Repetitive Transcranial Magnetic Stimulation for ... - SAGE Journals

Review Paper

Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression: A Systematic Review and Metaanalysis Raymond W Lam, MD, FRCPC1; Peter Chan, MD, FRCPC2; Michael Wilkins-Ho, MD, FRCPC3; Lakshmi N Yatham, MBBS, MRCPsych (UK), FRCPC4 Objective: Systematic reviews show that repetitive transcranial magnetic stimulation (rTMS) is superior to sham control conditions in patients with major depressive disorder, but the clinical relevance is not clear. None have specifically examined outcomes in patients with treatment-resistant depression (TRD). Method: A systematic review was conducted by identifying published randomized controlled trials of active rTMS, compared with a sham control condition in patients with defined TRD (that is, at least one failed trial). The primary outcome was clinical response as determined from global ratings, or 50% or greater improvement on a rating scale. Other outcomes included remission and standardized mean differences in end point scores. Metaanalysis was conducted for absolute risk differences using random effects models. Sensitivity and subgroup analyses were also conducted to explore heterogeneity and robustness of results. Results: A total of 24 studies (n = 1092 patients) met criteria for quantitative synthesis. Active rTMS was significantly superior to sham conditions in producing clinical response, with a risk difference of 17% and a number-needed-to-treat of 6. The pooled response and remission rates were 25% and 17%, and 9% and 6% for active rTMS and sham conditions, respectively. Sensitivity and subgroup analyses did not significantly affect these results. Dropouts and withdrawals owing to adverse events were very low. Conclusions: For patients with TRD, rTMS appears to provide significant benefits in short-term treatment studies. However, the relatively low response and remission rates, the short durations of treatment, and the relative lack of systematic follow-up studies suggest that further studies are needed before rTMS can be considered as a first-line monotherapy treatment for TRD. Can J Psychiatry 2008;53(9):621–631 Clinical Implications · Adjunctive treatment with rTMS may be efficacious for patients with TRD. · There are few adverse effects with rTMS and it is well-tolerated by patients. · s and rTMS can be used in combination. Limitations · Unpublished studies were not sought in this systematic review. · The identified randomized controlled trials had small sample sizes and short durations (1 to 4 weeks with a median of 2) of treatment. · Follow-up after treatment discontinuation was usually not systematically conducted.

Key Words: depressive disorders, transcranial magnetic stimulation, treatment resistant depression, metaanalysis, systematic review

The Canadian Journal of Psychiatry, Vol 53, No 9, September 2008 W

621

Review Paper

novel treatment for neuropsychiatric conditions such as depression is rTMS, a noninvasive procedure in which a sequence of high-intensity magnetic pulses is applied to stimulate cortical neurons.1 Advantages of rTMS, compared with other somatic treatments such as ECT, include it being deliverable in an office setting, it does not require anesthesia, and it has fewer associated side effects.1

A

Several systematic reviews and metaanalyses of rTMS studies in MDD have been conducted, including one for the Cochrane Collaboration.2–8 These reviews have found statistically significant effects of active rTMS over sham conditions. However, the clinical relevance of these findings is not as clear, as the overall clinical response of rTMS (whether measured as percentage improvement on depression rating scales, or as dichotomous outcomes on global improvement scales) has been rather limited. Hence, several of these systematic reviews concluded that there was insufficient evidence to support the clinical use of rTMS in treating depression. In part, this may have been owing to inclusion of earlier studies in which stimulus parameters were still being investigated and optimized. More recently, there has been consensus that high-intensity HFL-rTMS, or LFR-rTMS are associated with AD effects. Recent RCTs using these stimulation parameters have shown greater clinical effects than previous studies. 8 Episodes of depression that are refractory to one or more AD trials are referred to as TRD. Although there is still no clear consensus for criteria for medication resistance,9 TRD (as typically defined by failure of 2 AD trials) may affect 15% or more of patients treated for a major depressive episode.10 Given the large proportion of patients with TRD and the limited response to treatment, it is not surprising that TRD is associated with a significant burden of illness and disability.11–13

Abbreviations used in this article AD

antidepressant

ECT

electroconvulsive therapy

HDRS

Hamilton Depression Rating Scale

HFL

high-frequency to the left dorsolateral prefrontal cortex

LFR

low-frequency to the right dorsolateral prefrontal cortex

MADRS Montgomery–Asberg Depression Rating Scale MDD

major depressive disorder

NNT

number-needed-to-treat

RCT

randomized controlled trial

rTMS

repetitive transcranial magnetic stimulation

SMD

standardized mean difference

TRD

treatment-resistant depression

622

The management of TRD remains unclear as there is still limited ev id e n c e f o r o p tima l p h a r ma c o lo g ic an d psychotherapeutic strategies for TRD.14–16 Given the limited number of validated therapies for TRD, rTMS has been identified as an important investigational treatment.17 Indeed, several recently published sham-controlled trials of rTMS have focused on samples of patients with TRD. However, many of the previous systematic reviews combined studies with medication-resistant patients with those involving less resistant samples and they have not specifically examined efficacy of rTMS for TRD. The objective of this study was to systematically review the published studies of rTMS in patients with TRD, focusing on clinical outcomes that are relevant to clinicians.

Methods All relevant RCTs comparing rTMS with a sham control condition were identified. Inclusion criteria for studies were: diagnosis of MDD by the Diagnostic and Statistical Manual of Mental Disorders or the International Classification of Diseases criteria, an explicit definition of TRD that included at least one failed trial of an AD, a sham control condition, an outcome measure that included either a defined clinical response or a continuous score on a depression rating scale, and a description of the rTMS parameters used. Studies involving depression comorbid to other medical conditions (for example, Parkinson disease) were excluded. The primary outcome was clinical response as defined by either a defined percentage improvement on a continuous score from a depression rating scale (for example, 50% or greater improvement from baseline score to end of treatment on the HDRS or the MADRS), or by a global rating scale (for example, much improved or very much improved on the Clinical Global Impression Scale). Secondary outcomes included clinical remission, defined as either: a score on a depression rating scale within the normal range (for example, HDRS of 7 or less, or MADRS of 12 or less), or a global rating of not depressed or equivalent on the Clinical Global Impression Scale; and SMD (also known as the effect size) on end of treatment scores on depression rating scales. Adverse effects were evaluated by examining the number of dropouts owing to adverse effects, and total number of dropouts for any reason was examined as a proxy measure of treatment acceptability. Relevant RCTs were identified by electronically searching MEDLINE (from 1966 onward), EMBASE (from 1980 onward), PsycINFO (from 1974 onward) and the Cochrane Central Register of Controlled Trials databases up to May 15, 2008, using the search terms transcranial, magnetic, and depress*. Two independent reviewers examined titles and abstracts of the studies, and then checked full articles for W La Revue canadienne de psychiatrie, vol 53, no 9, septembre 2008

Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression: A Systematic Review and Metaanalysis

eligibility. To identify further trials, references of these selected studies and of other review papers were also checked. No language restriction was imposed. Two independent reviewers extracted data and assessed the quality of methodological reporting of selected studies, using data extraction forms. The criteria for quality assessment were based on recommendations in the Cochrane Handbook for Systematic Reviews of Interventions,18 and included the quality of allocation concealment, blinding to treatment allocation, and plausibility of the sham condition. Any disagreement was resolved by discussion with a third reviewer and consensus among all 3 reviewers. Posttreatment data were extracted from the end of blinded acute treatment and after a no-treatment, blinded follow-up period. When more than one active treatment (for example, HFL and LFR stimulation) was compared with sham, the results from the active treatment conditions were pooled together. For crossover studies, only data from the first crossover sequence were used. In some studies, after a defined period of blinded treatment, continuation treatment was offered only to responders (leading to differential retention of patients between conditions) or under unblinded, open-label conditions. For these studies, we used only the data from the blinded acute treatment period that included the original randomized sample. Data were double-entered into Review Manager 4.219 to check for accuracy. Metaanalyses were then performed. For dichotomous outcomes, an intent-to-treat analysis was adopted. When dropouts were excluded from any assessment in the studies (for example, those who never returned for assessment after randomization), they were considered nonresponders. Absolute risk differences, indicating the difference in response rates between the active and sham conditions, and 95%CIs were calculated. We used a random effects model rather than a fixed effects model because it is more appropriate when heterogeneity is likely to be present.20 For continuous outcomes, the SMD was calculated for end point data of completers, again using a random effects model. Results are reported as means and 95%CIs. Heterogeneity, referring to variability among studies in a systematic review arising from clinical, methodological, or statistical diversity, 21 was assessed by chi-square and I-squared statistics.22 We also planned sensitivity and subgroup analyses to examine robustness of findings, by limiting to trials with stricter criteria for TRD (2 or more failed trials of ADs), limiting to trials using high-intensity (motor threshold of 90% or greater) HFL (10 Hz or greater) stimulation, and limiting to trials with higher quality reporting (the following rated at least adequate: description of allocation concealment, double-blindness, and adequacy of sham The Canadian Journal of Psychiatry, Vol 53, No 9, September 2008 W

treatment). Publication bias was examined using funnel plots and visual inspection.

Results Included Studies A total of 32 RCTs of rTMS for TRD were identified. Among these, 8 studies were excluded for the following reasons: no sham treatment,23–25 no explicit definition for TRD,26,27 reporting cognitive or pain outcomes from another trial,28,29 and multiple crossovers with no data on the first treatment sequence.30 Among the remaining studies, one did not report clinical response or remission rates, or rating scale scores after the first crossover sequence,31 leaving 23 studies available for quantitative synthesis. All studies used the HDRS or MADRS as a primary outcome. Table 1 lists the definitions of TRD and rTMS parameters used in the 24 included trials. Nine studies used a definition of TRD as failing one or more trials of ADs; the rest used the more typical definition of failing 2 or more ADs. There was reasonable homogeneity of rTMS variables, with HFL-rTMS (10 Hz or higher), the most common active condition studied. Most studies used 1 to 2 weeks of treatment, with only 3 studies using 3 weeks and only 2 studies using 4 weeks; almost all studies limited treatment to weekdays (5 sessions for each week). Most studies also included patients who were on various medications, although doses were kept unchanged before and during treatment. Only 4 studies included medicationfree patients. In 2 studies, rTMS was used concomitantly with starting a new AD such as sertraline 50 mg32 and escitalopram 20 mg.33 Only 8 studies systematically followed all patients, untreated, after completing the double-blind phase (Table 2). Among these, 2 studies also started patients on an AD at the beginning of rTMS33,34 and 2 studies had only graphical presentation of group mean scores at follow-up.35,36 The remaining 4 studies were available for quantitative synthesis. Quantitative Synthesis The chi-square and I-squared tests were significant (P < 0.05 or I2 > 30%) for all comparisons, indicating significant heterogeneity in studies. The active rTMS condition had a significant risk difference for clinical response of 17% (95%CI, 10% to 23%; n = 22 studies, 996 total patients) (Figure 1) and for clinical remission of 14% (95%CI, 6% to 21%; n = 16 studies, 795 total patients) (Figure 2). The active rTMS also resulted in a significant and medium-sized SMD of 0.48 (95%CI, 0.28 to 0.69; n = 21 studies, 899 total patients), compared with sham conditions. The pooled response and remission rates were, respectively, 25% and 17% for active rTMS, and 9% and 6% for sham conditions. The NNT for clinical response was 6, and for remission was 7. 623

Review Paper

Table 1 Summary of clinical parameters of included studies rTMS placement

rTMS frequency

rTMS % MT

Duration, weeks

Sample size

Failed 2 or more AD (79% of sample)

L DLPFC

10

110

4

29

Avery et al41

Failed 2 or more AD, ATHF 3 or more

L DLPFC

10

110

3

68

Same medications

Berman et al42

Failed 1 or more AD, past or present episode, 4 weeks minimum

L DLPFC

20

80

2

20

Off all medications ´ 1 week

Boutros et al43

Failed 2 or more AD

L DLPFC

20

80

2

22

Same medications

Bretlau et al33

Failed 1 or more AD, 6 weeks minimum

L DLPFC

8

90

3

45

All started on escitalopram 20 mg

Fitzgerald et al44

Failed 2 or more AD; 6 weeks minimum

L DLPFC; R DLPFC

L = 10; R=1

100

2

60

Same medications

Fitzgerald et al45

Failed 2 or more AD; 6 weeks minimum

R then L DLPFC

L = 10; R=1

L = 100; R = 110

2

50

Garcia-Toro et al32


L DLPFC

20

90

2

40

Same medications

Garcia-Toro et al34


L DLPFC

20

90

2

28

All started on sertraline 50 mg

Garcia-Toro et al46

Failed 2 or more AD

L DLPFC; R DLPFC

L = 20; R=1

110


R DLPFC

1

110

Failed 1 or more AD, adequate trial

Bilat DLPFC

15

Failed 1 or more AD (55% of sample), but excluded if failed 2 or more AD in current episode

L DLPFC

10

Manes et al50


L DLPFC

20

80

1

20

Off all medications ´ 4 days

Miniussi et al31

Failed 2 or more AD, at least 2 classes

L DLPFC

17; 1

110

1

51

Same medications HFL, compared with LFR

Moller et al51

Failed 1 or more AD

L DLPFC

10

100

1

10

Same medications


L DLPFC

10

110

2

59

Same medications

Mosimann et al52

Failed 2 or more AD, adequate dose and duration

L DLPFC

20

100

2

24

Same medications

O’Reardon et al39

Failed at least 1 but less than 5 AD

L DLPFC

10

120

4

301

No medications

Study

TRD definition

Anderson et al40

Kauffmann et al

Loo et al

48

Loo et al

49

Mogg et al

47

36

Medications and comments Same medications 3 sessions per week

HFL, compared with LFR Same medications Sequential R then L

Also started on sertraline at start of rTMS 2

30


2

12

Same medications LFR

90

3

19

Same medications Bilateral L and R

110

2

40

Same medications Excluded patients with typical definition of TRD

Previous ECT was an exclusion criterion continued

624

W La Revue canadienne de psychiatrie, vol 53, no 9, septembre 2008


Table 1 continued rTMS placement

RTMS frequency

RTMS % MT

Duration, weeks

Sample size

Failed 2 or more AD, including 1 TCA, 4 weeks minimum

L DLPFC

10; 0.3

90

1

12

Padberg et al54

Failed 2 or more AD

L DLPFC

10

100 and 90

2

30

Rossini et al35

Failed 2 or more AD with different mechanisms, 6 weeks minimum

L DLPFC

15

100 and 80

2

54

Failed 1 or more AD

L DLPFC; R DLPFC

L = 10; R=1

110

2

L DLPFC

20; 5

100

Study

TRD definition

Padberg et al53

Stern et al37

Su et al

55

Failed 2 or more AD, 6 weeks min

Medications and comments Same medications HFL, compared with LFR Same medications Two MT conditions Same medications Two MT conditions

35

Off all medications ´ 14 days LFR condition not included

2

33


ATHF = treatment history form; DLPFC = dorsolateral prefrontal cortex; L = left; MT = motor threshold; R = right; TCA = tricyclic antidepressant

Sensitivity analyses were done using only studies with a stricter, but more usual, definition for TRD, namely, failure of 2 or more ADs within the current episode (Table 3). The risk difference for active rTMS was still significantly higher for clinical response at 16% (95%CI, 9% to 24%) and for clinical remission at 16% (95%CI, 5% to 27%). Pooled response and remission rates were, respectively, 24% and 17% for active rTMS and 9% and 5% for sham. The NNT was 6 for both clinical response and remission. The SMD was also significant at 0.37 (95%CI, 0.18 to 0.56). The sensitivity analyses of studies using higher quality reporting methods showed similar findings, as did studies using high-intensity, HFL stimulation (Table 3).

The 4 studies available for quantitative analysis that systematically followed all patients after the end of double-blind treatment included only 1- to 2-week follow-up periods (Table 2). The SMD was large at 1.04 (95%CI, 0.08 to 2.01; n = 4 studies, 122 patients). However, there was significant heterogeneity with one study by Stern et al37 potentially skewing results with a large individual SMD (2.67). However, the SMD was still significant when the study was omitted (0.58, 95%CI, 0.13 to 1.02). That study was also the only one that reported on responder and remitter status at follow-up; both rates were stable or increased at follow-up in the active rTMS conditions, but not in the sham condition.37

Discussion Examination of funnel plots of risk differences and SMD showed a single possible outlier for each outcome, but the plots were reasonably symmetrical. There were no indications of missing or unpublished negative studies, and only a suggestion of missing or unpublished studies showing positive risk difference effects for rTMS (data not shown). There were very few withdrawals reported due to adverse effects. Only 19 withdrawals occurred overall: 11 (2%) in active rTMS conditions and 8 (1.5%) in sham conditions. The number of dropouts for any reason were also very low (active rTMS = 4%, n = 595; sham = 6%, n = 497), with a risk difference of –0.01 (95%CI, –0.04 to 0.01; n = 24 studies). The low dropout rates, in part, may be due to the short durations of treatment. The Canadian Journal of Psychiatry, Vol 53, No 9, September 2008 W

Previous systematic reviews of rTMS have focused on weighted mean differences, SMDs or relative risks between active and sham treatments, but absolute risk differences and NNTs from categorical response and remission outcomes are more relevant and understandable outcomes for clinicians. Similarly, most systematic reviews pooled all patient groups irrespective of treatment resistance, or included treatment resistance as a subgroup analysis without examining this important population in greater detail. In our systematic review, studies were selected based on explicit criteria for TRD. Additionally, a clinical response measure (as typically defined, and which was used by all of the studies in this review, as 50% or greater reduction in HDRS or MADRS scores) was chosen as the primary outcome, with clinical remission (end point scores within the 625

Review Paper

Table 2 Studies with systematic, no-treatment follow-up after acute double-blind treatment Study

Sample size

Period of treatment and follow-up

Outcome measure(s) available

Bretlau et al33

45

3 weeks double-blind treatment

HDRS end point scores

9 weeks follow-up

Note that patients were also started on escitalopram (20 mg) at beginning of rTMS and continued on the drug during follow-up. Although the active rTMS group maintained improvement over the first 5 weeks of follow-up, by 9 weeks there was no difference in scores.



Garcia-Toro et al32

35

2 weeks follow-up Garcia-Toro et al34

Garcia-Toro et al46

22

37



2 weeks follow-up

Note that patients were also started on sertraline (50 mg) at beginning of rTMS and continued on the drug during follow-up.



2 weeks follow-up Manes et al50

20

5 days double-blind treatment


1 week follow-up Mogg et al36

59

2 weeks double-blind treatment 6 weeks follow-up

Rossini et al35

54


Stern et al37

35


Only graphical presentation of mean HDRS scores. Scores increased in the active rTMS group while scores decreased in the sham group during the follow-up; at 6 weeks there was no difference in scores.

Only graphical presentation of mean HDRS scores. Scores appeared to be stable, and authors commented that responders showed sustained response, during follow-up, but no data reported.

HDRS end point scores and response and (or) remission rates

Table 3 Sensitivity and subgroup analyses of rTMS study parameters Clinical response Risk difference (95%CI)

Clinical remission Risk difference (95%CI)

SMD (95%CI)

All studies

17% (10% to 23%)a n = 22 studies, 996 patients


0.48 (0.28 to 0.69)a n = 21 studies, 899 patients

Strict definition of TRD



0.37 (0.18 to 0.56) n = 11 studies, 607 patients

Higher qualityb



0.39 (0.23 to 0.55) n = 9 studies, 625 patients

High-intensity, LFR stimulation



0.48 (0.21 to 0.76)a n = 13 studies, 648 patients

Parameter

Significant heterogeneity of results (c2, P < 0.05; I2 > 30%)

a b

Adequate reporting of allocation concealment, blinding, and adequacy of sham treatment

626



Figure 1 Metaanalysis results for clinical response showing risk difference between active and sham rTMS in all studies

normal range) and SMDs as secondary outcomes. Our results show that active rTMS is significantly superior to sham in short-term acute treatment of TRD. The risk difference of 17% and the NNT of 6 are of clinically significant magnitude for these difficult to treat patients, and similar to those seen with medication-placebo comparisons in TRD. In addition, the results were similar with sensitivity analyses of studies using the stricter definition of TRD and high-intensity, HFL stimulation. The rTMS treatments were well-tolerated with very few dropouts owing to adverse effects. Only 2 other metaanalyses of rTMS have specifically addressed TRD, both within sensitivity analyses of mixed sample studies. Herrmann and Ebmeier 38 examined The Canadian Journal of Psychiatry, Vol 53, No 9, September 2008 W

medication resistance in a larger systematic review of rTMS trials. They included 18 trials (of which 15 were included in our metaanalysis) with a treatment-resistant sample and found a weighted ES (Cohen’s d) of 0.66 (95%CI, 0.47 to 0.86), not significantly different from the ES in trials without treatment-resistant samples (Cohen’s d = 0.61). In contrast, the SMD (ES) in end point scores in our review was slightly lower at 0.48 (95%CI, 0.28 to 0.69). The discrepancy between results cannot be further explored as there were no details in the Herrmann and Ebmeier38 review on the TRD studies included and their criteria for extracting data. Schutter8 reviewed 25 studies using HFL, with an overall weighted mean ES in change scores of 0.39. There was no difference by ANOVA between medication-resistance 627

Review Paper

Figure 2 Metaanalysis results for clinical remission showing risk difference between active and sham rTMS in all studies

studies (n = 17), defined as greater than 2 failed medication trials or history of failure to ECT, and nonmedication resistance studies (n = 8). This is comparable to our sensitivity analysis of high-intensity HFL studies (n = 13), in which the SMD for end point scores was 0.48 (95%CI, 0.21 to 0.76). Despite these significant findings, the included rTMS studies have major limitations in methodology that temper the clinical significance of the results. In particular, these studies had very short treatment durations, with most studies using only 1 to 2 weeks. The pooled response and remission rates of 25% and 17%, respectively, are low, compared with most medication studies of TRD. The clinically relevant risk difference of 17% is owing to the fact that the placebo response rates (averaging about 7.5%) are also very low. Although one can argue that patients with TRD should be expected to have lower placebo response, medication studies in TRD (which usually use longer treatment periods) have generally found higher placebo response rates. Several rTMS studies reported longer treatment periods with higher response rates at the end of treatment. Unfortunately, 628

these studies used a nonstandard methodology in which nonresponders at each week were dropped from the study and only partial responders continued with blinded treatment. The differential retention of patients in active and sham conditions precludes using the data to examine efficacy. However, the results suggest that longer duration of rTMS (4 or more weeks) may lead to higher clinical response. In this regard, the results of the large-sample, 4-week study by O’Reardon and colleagues,39 which included 301 patients randomized to sham or active rTMS treatment in a multicentre design, should be noted. In that study, there was no statistically significant difference between active and sham treatment in the primary outcome (change in MADRS scores). However, among the secondary outcomes, the HDRS response rates for active rTMS and placebo were 20.6% and 11.6% (P < 0.05), respectively, while remission rates were 7.1% and 6.2% (not significant). These results were very similar to the overall results from this systematic review, suggesting that 4 weeks of treatment may not be much better than 2. W La Revue canadienne de psychiatrie, vol 53, no 9, septembre 2008


Another important question, given that rTMS is labour-intensive and time-consuming (because patients must attend treatments at least several times each week), is whether the AD effects are sustained after initial treatment. Unfortunately, only 8 studies included some systematic follow-up after the acute course of treatment, and most involved only short-term follow-up of 1 to 3 weeks. The results from the 4 studies available for quantitative synthesis showed that AD effects persisted for 1 to 2 weeks after discontinuation of rTMS. Two studies had longer follow-up periods; one study in which rTMs was started with 20 mg of escitalopram showed maintenance of rTMS response, compared with sham, through 5 weeks, but no difference at 9 weeks;33 the other showed no difference between active and sham at 6 weeks.36 Other studies also included longer follow-up periods, but either followed responders only, or followed up after unblinded rTMS treatment. Given these limitations, it is not surprising that the results were inconsistent, with some studies showing relapse while others showed enduring therapeutic effects over several weeks and months of follow-up. No studies of maintenance rTMS treatment for TRD were identified. To summarize the clinical findings of this systematic review, rTMS with short treatment duration (1 to 4 weeks) has clear AD effects in TRD and is well-tolerated, but the overall response and remission rates are low and it is unclear whether the effects are sustained. These results are similar to previous systematic reviews of mixed populations of depressed p a tien ts th a t in c lu d e d b o th tr e a tmen t- n a iv e a n d treatment-resistant cases.2–8 Further studies in TRD are needed to determine: whether longer duration rTMS treatment (for example, 4 weeks or longer) results in higher response and remission rates, compared with sham treatments; whether the acute AD effects of rTMS are sustained over time, even without ongoing use of rTMS; whether rTMS speeds onset, and more importantly, results in greater overall response, when used in combination with starting an AD; and whether less frequent maintenance rTMS (for example, once weekly or less often) can sustain the acute effects. Some of these important questions must be answered before rTMS can be considered a first-line, monotherapy treatment for TRD or less refractory cases of depression. Funding and Support Dr Lam is on speaker and (or) advisory boards for, or has received research grants from: ANS, Inc, AstraZeneca, Biovail, Canadian Institutes of Health Research, Canadian Network for Mood and Anxiety Treatments, Eli Lilly, GlaxoSmithKline, GreatWest Life, Janssen, Litebook Company, Ltd, Lundbeck, Sanofi-Aventis, Servier, VGH and UBC Hospital Foundation, and Wyeth. Dr Chan is on speaker boards for: AstraZeneca, Eli Lilly, Janssen, Lundbeck, and Organon. Dr Yatham is on speaker and (or) advisory boards for, or has received research grants from: AstraAeneca, Bristol Myers Squibb, Canadian Institutes of Health Research, Canadian Network for Mood and Anxiety Treatments, The Canadian Journal of Psychiatry, Vol 53, No 9, September 2008 W

Eli Lilly, GlaxoSmithKline, Janssen, Michael Smith Foundation for Health Research, Pfizer, Servier, and Stanley Foundation.

References 1. Eitan R, Lerer B. Nonpharmacological, somatic treatments of depression: electroconvulsive therapy and novel brain stimulation modalities. Dialogues Clin Neurosci. 2006;8(2):241–258. 2. McNamara B, Ray JL, Arthurs OJ, et al. Transcranial magnetic stimulation for depression and other psychiatric disorders. Psychol Med. 2001;31(7):1141–1146. 3. Holtzheimer PE, III, Russo J, Avery DH. A meta-analysis of repetitive transcranial magnetic stimulation in the treatment of depression. Psychopharmacol Bull. 2001;35(4):149–169. 4. Burt T, Lisanby SH, Sackeim HA. Neuropsychiatric applications of transcranial magnetic stimulation: a meta analysis. Int J Neuropsychopharmacol. 2002;5(1):73–103. 5. Kozel FA, George MS. Meta-analysis of left prefrontal repetitive transcranial magnetic stimulation (rTMS) to treat depression. J Psychiatr Pract. 2002;8(5):270 –275. 6. Martin JL, Barbanoj MJ, Schlaepfer TE, et al. Repetitive transcranial magnetic stimulation for the treatment of depression. Systematic review and meta-analysis. Br J Psychiatry. 2003;182:480 – 491. 7. Couturier JL. Efficacy of rapid-rate repetitive transcranial magnetic stimulation in the treatment of depression: a systematic review and meta-analysis. J Psychiatry Neurosci. 2005;30(2):83–90. 8. Schutter DJ. efficacy of high-frequency transcranial magnetic stimulation over the left dorsolateral prefrontal cortex in double-blind sham-controlled designs: a meta-analysis. Psychol Med. 2008 Apr 30; [Epub ahead of print]. 9. Berlim MT, Turecki G. Definition, assessment, and staging of treatment-resistant refractory major depression: a review of current concepts and methods. Can J Psychiatry. 2007;52(1):46 –54. 10. Souery D, Papakostas GI, Trivedi MH. Treatment-resistant depression. J Clin Psychiatry. 2006;67(Suppl 6):16–22. 11. Dunner DL, Rush AJ, Russell JM, et al. Prospective, long-term, multicenter study of the naturalistic outcomes of patients with treatment-resistant depression. J Clin Psychiatry. 2006;67(5):688–695. 12. Kennedy SH, Lam RW. Enhancing outcomes in the management of treatment resistant depression: a focus on atypical antipsychotics. Bipolar Disord. 2003;5(Suppl 2):36–47. 13. Greden JF. The burden of disease for treatment-resistant depression. J Clin Psychiatry. 2001;62(Suppl 16):26–31. 14. Nierenberg AA, Katz J, Fava M. A critical overview of the pharmacologic management of treatment-resistant depression. Psychiatr Clin North Am. 2007;30(1):13–29. 15. Lam RW, Kennedy SH. Evidence-based strategies for achieving and sustaining full remission in depression: focus on metaanalyses. Can J Psychiatry. 2004;49(3 Suppl 1):17S-26S. 16. McPherson S, Cairns P, Carlyle J, et al. The effectiveness of psychological treatments for treatment-resistant depression: a systematic review. Acta Psychiatr Scand. 2005;111(5):331–340. 17. Anonymous. Transcranial magnetic stimulation: potential new treatment for resistant depression. J Clin Psychiatry. 2007;68:315–330. 18. Higgins J, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions 4.2. Chichester (GB): Cochrane Library, Wiley; 2007. 19. Cochrane Collaboration. Review Manager (RevMan) Version 4.2 for Windows. Copenhagen (DK): The Nordic Cochrane Centre; 2003. 20. Hunter JE, Schmidt FL. Fixed effects vs random effects meta-analysis models: Implications for cumulative research knowledge. Int J Select Assess. 2000;8:275–292. 21. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–560. 22. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–1558. 23. Fitzgerald PB, Huntsman S, Gunewardene R, et al. A randomized trial of low-frequency right-prefrontal-cortex transcranial magnetic stimulation as augmentation in treatment-resistant major depression. Int J Neuropsychopharmacol. 2006;9(6):655–666; [Epub 2006 Sep 7]. 24. Turnier-Shea Y, Bruno R, Pridmore S. Daily and spaced treatment with transcranial magnetic stimulation in major depression: a pilot study. Aust N Z J Psychiatry. 2006;40(9):759–763. 25. Fitzgerald PB, Hoy K, McQueen S, et al. Priming stimulation enhances the effectiveness of low-frequency right prefrontal cortex transcranial magnetic stimulation in major depression. J Clin Psychopharmacol. 2008;28(1):52–58. 26. Loo C, Mitchell P, Sachdev P, et al. Double-blind controlled investigation of transcranial magnetic stimulation for the treatment of resistant major depression. Am J Psychiatry. 1999;156(6):946–948. 27. Bortolomasi M, Minelli A, Fuggetta G, et al. Long-lasting effects of high frequency repetitive transcranial magnetic stimulation in major depressed patients. Psychiatry Res. 2007;150(2):181–186; [Epub 2007 Feb 14].

629

Review Paper

28. Moser DJ, Jorge RE, Manes F, et al. Improved executive functioning following repetitive transcranial magnetic stimulation. Neurology. 2002;58(8):1288–1290. 29. Avery DH, Holtzheimer PE III, Fawaz W, et al. Transcranial magnetic stimulation reduces pain in patients with major depression: a sham-controlled study. J Nerv Ment Dis. 2007;195(5):378–381. 30. Pascual-Leone A, Rubio B, Pallardo F, et al. Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression. Lancet. 1996;348(9022):233–237. 31. Miniussi C, Bonato C, Bignotti S, et al. Repetitive transcranial magnetic stimulation (rTMS) at high and low frequency: an efficacious therapy for major drug-resistant depression? Clin Neurophysiol. 2005;116(5):1062–1071. 32. Garcia-Toro M, Mayol A, Arnillas H, et al. Modest adjunctive benefit with transcranial magnetic stimulation in medication-resistant depression. J Affect Disord. 2001;64(2–3):271–275. 33. Bretlau LG, Lunde M, Lindberg L, et al. Repetitive transcranial magnetic stimulation (rTMS) in combination with escitalopram in patients with treatment-resistant major depression: a double-blind, randomised, sham-controlled trial. Pharmacopsychiatry. 2008;41(2):41–47. 34. Garcia-Toro M, Pascual-Leone A, Romera M, et al. Prefrontal repetitive transcranial magnetic stimulation as add on treatment in depression. J Neurol Neurosurg Psychiatry. 2001;71(4):546–548. 35. Rossini D, Lucca A, Zanardi R, et al. Transcranial magnetic stimulation in treatment-resistant depressed patients: a double-blind, placebo-controlled trial. Psychiatry Res. 2005;137(1–2):1–10; [Epub 2005 Oct 12]. 36. Mogg A, Pluck G, Eranti SV, et al. A randomized controlled trial with 4-month follow-up of adjunctive repetitive transcranial magnetic stimulation of the left prefrontal cortex for depression. Psychol Med. 2008;38(3):323–333. [ Epub 2007 Oct 15]. 37. Stern WM, Tormos JM, Press DZ, et al. effects of high and low frequency repetitive transcranial magnetic stimulation to the dorsolateral prefrontal cortex: a double-blind, randomized, placebo-controlled trial. J Neuropsychiatry Clin Neurosci. 2007;19(2):179–186. 38. Herrmann LL, Ebmeier KP. Factors modifying the efficacy of transcranial magnetic stimulation in the treatment of depression: a review. J Clin Psychiatry. 2006;67(12):1870–1876. 39. O’Reardon JP, Solvason HB, Janicak PG, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. 2007;62(11):1208–1216; [Epub 2007 Jun 14]. 40. Anderson IM, Delvai NA, Ashim B, et al. Adjunctive fast repetitive transcranial magnetic stimulation in depression. Br J Psychiatry. 2007;190:533–534. 41. Avery DH, Holtzheimer PE III, Fawaz W, et al. A controlled study of repetitive transcranial magnetic stimulation in medication-resistant major depression. Biol Psychiatry. 2006;59(2):187–194; [Epub 2005 Sep 1]. 42. Berman RM, Narasimhan M, Sanacora G, et al. A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression. Biol Psychiatry. 2000;47(4):332–337. 43. Boutros NN, Gueorguieva R, Hoffman RE, et al. Lack of a therapeutic effect of a 2-week sub-threshold transcranial magnetic stimulation course for treatment-resistant depression. Psychiatry Res. 2002;113(3):245–254. 44. Fitzgerald PB, Brown TL, Marston NA, et al. Transcranial magnetic stimulation in the treatment of depression: a double-blind, placebo-controlled trial. Arch Gen Psychiatry. 2003;60(10):1002–1008. 45. Fitzgerald PB, Benitez J, de Castella A, et al. A randomized, controlled trial of sequential bilateral repetitive transcranial magnetic stimulation for treatment-resistant depression. Am J Psychiatry. 2006;163(1):88–94.

630

46. Garcia-Toro M, Salva J, Daumal J, et al. High (20-Hz) and low (1-Hz) frequency transcranial magnetic stimulation as adjuvant treatment in medication-resistant depression. Psychiatry Res. 2006;146(1):53–57; [ Epub 2005 Dec 13]. 47. Kauffmann CD, Cheema MA, Miller BE. Slow right prefrontal transcranial magnetic stimulation as a treatment for medication-resistant depression: a double-blind, placebo-controlled study. Depress Anxiety. 2004;19:59–62. 48. Loo CK, Mitchell PB, Croker VM, et al. Double-blind controlled investigation of bilateral prefrontal transcranial magnetic stimulation for the treatment of resistant major depression. Psychol Med. 2003;33(1):33–40. 49. Loo CK, Mitchell PB, McFarquhar TF, et al. A sham-controlled trial of the efficacy and safety of twice-daily rTMS in major depression. Psychol Med. 2007;37(3):341–349. [Epub 2006 Dec 19]. 50. Manes F, Jorge R, Morcuende M, et al. A controlled study of repetitive transcranial magnetic stimulation as a treatment of depression in the elderly. Int Psychogeriatr. 2001;13:225–231. 51. Moller AL, Hjaltason O, Ivarsson O, et al. The effects of repetitive transcranial magnetic stimulation on depressive symptoms and the P(300) event-related potential. Nord J Psychiatry. 2006;60:282–285. 52. Mosimann UP, Schmitt W, Greenberg BD, et al. Repetitive transcranial magnetic stimulation: a putative add-on treatment for major depression in elderly patients. Psychiatry Res. 2004;126(2):123–133. 53. Padberg F, Zwanzger P, Thoma H, et al. Repetitive transcranial magnetic stimulation (rTMS) in pharmacotherapy-refractory major depression: comparative study of fast, slow and sham rTMS. Psychiatry Res. 1999;88(3):163–171. 54. Padberg F, Zwanzger P, Keck M, et al. Repetitive transcranial magnetic stimulation (rTMS) in major depression. Relation between efficacy and stimulation intensity. Neuropsychopharmacology. 2002;27(4):638–645. 55. Su TP, Huang CC, Wei IH. Add-on rTMS for medication-resistant depression: a randomized, double-blind, sham-controlled trial in Chinese patients. J Clin Psychiatry. 2005;66(7):930–937.

Manuscript received September 2007, revised, and accepted January 2008. 1 Professor and Head, Division of Clinical Neuroscience, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia; Medical Director, Mood Disorders Centre, UBC Hospital, Vancouver, British Columbia. 2 Clinical Associate Professor, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia; Head, ECT Program, Vancouver General Hospital, Vancouver, British Columbia. 3 Clinical Assistant Professor, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia; Physician Operations Leader, Geriatric Psychiatry, Mount Saint Joseph Hospital, Vancouver, British Columbia. 4 Professor and Associate Head, Research and International Affairs, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia; Medical Director, Mood Disorders Clinical Research Unit, UBC Hospital, Vancouver, British Columbia. Address for correspondence: Dr RW Lam, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 2A1; [email protected]



Résumé : La stimulation magnétique transcranienne répétitive pour la dépression réfractaire au traitement : un examen systématique et une méta-analyse Objectif : Les examens systématiques indiquent que la stimulation magnétique transcranienne répétitive (SMTr) est supérieure aux conditions de contrôle simulées chez les patients souffrant du trouble dépressif majeur, mais la pertinence clinique n’est pas manifeste. Personne n’a examiné spécifiquement les résultats chez les patients souffrant de dépression réfractaire au traitement (DRT). Méthode : Un examen systématique a été mené en identifiant les essais randomisés contrôlés publiés sur la SMTr active, comparativement à une condition de contrôle simulée chez les patients souffrant de DRT définie (c’est-à-dire, au moins un essai échoué d’antidépresseur). Le principal résultat était la réponse clinique telle qu’elle était déterminée par les notes globales, ou 50 % ou la plus grande amélioration à une échelle de cotation. Les autres résultats comprenaient la rémission et les différences moyennes normalisées des scores finals. Une méta-analyse a été menée pour les différences de risque absolu, à l’aide des modèles d’effets aléatoires. Des analyses de sensibilité et de sous-groupes ont aussi été menées afin d’explorer l’hétérogénéité et la robustesse des résultats. Résultats : Un total de 24 études (n = 1 092 patients) satisfaisaient aux critères de synthèse quantitative. La SMTr active était significativement supérieure aux conditions simulées pour produire une réponse clinique, avec une différence de risque de 17 % et un nombre de sujets nécessaire de 6. Les taux regroupés de réponse et de rémission étaient de 25 % et de 17 %, et de 9 % et de 6 % pour la SMTr active et les conditions simulées, respectivement. Les analyses de sensibilité et de sous-groupes n’ont pas affecté significativement ces résultats. Les abandons et les retraits attribuables aux effets indésirables étaient très faibles. Conclusions : Pour les patients souffrant de DRT, la SMTr semble procurer des avantages significatifs dans les études de traitement à court terme. Cependant, les taux relativement faibles de réponse et de rémission, les courtes durées du traitement, et le manque relatif d’études de suivi systématique suggèrent que d’autres recherches sont nécessaires avant de pouvoir considérer que la SMTr est une monothérapie de première ligne pour la DRT.

The Canadian Journal of Psychiatry, Vol 53, No 9, September 2008 W

631