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Preliminary assessment of the therapeutic efficacy of continuous theta-burst magnetic stimulation (cTBS) in major depression: A double-blind sham-controlled study
Journal of Affective Disorders 170 (2015) 225–229
Contents lists available at ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research report
Preliminary assessment of the therapeutic efficacy of continuous theta-burst magnetic stimulation (cTBS) in major depression: A double-blind sham-controlled study Andrei V. Chistyakov a, Bella Kreinin b, Sara Marmor b, Boris Kaplan a, Adel Khatib b, Nawaf Darawsheh b, Danny Koren b, Menashe Zaaroor a, Ehud Klein b,n a b
Department of Neurosurgery, Rambam Medical Center, B. Rappaport Faculty of Medicine, The Technion, Israel Institute of Technology, Haifa, Israel Department of Psychiatry, Rambam Medical Center, B. Rappaport Faculty of Medicine, The Technion, Israel Institute of Technology, Haifa 31096, Israel
art ic l e i nf o
a b s t r a c t
Article history: Received 29 April 2014 Received in revised form 11 August 2014 Accepted 25 August 2014 Available online 1 September 2014
Background: Theta-burst transcranial magnetic stimulation (TBS) has been shown to induce potent and long lasting effects on cortical excitability. In a previous open study, we demonstrated safety, tolerability and antidepressant properties of continuous TBS (cTBS) in major depression (MD). The present study was aimed to evaluate the therapeutic efficacy of cTBS in depressed patients using a double-blind, shamcontrolled design. Methods: Twenty nine patients with MD were randomized to receive either active cTBS to the right dorsolateral prefrontal cortex (n ¼15) or sham cTBS (n ¼ 14) for 10 consecutive work days. After the 10th session, patients who received sham TBS were crossed over to active cTBS which consisted of 10 daily sessions. Patients who received active cTBS continued with the same treatment protocol for additional 10 treatments. Each treatment session consisted of 3600 stimuli at an intensity of 100% of the active motor threshold. Severity of depression was assessed weekly. Results: Overall, there was no significant difference in the degree of clinical improvement between active and sham cTBS groups. However, in patients whose medication status remained unchanged before the trial (n ¼8) and in those who were medication-free (n ¼3), active cTBS resulted in a significantly greater reduction of Hamilton depression scores as compared to sham cTBS. Limitations: A small sample size, confounding effect of medication and short treatment period. Conclusions: Our results suggest that the antidepressant effect of cTBS is modest, yet it might be beneficial to patients nonresponsive to ongoing pharmacological treatment. A direct comparison between cTBS and conventional rTMS protocols is warranted. & 2014 Published by Elsevier B.V.
Keywords: Major depression Theta-burst transcranial magnetic stimulation Double-blind study Therapeutic efficacy
1. Introduction Repetitive transcranial magnetic stimulation (rTMS) has been shown to produce antidepressant effects in patients with major depression (MD). This is true for both high frequency rTMS administered to the left dorsolateral prefrontal cortex (DLPFC) (George et al., 2000) and low frequency rTMS administered to the right DLPFC (Fitzgerald et al., 2003; Klein et al., 1999). However, the therapeutic effect of currently available rTMS protocols is relatively moderate and short-lasting. It has been suggested that the antidepressant action of rTMS is related to its ability to modulate cortical excitability (Chistyakov et al., 2005). When applied at high frequencies (41 Hz) rTMS can n
Corresponding author. Tel.: þ 972 4 854 2559; fax: þ 972 4 854 3050. E-mail address: [email protected] (E. Klein).
http://dx.doi.org/10.1016/j.jad.2014.08.035 0165-0327/& 2014 Published by Elsevier B.V.
facilitate cortical activity (Pascual-Leone et al., 1998) while at low frequencies (r 1 Hz) it suppresses cortical excitability (Chen et al., 1997). Theta-burst stimulation (TBS), a novel form of rTMS, can induce larger and longer-lasting modulation of cortical excitability than standard rTMS (Huang et al., 2005) thus suggesting its potentially greater clinical efficacy. In a previous open study (Chistyakov et al., 2010), we have demonstrated safety, tolerability and antidepressant properties of continuous TBS (cTBS) applied to the right DLPFC in patients with MD using different stimulation protocols (600–900 stimuli per train, with a total of 1200 to 3600 per session). Yet, given the open design of the trial these results were viewed as preliminary and a further double-blind, shamcontrolled study was designed to assess the clinical utility of cTBS in MD. The present study was aimed to evaluate the therapeutic efficacy of cTBS in depressed patients using double-blind comparison with sham cTBS.
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A.V. Chistyakov et al. / Journal of Affective Disorders 170 (2015) 225–229
The study was approved by the local Ethical Committee and all patients gave written informed consent before participation.
2. Materials and methods 2.1. Subjects A total of 29 in patients with major depression (19 with unipolar and 10 with bipolar depression) were recruited for the study. Patients were hospitalized due to lack of response to previous medication or deterioration of their clinical condition. All patients met DSM IV criteria for MD, as determined by consensus of two senior staff psychiatrists, and were capable to provide written informed consent and to cooperate in the study. Demographic and clinical characteristics of the participants are depicted in Table 1. Overall, the average severity of depression at baseline was moderate to severe. Exclusion criteria were: (1) suicidal risk, (2) seizure disorder, (3) history of head trauma with documented brain damage in the last year, (4) uncontrolled medical conditions, (5) pacemaker, metallic implants, or any other contraindication to TMS as specified in the safety guidelines for that procedure (Rossi et al., 2009), and (6) drug or alcohol abuse in the last six months. Twenty six (90%) patients received concomitant pharmacotherapy and three were medication-free throughout the study. Among the patients who were receiving medication, eight (28%) remained on their existing pharmacological treatment (mean duration of previous treatment was 3.3 71.9 months) while in 18 patients (62%) medication status was changed before the trial (within the week prior to cTBS). Table 2 provides details on the type of medications that the patients were receiving. Initially, patients were randomized to receive either active cTBS (n ¼15) or sham cTBS (n¼ 14) to the right DLPFC for 10 consecutive work days (phase 1). After the 10th session, patients who received sham cTBS were crossed over to the active cTBS treatment which consisted of 10 daily sessions (phase 2). Patients who received active cTBS in phase 1 continued with the same treatment protocol in phase 2. In phase 1 (double-blind phase), the rater and patients were blinded to the treatment, whereas phase 2 was singleblinded. The technician who delivered cTBS was not blind and was not involved in the participant's care and assessment.
2.2. cTBS treatment Treatment with cTBS was delivered by a Magstim Super Rapid2 magnetic stimulator with a 70 mm figure-of-eight coil (peak magnetic field: 2.2 T) which was placed tangentially to the scalp over the right DLPC. The stimulation site was defined as a location 5 cm anterior to the optimal coil position (“hot-spot“) for producing the motor response in the contralateral abductor pollicis brevis (APB) muscle. The choice of this stimulation site and treatment parameters was based on our previous TBS study which demonstrated positive treatment response with a low attrition rate due to painful sensation and facial muscle twitches (Chistyakov et al., 2010). Similar to the Huang et al. (2005) original protocol, cTBS consisted of triple-pulse 50 Hz bursts given at a rate of 5 Hz (i.e. 200 ms between each burst) in uninterrupted trains. However, as shown to be superior in our previous study the number of stimuli per train was increased from 600 to 900, Thus, each treatment session included 3600 stimuli delivered in four consecutive trains of 900 stimuli each separated by at least a 15-min interval. The stimulation intensity was 100% of the active motor threshold (aMT). The aMT was defined as the minimum stimulus intensity required to evoke a reproducible motor response ( 4100 mV) to single-pulse TMS over the motor “hot-spot“ during a voluntary isometric contraction of the contralateral APB. Evoked and spontaneous muscle activity was recorded using integrated Magstim two-channel EMG amplifier and system acquisition software. In addition, the resting motor threshold (rMT) was measured as the lowest stimulus intensity capable of eliciting at least 5 motor responses with amplitude of at least 50 mV in a series of 10 consecutive trials of single-pulse TMS in the relaxed APB muscle. In the active cTBS group, motor thresholds (aMT, rMT) were assessed twice, at baseline and after 10-treatment sessions. No difference was observed between the two measurements. In the
Table 1 Socio-demographic and clinical characteristics of the total sample and groups (Mean7 SD). Total sample (n¼ 29)
Gender ( M/F) Age (years) Age at onset (years) Length of illness (years) Length of current episode (months) Number of episodes Number of previous hospitalizations HDRS at baseline
F(1,27)/χ2
Groups
11/18 51.8 7 14.2 36.9 7 13.2 14.9 7 11.9 12.6 7 14.8 2.9 7 2.3 0.9 7 1.6 25.8 7 3.7
Active cTBS (n¼ 15)
Sham cTBS (n¼14)
5/10 52.7 7 11.1 39.8 7 12.4 12.9 7 9.9 10.9 713.4 3.7 7 2.6 1.1 71.8 26.7 7 3.9
6/8 50.9 7 17.3 33.9713.7 16.9 7 13.9 14.4 7 16.4 2.17 1.7 0.8 7 1.4 24.873.2
0.28, N.S 0.12, N.S 1.48, N.S 0.82, N.S 0.4, N.S 3.3, N.S 0.23, N.S 2.14, N.S
N.S – Non-significant difference.
Table 2 Pharmacological treatment in the total sample and groups (n, %). Total sample (n¼29)
Medication change before trial Antidepressants Mood Stabilizers Antipsychotics N.S – Non-significant difference.
18 23 14 14
(62.1%) (79.3%) (48.3%) (48.3%)
χ2
Groups Active cTBS (n ¼15)
Sham cTBS (n ¼14)
11 12 8 8
7 11 6 6
(73.3%) (80%) (53.3%) (53.3%)
(50%) (78.6%) (42.9%) (42.9%)
1.67, N.S 0.01, N.S 0.32, N.S 0.31, N.S
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Fig. 1. Clinical improvement following active and sham cTBS (Total sample, n¼ 29, Mean 7 S.D).
sham group, which received a total of 10 active cTBS sessions, motor thresholds were assessed once, before the beginning of the active treatment phase (after two weeks of sham treatment). Sham cTBS was applied using a specially designed sham coil which produces identical sounds but is not associated with a stimulus sensation compared to the coil delivering real stimulation. cTBS treatment was administered in a quiet room while patients were seated in an armchair. Earplugs were used throughout evaluation and treatment sessions. In order to assess treatment tolerability, patients were asked to report any side effects or symptoms which they experienced during the treatment. 2.3. Clinical assessment The therapeutic efficacy of cTBS was assessed by the Hamilton Depression Rating Scale (HDRS, 21-item version) (Hamilton, 1960). Clinical response was defined categorically as a reduction of 50% or more in HDRS (improved, not improved). Clinical ratings were assessed by a trained psychiatrist at weekly intervals. 2.4. Statistical procedures Repeated-measures ANOVA with GROUP (active cTBS, sham cTBS) as the between-subject factor, and TIME (baseline, after one week, after two weeks) as the inter-subject term was used to evaluate changes in HDRS. In order to assess the possible effect of medication status, another set of repeated-measures ANOVA was performed in a subgroup of patients who were medication-free or remained on their previous pharmacological treatment throughout the trial. Post-hoc analysis was done with the Bonferroni method. Continuous demographic and clinical variables were analyzed using one-way ANOVA. Categorical variables (clinical response, gender, medication status) were compared by the ChiSquare (χ2) test. Results were considered significant if po 0.05. In addition, effect size and number needed to treat (NNT) were
assessed. The effect size was calculated based on the reduction in HDRS scores (delta) compared to baseline in the two groups, after two and four weeks, respectively. NNT was calculated on the basis of improvement rates after two weeks of active vs. sham treatment and after two weeks vs. four weeks of active treatment.
3. Results 3.1. Baseline assessment A set of one-way ANOVA and χ2 tests did not reveal any significant between-group differences in baseline HDRS scores and demographic data (Table 1). The mean aMT and rMT for the total sample was 45.47 5.3% and 58.4 710.1%, respectively. There was no significant difference in the motor thresholds and stimulus intensities between active and sham cTBS groups. 3.2. Treatment outcome and antidepressant effect of cTBS Three patients dropped out from the study, all from the group that initially received sham cTBS. One patient withdrew after 2 treatment sessions and two additional patients dropped out two days after they crossed over to the active cTBS. All patients who initially received active cTBS completed the entire 4-week treatment protocol without any adverse effects. None of the subjects in the sham group spontaneously reported a difference in the sensation between active and sham stimulation. Repeated-measures ANOVA for HDRS revealed a significant main effect of TIME after two weeks (F(2,26) ¼42.2, po 0.00001) and four weeks (F(4,24)¼41.8, p o0.00001) of treatment. There was no significant difference in the degree of clinical improvement between active and sham cTBS groups after phase 1 (TIME GROUP interaction, F(2,26) ¼0.8, p 40.05) as well as after phase 2 (TIMExGROUP interaction, F(4,24)¼ 1.4, p 40.05) of the trial (Fig. 1). However, further analysis showed a significant interaction
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Fig. 2. Clinical improvement in eight patients (including one patient who dropped out) whose medication status was not changed and three patients who were medicationfree. Comparison of 4 weeks of active cTBS (n ¼4) and 2 weeks of active cTBS following 2 weeks of sham cTBS (n¼ 6) (* p o0.05, Mean 7 S.D).
Table 3 Response rates in the different treatment protocols. Total Sample
Improved ( 4 ¼ 50%) Not improved Total
9 (32.1%) 19 28
Phase 1 (double-blind)
Phase 2 (single-blind)
Active cTBS (2 weeks)
Sham cTBS (2 weeks)
Active cTBS (4 weeks)
Active cTBS (2 weeks)
5 (33.3%) 10 15
4 (30.8%) 9 13
9 (60%) 6 15
4 (36.4%) 7 11
TIME GROUP (F(4,8)¼ 2.84, po 0.05) in a subgroup of 11 patients whose medication status was not changed before the cTBS intervention (n ¼8, including one patient who dropped out after two treatment sessions) and in those who were medication-free throughout the trial (n ¼3,). In this subgroup, four weeks of active cTBS treatment in 4 patients resulted in a significantly greater reduction of HDRS scores as compared to two weeks of active cTBS in 6 patients after the cross-over from sham treatment (Fig. 2). In contrast, in those patients whose medications were changed prior to the sham-controlled phase (n ¼18) there was no difference in HDRS reduction (TIMExGROUP interaction, F(4,16) ¼ 0.3, p 40.05) between active cTBS (n ¼11) and sham treatment (n¼ 7). Between-group comparisons of proportions of patients with at least 50% reduction in the HDRS pointed to a higher clinical response after 4 weeks of active cTBS treatment as compared to sham as well as to two weeks of active cTBS treatment (Table 3). However, these differences did not reach statistical significance. The effect size was 0.44 and 0.69 after two and four weeks, respectively. This estimate was not significant as evident from the confidence intervals ( 0.5–1.47 and 0.35–1.74, respectively). The number needed to treat (NNT) was 40 after two weeks and 4 after four weeks of treatment. No differences in baseline ratings and treatment response to active and sham cTBS were observed when unipolar (n ¼19) and bipolar (n¼ 10) patients were compared.
The results remained unchanged when we repeated the same set of ANOVA and χ2 tests after imputing the estimated posttreatment scores of the two subjects from the sham group who withdrew after 10 treatment sessions. The imputation method used for calculation of the missing observations was based on a regression equation that predicts post-treatment ratings taking into account age, gender, length of illness, medication status and clinical ratings (R2 ¼0.8). We also calculated the estimated sample size required to detect a statistically significant between-group difference. Accordingly, at least 56 patients per group would be necessary to reach statistical significance (p o0.05) with 80% power, after four weeks of treatment.
4. Discussion In the present study, cTBS when given at a dose of 3600 stimuli per session in four consecutive trains and at an intensity of 100% aMT to the right DLPFC was well tolerated and not associated with side effects. This further confirms our previous findings demonstrating safety and tolerability of cTBS in patients with MD (Chistyakov et al., 2010). Following two and four weeks of treatment, significant clinical improvement was observed in the entire study sample with no
A.V. Chistyakov et al. / Journal of Affective Disorders 170 (2015) 225–229
significant difference in HDRS scores between active- and shamcTBS groups. The proportion of responders in the group that received four weeks of active cTBS (60%) tended to be higher compared to the group that received two weeks of sham cTBS followed by two weeks of active cTBS (36.4%) but this difference was not statistically significant. The effect size after four weeks of treatment was also not statistically significant. While these findings do not lend support to the therapeutic efficacy of cTBS, the favorable NNT after four weeks of treatment may suggest that cTBS does have modest antidepressant properties. The robust reduction of the NNT from 40 after two weeks to 4 after four weeks might indicate that, similar to conventional rTMS protocols (Berlim et al., 2013), cTBS requires at least four weeks of treatment to gain a therapeutic effect. The lack of significant advantage of active cTBS over sham treatment could be, at least in part, due to the low power of the study. Our sample size calculation indicates that a fourfold increase in the number of subjects would be needed to obtain statistical significance. This could be related to a high inter-individual variability in response to non-invasive brain stimulation protocols including conventional rTMS and TBS (Lopez-Alonso et al., 2014). Another point to be considered is the confounding effect of medication heterogeneity in our subjects and, especially, newly started pharmacological treatment concomitantly with cTBS which makes the interpretation of the results more complicated. Nevertheless, it is noteworthy that only in those patients whose medication status was not changed before the trial and in those who were medication-free, active cTBS resulted in a significantly greater clinical improvement in comparison with sham cTBS. The sham-controlled period of our study was only two weeks. This was based on the results of our preliminary open study (Chistyakov et al., 2010) demonstrating antidepressant action of cTBS after two weeks of treatment, as well as findings of Huang et al. (2005) showing a more robust effect of TBS on cortical functions than that previously reported for conventional rTMS. However, the results of the present study do not suggest that cTBS has a more rapid onset of antidepressant action than conventional rTMS. Previous randomized controlled rTMS studies have shown that the placebo response is often indistinguishable from the verum response in the first two weeks, with differences emerging afterwards (O’Reardon et al., 2007). Thus, the short sham period could be a limitation of our study. Nevertheless, results of recent study using a bilateral TBS in MD patients demonstrated that even after six weeks of treatment only a marginal advantage of active TBS over sham TBS was evident (Plewnia et al., 2014). A possible explanation for the non-significant antidepressant effect of our treatment protocol could be that cTBS delivered at non-subthreshold stimulus intensity (100% aMT as compared to 80% aMT in the original protocol used by Huang et al. 2005) might have resulted in failing to inhibit the right DLPFC. Nevertheless, our previous open study (Chistyakov et al., 2010) indicated that enhancement of stimulation parameters including increase of intensity up to 100% aMT resulted in a more pronounced antidepressant effect of cTBS. Another point to be mentioned, which might be considered as a limitation, relates to coil positioning for stimulation of the DLPFC. While most rTMS studies have used a 6 cm-rule, namely moving the coil 6 cm anteriorily from the motor cortex “hot-spot“ we used a 5 cm rule. This site choice was based on our previous study which demonstrated antidepressant effect of cTBS with better tolerability compared to the 6 cm location. The blinding in our study was compromised by the fact that the Magstim sham coil does not produce similar scalp sensations as real stimulation. Although none of the subjects in the sham group noted a difference between active and sham stimulation this does
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not guarantee optimal blinding of the treatment condition, as it was not assessed in subjects and raters. In conclusion, the results of this study suggest that an antidepressant effect of cTBS to the right DLPFC is, at the best, modest and does not seem to exceed that of conventional low frequency rTMS to the right DLPFC or high frequency rTMS to the left DLPFC. However, given the safety, tolerability and convenience of application of cTBS and the limitations of the present study, its potential clinical utility should not be dismissed at this point and a direct comparison between cTBS and standard rTMS protocols in studies with a larger sample size is warranted.
Role of funding source Funding for this study was provided by the Niedersachsen Research Foundation.
Conflict of interest All authors declare that they have no conflicts of interest.
Acknowledgment None.
References Berlim, M.T., Van den Eynde, F., Jeff Daskalakis, Z., 2013. Clinically meaningful efficacy and acceptability of low-frequency repetitive transcranial magnetic stimulation (rTMS) for treating primary major depression: a meta-analysis of randomized, double-blind and sham-controlled trials. Neuropsychopharmacology 38, 543–551. Chen, R., Classen, J., Gerloff, C., Celnik, P., Wassermann, E.M., Hallett, M., Cohen, L.G., 1997. Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology 48, 1398–1403. Chistyakov, A.V., Kaplan, B., Rubichek, O., Kreinin, I., Koren, D., Feinsod, M., Klein, E., 2005. Antidepressant effects of different schedules of repetitive transcranial magnetic stimulation vs. clomipramine in patients with major depression: relationship to changes in cortical excitability. Int. J. Neuropsychopharmacol. 8, 223–233. Chistyakov, A.V., Rubicsek, O., Kaplan, B., Zaaroor, M., Klein, E., 2010. Safety, tolerability and preliminary evidence for antidepressant efficacy of thetaburst transcranial magnetic stimulation in patients with major depression. Int. J. Neuropsychopharmacol. 13, 387–393. Fitzgerald, P.B., Brown, T.L., Marston, N.A., Daskalakis, Z.J., De Castella, A., Kulkarni, J., 2003. Transcranial magnetic stimulation in the treatment of depression: a double-blind, placebo-controlled trial. Arch. Gen. Psychiatry 60, 1002–1008. George, M.S., Nahas, Z., Molloy, M., Speer, A.M., Oliver, N.C., Li, X.B., Arana, G.W., Risch, S.C., Ballenger, J.C., 2000. A controlled trial of daily left prefrontal cortex TMS for treating depression. Biol. Psychiatry 48, 962–970. Hamilton, M., 1960. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23, 56–62. Huang, Y.Z., Edwards, M.J., Rounis, E., Bhatia, K.P., Rothwell, J.C., 2005. Theta burst stimulation of the human motor cortex. Neuron 45, 201–206. Klein, E., Kreinin, I., Chistyakov, A., Koren, D., Mecz, L., Marmur, S., Ben Shachar, D., Feinsod, M., 1999. Therapeutic efficacy of right prefrontal slow repetitive transcranial magnetic stimulation in major depression: a double-blind controlled study. Arch. Gen. Psychiatry 56, 315–320. Lopez-Alonso, V., Cheeran, B., Rio-Rodriguez, D., Fernandez-Del-Olmo, M., 2014. Inter-individual variability in response to non-invasive brain stimulation paradigms. Brain Stimul. 7 (3), 372–380. O’Reardon, J.P., Solvason, H.B., Janicak, P.G., Sampson, S., Isenberg, K.E., Nahas, Z., McDonald, W.M., Avery, D., Fitzgerald, P.B., Loo, C., Demitrack, M.A., George, M. S., Sackeim, H.A., 2007. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol. Psychiatry 62, 1208–1216. Pascual-Leone, A., Tormos, J.M., Keenan, J., Tarazona, F., Canete, C., Catala, M.D., 1998. Study and modulation of human cortical excitability with transcranial magnetic stimulation. J. Clin. Neurophysiol. 15, 333–343. Plewnia, C., Pasqualetti, P., Grosse, S., Schlipf, S., Wasserka, B., Zwissler, B., Fallgatter, A., 2014. Treatment of major depression with bilateral theta burst stimulation: a randomized controlled pilot trial. J. Affect. Disord. 156, 219–223. Rossi, S., Hallett, M., Rossini, P.M., Pascual-Leone, A., 2009. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin. Neurophysiol. 120, 2008–2039.
Contents lists available at ScienceDirect
Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research report
Preliminary assessment of the therapeutic efficacy of continuous theta-burst magnetic stimulation (cTBS) in major depression: A double-blind sham-controlled study Andrei V. Chistyakov a, Bella Kreinin b, Sara Marmor b, Boris Kaplan a, Adel Khatib b, Nawaf Darawsheh b, Danny Koren b, Menashe Zaaroor a, Ehud Klein b,n a b
Department of Neurosurgery, Rambam Medical Center, B. Rappaport Faculty of Medicine, The Technion, Israel Institute of Technology, Haifa, Israel Department of Psychiatry, Rambam Medical Center, B. Rappaport Faculty of Medicine, The Technion, Israel Institute of Technology, Haifa 31096, Israel
art ic l e i nf o
a b s t r a c t
Article history: Received 29 April 2014 Received in revised form 11 August 2014 Accepted 25 August 2014 Available online 1 September 2014
Background: Theta-burst transcranial magnetic stimulation (TBS) has been shown to induce potent and long lasting effects on cortical excitability. In a previous open study, we demonstrated safety, tolerability and antidepressant properties of continuous TBS (cTBS) in major depression (MD). The present study was aimed to evaluate the therapeutic efficacy of cTBS in depressed patients using a double-blind, shamcontrolled design. Methods: Twenty nine patients with MD were randomized to receive either active cTBS to the right dorsolateral prefrontal cortex (n ¼15) or sham cTBS (n ¼ 14) for 10 consecutive work days. After the 10th session, patients who received sham TBS were crossed over to active cTBS which consisted of 10 daily sessions. Patients who received active cTBS continued with the same treatment protocol for additional 10 treatments. Each treatment session consisted of 3600 stimuli at an intensity of 100% of the active motor threshold. Severity of depression was assessed weekly. Results: Overall, there was no significant difference in the degree of clinical improvement between active and sham cTBS groups. However, in patients whose medication status remained unchanged before the trial (n ¼8) and in those who were medication-free (n ¼3), active cTBS resulted in a significantly greater reduction of Hamilton depression scores as compared to sham cTBS. Limitations: A small sample size, confounding effect of medication and short treatment period. Conclusions: Our results suggest that the antidepressant effect of cTBS is modest, yet it might be beneficial to patients nonresponsive to ongoing pharmacological treatment. A direct comparison between cTBS and conventional rTMS protocols is warranted. & 2014 Published by Elsevier B.V.
Keywords: Major depression Theta-burst transcranial magnetic stimulation Double-blind study Therapeutic efficacy
1. Introduction Repetitive transcranial magnetic stimulation (rTMS) has been shown to produce antidepressant effects in patients with major depression (MD). This is true for both high frequency rTMS administered to the left dorsolateral prefrontal cortex (DLPFC) (George et al., 2000) and low frequency rTMS administered to the right DLPFC (Fitzgerald et al., 2003; Klein et al., 1999). However, the therapeutic effect of currently available rTMS protocols is relatively moderate and short-lasting. It has been suggested that the antidepressant action of rTMS is related to its ability to modulate cortical excitability (Chistyakov et al., 2005). When applied at high frequencies (41 Hz) rTMS can n
Corresponding author. Tel.: þ 972 4 854 2559; fax: þ 972 4 854 3050. E-mail address: [email protected] (E. Klein).
http://dx.doi.org/10.1016/j.jad.2014.08.035 0165-0327/& 2014 Published by Elsevier B.V.
facilitate cortical activity (Pascual-Leone et al., 1998) while at low frequencies (r 1 Hz) it suppresses cortical excitability (Chen et al., 1997). Theta-burst stimulation (TBS), a novel form of rTMS, can induce larger and longer-lasting modulation of cortical excitability than standard rTMS (Huang et al., 2005) thus suggesting its potentially greater clinical efficacy. In a previous open study (Chistyakov et al., 2010), we have demonstrated safety, tolerability and antidepressant properties of continuous TBS (cTBS) applied to the right DLPFC in patients with MD using different stimulation protocols (600–900 stimuli per train, with a total of 1200 to 3600 per session). Yet, given the open design of the trial these results were viewed as preliminary and a further double-blind, shamcontrolled study was designed to assess the clinical utility of cTBS in MD. The present study was aimed to evaluate the therapeutic efficacy of cTBS in depressed patients using double-blind comparison with sham cTBS.
226
A.V. Chistyakov et al. / Journal of Affective Disorders 170 (2015) 225–229
The study was approved by the local Ethical Committee and all patients gave written informed consent before participation.
2. Materials and methods 2.1. Subjects A total of 29 in patients with major depression (19 with unipolar and 10 with bipolar depression) were recruited for the study. Patients were hospitalized due to lack of response to previous medication or deterioration of their clinical condition. All patients met DSM IV criteria for MD, as determined by consensus of two senior staff psychiatrists, and were capable to provide written informed consent and to cooperate in the study. Demographic and clinical characteristics of the participants are depicted in Table 1. Overall, the average severity of depression at baseline was moderate to severe. Exclusion criteria were: (1) suicidal risk, (2) seizure disorder, (3) history of head trauma with documented brain damage in the last year, (4) uncontrolled medical conditions, (5) pacemaker, metallic implants, or any other contraindication to TMS as specified in the safety guidelines for that procedure (Rossi et al., 2009), and (6) drug or alcohol abuse in the last six months. Twenty six (90%) patients received concomitant pharmacotherapy and three were medication-free throughout the study. Among the patients who were receiving medication, eight (28%) remained on their existing pharmacological treatment (mean duration of previous treatment was 3.3 71.9 months) while in 18 patients (62%) medication status was changed before the trial (within the week prior to cTBS). Table 2 provides details on the type of medications that the patients were receiving. Initially, patients were randomized to receive either active cTBS (n ¼15) or sham cTBS (n¼ 14) to the right DLPFC for 10 consecutive work days (phase 1). After the 10th session, patients who received sham cTBS were crossed over to the active cTBS treatment which consisted of 10 daily sessions (phase 2). Patients who received active cTBS in phase 1 continued with the same treatment protocol in phase 2. In phase 1 (double-blind phase), the rater and patients were blinded to the treatment, whereas phase 2 was singleblinded. The technician who delivered cTBS was not blind and was not involved in the participant's care and assessment.
2.2. cTBS treatment Treatment with cTBS was delivered by a Magstim Super Rapid2 magnetic stimulator with a 70 mm figure-of-eight coil (peak magnetic field: 2.2 T) which was placed tangentially to the scalp over the right DLPC. The stimulation site was defined as a location 5 cm anterior to the optimal coil position (“hot-spot“) for producing the motor response in the contralateral abductor pollicis brevis (APB) muscle. The choice of this stimulation site and treatment parameters was based on our previous TBS study which demonstrated positive treatment response with a low attrition rate due to painful sensation and facial muscle twitches (Chistyakov et al., 2010). Similar to the Huang et al. (2005) original protocol, cTBS consisted of triple-pulse 50 Hz bursts given at a rate of 5 Hz (i.e. 200 ms between each burst) in uninterrupted trains. However, as shown to be superior in our previous study the number of stimuli per train was increased from 600 to 900, Thus, each treatment session included 3600 stimuli delivered in four consecutive trains of 900 stimuli each separated by at least a 15-min interval. The stimulation intensity was 100% of the active motor threshold (aMT). The aMT was defined as the minimum stimulus intensity required to evoke a reproducible motor response ( 4100 mV) to single-pulse TMS over the motor “hot-spot“ during a voluntary isometric contraction of the contralateral APB. Evoked and spontaneous muscle activity was recorded using integrated Magstim two-channel EMG amplifier and system acquisition software. In addition, the resting motor threshold (rMT) was measured as the lowest stimulus intensity capable of eliciting at least 5 motor responses with amplitude of at least 50 mV in a series of 10 consecutive trials of single-pulse TMS in the relaxed APB muscle. In the active cTBS group, motor thresholds (aMT, rMT) were assessed twice, at baseline and after 10-treatment sessions. No difference was observed between the two measurements. In the
Table 1 Socio-demographic and clinical characteristics of the total sample and groups (Mean7 SD). Total sample (n¼ 29)
Gender ( M/F) Age (years) Age at onset (years) Length of illness (years) Length of current episode (months) Number of episodes Number of previous hospitalizations HDRS at baseline
F(1,27)/χ2
Groups
11/18 51.8 7 14.2 36.9 7 13.2 14.9 7 11.9 12.6 7 14.8 2.9 7 2.3 0.9 7 1.6 25.8 7 3.7
Active cTBS (n¼ 15)
Sham cTBS (n¼14)
5/10 52.7 7 11.1 39.8 7 12.4 12.9 7 9.9 10.9 713.4 3.7 7 2.6 1.1 71.8 26.7 7 3.9
6/8 50.9 7 17.3 33.9713.7 16.9 7 13.9 14.4 7 16.4 2.17 1.7 0.8 7 1.4 24.873.2
0.28, N.S 0.12, N.S 1.48, N.S 0.82, N.S 0.4, N.S 3.3, N.S 0.23, N.S 2.14, N.S
N.S – Non-significant difference.
Table 2 Pharmacological treatment in the total sample and groups (n, %). Total sample (n¼29)
Medication change before trial Antidepressants Mood Stabilizers Antipsychotics N.S – Non-significant difference.
18 23 14 14
(62.1%) (79.3%) (48.3%) (48.3%)
χ2
Groups Active cTBS (n ¼15)
Sham cTBS (n ¼14)
11 12 8 8
7 11 6 6
(73.3%) (80%) (53.3%) (53.3%)
(50%) (78.6%) (42.9%) (42.9%)
1.67, N.S 0.01, N.S 0.32, N.S 0.31, N.S
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Fig. 1. Clinical improvement following active and sham cTBS (Total sample, n¼ 29, Mean 7 S.D).
sham group, which received a total of 10 active cTBS sessions, motor thresholds were assessed once, before the beginning of the active treatment phase (after two weeks of sham treatment). Sham cTBS was applied using a specially designed sham coil which produces identical sounds but is not associated with a stimulus sensation compared to the coil delivering real stimulation. cTBS treatment was administered in a quiet room while patients were seated in an armchair. Earplugs were used throughout evaluation and treatment sessions. In order to assess treatment tolerability, patients were asked to report any side effects or symptoms which they experienced during the treatment. 2.3. Clinical assessment The therapeutic efficacy of cTBS was assessed by the Hamilton Depression Rating Scale (HDRS, 21-item version) (Hamilton, 1960). Clinical response was defined categorically as a reduction of 50% or more in HDRS (improved, not improved). Clinical ratings were assessed by a trained psychiatrist at weekly intervals. 2.4. Statistical procedures Repeated-measures ANOVA with GROUP (active cTBS, sham cTBS) as the between-subject factor, and TIME (baseline, after one week, after two weeks) as the inter-subject term was used to evaluate changes in HDRS. In order to assess the possible effect of medication status, another set of repeated-measures ANOVA was performed in a subgroup of patients who were medication-free or remained on their previous pharmacological treatment throughout the trial. Post-hoc analysis was done with the Bonferroni method. Continuous demographic and clinical variables were analyzed using one-way ANOVA. Categorical variables (clinical response, gender, medication status) were compared by the ChiSquare (χ2) test. Results were considered significant if po 0.05. In addition, effect size and number needed to treat (NNT) were
assessed. The effect size was calculated based on the reduction in HDRS scores (delta) compared to baseline in the two groups, after two and four weeks, respectively. NNT was calculated on the basis of improvement rates after two weeks of active vs. sham treatment and after two weeks vs. four weeks of active treatment.
3. Results 3.1. Baseline assessment A set of one-way ANOVA and χ2 tests did not reveal any significant between-group differences in baseline HDRS scores and demographic data (Table 1). The mean aMT and rMT for the total sample was 45.47 5.3% and 58.4 710.1%, respectively. There was no significant difference in the motor thresholds and stimulus intensities between active and sham cTBS groups. 3.2. Treatment outcome and antidepressant effect of cTBS Three patients dropped out from the study, all from the group that initially received sham cTBS. One patient withdrew after 2 treatment sessions and two additional patients dropped out two days after they crossed over to the active cTBS. All patients who initially received active cTBS completed the entire 4-week treatment protocol without any adverse effects. None of the subjects in the sham group spontaneously reported a difference in the sensation between active and sham stimulation. Repeated-measures ANOVA for HDRS revealed a significant main effect of TIME after two weeks (F(2,26) ¼42.2, po 0.00001) and four weeks (F(4,24)¼41.8, p o0.00001) of treatment. There was no significant difference in the degree of clinical improvement between active and sham cTBS groups after phase 1 (TIME GROUP interaction, F(2,26) ¼0.8, p 40.05) as well as after phase 2 (TIMExGROUP interaction, F(4,24)¼ 1.4, p 40.05) of the trial (Fig. 1). However, further analysis showed a significant interaction
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Fig. 2. Clinical improvement in eight patients (including one patient who dropped out) whose medication status was not changed and three patients who were medicationfree. Comparison of 4 weeks of active cTBS (n ¼4) and 2 weeks of active cTBS following 2 weeks of sham cTBS (n¼ 6) (* p o0.05, Mean 7 S.D).
Table 3 Response rates in the different treatment protocols. Total Sample
Improved ( 4 ¼ 50%) Not improved Total
9 (32.1%) 19 28
Phase 1 (double-blind)
Phase 2 (single-blind)
Active cTBS (2 weeks)
Sham cTBS (2 weeks)
Active cTBS (4 weeks)
Active cTBS (2 weeks)
5 (33.3%) 10 15
4 (30.8%) 9 13
9 (60%) 6 15
4 (36.4%) 7 11
TIME GROUP (F(4,8)¼ 2.84, po 0.05) in a subgroup of 11 patients whose medication status was not changed before the cTBS intervention (n ¼8, including one patient who dropped out after two treatment sessions) and in those who were medication-free throughout the trial (n ¼3,). In this subgroup, four weeks of active cTBS treatment in 4 patients resulted in a significantly greater reduction of HDRS scores as compared to two weeks of active cTBS in 6 patients after the cross-over from sham treatment (Fig. 2). In contrast, in those patients whose medications were changed prior to the sham-controlled phase (n ¼18) there was no difference in HDRS reduction (TIMExGROUP interaction, F(4,16) ¼ 0.3, p 40.05) between active cTBS (n ¼11) and sham treatment (n¼ 7). Between-group comparisons of proportions of patients with at least 50% reduction in the HDRS pointed to a higher clinical response after 4 weeks of active cTBS treatment as compared to sham as well as to two weeks of active cTBS treatment (Table 3). However, these differences did not reach statistical significance. The effect size was 0.44 and 0.69 after two and four weeks, respectively. This estimate was not significant as evident from the confidence intervals ( 0.5–1.47 and 0.35–1.74, respectively). The number needed to treat (NNT) was 40 after two weeks and 4 after four weeks of treatment. No differences in baseline ratings and treatment response to active and sham cTBS were observed when unipolar (n ¼19) and bipolar (n¼ 10) patients were compared.
The results remained unchanged when we repeated the same set of ANOVA and χ2 tests after imputing the estimated posttreatment scores of the two subjects from the sham group who withdrew after 10 treatment sessions. The imputation method used for calculation of the missing observations was based on a regression equation that predicts post-treatment ratings taking into account age, gender, length of illness, medication status and clinical ratings (R2 ¼0.8). We also calculated the estimated sample size required to detect a statistically significant between-group difference. Accordingly, at least 56 patients per group would be necessary to reach statistical significance (p o0.05) with 80% power, after four weeks of treatment.
4. Discussion In the present study, cTBS when given at a dose of 3600 stimuli per session in four consecutive trains and at an intensity of 100% aMT to the right DLPFC was well tolerated and not associated with side effects. This further confirms our previous findings demonstrating safety and tolerability of cTBS in patients with MD (Chistyakov et al., 2010). Following two and four weeks of treatment, significant clinical improvement was observed in the entire study sample with no
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significant difference in HDRS scores between active- and shamcTBS groups. The proportion of responders in the group that received four weeks of active cTBS (60%) tended to be higher compared to the group that received two weeks of sham cTBS followed by two weeks of active cTBS (36.4%) but this difference was not statistically significant. The effect size after four weeks of treatment was also not statistically significant. While these findings do not lend support to the therapeutic efficacy of cTBS, the favorable NNT after four weeks of treatment may suggest that cTBS does have modest antidepressant properties. The robust reduction of the NNT from 40 after two weeks to 4 after four weeks might indicate that, similar to conventional rTMS protocols (Berlim et al., 2013), cTBS requires at least four weeks of treatment to gain a therapeutic effect. The lack of significant advantage of active cTBS over sham treatment could be, at least in part, due to the low power of the study. Our sample size calculation indicates that a fourfold increase in the number of subjects would be needed to obtain statistical significance. This could be related to a high inter-individual variability in response to non-invasive brain stimulation protocols including conventional rTMS and TBS (Lopez-Alonso et al., 2014). Another point to be considered is the confounding effect of medication heterogeneity in our subjects and, especially, newly started pharmacological treatment concomitantly with cTBS which makes the interpretation of the results more complicated. Nevertheless, it is noteworthy that only in those patients whose medication status was not changed before the trial and in those who were medication-free, active cTBS resulted in a significantly greater clinical improvement in comparison with sham cTBS. The sham-controlled period of our study was only two weeks. This was based on the results of our preliminary open study (Chistyakov et al., 2010) demonstrating antidepressant action of cTBS after two weeks of treatment, as well as findings of Huang et al. (2005) showing a more robust effect of TBS on cortical functions than that previously reported for conventional rTMS. However, the results of the present study do not suggest that cTBS has a more rapid onset of antidepressant action than conventional rTMS. Previous randomized controlled rTMS studies have shown that the placebo response is often indistinguishable from the verum response in the first two weeks, with differences emerging afterwards (O’Reardon et al., 2007). Thus, the short sham period could be a limitation of our study. Nevertheless, results of recent study using a bilateral TBS in MD patients demonstrated that even after six weeks of treatment only a marginal advantage of active TBS over sham TBS was evident (Plewnia et al., 2014). A possible explanation for the non-significant antidepressant effect of our treatment protocol could be that cTBS delivered at non-subthreshold stimulus intensity (100% aMT as compared to 80% aMT in the original protocol used by Huang et al. 2005) might have resulted in failing to inhibit the right DLPFC. Nevertheless, our previous open study (Chistyakov et al., 2010) indicated that enhancement of stimulation parameters including increase of intensity up to 100% aMT resulted in a more pronounced antidepressant effect of cTBS. Another point to be mentioned, which might be considered as a limitation, relates to coil positioning for stimulation of the DLPFC. While most rTMS studies have used a 6 cm-rule, namely moving the coil 6 cm anteriorily from the motor cortex “hot-spot“ we used a 5 cm rule. This site choice was based on our previous study which demonstrated antidepressant effect of cTBS with better tolerability compared to the 6 cm location. The blinding in our study was compromised by the fact that the Magstim sham coil does not produce similar scalp sensations as real stimulation. Although none of the subjects in the sham group noted a difference between active and sham stimulation this does
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not guarantee optimal blinding of the treatment condition, as it was not assessed in subjects and raters. In conclusion, the results of this study suggest that an antidepressant effect of cTBS to the right DLPFC is, at the best, modest and does not seem to exceed that of conventional low frequency rTMS to the right DLPFC or high frequency rTMS to the left DLPFC. However, given the safety, tolerability and convenience of application of cTBS and the limitations of the present study, its potential clinical utility should not be dismissed at this point and a direct comparison between cTBS and standard rTMS protocols in studies with a larger sample size is warranted.
Role of funding source Funding for this study was provided by the Niedersachsen Research Foundation.
Conflict of interest All authors declare that they have no conflicts of interest.
Acknowledgment None.
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