Introduction
Repetitive transcranial magnetic stimulation (rTMS) is a safe and non-invasive neuromodulation technique that is being intensively explored as a novel treatment for major neuropsychiatric disorders (Rosa & Lisanby, Reference Rosa and Lisanby2012). rTMS is capable of inducing electrical currents and depolarizing neurons in focal brain areas with the use of rapidly changing electromagnetic fields generated by a coil placed over the scalp (George & Post, Reference George and Post2011). When applied repetitively, these electrical currents can modulate cortical excitability, decreasing it or increasing it, depending on the parameters of stimulation (Fregni & Pascual-Leone, Reference Fregni and Pascual-Leone2007). Accordingly, frequencies ⩽1 Hz [low-frequency (LF)-rTMS] are usually inhibitory, while higher frequencies [usually 5–20 Hz or high-frequency (HF)-rTMS] are usually excitatory (Fitzgerald et al. Reference Fitzgerald, Brown and Daskalakis2002; Marangell et al. Reference Marangell, Martinez, Jurdi and Zboyan2007).
To date, several randomized controlled trials (RCTs) have shown the efficacy and safety of both HF-rTMS and LF-rTMS applied to the left dorsolateral prefrontal cortex (DLPFC) and the right DLPFC, respectively, for treating major depression (MD) (Fitzgerald et al. Reference Fitzgerald, Brown, Marston, Daskalakis, De Castella and Kulkarni2003; O'Reardon et al. Reference O'Reardon, Solvason, Janicak, Sampson, Isenberg, Nahas, McDonald, Avery, Fitzgerald, Loo, Demitrack, George and Sackeim2007; George et al. Reference George, Lisanby, Avery, McDonald, Durkalski, Pavlicova, Anderson, Nahas, Bulow, Zarkowski, Holtzheimer, Schwartz and Sackeim2010). More recently, a third rTMS treatment protocol for MD has been described, namely bilateral stimulation (either simultaneously or sequentially) targeting both the left and the right DLPFC (Daskalakis et al. Reference Daskalakis, Levinson and Fitzgerald2008). The use of this novel neuromodulation approach in MD is supported by several lines of neurobiological evidence. For example, neuroimaging studies have demonstrated that the underlying neural circuitry of MD probably involves dysregulation of cortical functioning, with lower and higher activity observed in the left and the right DLPFC, respectively (Fitzgerald et al. Reference Fitzgerald, Oxley, Laird, Kulkarni, Egan and Daskalakis2006b, Reference Fitzgerald, Laird, Maller and Daskalakis2008). Furthermore, neurophysiological studies have shown asymmetrical differences in cortical excitability in depressed subjects compared with healthy controls (Bajbouj et al. Reference Bajbouj, Lisanby, Lang, Danker-Hopfe, Heuser and Neu2006; Salustri et al. Reference Salustri, Tecchio, Zappasodi, Bevacqua, Fontana, Ercolani, Milazzo, Squitti and Rossini2007). This has led to the assertion that bilateral rTMS might be a more optimal neuromodulation treatment for MD compared with unilateral stimulation, as the combination of HF-rTMS and LF-rTMS could be therapeutically synergistic because both may act via reciprocal and potentially complementary mechanisms (Rotenberg, Reference Rotenberg2008).
However, the efficacy of bilateral rTMS for MD remains unclear, as RCTs to date have produced conflicting results. For example, Loo et al. (Reference Loo, Mitchell, Croker, Malhi, Wen, Gandevia and Sachdev2003) and McDonald et al. (Reference McDonald, Easley, Byrd, Holtzheimer, Tuohy, Woodard, Beyer and Epstein2006) have shown bilateral rTMS to be no better than sham rTMS for MD, whereas Fitzgerald et al. (Reference Fitzgerald, Benitez, de Castella, Daskalakis, Brown and Kulkarni2006a) and Blumberger et al. (Reference Blumberger, Mulsant, Fitzgerald, Rajji, Ravindran, Young, Levinson and Daskalakis2012) have reported that bilateral rTMS produced significantly higher rates of clinical improvement in depressed subjects when compared with sham rTMS. These discrepant findings are probably due to a lack of statistical power among some of the individual RCTs (Maxwell et al. Reference Maxwell, Kelley and Rausch2008). Therefore, the use of meta-analytical approaches could produce more accurate estimates of the treatment effect by integrating the findings from multiple studies (Huf et al. Reference Huf, Kalcher, Pail, Friedrich, Filzmoser and Kasper2011). Accordingly, we have carried out a systematic review and meta-analysis of randomized, double-blind and sham-controlled trials (RCTs) on bilateral rTMS for MD with a focus on clinically meaningful outcomes, namely response and remission rates. Furthermore, we have assessed the acceptability of bilateral rTMS by comparing the differential drop-out rates between subjects receiving active or sham bilateral rTMS.
Methodology of the literature review
Search strategy
We identified articles for inclusion in this meta-analysis by:
(1) Screening the bibliographies of all meta-analyses on rTMS for MD published to date (McNamara et al. Reference McNamara, Ray, Arthurs and Boniface2001; Burt et al. Reference Burt, Lisanby and Sackeim2002; Kozel & George, Reference Kozel and George2002; Martin et al. Reference Martin, Barbanoj, Schlaepfer, Clos, Perez, Kulisevsky and Gironell2002, Reference Martin, Barbanoj, Schlaepfer, Thompson, Perez and Kulisevsky2003; Couturier, Reference Couturier2005; Herrmann & Ebmeier, Reference Herrmann and Ebmeier2006; Gross et al. Reference Gross, Nakamura, Pascual-Leone and Fregni2007; Lam et al. Reference Lam, Chan, Wilkins-Ho and Yatham2008; Schutter, Reference Schutter2009, Reference Schutter2010; Slotema et al. Reference Slotema, Blom, Hoek and Sommer2010; Allan et al. Reference Allan, Herrmann and Ebmeier2011) as well as of all included RCTs;
(2) Searching Medline from 1 October 2008 until 20 July 2012 (as previous meta-analyses have screened this database up to late 2008: Slotema et al. Reference Slotema, Blom, Hoek and Sommer2010; Allan et al. Reference Allan, Herrmann and Ebmeier2011);
(3) Searching EMBASE, PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), SCOPUS and ProQuest Dissertations and Theses (PQDT) from 1 January 1995 until 20 July 2012.
The search procedures (including syntaxes, parameters and results) are described in detail in the Supplementary online material.
Study selection
Candidate studies had to satisfy the following criteria (Higgins & Green, Reference Higgins and Green2008):
(1) Study validity: random allocation; double-blind (i.e. patients and clinical raters blinded to treatment conditions); sham-controlled (i.e. coil angled on the scalp or use of a specific sham coil); parallel or cross-over design (with only data from the initial randomization being used for the latter to avoid carry-over effects); five or more subjects with MD randomized per study arm;
(2) Sample characteristics: subjects aged 188–75 years with a diagnosis of primary major depressive episode (unipolar or bipolar) according to the Diagnostic and Statistical Manual of Mental Disorders or the International Classification of Diseases criteria;
(3) Treatment characteristics: bilateral rTMS (administered sequentially or simultaneously) given for five or more sessions either as a monotherapy or as an augmentation strategy for MD;
(4) Publication-related: articles written in English.
Studies were excluded if they:
(1) enrolled subjects with ‘narrow’ diagnoses (e.g. postpartum depression) or secondary MD (e.g. vascular depression);
(2) started rTMS concomitantly with a new antidepressant;
(3) did not report rates of response to treatment and/or remission.
Data extraction
Data were recorded in a structured fashion as follows:
(1) Sample characteristics: mean age, gender, treatment strategy used (i.e. augmentation or monotherapy), presence of treatment-resistant MD;
(2) rTMS-related: stimulation frequency and intensity (including the total number of stimuli delivered), number of treatment sessions, type of sham;
(3) Primary outcome measure: number of responders to treatment based on the RCT's primary efficacy measure [defined as a ⩾50% reduction in post-treatment scores on the Hamilton Depression Rating Scale (HAMD; Hamilton, Reference Hamilton1960) or on the Montgomeryy–Asberg Depression Rating Scale (MADRS; Montgomery & Asberg, Reference Montgomery and Asberg1979)] at study end;
(4) Secondary outcome measure: number of remitters based on the RCT's primary efficacy measure (e.g. 17-item or 21-item HAMD scores ⩽7 or ⩽8, respectively, or MADRS scores ⩽6) at study end;
(5) Acceptability of treatment: overall drop-out rates of active and sham rTMS groups at study end.
Data synthesis and analyses
Analyses were performed using Comprehensive Meta-Analyses Version 2.0 (Biostat, USA), and IBM SPSS version 20 (IBM Corp., USA).
We used a random-effects model because it was assumed that the true treatment effects had probably varied between the included RCTs (Riley et al. Reference Riley, Higgins and Deeks2011). If provided, intention-to-treat data, using a method such as ‘last observation carried forward’, were preferred over data from completers (Fergusson et al. Reference Fergusson, Aaron, Guyatt and Hebert2002). The efficacy of bilateral rTMS for MD as well as its acceptability were investigated by odds ratios (ORs) and the number needed to treat (NNT) (Borenstein et al. Reference Borenstein, Hedges, Higgins and Rothstein2009) for rates of response/remission and drop-outs. We considered a NNT ⩽10 as clinically meaningful because such a treatment difference would be routinely encountered in day-to-day clinical practice (Citrome, Reference Citrome2011). Also, to rule out the presence of baseline differences in depressive symptoms between active and sham rTMS groups, we computed the pooled standardized mean difference (SMD) of subjects' baseline scores on the HAMD or the MADRS.
Heterogeneity was assessed using the Q statistics and I 2 (Cooper et al. Reference Cooper, Hedges and Valentine2009). Values of p < 0.10 for the former and >35% for the latter were deemed as indicative of study heterogeneity (Borenstein et al. Reference Borenstein, Hedges, Higgins and Rothstein2009). Finally, we used funnel plots (Rothstein et al. Reference Rothstein, Sutton and Borenstein2005), Egger's regression intercept (Egger et al. Reference Egger, Davey Smith, Schneider and Minder1997), and Duval and Tweedie's trim-and-fill procedure (random effects) (Duval & Tweedie, Reference Duval and Tweedie2000) to test for the presence of publication bias (Borenstein et al. Reference Borenstein, Hedges, Higgins and Rothstein2009; Cooper et al. Reference Cooper, Hedges and Valentine2009).
Results
Literature search
Of the five RCTs on bilateral rTMS for MD included in the previous meta-analyses, four were selected for the present investigation (Loo et al. Reference Loo, Mitchell, Croker, Malhi, Wen, Gandevia and Sachdev2003; Fitzgerald et al. Reference Fitzgerald, Benitez, de Castella, Daskalakis, Brown and Kulkarni2006a; Garcia-Toro et al. Reference Garcia-Toro, Salva, Daumal, Andres, Romera, Lafau, Echevarria, Mestre, Bosch, Collado, Ibarra and Aguirre2006; McDonald et al. Reference McDonald, Easley, Byrd, Holtzheimer, Tuohy, Woodard, Beyer and Epstein2006). Also, we retrieved three RCTs on bilateral rTMS for MD from Medline, PsycINFO, EMBASE, CENTRAL, SCOPUS and PQDT, and they were all included in this study (Pallanti et al. Reference Pallanti, Bernardi, Di Rollo, Antonini and Quercioli2010; Blumberger et al. Reference Blumberger, Mulsant, Fitzgerald, Rajji, Ravindran, Young, Levinson and Daskalakis2012; Fitzgerald et al. Reference Fitzgerald, Hoy, Herring, McQueen, Peachey, Segrave, Maller, Hall and Daskalakis2012). Please refer to the Supplementary material for a detailed description of the study selection procedures.
Included RCTs: main characteristics
Overall, seven RCTs were included in our meta-analysis, totaling 279 subjects with MD, of whom 162 were randomized to active bilateral rTMS [mean age = 49.3 (s.d. = 5.7) years, 56.2% females] and 117 were randomized to sham rTMS [mean age = 47.4 (s.d. = 3.3) years, 58.1% females]. The mean number of rTMS sessions delivered was 12.9 (s.d. = 2.7). Also, bilateral rTMS was used as an augmentation strategy for MD in almost all RCTs (six out of seven), and all included subjects had some degree of treatment-resistant depressive illness. The main characteristics of the included RCTs are described on Tables 1 and 2.
Table 1. Included randomized, double-blind and sham-controlled trials on bilateral rTMS for major depression: demographic/clinical characteristics and rTMS parameters
rTMS, Repetitive transcranial magnetic stimulation; s.d., standard deviation; TRD, treatment-resistant depression; n.a., information not available; BD, bipolar depression; MDD, major depressive disorder; HAMD, Hamilton Depression Rating Scale.
a Montgomery–Asberg Depression Rating Scale.
b 21-item HAMD.
c 17-item HAMD.
d Failure to respond to ⩾1 antidepressants in the current major depressive episode.
e Failure to respond to ⩾2 antidepressants in the current major depressive episode.
f Median.
g Failure to respond to ⩾3 antidepressants in the current major depressive episode.
Table 2. Included randomized, double-blind and sham-controlled trials on bilateral rTMS for major depression: rTMS parameters
rTMS, Repetitive transcranial magnetic stimulation; DLPFC, dorsolateral prefrontal cortex; rMt, resting motor threshold.
a 120% of the rMT in subjects older than 60 years old.
Response rates
Data relating to response rates were available from all seven RCTs. Overall, 40 (out of 162, 24.7%) and eight (out of 117, 6.8%) subjects receiving active bilateral rTMS or sham rTMS were classified as responders to treatment, respectively. The pooled OR was 4.3 [95% confidence interval (CI) 1.95–9.52, z = 3.6, p < 0.0001], indicating a significant difference in outcome favoring active bilateral rTMS (Fig. 1). The risk difference translated into a NNT of six (95% CI 3.9–10.2), meaning that about one in every six patients will present a response following bilateral rTMS.
Fig. 1. Meta-analysis of bilateral repetitive transcranial magnetic stimulation (rTMS) versus sham rTMS for major depression: response rates. CI, Confidence interval.
Heterogeneity between RCTs did not exceed that expected by chance [degrees of freedom (df) = 6, Q 6 = 1.77, p = 0.94, I 2 = 0], implying that the variance among the effect sizes was no greater than expected by sampling error. Furthermore, the associated funnel plot was reasonably symmetrical (please refer to the Supplementary material). Publication bias was assessed more conservatively with Egger's regression intercept, which was −0.72 (df = 5, t = 0.86, two-tailed p = 0.43), suggesting a low risk of publication bias. In the Duval and Tweedie's trim-and-fill procedure, no RCT was trimmed and filled on the opposite side of zero, thus reinforcing the low risk of publication bias.
Remission rates
Data relating to remission rates were available from four RCTs. Overall, significantly more patients receiving active bilateral rTMS were remitters as compared with those receiving sham rTMS [19% (23/121) v. 2.6% (2/77), respectively]. The pooled OR was 6 (95% CI 1.65–21.8, z = 2.72, p = 0.006) (Fig. 2). The risk difference translated into a NNT of 7 (95% CI 4.1–11.7).
Fig. 2. Meta-analysis of bilateral repetitive transcranial magnetic stimulation (rTMS) versus sham rTMS for major depression: remission rates. CI, Confidence interval.
Heterogeneity between RCTs did not exceed that expected by chance (df = 3, Q 3 = 2.62, p = 0.45, I 2 = 0). The associated funnel plot was reasonably symmetrical (please refer to the Supplementary material), and Egger's regression intercept was −0.68 (df = 2, t = 0.16, two-tailed p = 0.89), suggesting a low risk of publication bias. In the Duval and Tweedie's trim-and-fill procedure, no RCT was trimmed and filled on the opposite side of zero, thus reinforcing the low risk of publication bias.
Bilateral rTMS versus unilateral rTMS: response and remission rates
Data relating to response and remission rates following active bilateral and unilateral rTMS were available from three and two RCTs, respectively. Overall, there was no significant difference between these two neuromodulation approaches in terms of both response (OR 2.39, 95% CI 0.24–24.04, z = 0.74, p = 0.46) and remission rates (OR 1.6, 95% CI 0.04–63.72, z = 0.25, p = 0.8). For the associated forest plots, please refer to the Supplementary material.
Bilateral rTMS versus sham rTMS: baseline depression severity
No differences on mean baseline depression scores for active versus sham rTMS groups were found (SMD = 0.18, z = 1.3, p = 0.2), thus ruling out illness severity at baseline as a confounding factor. For the associated forest plot, please refer to the Supplementary material.
Acceptability of bilateral rTMS treatment
Data relating to drop-out rates from bilateral rTMS versus sham rTMS and active unilateral rTMS were available from six and three RCTs, respectively. Overall, no difference was observed between bilateral rTMS and sham rTMS groups [7.15% (8/112) v. 13.4% (14/105), respectively; OR 0.53, z = − 1.32, p = 0.19] (Fig. 3), and bilateral rTMS and active unilateral rTMS groups [11.8% (8/68) v. 5.9% (4/68), respectively; OR 1.8, z = 0.87, p = 0.38]. For the associated forest plot, please refer to the Supplementary material.
Fig. 3. Meta-analysis of bilateral repetitive transcranial magnetic stimulation (rTMS) versus sham rTMS for major depression: drop-out rates. CI, Confidence interval.
Sensitivity analysis
We reanalysed the effect size estimate for response rates after excluding the study by Loo et al. (Reference Loo, Mitchell, Croker, Malhi, Wen, Gandevia and Sachdev2003), as they delivered bilateral HF-rTMS (instead of HF-rTMS to the left DLPFC and LF-rTMS to the right DLPFC). Our results show that its exclusion did not significantly affect the initial effect size estimates for the whole sample (adjusted OR 4.54, z = 3.6, p < 0.0001). For the associated forest plot, please refer to the Supplementary material.
Discussion
This is the first meta-analysis to assess the efficacy of bilateral rTMS for MD. Our results show that this neuromodulation technique is significantly more effective than sham rTMS in achieving response and remission (with pooled ORs of 4.3 and 6, and NNTs of 6 and 7, respectively). Indeed, 24.7% and 19% of depressed subjects receiving bilateral rTMS were responders and remitters following a mean of 13 sessions, respectively, compared with only 6.8% and 2.6% of those receiving sham rTMS. Furthermore, we found no significant between-group differences in drop-out rates or baseline depressive symptomatology. Also, we found no significant difference between active bilateral and unilateral rTMS in terms of efficacy and acceptability, although this finding should be interpreted with caution owing to the limited number of RCTs included in that analysis. Thus, bilateral rTMS seems to be an effective treatment for MD as it is associated with clinically meaningful improvements and is overall well tolerated.
This notion is further strengthened by the fact that the observed effect sizes and drop-out rates for bilateral rTMS are comparable with those reported for several commercially available antidepressants as well as for unilateral rTMS. For example, a recent meta-analysis of 122 trials on antidepressants for MDD found a pooled drug–placebo rate ratio for response to treatment of 1.42 (95% CI 1.38–1.48) and a corresponding NNT of 8 (95% CI 7.1–9.1) (Undurraga & Baldessarini, Reference Undurraga and Baldessarini2012); our estimate, when converted to rate ratio, is 3.3 (95% CI 1.66–6.6). Moreover, we have recently shown that the ORs for response and remission after unilateral HF-rTMS in MD were 3 (M. T. Berlim et al. unpubished observations). Furthermore, our findings are comparable with those observed in the large and representative Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (Rush et al. Reference Rush, Trivedi, Wisniewski, Nierenberg, Stewart, Warden, Niederehe, Thase, Lavori, Lebowitz, McGrath, Rosenbaum, Sackeim, Kupfer, Luther and Fava2006). More specifically, in the latter, remission rates after lithium carbonate or triiodothyronine augmentation of a second unsuccessful antidepressant course were 20.4% (Nierenberg et al. Reference Nierenberg, Fava, Trivedi, Wisniewski, Thase, McGrath, Alpert, Warden, Luther, Niederehe, Lebowitz, Shores-Wilson and Rush2006). In the current meta-analysis, remission rates following HF-rTMS in depressed individuals who had usually not responded to ⩾2 antidepressant trials were 19%. Such similar results reinforce the notion that the efficacy of bilateral rTMS is at least comparable with that of second- or third-line pharmacological strategies for MD.
The combination of HF-rTMS and LF-rTMS could potentially enhance treatment response in MD in a number of ways. For example, it is possible that some patients have left-side treatment-responsive MD and some have right-side treatment-responsive MD (Rossini et al. Reference Rossini, Lucca, Magri, Malaguti, Smeraldi, Colombo and Zanardi2010). Therefore, it is conceivable that offering both treatments to all patients can maximize the likelihood of clinical improvement in any individual patient. Alternatively, the two rTMS protocols may have synergistic therapeutic effects by reversing both the hypo-function in the left DLPFC and the hyper-function in the right DLPFC. Interestingly, this hypothesis has been recently supported by multi-modal neuroimaging data suggesting a relationship between the targeting of the underlying hyper- or hypo-metabolism in the DLPFC and overall treatment efficacy (Kimbrell et al. Reference Kimbrell, Little, Dunn, Frye, Greenberg, Wassermann, Repella, Danielson, Willis, Benson, Speer, Osuch, George and Post1999; Kito et al. Reference Kito, Hasegawa and Koga2011; Martinot et al. Reference Martinot, Martinot, Ringuenet, Galinowski, Gallarda, Bellivier, Lefaucheur, Lemaitre and Artiges2011).
Nevertheless, as the therapeutic use of bilateral rTMS involves several variables, it is possible that the optimum protocol is yet to be determined. Accordingly, future studies should investigate new ways of improving the antidepressant effects of bilateral rTMS, such as the identification of more clinically relevant stimulation parameters (e.g. different frequencies, intensities, number of sessions, brain targets), as well as the use of baseline electrophysiological and/or neuroimaging evaluations to better predict which patients might benefit from bilateral rTMS (Arns et al. Reference Arns, Drinkenburg, Fitzgerald and Kenemans2012). Furthermore, there is a need for larger RCTs comparing active bilateral and unilateral rTMS protocols in MD in order to better determine their differential efficacy and tolerability.
Limitations
First, the included RCTs enrolled a relatively small number of depressed subjects. Second, the quality of the available sham rTMS conditions is still unresolved (Rosa & Lisanby, Reference Rosa and Lisanby2012), and the use of coil tilting and/or first-generation sham coils is clearly not optimal (Rossi et al. Reference Rossi, Hallett, Rossini and Pascual-Leone2009; George & Aston-Jones, Reference George and Aston-Jones2010). Also, included RCTs differed in terms of their chosen sham configuration (i.e. unilateral versus bilateral sham rTMS). Third, the most commonly used strategy for locating the DLPFC (i.e. the ‘5 cm method’) has been recently criticized for its inaccuracy (Rossi et al. Reference Rossi, Hallett, Rossini and Pascual-Leone2009; Rosa & Lisanby, Reference Rosa and Lisanby2012), and future studies might benefit from neuronavigation approaches (Schonfeldt-Lecuona et al. Reference Schonfeldt-Lecuona, Lefaucheur, Cardenas-Morales, Wolf, Kammer and Herwig2010). Fourth, we have only examined the efficacy of bilateral rTMS at study end, and thus cannot estimate the stability of its medium- to long-term antidepressant effects and/or its cost-effectiveness. This is especially relevant considering the labor-intensive and time-consuming nature of rTMS (Wassermann & Zimmermann, Reference Wassermann and Zimmermann2012). Fifth, owing to the relatively small number of trials, we were unable to assess whether bilateral rTMS is differentially effective in unipolar and bipolar depression or when it is used as an augmentation strategy or as a monotherapy for MD. Sixth, the overall dose of rTMS treatment provided in most included RCTs, especially with left-sided HF-rTMS, was relatively low compared with more recent studies in MD (e.g. O'Reardon et al. Reference O'Reardon, Solvason, Janicak, Sampson, Isenberg, Nahas, McDonald, Avery, Fitzgerald, Loo, Demitrack, George and Sackeim2007; George et al. Reference George, Lisanby, Avery, McDonald, Durkalski, Pavlicova, Anderson, Nahas, Bulow, Zarkowski, Holtzheimer, Schwartz and Sackeim2010). Finally, meta-analyses have been often criticized for combining heterogeneous studies, for the potential of publication bias, and for the inclusion of poor-quality trials (Borenstein et al. Reference Borenstein, Hedges, Higgins and Rothstein2009). In the present study, however, these concerns were tackled by the comprehensive systematic review of the literature and the use of stringent inclusion criteria, and by the objective examination of both publication bias and study heterogeneity. In particular, the lack of significant heterogeneity among the included RCTs shows that our results are reliable overall, and we found the risk of publication bias to be low.
Conclusion
The current meta-analysis, which included 279 depressed subjects, shows that bilateral rTMS is a promising new treatment for MD that seems to be at least as effective and acceptable as standard antidepressants and unilateral rTMS. Considering that most trials to date have included patients with categorically defined treatment-resistant depression (Berlim & Turecki, Reference Berlim and Turecki2007), bilateral rTMS could be seen as a potential second- or third-line treatment for MD. Furthermore, its clinical utility as a therapeutic alternative to depressed patients who did not improve following unilateral rTMS treatment should be further explored (as, for example, previous studies have shown that left-sided HF-rTMS can be effective in non-responders to right-sided LF-rTMS and vice-versa; Fitzgerald et al. Reference Fitzgerald, Hoy, Daskalakis and Kulkarni2009; Speer et al. Reference Speer, Benson, Kimbrell, Wassermann, Willis, Herscovitch and Post2009).
In summary, bilateral rTMS is a welcome addition to the therapeutic armamentarium for MD owing to its overall efficacy, favorable side-effects profile and lack of drug interactions. Nevertheless, major tasks for future research include the investigation of whether patients with distinct subtypes of MD preferentially respond to this neuromodulation technique, whether its beneficial effects are maintained over time and how it compares with other rTMS protocols. Also, the search for optimal stimulation parameters for bilateral rTMS as well as the investigation of its neurobiological underpinnings should be the focus of further studies.
Supplementary material
For supplementary material accompanying this paper visit http://dx.doi.org/10.1017/S0033291712002802.
Declaration of Interest
Z.J.D. received external funding through Neuronetics and Brainsway Inc., Aspect Medical and a travel allowance through Pfizer and Merck. Z.J.D. has also received speaker funding through Sepracor Inc. and served on the advisory board for Hoffmann-La Roche Ltd.
