More female patients and fewer stimuli per session are associated with the short-term antidepressant properties of repetitive transcranial magnetic stimulation (rTMS): a meta-analysis of 54 sham-controlled studies published between 1997–2013

Figures & data

Table 1 Details of the systematic search strategy (all searches were performed in English with no language restrictions)

Search	Search terms	Databases (time frame)
Search 1 N=821	[TI or SU (“transcranial magnetic stimulation” or “trans- cranial magnetic stimulation” or “repetitive transcranial magnetic stimulation” or “repetitive trans- cranial magnetic stimulation” or TMS or rTMS)] AND [TI or SU (depress* or dysthy* or MDD or cyclothym* or bipolar or “mani*- depress*”)]	PsycInfo and Medline (any date – 2008)
Search 2 N=584a	[TI or SU (“transcranial magnetic stimulation” or “trans- cranial magnetic stimulation” or “repetitive transcranial magnetic stimulation” or “repetitive trans- cranial magnetic stimulation” or TMS or rTMS)] AND [TI or SU (depress* or dysthy* or MDD or cyclothym* or bipolar or “mani*- depress*”)]	EBSCO PsycInfo and Medline (2008 – August 2013)
Search 3 N=128a	[Title, Abstract, Keywords (“transcranial magnetic stimulation” or “trans-cranial magnetic stimulation” or “repetitive transcranial magnetic stimulation” or “repetitive trans- cranial magnetic stimulation” or TMS or rTMS)] AND [Title, Abstract, Keywords (depress* or dysthy* or MDD or cyclothym* or bipolar or “mani*- depress*”)]	Cochrane Library (Category searched: Trials) (2008 – August 2013)

Notes: Search 1 was a “control search” to find out if the N=40 studies included in the past 13 meta-analyses (published in 2001–2010) could be located using two databases only. Since the search detected all these resources, Search 2 was conducted on PsycInfo and Medline that appeared to have an adequate coverage of studies in this area. Search 3 of the Cochrane library did not identify any additional studies than Search 2.

a Duplicates excluded within search.

Abbreviations: MDD, major depressive disorder; N, number of sources; rTMS, repetitive transcranial magnetic stimulation; SU, subject; TI, title.

Figure 1 Study assessment and exclusionary criteria.

Abbreviations: DLPFC, dorsolateral prefrontal cortex; rTMS, repetitive transcranial magnetic stimulation.

Table 2 rTMS parameters in the N=18 studies included in the current meta-analysis

Year	Study country	DLPFC location	Definition of location	Frequency (Hz)	Motor threshold (%)	Coil type	Coil diameter (mm)	Coil angle sham (°)	Stimuli/session	Trains/session	Inter-train interval (s)	Number of sessions	Stimulator (company)
2010	George et al^Citation46; USA	L	5 cm/MRI	10	120	F8	–	TS	3,000	75	26	15	Neuronetics
	Paillere Martinot et al^Citation50; Francea	L	5 cm	10	90	F8	–	TS	1,600	20	60	10	MagStim
	Pallanti et al^Citation51; ltalyb	B R L	5 cm	6*	105*	F8	70	TS	1,420	23	28*	15	MagStim
	Triggs et al^Citation52; USA	L R	5 cm	5	100	F8	70	TS	2,000	50	22	10	MagStim
	Zheng et al^Citation41; People’s Republic of China	L	5 cm	15	110	F8	–	90	3,000	50	–	20	MagPro
2011	Aguirre et al^Citation53; Spain	R	5 cm	1	110	F8	85	90	1,200	20	45	20	MagPro
	He et al^Citation54; People’s Republic of Chinac	B	–	9*	–	–	–	T1	–	–	–	10	Self-made
	Lingeswaran^Citation55; India	L	5 cm	10	100	F8	–	90	–	10	60	12	MagStim
	Ray et al^Citation39; India	L	5 cm	10	90	F8	–	45	1,200	20	24	10	MagStim
2012	Bakim et al^Citation56; Turkeyd	L	5 cm	20	110	F8	–	45	800	20	28	30	MagStim
	Blumberger et al^Citation57; Canadae	L	5 cm	10	110*	F8	70	90	1,450	39*	30	15	MedTronic
	Fitzgerald et al^Citation58; Australiaf	B R L	MRI	6*	120	F8	70	45	–	31	–	15	MagPro
	Huang et al^Citation59; People’s Republic of China	L	5.5 cm	10	90	F8	–	90	800	20	56	10	MagStim
	Peng et al^Citation38; People’s Republic of China	L	5 cm	15	110	F8	–	90	3,000	50	30	20	MagPro
2013	Chen et al^Citation60; People’s Republic of China	L	5 cm	20	90	F8	–	90	–	20	34	10	MagStim
	Hernandez-Ribas et al^Citation61; Spain	L	5 cm	15	100	F8	–	90	1,500	20	60	15	MagStim
	Spampinato et al^Citation40; Italy	L	5 cm	10	120	F8	70	45	3,000	–	26	20	MagStim
	Speer et al^Citation62; USA	L	5 cm	20	110	F8	–	45	1,600	1 40	28	15	Cadwell

Notes:

* Mean values;

a only the “standard rTMS” group is included in the current analysis (patients in the positron emission tomography [PET]-guided rTMS group received rTMS at individually-determined target positions on the left or on the right hemisphere);

b since sham was applied bilaterally, only the active bilateral rTMS condition is included in the current analysis;

c only the “conventional rTMS” group is included in the current analysis (patients in the sleep electroencephalogram [SEM]-modulated rTMS group received rTMS to the frontal, occipital, and temporal areas);

d since sham was administered at 110% MT, only the active rTMS with 110% MT group is included in the current analysis;

e since sham was administered unilaterally, only the unilateral rTMS group is included in the current analysis;

f since sham was administered bilaterally, only the bilateral rTMS group is included in the current analysis. The left rTMS condition included sham to the right DLPFC. For the definition of location, 5 cm refers to 5 cm rostral (anterior) to the sagittal (parasagittal) plane.

Abbreviations: B, bilateral DLPFC; DLPFC, dorsolateral prefrontal cortex; F8, figure-of-eight shape; L, left DLPFC; MRI, magnetic resonance imaging; R, right DLPFC; rTMS, repetitive transcranial magnetic stimulation; TI, tangential with inactive coil; TS, tangential with sham coil containing embedded magnetic shield.

Table 3 Patient characteristics and depression scores in the active rTMS and sham groups in N=18 studies

Study diagnostic system; diagnosis	Data source	Mean age (all patients)	% female (all patients)	Treatment-resistance (failed trials)A	Bipolar depression (%)B	Psychotic depression (%)C	MedicationD	ScaleE	Mean ± SD (N) depression severity score				Mean ± SD (N) depression severity score
									Baseline (pre)		Last session (post)F		Baseline – last sessionF
									Sham	Active rTMS	Sham	Active rTMS	Sham	Active rTMS
George et al^Citation46; DSM-IV, MDDa	Tab 5	47	57	some (1–4)	–	–	–	HAMD24	27±5 (98)	26±5 (92)	23±7 (91)	22±9 (83)	4±6 (94)	4±8 (88)
			108/190					MADRS	30±6 (98)	29±7 (92)	28±9 (91)	25±11 (83)	2±8 (94)	4±10 (88)
Paillere Martinot et al^Citation50; DSM-IV, MDD	Auth	47	66	+ (≥2)	+ 28%	N/A	+	HAMD21	26±7 (14)	26±6 (18)	19±10 (14)	15±11 (18)	7±9 (14)	11±10 (18)
			21/32					MADRS	35±6 (14)	32±8 (18)	24±12 (14)	17±12 (18)	11±10 (14)	15±11 (18)
Pallanti et al^Citation51; DSM-IV, MDD	Tab 1B	48	58	+ (≥2)	N/A	–	+	HAMD21	29±4 (20)	29±6 (20)	28±4 (20)	22±4 (20)	1±4 (20)	7±5 (20)
	Fig 1B		23/40
Triggs et al^Citation52; DSM-IV, MDD	Tab 3 (all)	46	60	+ (≥2)	+	N/A	+	HAMD24	28±3 (14)	28±5 (34)	18±10 (14)	17±9 (34)	10±9 (14)	11±8 (34)
	Tab 3 R Tab 3 L		29/48		4%				27±3 (7)	27±5 (16)	13±7 (7)	14±8 (16)	14±6 (7)	13±7 (16)
	Tab 3 (all)								28±4 (7)	28±6 (18)	22±12 (7)	20±9 (18)	6±11 (7)	8±8 (18)
	Tab 3 R Tab 3 L							BDI21	29±7 (14)	31±10 (34)	19±12 (14)	18±13 (34)	10±10 (14)	13±12 (34)
									31±6 (7)	32±9 (16)	15±10 (7)	15±13 (16)	16±9 (7)	17±12 (16)
									27±7 (7)	30±11 (18)	23±13 (7)	21±12 (18)	4±11 (7)	9±12 (18)
Zheng et al^Citation41; DSM-IV, MDE	Tab 1	27	35	+ (≥2)	–	–	+	HAMD17	25±3 (15)	25±3 (19)	23±3 (15)	14±5 (19)	2±3 (15)	11±4 (19)
			12/34					BDI21	21±4 (15)	21±4 (19)	20±5 (15)	14±5 (19)	1±5 (15)	7±5 (19)
Aguirre et al^Citation53; DSM-IV, MDD	Auth	47	68 23/34	some (≥1)	–	–	+	HAMD17	19±5 (15)	19±6 (19)	16±4 (15)	15±5 (19)	3±5 (15)	4±6 (19)
He et al^Citation54; DSM-IV, DYS/MDD	Auth	39	70 56/80	N/A	–	N/A	–	HAMD24	24±4 (43)	23±4 (37)	24±5 (43)	21±4 (37)	0±5 (43)	2±4 (37)
Lingeswaran^Citation55; DSM-IV, DYS/MDD	Tab 2	36	61	some	–	–	+	HAMD17	22±3 (14)	23±4 (9)	12±3 (14)	13±5 (9)	10±3 (14)	10±5 (9)
	Tab 3		14/23					MADRS	31±6 (14)	32±5 (9)	17±5 (14)	17±4 (9)	14±6 (14)	15±5 (9)
Ray et al^Citation39; ICD-10, MDEb	Tab 2	34	20	N/A	+	+	+ D1	HAMD17	29±6 (20)	30±4 (20)	20±6 (20)	4±5 (20)	10±5 (20)	25±6 (20)
	Auth		8/40		30%	68%
Bakim et al^Citation56; DSM-IV, MDD	Tab 3	44	91	+ (≥2)	–	–	+	HAMD17	26±4 (12)	24±3 (11)	20±8 (12)	12±8 (11)	6±7 (12)	12±7 (11)
	Tab 4		21/23					MADRS	29±6 (12)	28±3 (11)	22±8 (12)	14±8 (11)	7±7 (12)	14±7 (11)
Blumberger et al^Citation57 DSM-IV, MDDa	; Tab IV L	47	62 26/42	+ (≥2)	–	–	+	HAMD17	25±3 (18)	26±3 (19)	18±4 (18)	20±6 (19)	7±4 (18)	6±5 (19)
Fitzgerald et al^Citation58; DSM-IV/ICD-10, MDD a	Tab 2	43	52	+ (≥2)	–	N/A	+	HAMD17	23±2 (20)	24±4 (22)	23±5 (17)	22±6 (19)	0±4 (18)	2±5 (21)
			22/42					BDI-II	28±10 (20)	38±10 (22)	27±11 (16)	30±13 (19)	1±11 (18)	8±12 (21)
								MADRS	32±4 (20)	34±6 (22)	30±6 (17)	31±10 (19)	2±5 (18)	3±9 (21)
Huang et al^Citation59; DSM-IV, MDE	Tab 2	32	70	–	–	–	+D1	HAMD17	22±3 (28)	23±2 (28)	17±2 (28)	15±2 (28)	5±3 (28)	8±2 (28)
	Tab 3		39/56					MADRS	36±5 (28)	35±4 (28)	28±4 (28)	24±2 (28)	8±5 (28)	11±3 (28)
Peng et al^Citation38; DSM-IV, MDE	Tab 2	27	37	+ (≥2)	–	–	+	HAMD17	25±3 (13)	25±3 (17)	23±3 (13)	14±2 (17)	2±3 (13)	11±3 (17)
			11/30					BDI	22±2 (13)	21±2 (17)	20±2 (13)	14±3 (17)	2±2 (13)	7±3 (17)
Chen et al^Citation60; DSM-IV, MDD	Tab 1	46	55	+ (2)	N/A	+	+	HAMD17	25±2 (10)	24±2 (10)	12±1 (10)	10±2 (10)	13±2 (10)	14±2 (10)
			11/20					BDI-II21	38±2 (10)	31±4 (10)	26±5 (10)	24±4 (10)	12±4 (10)	7±4 (10)
Hernandez-Ribas et al^Citation61; DSM-IV, MDE	Tab 2	46	76 16/21	some (≥1)	+ 29%	–	+	HAMD21	17±2 (11)	20±4 (10)	10±5 (11)	9±5 (10)	7±4 (11)	11±5 (10)
Spampinato et al^Citation40; DSM-IV-TR, MDE	Tab III	53	36	+ (3)	–	–	+	HAMD21	20±2 (10)	22±2 (12)	17±1 (10)	10±6 (12)	3±2 (10)	12±5 (12)
			8/22					MADRS	26±1 (10)	28±2 (12)	20±3 (10)	12±8 (12)	6±3 (10)	16±7 (12)
Speer et al^Citation62; DSM-IV, MDE	Tab 1 (all)	42	54	+ (≥2)	+	N/A	–	HAMD28	24±5 (8)	32±10 (16)	29±6 (8)	29±9 (16)	−5±6 (8)	3±10 (16)
	Tab 1 1 Hz		13/24		38%				24±5 (8)	29±8 (8)	29±6 (8)	25±7 (8)	−5±6 (8)	4±8 (8)
	Tab 1 20 Hz								24±5 (8)	36±11 (8)	29±6 (8)	32±10 (8)	−5±6 (8)	4±11 (8)

Notes: All studies included patients with a major depressive episode and/or disorder according to DSM-IV or ICD-10. The mean number of patients per group was used in the final calculations if patients dropped out throughout the study between baseline and final sessions (for example, in George et al⁴⁶). All values ending with exactly 0.5 were rounded as follows to reduce the rounding error in the current analysis: zero and uneven numbers were rounded upwards (1.5=2), even numbers were rounded downwards (2.5=2).

A Treatment-resistance: + are studies in which all (active and sham) patients failed (or showed intolerance to) ≥2 AD trials (of same or different class) of an adequate dose/length during current or lifetime episode; − are studies in which all patients failed 0–1 AD trials; “some” are studies in which patients failed ≥1 AD trials (these studies were excluded from all analyses because this category overlapped with the + and − category);

B Bipolar depression (%): + are studies including any proportion of patients with bipolar disorder I and/or II at baseline; − means that all patients had unipolar depression (no history of bipolar disorder, mania, hypomania, Axis I disorders);

C Psychotic depression (%): + are studies including any proportion of patients with psychotic features at baseline; − means that all patients had non-psychotic depression (no history of psychosis, Axis I disorders);

D medication = antidepressants (+ means any proportion of patients/study received stable doses, +D1 means that antidepressants were started on day 1 concurrently with rTMS, − means that all patients were antidepressant-free but some might have received mood stabilizers);

E it was assumed that the HAMD21 or BDI21 were used if no further information was provided;

F the “last session” refers to the last stimulation session of the double-blind phase of a study.

a Mean age and % female variables include patients who either withdrew before the end of study or were included in groups not included in the current study;

b according to the correspondence with authors, the mean and SD scores for the post-rTMS condition of the study should be reversed for the active and sham groups (correct scores are reported in this table). All means that scores for all independent subgroups within studies were combined.

Abbreviations: AD, antidepressant; Auth, authors; BDI, Beck Depression Inventory; DYS, dysthymia; D1, antidepressants started on day 1; DLPFC, dorsolateral prefrontal cortex; Fig, Figure; HAMD, Hamilton Depression Rating Scale; L, left DLPFC; MADRS, Montgomery Åsberg Depression Rating Scale; MDD, major depressive disorder; MDE, major depressive episode; N/A, not reported or inadequate information; R, right DLPFC; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders; ICD-10, International Statistical Classification of Diseases and Related Health Problems; rTMS, repetitive transcranial magnetic stimulation; SD, standard deviation; Tab, Table.

Table 4 Results of the random-effects meta-analysis of the N=14 “new” studies (2010–2013) and all N=54 studies: N=40 “old” studies (1997–2008) and N=14 “new” studies

	N studies (%)	d (95% CI)	Ptwo–tailed
Overall mean weighted d
“old 40” studies (1997–2008)	40	−0.54 (−0.68, −0.41)	<0.001*
“new 18” studies (2010–2013)	18	−0.80 (−1.16, −0.44)	<0.001*
“new 14” studies, outliers excluded	14	−0.42 (−0.66, −0.18)	<0.001*
“old 40” versus “new 14” studies			0.151
“New” N=14 studies	2010–2013
Total N patients	rTMS/sham	659 (340/319)
Heterogeneity	Q(df); Ptwo-tailed; I^2	Q(df 13)=25.9; P=0.018*; I^2=50%
Rosenthal’s Fail-safe N for P>0.05	N–studies needed to reduce the overall mean weighted d to 0	N=71 (N=5 studies missing for every study included in the current analysis)
Duval and Tweedie’s trim-and-fill analysis	Funnel plot symmetrical? N studies missing on either side of the overall mean weighted d	Yes None
Begg and Mazumdar rank order correlation	τ; Ptwo–tailed	−0.09; P=0.661
Egger’s regression	Intercept; Ptwo–tailed	−1.21; P=0.276

Note:

* P<0.05.

Abbreviations: CI, confidence interval; d, standardized mean difference (effect size); df, degrees of freedom; rTMS, repetitive transcranial magnetic stimulation; τ, Kendall’s correlation coefficient tau b with continuity correction.

Figure 2 Random-effects meta-analysis of N=14 “new” studies (2010–2013) comparing the change in mean depression scores on HAMD, BDI, and/or MADRS (baseline – final), after rTMS versus sham.

Notes: In the studies by Triggs et al⁵² and Speer et al,⁶² rTMS was administered using different properties into different subgroups of patients in a study and the depression scores for such subgroups were combined. The mean number of patients per group was used in the final calculations if patients dropped out throughout the study between baseline and final sessions. The forest plot (top) shows the weighted effect size d (box) and its 95% CI (vertical line through the box) for each study in the analysis (“combined” indicates that more than one depression scale was used in a study and the effect sizes according to the multiple scales were combined). The diamond depicts the overall mean weighted d of all studies and its 95% CI (width of the diamond). The mean depression scores (baseline – final) were significantly reduced after rTMS compared to sham (overall mean weighted d=−0.41, 95% CI: −0.64, −0.18). The funnel plot (bottom) shows the effect sizes d plotted versus SEM for each study in the analysis. The plot was symmetrical around the overall mean weighted d suggesting that publication bias had little effect on the results of the current meta-analysis.
Abbreviations: BDI, Beck Depression Inventory; CI, confidence interval; HAMD, Hamilton Depression Rating Scale; MADRS, Montgomery Åsberg Depression Rating Scale; rTMS, repetitive transcranial magnetic stimulation; SEM, standard error of mean; Std diff, standardized mean difference d.

Table 5 Random-effects subgroup analyses and meta-regressions of the change in depression scores (baseline – final) after rTMS compared to sham in N=54 sham-controlled studies published in 1997 – August 2013

Studies		N studies (%)a		d (95% CI)		Ptwo–tailed
All studies (1997–2013)		54		−0.51 (−0.63, −0.39)		<0.001*
Subgroups
Location-frequencyb		54
Left-slow (≤1 Hz)		4 (7%)		−0.61 (−1.21, −0.01)		0.046*
Left-fast (>1 Hz)		43 (80%)		−0.49 (−0.63, −0.34)		<0.001*
Right-slow		6 (11%)		−1.01 (−1.61, −0.42)		0.001*
Right-fast		1 (2%)		0.03 (−0.86, 0.92)		0.948
Bilateral or sequential (left then right)		7 (13%)		−0.55 (−0.82, −0.29)		<0.001*
Treatment resistance		27
Yes (all failed ≥2 AD trials)		21 (78%)		−0.52 (−0.70, −0.35)		<0.001*
No (all failed 0–1 AD trials)		6 (22%)		−0.80 (−1.02, −0.50)		<0.001*
Yes versus noc						0.108
Concurrent medication		54
YES (any % of patients)		42 (78%)		−0.51 (−0.63, −0.38)		<0.001*
Stable dose		35 (83%)		−0.51 (−0.65, −0.36)		<0.001*
Started on day 1		7 (17%)		−0.50 (−0.77, −0.23)		<0.001*
NO (all patients)		12 (22%)		−0.56 (−0.84, −0.28)		<0.001*
YES versus NOc						0.229
Bipolar depression		42
YES (any % of patients)		23 (55%)		−0.44 (−0.60, −0.28)		<0.001*
NO (all patients)		19 (45%)		−0.54 (−0.72, −0.34)		<0.001*
YES versus NOc						0.921
Psychotic depression		28
YES (any % of patients)		5 (18%)		−0.51 (−1.14, 0.13)		0.117
NO (all patients)		23 (82%)		−0.58 (−0.77, −0.40)		<0.001*
YES versus NOc						0.745
Coil-type		51
F8		47 (92%)		−0.52 (−0.65, −0.38)		<0.001*
Circular		4 (8%)		−0.62 (−1.05, −0.19)		0.005*
F8 versus circularc						0.561
Coil angle sham		54
0° (inactive coil)		5 (9%)		−0.36 (−0.64, −0.07)		0.015*
0° (sham coil)		10 (19%)		−0.63 (−0.92, −0.34)		<0.001*
45°		18 (33%)		−0.40 (−0.57, −0.22)		<0.001*
90°		21 (39%)		−0.56 (−0.77, −0.35)		<0.001*
0° (sham coil) versus 45°						0.757
0° (sham coil) versus 90°						0.150
	N studies	T^Citation2total	T^Citation2model	R^Citation2	B	Ptwo–tailed
Meta-regression predictorsd
% female patients	53	0.046	0.022	0.52	−0.01	0.002*
Stimuli/session	33	0.043	0.004	0.91	0.0002	<0.001*
Trains/sessione	48	0.071	0.044	0.38	0.007	0.013*

Notes: Total patients in N=54 studies totaled N=2,242 (rTMS N=1,184, sham N=1,058).

a The percent values are reported based on the number of studies that reported a particular characteristic;

b effect sizes in subgroups based on location-frequency of rTMS were not compared statistically because some studies used multiple active rTMS groups but the same sham groups, and thus the subgroups were not independent;

c subgroups were compared using the mixed-effect model; random-effects model was used to compute the overall mean weighted d in each subgroup and overall mean weighted d of subgroups were compared using the fixed-effect model because the number of subgroups was fixed;

d proportion of the between-study variance in weighted d explained by the predictor was computed as R²=1 − (T²_model/T²_total), where T²_model is the between-study variance in the weighted d (outcome) unexplained by the regression model containing the predictor and T²_total is the within- and between-study variance;²⁹

e following the Bonferroni correction for multiple regressions (new significance threshold of 0.05/7=0.007), the regression of trains/session on weighted d became non-significant.

* P<0.05.

Abbreviations: AD, antidepressant; CI, confidence interval; rTMS, repetitive transcranial magnetic stimulation.

Figure 3 Univariate random-effects meta-regressions of various study characteristics used as predictors (proportion of female patients/study and stimuli/session) on the weighted effect sizes d (the outcome) in studies published in 1997–2013.

Notes: The figures are scatterplots of the outcome (weighted d/study; Y-axes) versus predictors (X-axes): (A) proportion of female patients/study and (B) stimuli/session. Depression scores (baseline – final) were significantly reduced after rTMS compared to sham in studies with more female patients and less stimuli/session.
Abbreviations: rTMS, repetitive transcranial magnetic stimulation; Std diff, standardized mean difference d.

Figure S1 Random-effects meta-analysis of N=58 studies with standardized residuals and their P-values.

Notes: “All” indicates that rTMS was administered using different properties into different subgroups of patients in a study and the depression scores for such subgroups were combined. “Combined” indicates that more than one depression scale was used in a study and the effect sizes according to the multiple scales were combined). According to the P-values, 4/18 “new” studies were classified as outliers: Zheng et al 2010,⁹⁰ Ray et al 2011,⁷⁵ Peng et al 2012,⁷⁴ and Spampinato et al 2013.⁸¹ These studies were excluded from all subsequent analyses.

Abbreviations: CI, confidence interval; HAMD, Hamilton Depression Rating Scale; MADRS, Montgomery Åsberg Depression Rating Scale; rTMS, repetitive transcranial magnetic stimulation; Std diff, standardized mean difference d; Std, standardized.

Figure S2 Forest plot showing the comparison of the N=4 outliers with N=54 studies.

Notes: Subgroup analysis using the mixed-effects model revealed that the overall mean weighted effect size d was significantly higher in the N=4 outlier studies (d=−2.26) compared to the N=54 studies (d=−0.51): Q(df 1)=58.3, P<0.001. The variability of the weighted effect sizes was high among the N=4 outlier studies (SEM =0.23) compared to the N=54 studies (SEM =0.06).

Abbreviations: CI, confidence interval; rTMS, repetitive transcranial magnetic stimulation; SEM, standard error of mean; Std diff, standardized mean difference d.

Figure S3 Random-effects meta-analysis of N=54 studies.

Notes: “All” indicates that rTMS was administered using different properties into different subgroups of patients in a study and the depression scores for such subgroups were combined. “Combined” indicates that more than one depression scale was used in a study and the effect sizes according to the multiple scales were combined). The mean number of patients per group was used in the final calculations if patients dropped out throughout the study between baseline and final sessions.

Abbreviations: CI, confidence interval; HAMD, Hamilton Depression Rating Scale; MADRS, Montgomery Åsberg Depression Rating Scale; rTMS, repetitive transcranial magnetic stimulation; Std diff, standardized mean difference d.

Figure S4 One study removed analysis (N=54 studies).

Notes: “All” indicates that rTMS was administered using different properties into different subgroups of patients in a study and the depression scores for such subgroups were combined. “Combined” indicates that more than one depression scale was used in a study and the effect sizes according to the multiple scales were combined). “Point” refers to the overall mean weighted d of all studies except for the study listed in each row.

Abbreviations: CI, confidence interval; HAMD, Hamilton Depression Rating Scale; MADRS, Montgomery Åsberg Depression Rating Scale; rTMS, repetitive transcranial magnetic stimulation; Std diff, standardized mean difference d.

Figure S5 Cumulative meta-analysis (N=54 studies).

Notes: “All” indicates that rTMS was administered using different properties into different subgroups of patients in a study and the depression scores for such subgroups were combined. “Combined” indicates that more than one depression scale was used in a study and the effect sizes according to the multiple scales were combined). “Point” refers to the overall mean weighted d of all studies before and including the study listed in each row.

Abbreviations: CI, confidence interval; HAMD, Hamilton Depression Rating Scale; MADRS, Montgomery Åsberg Depression Rating Scale; rTMS, repetitive transcranial magnetic stimulation; Std diff, standardized mean difference d.

Figure S6 Univariate meta-regression of the total stimuli/study on the effect size d weighted according to the random-effects model.

Notes: Total stimuli = stimuli/session × total number of sessions. (A) The top figure shows the results of a significant meta-regression (slope P=0.015) in N=33 studies. However, the significance of this regression was due to two largest RCTs by O’Reardon et al³⁷ and George et al⁵⁵ (depicted as two largest circles on the right-hand side of (A). (B) These two RCTs are removed from the analysis in the bottom figure (slope, P=0.208).

Abbreviations: RCT, randomized controlled trial; std diff, standardized mean difference d.

Figure S7 Univariate meta-regression of the stimuli/session on the effect size d weighted according to the random-effects model (two largest RCTs removed).

Notes: The slope of meta-regression conducted on N=31 studies remained positive and statistically significant (P=0.018) following the removal of O’Reardon et al³⁷ and George et al⁵⁵ studies.

Abbreviations: RCT, randomized controlled trial; std diff, standardized mean difference d.

Table S1 A list of N=40 “old” studies on the association between rTMS from our previous meta-analysis (unpublished). These studies were included in sensitivity and moderator analyses in the current study

Author, year, country
George et al,^Citation1 1997, USA
Avery et al,^Citation2 1999, USA
Kimbrell et al,^Citation3 1999, USA
Klein et al,^Citation4 1999, Israel
Loo et al,^Citation5 1999, Australia
Padberg et al,^Citation6 1999, Germany
Berman et al,^Citation7 2000, USA
Eschweiler et al,^Citation8 2000, Germany
George et al,^Citation9 2000, USA
Garcia-Toro et al,^Citation10 2001, Spain
Garcia-Toro et al,^Citation11 2001, Spain
Manes et al,^Citation12 2001, USA
Boutros,^Citation13 2002, USA
Padberg et al,^Citation14 2002, Germany
Fitzgerald et al,^Citation15 2003, Australia
Höppner et al,^Citation16 2003, Germany
Loo et al,^Citation17 2003 Australia
Nahas et al,^Citation18 2003, USA
Buchholtz et al,^Citation19 2004, Denmark
Hausmann et al,^Citation20 2004, Austria
Holtzheimer et al,^Citation21 2004, USA
Kauffmann et al,^Citation22 2004, USA
Koerselman et al,^Citation23 2004, the Netherlands
Mosimann et al,^Citation24 2004, Switzerland
Poulet et al,^Citation25 2004, France
Rossini et al,^Citation26 2005, Italy
Rumi et al,^Citation27 2005, Brazil
Su et al,^Citation28 2005, Taiwan
Avery et al,^Citation29 2006, USA
Fitzgerald et al,^Citation30 2006, Australia
Garcia-Toro et al,^Citation31 2006, Spain
Januel et al,^Citation32 2006, France
Anderson et al,^Citation33 2007, UK
Bortolomasi et al,^Citation34 2007, Italy
Herwig et al,^Citation35 2007, Germany/Austria
Loo et al,^Citation36 2007, Australia
O’Reardon et al,^Citation37 2007, USA, Australia, Canada
Stern et al,^Citation38 2007, USA
Bretlau et al,^Citation39 2008, Denmark
Mogg et al,^Citation40 2008, UK

Abbreviation: rTMS, repetitive transcranial magnetic stimulation.

Table S2 A list of N=50 studies on the association between rTMS and depression assessed in full-length and reasons for exclusion from the current meta-analysis

Author, year	Included/reason for exclusion
Aguirre et al,^Citation41 2011	Included (additional data provided by authors)
Avery et al,^Citation42 2007	No new data (data from Avery et al,^Citation29 2006)
Baeken et al,^Citation43 2010	Cross-over design, only one session
Bakim et al,^Citation44 2012	Included
Bares et al,^Citation45 2009	No sham (rTMS and placebo medication versus sham and venlafaxine)
Blumberger et al,^Citation46 2012	Included
Brakemeier et al,^Citation47 2007	No sham
Brakemeier et al,^Citation48 2008	No sham
Chen et al,^Citation49 2013	Included
Cohen et al,^Citation50 2009	No sham
Dell’Osso et al,^Citation51 2009	No sham
Fitzgerald et al,^Citation52 2012	Included
Furtado et al,^Citation53 2012	No sham
Galletly et al,^Citation54 2012	No sham
George et al,^Citation55 2010	Included
Hadley et al,^Citation56 2011	No sham
He et al,^Citation57 2011	Included (additional data provided by authors)
Herbsman et al,^Citation58 2009	No new data (data from Avery et al,^Citation29 2006)
Hernández-Ribas et al,^Citation59 2013	Included
Herwig et al,^Citation60 2010	No new data (data from Herwig et al,^Citation35 2007)
Höppner et al,^Citation61 2010	No new data (data from Herwig et al,^Citation35 2007)
Hoy et al,^Citation62 2012	No sham
Huang et al,^Citation63 2008	No sham
Huang et al,^Citation64 2012	Included
Jacob et al,^Citation65 2008	Inadequate data reported (SD values missing on Figure 1)
Kozel et al,^Citation66 2011	No new data (data from O’Reardon et al,^Citation37 2007)
Kreuzer et al,^Citation67 2012	rTMS after sleep deprivation
Lingeswaran et al,^Citation68 2011	Included
Lisanby et al,^Citation69 2009	No new data (data from O’Reardon et al,^Citation37 2007)
Myczkowski et al,^Citation70 2012	Depression secondary to birth (postpartum depression)
Nongpiur et al,^Citation71 2011	No sham (primed all conditions with right 1 Hz stimulation)
Paillère Martinot et al,^Citation72 2010	Included (additional data provided by authors)
Pallanti et al,^Citation73 2010	Included (week 3 data extrapolated from Figure 1)
Peng et al,^Citation74 2012	Included
Ray et al,^Citation75 2011	Included
Rosenquist et al,^Citation76 2013	No new data (data from O’Reardon et al,^Citation37 2007)
Schrijvers et al,^Citation77 2012	No sham (one single sham session followed by active treatment)
Schutter et al,^Citation78 2009	DLPFC not stimulated (parietal cortex stimulated)
Schutter et al,^Citation79 2010	No new data (data from Schutter et al,^Citation78 2009)
Simpson et al,^Citation80 2009	No new data (data from O’Reardon et al,^Citation37 2007)
Spampinato et al,^Citation81 2013	Included
Speer et al,^Citation82 2009	Inadequate data reported (baseline scores/group missing)
Speer et al,^Citation83 2013	Included
Tamas et al,^Citation84 2007	Inadequate data reported (HAMD scores missing)
Triggs et al,^Citation85 2010	Included
Trojak et al,^Citation86 2011	Case study
Ullrich et al,^Citation87 2012	No sham (sham was the active left-slow stimulation of the DLPFC)
Zarkowski et al,^Citation88 2009	No sham
Zheng et al,^Citation89 2010	No new data (same cases as in Zheng et al,^Citation90 2010)
Zheng et al,^Citation90 2010	Included

Note: A total of N=18/50 studies were included in the final meta-analysis.

Abbreviations: DLPFC, dorsolateral prefrontal cortex; HAMD, Hamilton Depression Rating Scale; rTMS, repetitive transcranial magnetic stimulation; SD, standard deviation;

Table S3 Location (country) where the N=54 studies published from 1997 to August 2013 were conducted

Rank	Country	Number of studies
1	USA	16
2	Australia	7
3	Spain	6
4	Germany	4
5	People’s Republic of China, France, Italy	3 each
6	Austria, Canada, Denmark, UK	2 each
7	Brazil, India, the Netherlands, Switzerland, Taiwan, Turkey	1 each

Note: N does not add up to 54 because some studies were conducted in more than one country.

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