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

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1 Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression: A Systematic Review and Metaanalysis Raymond W Lam, MD, FRCPC 1 ; Peter Chan, MD, FRCPC 2 ; Michael Wilkins-Ho, MD, FRCPC 3 ; Lakshmi N Yatham, MBBS, MRCPsych (UK), FRCPC 4 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): 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

2 Anovel 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 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 Abbreviations used in this article AD ECT HDRS HFL LFR MADRS MDD NNT RCT rtms SMD TRD antidepressant electroconvulsive therapy Hamilton Depression Rating Scale high-frequency to the left dorsolateral prefrontal cortex low-frequency to the right dorsolateral prefrontal cortex Montgomery Asberg Depression Rating Scale major depressive disorder number-needed-to-treat randomized controlled trial repetitive transcranial magnetic stimulation standardized mean difference treatment-resistant depression The management of TRD remains unclear as there is still limited evidence for optimal pharmacologic and psychotherapeutic strategies for TRD 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 622 La Revue canadienne de psychiatrie, vol 53, no 9, septembre 2008

3 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 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 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, 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 mg 32 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 rtms 33,34 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 I 2 > 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. The Canadian Journal of Psychiatry, Vol 53, No 9, September

4 Table 1 Summary of clinical parameters of included studies Study TRD definition rtms placement rtms frequency rtms %MT Duration, weeks Sample size Medications and comments Anderson et al 40 Avery et al 41 Berman et al 42 Failed 2 or more AD (79% of sample) Failed 2 or more AD, ATHF 3 or more Failed 1 or more AD, past or present episode, 4 weeks minimum L DLPFC Same medications 3 sessions per week L DLPFC Same medications L DLPFC Off all medications 1 week Boutros et al 43 Failed 2 or more AD L DLPFC Same medications Bretlau et al 33 Fitzgerald et al 44 Fitzgerald et al 45 Garcia-Toro et al 32 Garcia-Toro et al 34 Failed 1 or more AD, 6 weeks minimum Failed 2 or more AD; 6 weeks minimum Failed 2 or more AD; 6 weeks minimum Failed 2 or more AD, 6 weeks minimum Failed 1 or more AD (57% of sample) L DLPFC All started on escitalopram 20 mg L DLPFC; R DLPFC R then L DLPFC Garcia-Toro Failed 2 or more AD L DLPFC; et al 46 R DLPFC Kauffmann et al 47 Loo et al 48 Loo et al 49 Manes et al 50 Miniussi et al 31 Failed 2 or more AD, 8 weeks minimum Failed 1 or more AD, adequate trial Failed 1 or more AD (55% of sample), but excluded if failed 2 or more AD in current episode Failed 1 or more AD, 4 weeks minimum Failed 2 or more AD, at least 2 classes L = 10; R=1 L = 10; R= Same medications HFL, compared with LFR L = 100; R = Same medications Sequential R then L L DLPFC Same medications L DLPFC All started on sertraline 50 mg Also started on sertraline at start of rtms L = 20; R= Same medications HFL, compared with LFR R DLPFC Same medications LFR Bilat DLPFC Same medications Bilateral L and R L DLPFC Same medications Excluded patients with typical definition of TRD L DLPFC Off all medications 4 days L DLPFC 17; Same medications HFL, compared with LFR Moller et al 51 Failed 1 or more AD L DLPFC Same medications Mogg et al 36 Failed 2 or more AD L DLPFC Same medications (78% of sample) Mosimann et al 52 O Reardon et al 39 Failed 2 or more AD, adequate dose and duration Failed at least 1 but less than 5 AD L DLPFC Same medications L DLPFC No medications Previous ECT was an exclusion criterion continued 624 La Revue canadienne de psychiatrie, vol 53, no 9, septembre 2008

5 Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression: A Systematic Review and Metaanalysis Table 1 continued Study TRD definition rtms placement RTMS frequency RTMS %MT Duration, weeks Sample size Medications and comments Padberg et al 53 Failed 2 or more AD, including 1 TCA, 4 weeks minimum L DLPFC 10; Same medications HFL, compared with LFR Padberg et al 54 Failed 2 or more AD L DLPFC and Same medications Two MT conditions Rossini et al 35 Failed 2 or more AD with different mechanisms, 6 weeks minimum Stern et al 37 Failed 1 or more AD L DLPFC; R DLPFC Su et al 55 Failed 2 or more AD, 6 weeks min L DLPFC and 80 L = 10; R= Same medications Two MT conditions Off all medications 14 days LFR condition not included L DLPFC 20; Same medications HFL, compared with LFR 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). 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 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 al 37 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 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 The Canadian Journal of Psychiatry, Vol 53, No 9, September

6 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 al 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 al weeks double-blind treatment HDRS end point scores 2 weeks follow-up Garcia-Toro et al weeks double-blind treatment HDRS end point scores 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. Garcia-Toro et al weeks double-blind treatment HDRS end point scores 2 weeks follow-up Manes et al days double-blind treatment HDRS end point scores 1 week follow-up Mogg et al weeks double-blind treatment 6 weeks follow-up 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. Rossini et al weeks double-blind treatment 3 weeks follow-up 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. Stern et al weeks double-blind treatment 2 weeks follow-up HDRS end point scores and response and (or) remission rates Table 3 Sensitivity and subgroup analyses of rtms study parameters Parameter 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 14% (6% to 21%) a n = 16 studies, 795 patients 0.48 (0.28 to 0.69) a n = 21 studies, 899 patients Strict definition of TRD 16% (9% to 24%) a n = 14 studies, 795 patients 16% (5% to 27%) a n = 10 studies, 641 patients 0.37 (0.18 to 0.56) n = 11 studies, 607 patients Higher quality b 15% (7% to 22%) a n = 10 studies, 713 patients 11% (2% to 20%) a n = 8 studies, 623 patients 0.39 (0.23 to 0.55) n = 9 studies, 625 patients High-intensity, LFR stimulation 19% (10% to 27%) a n = 15 studies, 782 patients 16% (6% to 27%) a n = 11 studies, 630 patients 0.48 (0.21 to 0.76) a n = 13 studies, 648 patients a Significant heterogeneity of results ( 2, P < 0.05; I 2 30%) b Adequate reporting of allocation concealment, blinding, and adequacy of sham treatment 626 La Revue canadienne de psychiatrie, vol 53, no 9, septembre 2008

7 Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression: A Systematic Review and Metaanalysis 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 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 Ebmeier 38 review on the TRD studies included and their criteria for extracting data. Schutter 8 reviewed 25 studies using HFL, with an overall weighted mean ES in change scores of There was no difference by ANOVA between medication-resistance The Canadian Journal of Psychiatry, Vol 53, No 9, September

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

9 Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression: A Systematic Review and Metaanalysis 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 patients that included both treatment-naive and 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, 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. 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J Clin Psychiatry. 2005;66(7): Manuscript received September 2007, revised, and accepted January 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; r.lam@ubc.ca 630 La Revue canadienne de psychiatrie, vol 53, no 9, septembre 2008

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