Repetitive transcranial magnetic stimulation (rTMS) for treating major depression and schizophrenia: a systematic review of recent meta-analyses

Figures & data

Figure 1. Flow diagram describing search techniques and inclusion/exclusion of meta-analyses.

Table I. Summary of meta-analyses methods for study selection and patient medication characteristics.

Meta-analytical methods					Patient medication characteristics
Major Depression
Authors	Database / Period How about period searched / include	Primary outcome/ secondary outcome	Inclusion criteria	Exclusion criteria	Medication-resistant (#yes / #no / #N/A)	Medications at the start of rTMS (#stable/#unstable/ #off meds/#N/A)
McNamara et al. 2001	MEDLINE (1966-Jan 2000) EMBASE (1980-Jan 2000) Biological Abstracts and Index of Scientific and Technical Proceedings, Meta register of Controlled Trials, national register, Cochrane Library	HAM-D 17-21-25	• Must be a randomized controlled trial • Must be a placebo-controlled trial	N/A	N/A	0/0/1/4
Holtzheimer et al. 2001	MEDLINE Avery–George–Holtzheimer Database of rTMS Depression Trials	HAM-D 17-21-25	• Sham controlled design with cross-over or parallel groups •Diagnosis of depression (MDD, bipolar disorder, depressed) • Must have reported means and standard deviations for HAM-D (pre/post) • Prefrontal cortical stimulation (left or right) • Cannot have any overlap with another included study	•Studies that used alternative depression treatments as their ‘control’ condition	8/2/2	4/5/0/0
Kozel et al. 2002	PsycINFO (1887-Apr 2002), MEDLINE (1966-Apr 2002), CURRENT CONTENTS (Apr 2001-Apr 2002)	HAM-D	•English language only •Randomized sham-controlled trials •Double-blinded; naïve to TMS • rTMS of left prefrontal cortex treatment	N/A	N/A	7/2/3/0
Burt et al. 2002	N/A	HAM-D MADRS	N/A	N/A	7/1/1	N/A
Martin et al. 2003	MEDLINE (1966- Mar 2002), EMBASE (1974-Mar 2002, PsycLit (1980-2001), Register of Clinical Trials of the Cochrane Collaboration Depression, Neurosis and Anxiety Review Group (Jan 2002), Cochrane Controlled Trials Register (Jan 2002)	Symptom remission	•Randomized, sham-controlled trials •Any localization of coil, any rTMS frequency • Diagnosis of depression without psychotic symptoms	N/A	7/7/0	3/0/0/11
Couturier 2005	MEDLINE/2000-2003	HAM-D 21 BDI MADRS CGI	• Randomized parallel or cross-over design with sham control •Allocation concealment; double-blind; use of an intent-to-treat analysis •MDD diagnosis (DSM-IV)	• Open trials •Investigations including MDD with psychotic features •Populations including children and elderly	2/0/4	6/0/0/0
			•If cross-over design, then must have attest for interaction or carry-over effect that is non-significant •TMS parameters: rTMS frequency ≥ 10 Hz, applied over L-DLPFC; intensity greater than 80%; duration of 5-10 days; coil angled between 45˚ to 90˚ from scalp for sham condition •Outcome: Data reported must be adequate to be used for meta-analysis (i.e. post-treatment SD) • 21-item HAM-D must be primary outcome measure	• rTMS protocols combined with initiation of medications
Herrmann et al. 2006	MEDLINE, EMBASE, Cochrane/N/A	HAM-D MADRS	•Double-blind randomized parallel or cross-over design with sham control •Diagnosis of depression •Must use HAM-D or MADRS as outcome measure • Must have required info needed for meta-analysis (baseline and follow-up depression scores, SD, etc.)	N/A	18/12/0	25/5/0/0
Gross et al. 2007	PubMed Dec 2005-Nov 2006	HAM-D, MADRS	•Must be written in the English language •Randomized double-blind studies with sham •rTMS at any frequency and any localization •DSM diagnosis of MDD • Mood assessment using the following scales: HAM-D, BDI, or MADRS • Pre/post-treatment mean and SD of scores (from above-mentioned scales)	•Reviews •Neuropsychiatric diseases other than MDD •Case reports • No sham	3/2/0	4/5 studies were taking meds (no info as to whether they were stable)
Lam et al. 2008	MEDLINE (1966-2008), EMBASE (1980-2008), PsycINFO (1974-2008), Cochrane (up to May 2008)	Clinical response / clinical remission	•RCTs with sham condition •Well-defined TRD (must include at least 1 failed AD trial) •Details rTMS parameters	•Inclusion of depression co-morbid to other conditions	24/0/0	18/2/4/0
Schutter 2009	PubMed, Web of Science/ January 1980-November 2007	HAM-D 6,17,21,28 MADRS	•English language •MDD without psychotic features •High frequency rTMS over L-DLPFC, 80% MT, min 5 treatments, sham coil or 45° and 90° from scalp • HAM-D or MADRS as primary outcome measure	N/A	17/8/5	N/A
Slotema et al. 2010	PubMed (1990-Oct 2008), Ovid MEDLINE (1990-Oct 2008), EMBASE Psychiatry (1997-Oct 2008),	N/A	• English language •Parallel, double-blind, randomized controlled parallel design using a sham condition	N/A	N/A	N/A
	Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, PsycINFO (1990-Oct 2008)		•Diagnosis of psychiatric disorder in accordance with the DSM and or ICD criteria; not a ‘narrow’ diagnosis such as vascular depression •Sufficient data to calculate Hedges's g •Minimum of 3 studies for the psychiatric disorder •Minimum of 3 patients per study • If articles describe overlapping samples, the study with the largest sample size was included
Schizophrenia
Aleman et al. 2007	PubMed, Web of Science /1966-February 2006	PANSS, BPRS	•Parallel or cross-over design with sham or active control •Diagnosis of schizophrenia • Hallucination rating scale or item from a standardized psychiatric interview (i.e. PANSS or Brief Psychiatric Rating Scale	•Open trials •Insufficient data to calculate effect size • No sham control	N/A	N/A
Tranulis et al. 2008	MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials/1985–1 May 2006	AHRS, SAH, HCS, PSYRATS-AH, PANSS-AH	•Human experimental studies of rTMS •Treatment of AH • Diagnosis of SSD	•Not randomized •No placebo •Fewer than 3 treatment sessions •Lack of validated psychometric scale for AH •Coil placed other than over the left TPC •TMS not given at a low frequency	N/A	N/A
Freitas et al. 2009	Web of Science/up to July 2008	PANSS, SANS, SAPS, AHRS, HCS, SAH	•English language •Open, cross-over, or parallel study design •TMS applied for more than 1 session •Stabilization of psychotropics at least 4 weeks prior to treatment and maintained during treatment Negative symptoms: •High-frequency rTMS over L-DLPFC •PANSS-N or SANS used for outcome measure Positive symptoms: • Low-frequency rTMS over left TPC (specific criteria for locating TPC) • PANSS-P or SAPS used for outcome measure	• Single or paired pulse TMS • Did not meet inclusion criteria • Failure to report mean and standard deviation of outcome measures before and after treatment Negative symptoms: • Low-frequency rTMS • Bilateral or R-DLPFC • Non-specific outcome measures for negative symptoms	N/A	N/A
				Positive symptoms: • High-frequency on brain sites other than TPC • Non-specific outcome measures for positive symptoms
Dlabac-de Lange et al. 2010	PubMed, Web of Science, EMBASE, 1985-July 2008	SANS, PANSS	•Parallel or cross-over design with sham • Diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder	•Cross-over studies with wash-out phase of less than 4 weeks •Insufficient information to calculate effect size • No sham control	N/A	N/A
Slotema et al. 2010	PubMed (1990-Oct 2008), Ovid MEDLINE (1990-Oct 2008), EMBASE Psychiatry (1997-Oct 2008), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, PsycINFO (1990-Oct 2008)	N/A	•English language •Parallel, double-blind, randomized controlled parallel design using a sham condition •Diagnosis of psychiatric disorder in accordance with the DSM and or ICD criteria; not a ‘narrow’ diagnosis such as vascular depression •Sufficient data to calculate Hedges's g •Minimum of 3 studies for the psychiatric disorder •Minimum of 3 patients per study • If articles describe overlapping samples, the study with the largest sample size was included	N/A	‘most studies included patients with medication resistant AVH’	N/A

AD = antidepressant; AH = auditory hallucinations; AHRS = Auditory Hallucination Rating Scale; AVH = auditory verbal hallucinations; BDI = Beck Depression Inventory; BPRS = Brief Psychiatric Rating Scale; CGI = Clinical Global Impression Severity of Illness Rating; DSM = Diagnostic and Statistical Manual; HAM-D = Hamilton Rating Scale for Depression; HCS = Hallucination Change Scale; ICD = International Classification of Diseases and Related Health Problems; L-DLPFC = left dorsolateral prefrontal cortex; MADRS = Montgomery–Åsberg Depression Rating Scale; MDD = major depression disorder; MT = motor threshold; N/A = information was not available; PANSS = Positive and Negative Syndrome Scale; PSYRATS = Psychotic Symptoms Rating Scale; RCT = randomized controlled trial; R-DLPFC = right dorsolateral prefrontal cortex; rTMS = repetitive transcranial magnetic stimulation; SAH = Scale for Auditory Hallucinations; SANS = Scale for the Assessment of Negative Symptoms; SAPS = Scale for the Assessment of Positive Symptoms;SD = standard deviation; SSD = schizophrenia spectrum disorders; TPC = temporo-parietal cortex; TRD = treatment-resistant depression.

Table II. Summary of rTMS parameters and efficacy in meta-analytical studies.

Authors	Total studies/total subjects	Stimulation site	Frequency (Hz)	Intensity (% MT)	Pulses per session	No. of sessions (days)	Weighted effect size	Significance of test of heterogeneity yes/no	Clinical response(s)
Major depression disorder
McNamara et al. 2001	5/151	N/A	N/A	N/A	N/A	N/A	13.3	No	• rTMS appears to be beneficial in treating depression
Holtzheimer et al. 2001	12/264	L-DLPFC R-DLPFC	0.3–20	80–110		5–10	0.81	N/A	•rTMS was shown to be more beneficial than sham in treating MDD
Kozel et al. 2002	12/230	L-DLPFC	0.3–20	80–110	250–2000	5–10	0.53	No	• Clinical improvements in depression can be achieved by rTMS to the L-DLPFC
Burt et al. 2002	32/455 (9 were open-labelled)	Vertex Motor cortex 8 site TMS Bilateral L-DLPFC R-DLPFC	0.017–40	80–110	30–4800	1–15	Open 1.37; sham 0.67	Open: No; Sham: Yes	• rTMS is an effective methods of reducing depressive symptoms
Martin et al. 2003	14/324	L-DLPFC R-DLPFC	0.3–20	80–110	120–2000	5–10	–0.35	Yes	•Due to the poor quality of studies, insufficient data were obtained to determine whether rTMS is effective at treating depression
Couturier 2005	6/91	L-DLPFC	10–20	80–100	250–2000	5–10	–1.1	No	• rTMS was not more effective than placebo at treating MDD
Herrmann et al. 2006	33/877	L-DLPFC R-DLPFC	± 15^A	80 to > 100	N/A	5 to > 10	0.65*	Yes	•Active rTMS is more effective than sham at reducing symptoms of MDD (33.6% reduction of symptoms)
Gross et al. 2007	5/274	R-DLPFC: 20% 1 Hz; L-DLPFC: 40% 10, 15, 20 Hz; Bilateral: 40%		90–110	120–3000	10–16	0.76	No	• Effect sizes appear to be increasing compared to past meta-analyses of rTMS and depression (see Martin et al.) suggesting an improvement over the years of methodology and outcomes
Lam et al. 2008	24/1092	L-DLPFC: 1,8,10,17,20 Hz; R-DLPFC: 1 Hz; Bilateral: 15 Hz		80–120	N/A	5–20	0.48	Yes	• Active rTMS appears to be more effective at treating TRD than sham rTMS
Schutter 2009	30/1164	L-DLPFC	5–20	80–120	250–3000	5–20	0.39	No	• rTMS over the L-DLPFC is more effective than sham rTMS at reducing depression symptoms
Slotema et al. 2010	34/1383	L-DLPFC; R-DLPFC; Bilateral	0.3–20	80–100	120–3000	5–25	0.55	Yes	• rTMS is more effective than sham at treating depression
Schizophrenia
Aleman et al. 2007	10/212	L TPC	1	80–100	N/A	4–10	0.76	Yes	• When compared to sham, rTMS applied to the left TPC is more effective at specifically reducing hallucinations in schizophrenia and not positive symptoms in general
Tranulis et al. 2008	10/232	L TPC	1	80–100	300–2000	4–10	0.514	No	• Low-frequency rTMS over the left TPC is more effective than sham at reducing medication-resistant AH
Freitas et al. 2009 NegSym	8/107	L-DLPFC	10–20	80–110	400–2000	5–20	0.27	No	• rTMS to the L-DLPFC is not statistically more effective than sham at reducing negative symptoms in schizophrenia
Freitas et al. 2009 PosSym	12/232	Left TPC	0.9–1	80–100	120–1200	4–15	PS: 0.17; AH: 1.04	PS: No; AH: Yes	• Low-frequency rTMS to the left TPC is not significantly better than placebo at reducing positive symptoms in schizophrenia
Dlabac-de Lange et al. 2010	9/213	L-DLPFC Right PFC Bilateral DLPFC	1–20	90–110	120–2000	10–20	0.43	Yes	• Effect size increased when studies stimulating at 1 Hz frequency were excluded (d = 0.63), and heterogeneity disappeared
Slotema et al. 2010 NegSym	7/148	Bilateral L-DLPFC R-DLPFC	1–20	90–110	120–2000	10–15	0.39	Yes	•When compared to sham, active rTMS over DLPFC, rTMS was not significantly better at improving NS. (This lack of significance may be attributed to a lack of studies)
Slotema et al. 2010 PosSym	7/189	T3P3; T4P4	1	80–100	300–1600	4–10	0.54	No	• When compared to sham, active rTMS over the TPC seems to be more effective at reducing medication-resistant AH

AH = auditory hallucinations; L-DLPFC = left dorsolateral prefrontal cortex; N/A = information was not available; NS = negative symptoms; PFC = prefrontal cortex; PS = positive symptoms; R-DLPFC = right dorsolateral prefrontal cortex; rTMS = repetitive transcranial magnetic stimulation; T3P3 = midpoint between T3 and P3 using 10–20 EEG system; T4P4 = midpoint between T4 and P4 using 10–20 EEG system; TPC = temporo-parietal cortex. ^AAuthors did not provide information about individual studies.

Table III. Summary of effect sizes of the reviewed meta-analyses.

		Schizophrenia
Reference	Major depression	Positive symptoms	Auditory hallucinations	Negative symptoms
Holtzheimer et al. 2001 (42)	0.81^a	–	–	–
Kozel et al. 2002 (37)	0.53^b	–	–	–
Burt et al. 2002 (39)	0.67^b	–	–	–
Martin et al. 2003 (45)	0.35^c	–	–	–
Couturier 2005 (40)	–1.1^c	–	–	–
Herrmann et al. 2006 (41)	0.65^b	–	–	–
Gross et al. 2007 (46)	0.76^a	–	–	–
Lam et al. 2008 (43)	0.48^b	–	–	–
Schutter et al. 2009 (44)	0.39^b	–	–	–
Schutter et al. 2010 (38)	0.63^b	–	–	–
Aleman et al. 2007 (47)	–	0.21^c	0.76^b	–
Tranulis et al. 2008 (50)	–	0.51^b	–	–
Freitas et al. 2009 (49)	–	0.17^c	1.04^a	0.27^c
Dlabac-de Lange et al. 2010 (48)	–	–	–	0.43^b
Slotema et al. 2010 (24)	0.55^b	–	0.54^b	0.39^b

^aLarge effect size = ≥ 0.65.

^bMedium effect size = 0.36–0.65.

^cSmall effect size = ≤ 0.35.

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