0.79 to 1.75) [17 studies]
I2, %	77.52		63.38	44.11	84.21	3.66	20.87
Whole sample; low risk of bias	0.29 (0.15 to 0.42) [15 studies]	0.188	1.44 (1.12 to 1.85) [11 studies]	1.46 (1.14 to 1.87) [14 studies]	0.34 (0.17 to 0.50) [11 studies]	1.09 (0.94 to 1.28) [12 studies]	1.43 (0.87 to 2.34) [9 studies]
I2, %	69.18		51.61	48.07	77.95	0	15.34
α2 + RI	0.37 (0.19 to 0.55) [18 studies]	0.305	1.42 (1.01 to 2.01) [12 studies]	1.49 (1.18 to 1.87) [15 studies]	0.44 (0.22 to 0.66) [15 studies]	1.02 (0.86 to 1.21) [14 studies]	1.06 (0.49 to 2.31) [10 studies]
I2, %	80.58		74.27	47.77	85.10	0	34.82
α2 + RI; low risk of bias	0.36 (0.19 to 0.53) [11 studies]	0.221	1.39 (1.11 to 1.75) [9 studies]	1.52 (1.15 to 2.00) [11 studies]	0.36 (0.16 to 0.56) [9 studies]	1.04 (0.88 to 1.24) [9 studies]	1.17 (0.43 to 3.19) [6 studies]
I2, %	75.28		37.42	53.44	78.26	0	49.63
α2 + RI; nonresponder/TRD	0.24 (0.03 to 0.45) [12 studies]	0.283	1.17 (0.82 to 1.67) [8 studies]	1.35 (1.08 to 1.69) [10 studies]	0.23 (−0.01 to 0.48) [9 studies]	1.00 (0.83 to 1.20) [8 studies]	0.75 (0.31 to 1.82) [6 studies]
I2, %	79.52		68.26	34.11	82.55	0	0
α2 + RI; first-line	0.64 (0.12 to 1.15) [5 studies]	0.523	1.80 (0.74 to 4.37) [3 studies]	1.54 (0.77 to 3.09) [3 studies]	0.84 (0.30 to 1.38) [2 studies]	0.81 (0.38 to 1.72) [3 studies]	0.62 (0.15 to 2.62) [2 studies]
I2, %	84.21		72.19	58.54	44.05	0	0
Combination with bupropion	0.10 (−0.07 to 0.27) [7 studies]	0.161	1.29 (0.95 to 1.74) [6 studies]	1.06 (0.88 to 1.29) [5 studies]	0.06 (−0.19 to 0.31) [4 studies]	1.45 (0.95 to 2.23) [2 studies]	1.79 (0.50 to 6.35) [2 studies]
I2, %	59.48		45.52	0	74.07	0	29.45
Combination with bupropion; low risk of bias	0.12 (−0.07 to 0.31) [4 studies]	0.106	1.13 (0.80 to 1.59) [3 studies]	1.05 (0.75 to 1.48) [3 studies]	0.09 (−0.14 to 0.32) [2 studies]	1.45 (0.95 to 2.23) [2 studies]	1.79 (0.50 to 6.35) [2 studies]
I2, %	30.22		13.78	0	60.35	0	29.45
Combination with bupropion; nonresponder/TRD	0.17 (0.02 to 0.31) [3 studies]	0.000	2.24 (0.61 to 8.26) [2 studies]	1.15 (0.89 to 1.48) [2 studies]	0.51 (−0.01 to 1.02) [1 study only]	No data	No data
I2, %	0		80.93	0	NA
Combination with bupropion; first-line	0.04 (−0.20 to 0.29) [4 studies]	0.200	1.09 (0.83 to 1.43) [4 studies]	0.95 (0.70 to 1.28) [3 studies]	−0.01 (−0.26 to 0.23) [3 studies]	1.45 (0.95 to 2.23) [2 studies]	1.79 (0.50 to 6.35) [2 studies]
I2, %	71.05		0	0	74.60	0	29.45

Abbreviations: α2, antagonists of presynaptic α2-autoreceptors; AE, adverse events; NA, not applicable; OR, odds ratio; RI, (monoamine) reuptake inhibitor; SMD, standardized mean difference; TRD, treatment-resistant depression.

^a Of note, depending on design specifics, not all studies may be included in all outcome analyses (eg, only 17 randomized double-blind studies reported data on the number of dropouts due to AE).

^b For the primary outcome, SMD >0 in favor of combination.

^c For the secondary outcomes remission, response, and continuous change from baseline, OR >1 designates superiority of combination treatment; SMD >0 designates superiority of combination treatment.

^d For the secondary outcomes dropouts and dropouts due to AE, OR >1 designates superiority of monotherapy, ie, fewer dropouts in monotherapy groups.