The World Journal of Biological Psychiatry, 2015; 16: 57–65
ORIGINAL INVESTIGATION
Bilateral prefrontal rTMS and theta burst TMS as an add-on treatment for depression: A randomized placebo controlled trial
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JULIA PRASSER1, MARTIN SCHECKLMANN1, TIMM B. POEPPL1, ELMAR FRANK1, PETER M. KREUZER1, GOERAN HAJAK1,2, RAINER RUPPRECHT1, MICHAEL LANDGREBE1,3 & BERTHOLD LANGGUTH1 1Department
of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany, of Psychiatry, Psychosomatics, and Psychotherapy, Social Foundation Bamberg, Bamberg, Germany, and 3Department of Psychiatry, Psychosomatics and Psychotherapy, kbo-Lech-Mangfall-Klinik Agatharied, Germany 2Department
Abstract Objectives. Repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral-prefrontal cortex (DLPFC) exerts antidepressant effects. In this randomised controlled clinical trial we aimed to test the safety and therapeutic efficacy of bilateral theta-burst stimulation (TBS) as an add-on therapy to standard treatment of major depression. Methods. Fifty-six patients diagnosed with a moderate to severe depressive episode received 15 daily treatments of either rTMS (110% motor-threshold; rightDLPFC, 1000 stimuli at 1 Hz ⫹ leftDLPFC, 1000 stimuli at 10 Hz), theta-burst stimulation (80% motor-threshold; rightDLPFC, continuous TBS, 1200 stimuli ⫹ leftDLPFC, intermittent TBS, 1200 stimuli), or sham TMS (N ⫽ 17, sham coil with the TBS protocol). Results. There was no significant effect in the primary outcome measures (change of the 21-item Hamilton Rating Scale for Depression). However, there was a tendency towards an increased responder rate at the end of the follow-up period for both active treatments as compared to sham, and this tendency was most pronounced for the TBS group. Conclusions. This pilot study did not reveal significant advantages of bilateral TBS or rTMS over sham treatment as an add-on treatment for major depression. A tendency towards a superior effect of bilateral TBS at the end of the follow-up period may warrant further studies. Key words: depression, bilateral, theta burst, repetitive transcranial magnetic stimulation, prefrontal cortex
Introduction Depression is a common mental disorder in the general population and causes the highest burden of disease measured in disability adjusted life years (Collins et al. 2011). Standard treatments like antidepressant medication and structured forms of psychotherapy are effective only in 60–80% of those affected, while 20–40% of depressive patients never completely recover (Fava and Davidson 1996). Therefore, additional therapeutic strategies are greatly needed. Transcranial magnetic stimulation (TMS) of the prefrontal cortex has been proposed as a new therapeutic tool for the treatment of depression (George et al. 2014b). TMS is a non-invasive brain stimulation technique that applies the principles of electromagnetism to transmit an electrical field to the brain. By using a coil placed on the scalp over a cortical region,
a magnetic stimulus passes mostly undistorted through the skull and induces a neuronal depolarization in superficial cortical areas. TMS is a safe technique with only few side effects (Rossi et al. 2009), which has proven to be feasible for both in- and outpatient treatment (Frank et al. 2010). Repetitive rhythmic application of TMS (rTMS) can induce effects which outlast the stimulation period. Studies of the motor cortex demonstrated that high-frequency rTMS (ⱖ 5 Hz) tends to increase cortical excitability, whereas low-frequency rTMS (ⱕ 1 Hz) is supposed to act in the contrary (Ridding and Rothwell 2007). Based on the concepts that emotional reactivity (Allen et al. 2004) depends on the relationship between left and right frontal activity and that a right dominance relates to depression (Davidson 1992), high-frequency rTMS of the left dorsolateral
Correspondence: Berthold Langguth, MD, Department of Psychiatry and Psychotherapy, University of Regensburg, Universitätsstrasse 84, 93053 Regensburg, Germany. Tel: ⫹ 49-941-9412099. Fax: ⫹ 49-941-9412025. E-mail: [email protected] (Received 20 June 2014 ; accepted 2 September 2014 ) ISSN 1562-2975 print/ISSN 1814-1412 online © 2015 Informa Healthcare DOI: 10.3109/15622975.2014.964768
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58 J. Prasser et al. prefrontal cortex (DLPFC) and low-frequency rTMS of the right DLPFC have been investigated for the treatment of depression (for review see Berlim et al. 2013a,b; Schutter 2009, 2010). Antidepressive effects of both approaches are well documented and high-frequency rTMS of the left prefrontal cortex has been approved by the FDA as a treatment for depression based on positive results in some (O’Reardon et al. 2007; George et al. 2010), but not all (Herwig et al. 2007) multicentric studies. However effect sizes are only moderate and a substantial number of patients do not respond at all (Padberg and George 2009). Thus there is an urgent need for the development of more effective stimulation protocols. One approach has been bilateral rTMS, i.e. the combination of high-frequency rTMS to the left DLPFC with low-frequency rTMS to the right DLPFC. The first promising results of this technique (Fitzgerald et al. 2006; Garcia-Toro et al. 2006) could not be consistently replicated (McDonald et al. 2006; Pallanti et al. 2010; Fitzgerald et al. 2011). However, a recent systematic review and meta-analysis (Berlim et al. 2012) concluded that bilateral stimulation is more effective than sham stimulation and provides clinically relevant benefits comparable with standard antidepressant drug treatment and unilateral rTMS. Pilot data indicate that theta-burst stimulation (TBS), a special pattern of rTMS, might be a promising approach for increasing the antidepressant effects of rTMS therapy (Chistyakov et al. 2010; Holzer and Padberg 2010). The TBS protocol was first reported by Huang et al. (2005) and consists of bursts of three stimuli at 50 Hz which are applied every 200 ms (5 Hz ⫽ theta). This protocol has been found to reduce motor cortical excitability when applied continuously (cTBS) and to increase motor cortex excitability when applied intermittently (iTBS) (Huang et al. 2005), even if there is a considerable inter-individual variability in stimulation effects (Hinder et al. 2014). Here we performed a pilot study to investigate bilateral TBS and rTMS as add-on therapy to standard routine treatment of major depression. Specifically, we compared bilateral TBS of the DLPFC with bilateral rTMS and sham stimulation.
Methods and materials Patients Patients with a moderate to severe depressive episode (according to ICD-10) were recruited between April 2010 and September 2011 from the Department of Psychiatry and Psychotherapy at the University of Regensburg. All patients gave written informed consent to participate in the study, which was
approved by the ethics committee of the University of Regensburg and conducted according to the Code of Ethical Principles for Medical Research Involving Human Subjects of the World Medical Association (Declaration of Helsinki, 1964). The study trial was registered at the US National Institutes of Health (www.clinicaltrials.gov) under the access code NCT01240083. Exclusion criteria were baseline scores in the 21-item Hamilton Rating Scale for Depression (HAMD) below 18 points, contraindications for TMS treatment (cardiac pacemaker or other implanted electrical devices, history of epilepsy or organic brain damage), alcohol and substance abuse, instable medical conditions, concurrent medication with large doses of benzodiazepines (lorazepam ⬎ 1 mg/day, diazepam ⬎ 5 mg/day), and inability to comply with study procedures (e.g., insufficient knowledge of the German language to complete self-assessment questionnaires). TMS was performed as an add-on therapy to standard in- or out-patient treatment. Fifty-six patients (49 inpatients, seven outpatients, 29 (51.8%) women; mean age 47.1 ⫾ 11.3 years) were randomized to receive either rTMS (rTMSgroup), theta burst stimulation (TBS group), or sham treatment (sham group). An overview of the study design is given in Figure 1, the patient details throughout the study are shown in Figure 2. Transcranial magnetic stimulation rTMS and TBS were applied with a figure-of-eight coil (Cool-B 65, Magventure A/S, Denmark) connected to a stimulator (MagPro X 100, Magventure); sham stimulation was performed with a sham-coil (MCF-B 65, Magventure). rTMS was performed at 110% resting motor threshold (RMT) or at 60% maximum stimulator output (MSO), when RMT exceeded 54% MSO. TBS was performed at 80% resting motor threshold. RMT was defined as the lowest intensity sufficient to produce left thenar muscle activation (magnetic evoked potentials ⬎ 50 μV) with a single pulse delivered to the motor cortex in at least five of 10 trials. For treatment of the left DLPFC the coil was positioned 6 cm anterior of the left motor hotspot in the sagittal direction (Frank et al. 2010). For treatment of the right DLPFC this position was mirrored over the midsagittal line. Treatment was started on Mondays and patients received 2000 stimuli/day (rTMS group) or 2400 stimuli/day (TBS and sham group) on the 15 subsequent working days. The rTMS protocol consisted of 1000 stimuli at a frequency of 1 Hz to the right DLPFC, immediately followed by 1000 stimuli at a frequency of 10 Hz (20 trains with 50 stimuli and an intertrain interval of 25 s) to left DLPFC.
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Bilateral TBS, rTMS and sham for treating depression
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Figure 1. Study design. DLPFC, dorsolateral prefrontal cortex; RMT, resting motor threshold; cTBS, continuous theta burst stimulation; iTBS, intermittent theta burst stimulation.
The TBS treatment protocol consisted of 1200 stimuli of cTBS applied to the right DLPFC, immediately followed by 1200 stimuli of iTBS to the left DLPFC. For sham stimulation the TBS protocol was applied with the sham coil.
Outcome measurement The severity of depression was assessed by the 21-item version of the Hamilton Depression Rating Scale (HAMD; Hamilton 1967) at screening, at baseline, after each week of the 3-week treatment
Figure 2. Study participants. SAE, serious adverse event; DLPFC, dorsolateral prefrontal cortex; RMT, resting motor threshold; cTBS, continuous theta burst stimulation; iTBS, intermittent theta burst stimulation.
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60 J. Prasser et al. (week 1, week 2, week 3), 4 and 8 weeks after treatment (follow-up week 7 and 11). A HAMD reduction of 50% or more was defined as a response to therapy; a HAMD score below 11 points was defined as remission. Additional assessment instruments included the Beck Depression Inventory (BDI) (Beck and Steer 1984), the Clinical Global Impression scale (CGI) and the Global Assessment of Functioning scale (GAF). The comparison in the HAMD change between baseline and at the end of treatment (week 3) served as the primary outcome. Secondary outcome measures were HAMD change over the course of the trial, responder and remitter rates at end of treatment and at end of the follow-up period, as well as changes in the Beck Depression Inventory (BDI), the Clinical Global Impression scale (CGI) and the Global Assessment of Functioning scale (GAF) over the course of the trial.
Statistical analysis For statistical analysis, only data of patients who had at least one data entry for HAMD after the baseline visit were included. In case of missing data, the last observation was carried forward. For primary and secondary outcome measures we calculated analyses of variance (ANOVA) with the within-subjects factor “time” (primary: baseline vs. week 3; secondary: all visits) and the betweensubjects factor “group” (rTMS vs. TBS vs. sham). Responder and remitter rates were compared for the three treatments by chi-square tests of independence. All statistical tests that were conducted were two-tailed and unadjusted for multiple comparisons; statistical significance was set to P ⬍ 0.05. Effect size was defined according to Cohen’s d. Data in the text are given as mean ⫾ standard deviation. Statistical data analysis was performed with SPSS 15 (SPSS Inc., Chicago, IL).
Results Patient population Clinical characteristics and medication of the patients are given in Tables I and II. Two of the 56 randomized patients withdrew their consent (one patient of the rTMS group after randomization, but before the first treatment session; one patient of the sham group after the first treatment session) and were therefore not included in the analysis (see above). The comparison of participants in the three treatment groups revealed no differences in the clinical or demographic baseline characteristics. Safety Three serious adverse effects occurred during the study. Two patients committed suicide and one patient committed a suicide attempt. One patient committed suicide after the baseline assessment, but before randomisation and the start of treatment. One patient, who was treated with rTMS committed suicide 1 week after the end of treatment. In both cases the suicides were completely unexpected and were committed at home during weekend leave (case 1) and after discharge (case 2). There was no clinical suggestion for a potential causal relationship between TMS treatment and the suicides. The suicide attempt was committed by a patient 6 weeks after the end of a sham treatment. Seven patients (rTMS group: 3; TBS group: 3; sham group: 1) complained about irritations at the stimulation site or slight headaches during treatment. One patient (sham group) felt exhausted after treatment and one patient (rTMS group) reported imbalance after stimulation. All mentioned symptoms were reported to be mild, could well be tolerated by the patients and the treatment was regularly completed without the necessity to adapt stimulation procedures or initiate other medical diagnostic or therapeutic steps.
Table I. Baseline characteristics of patients who completed treatment.
Age (years) Gender (female/male) HAMD baseline BDI baseline Clinical global impression Global assessment of functioning
rTMS (N ⫽ 17)
TBS (N ⫽ 20)
Sham (N ⫽ 17)
Statistics
50.4 ⫾ 9.9 8/9 25.0 ⫾ 4.4 21.6 ⫾ 9.8 4.6 ⫾ 0.8 50.1 ⫾ 7.0
48.2 ⫾ 10.9 10/10 27.4 ⫾ 6.5 23.7 ⫾ 12.7 4.7 ⫾ 0.7 49.1 ⫾ 7.3
42.6 ⫾ 12.4 9/8 25.3 ⫾ 5.4 26.5 ⫾ 9.1 4.7 ⫾ 0.6 51.1 ⫾ 6.8
F ⫽ 2.258; df ⫽ 2,51; P ⫽ 0.115 χ2 ⫽ 0.118; df ⫽ 2; P ⫽ 0.943 F ⫽ 0.966; df ⫽ 2,51; P ⫽ 0.387 F ⫽ 0.882; df ⫽ 2,51; P ⫽ 0.420 F ⫽ 0.151; df ⫽ 2,51; P ⫽ 0.860 F ⫽ 0.354; df ⫽ 2,51; P ⫽ 0.703
rTMS, right frontal 1 Hz followed by left frontal 10 Hz; TBS, theta burst stimulation (right frontal continuous theta burst stimulation followed by left frontal intermittent theta burst stimulation); Sham, sham stimulation (TBS protocol with sham coil); HAMD, 21-item Hamilton Rating Scale for Depression; BDI, Beck Depression Inventory; data are given as mean ⫾ standard deviation.
Bilateral TBS, rTMS and sham for treating depression Table II. Medication intake.
Medication
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SSRI SNRI TCA Other antidepressants Lithium Anticonvulsants Antipsychotics
rTMS TBS Sham (N ⫽ 17) (N ⫽ 20) (N ⫽ 17) 2 7 6 6 4 2 7
7 10 5 13 3 5 12
7 7 5 10 2 1 8
Statistics P ⫽ 0.303 P ⫽ 0.768 P ⫽ 0.428 P ⫽ 0.561 P ⫽ 0.367 P ⫽ 0.286 P ⫽ 0.734
The number in each cell indicates how many patients of the respective treatment groups were taking medications of the indicated classification. SSRI, selective serotonin reuptake inhibitors; SNRI, serotonin and noradrenaline reuptake inhibitors; TCA, tricyclic antidepressants; “other antidepressants” were agomelatine, mirtazapine and bupropion in most cases. Benzodiazepines were categorized as “anticonvulsants”.
Outcome In the primary outcome criterion (HAMD change between baseline and end of treatment) there was a significant main effect of “time” (F ⫽ 55.434; df ⫽ 1,51; P ⬍ 0.001), but not for “group” (F ⫽ 0.122; df ⫽ 2,51; P ⫽ 0.886) or for “group ⫻ time” (F ⫽ 0.862; df ⫽ 2,51; P ⫽ 0.428). The HAMD change for TBS (week 3 minus baseline) was superior to sham (d ⫽ 0.359) and rTMS (d ⫽ 0.406) with medium effect sizes according to Cohen. Effect size between rTMS and sham was negligible (d ⫽ 0.088) (Figure 3). Regarding secondary outcome measures, there were also no statistically significant differences in response and remission rates among the three treatment groups neither at end of treatment (week 3: responders: χ2 ⫽ 2.468; df ⫽ 2; P ⫽ 0.291; remitters: χ2 ⫽ 0.117; df ⫽ 2; P ⫽ 0.943) nor at the last follow-up
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visit (week 11: responders: χ2 ⫽ 5.019; df ⫽ 2; P ⫽ 0.081; remitters: χ2 ⫽ 2.078; df ⫽ 2; P ⫽ 0.354). At week 11 responder rates were highest for TBS (12 out of 20), followed by rTMS (eight out of 17) and lowest for sham (four out of 17), but this difference failed to reach statistical significance (Figure 4). Secondary outcome measure ANOVAs did not show any significant main effects of “group” (HAMD: F ⫽ 0.065; df ⫽ 2,51; P ⫽ 0.937; BDI: F ⫽ 0.739; df ⫽ 2,51; P ⫽ 0.482; GAF: F ⫽ 0.195; df ⫽ 2,51; P ⫽ 0.823; CGI: F ⫽ 0.325; df ⫽ 2,51; P ⫽ 0.724) or “group by time” (HAMD: F ⫽ 1.316; df ⫽ 12,306; P ⫽ 0.208; BDI: F ⫽ 0.461; df ⫽ 10,255; P ⫽ 0.914; GAF: F ⫽ 0.994; df ⫽ 6,153; P ⫽ 0.432; CGI: F ⫽ 0.319; df ⫽ 6,153; P ⫽ 0.926). The main effect “time” was significant for all secondary outcomes (HAMD: F ⫽ 51.021; df ⫽ 6,306; P ⬍ 0.001; BDI: F ⫽ 19.360; df ⫽ 5,255; P ⬍ 0.001; GAF: F ⫽ 31.222; df ⫽ 3,153; P ⬍ 0.001; CGI: F ⫽ 28.113; df ⫽ 3,153; P ⬍ 0.001). However, on a descriptive level TBS tended to demonstrate larger effects compared to rTMS which in turn tended to have larger effects than sham. An exploratory comparison at the last follow-up visit (week 11) suggested a potential advantage of TBS compared to sham (T ⫽ 1.972; df ⫽ 35; P ⫽ 0.057; d ⫽ 0.651). Contrasts between TBS and rTMS (T ⫽ 0.963; df ⫽ 35; P ⫽ 0.342; d ⫽ 0.324) and between rTMS and sham (T ⫽ 1.357; df ⫽ 32; P ⫽ 0.184; d ⫽ 0.465) showed no significant effect with small effect sizes. This fits with the observed near-significant differences in response rate at the last follow-up visit (see above). Efficacy of blinding was assessed by asking both patients and rating physicians at week 11 to guess about their treatment group allocation. This analysis revealed that neither patients nor physicians were
Figure 3. Changes in HAMD. HAMD, 21-item Hamilton Rating Scale for Depression; TBS, right frontal continuous theta burst stimulation followed by left frontal intermittent theta burst stimulation; rTMS, right frontal 1 Hz followed by left frontal 10 Hz; sham, sham stimulation. There was no significant difference between the three treatment groups. Pairwise comparisons of the reduction in the HAMD score at the last follow-up assessment revealed a near-significant difference between TBS and sham treatment.
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62 J. Prasser et al.
Figure 4. Responder rates. Responder rates at the different visits. Response was defined as a reduction of the 21-item Hamilton Rating Scale for Depression by at least 50%. rTMS, right frontal 1 Hz followed by left frontal 10 Hz; TBS, right frontal continuous theta burst stimulation followed by left frontal intermittent theta burst stimulation. There was no significant difference in the response rates between the three treatment groups. At the last follow-up assessment there was a non-significant trend towards higher response rates for TBS treatment.
able to identify the treatment group allocation with a significant accuracy above chance level (patients’ rating: χ2 ⫽ 0.435; df ⫽ 4; P ⫽ 0.980; physicians’ ratings: χ2 ⫽ 4.083; df ⫽ 4; P ⫽ 0.395).
Discussion In our pilot study, 15 sessions of bilateral rTMS or TBS were not significantly superior to shamtreatment when used as an add-on therapy to standard treatment of depression. However, our data also suggest a possible delayed effect of both active TMS treatments. More specifically, there was a more pronounced HAMD improvement in the TBS group at the end of follow-up in contrast to rTMS, which in turn showed higher amelioration of symptoms in contrast to the sham group. These differences did not reach statistical significance, but with small effect sizes for the comparisions rTMS vs. sham and with a medium effect size for TBS vs. sham they may be clinically meaningful. The tendency towards a delayed effect was also reflected by a higher rate of responders at the end of the follow-up period, but this effect also failed to reach significance. The improvement over time, which has been observed in all three groups is probably related to the standard treatment, which all patients received. We are well aware that the investigation of TMS as an add-on treatment to a non-standardized treatment makes it more difficult to detect TMS effects (Herwig et al. 2007) since interindividual variability in the response to “standard treatment” may confound
results even if medication intake was similar in the three groups (Table I). However, the study design was chosen to provide an answer to the question whether a bilateral rTMS protocol as add-on to standard treatment has antidepressant efficacy. Based on the literature, best evidence for the antidepressant effect ofTMS is available from studies investigating its effect in drug-free treatment-resistant patients (O’Reardon et al. 2007; George et al. 2010). Whether bilateral rTMS or burst stimulation may be advantageous in treatment -esistant unmedicated patients, cannot be concluded from our data. However, our data enable a realistic estimation of the added value of TMS under “real life conditions”. We chose this study design, to answer the clinically important question whether response or remission rates can be enhanced by TMS as an add-on treatment to standard in-patient treatment. We are also aware of the limited power of our pilot study since both stimulation duration and sample size were relatively small, especially for the detection of add-on effects. Nevertheless, we found suggestion for a possible therapeutic effect of the two active stimulation protocols, which took place during the follow-up period. Even though this effect did not reach statistical significance the effect size was remarkable, especially for the TBS group. A recently published study (Plewnia et al. 2014), which compared 6 weeks of bilateral TBS with sham stimulation as an add-on to pharmacological and psychotherapeutical treatment, revealed very comparable responder rates. If this effect of bilateral TBS can be confirmed by further studies, it might represent a clinically relevant improvement of treatment options. The effect of bifrontal rTMS in our study (response rate at end of treatment of rTMS 41.2% and of sham 17.6%) corresponds largely to the results of a recent meta-analysis of bilateral rTMS in the treatment of major depression (Berlim et al. 2012) (average response rate of rTMS 24.7%, of sham 6.8%). The overall higher response rates in our study can be explained by the add-on treatment design and the fact that we did not primarily include treatmentresistant patients. Additionally we found that the effects of bilateral TBS were larger than those of bilateral rTMS. While this finding has to be interpreted carefully due to its statistical non-significance, it warrants the further investigation of TBS for the treatment of depression. An important advantage of TBS as compared to rTMS is the shorter duration of each treatment session which would allow substantially more treatments per hour on a given device, thus reducing cost and improving access several-fold over common protocols such as the standard 37.5 min FDA-approved protocol (O’Reardon et al. 2007). As access and cost
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Bilateral TBS, rTMS and sham for treating depression are among the major impediments to more widespread use of rTMS, the potential role of TBS is of considerable clinical interest even if it turns out to be not superior to rTMS in its efficacy. Studies investigating TBS for the treatment of depression are scarce (Chistyakov et al. 2010; Holzer and Padberg 2010; Plewnia et al. 2014). Very little is known about the exact influence of stimulation parameters, such as intensity or number of stimuli, in the use of TBS over the DLPFC. Here we doubled the duration of the original TBS protocols for both cTBS and iTBS in order to apply a comparable number of stimuli in the rTMS and TBS treatment groups. This approach was further motivated by a report of extended plastic changes after repeated application of the TBS protocol over the frontal eye field (Nyffeler et al. 2006) and by preliminary results of increasing antidepressant effects of cTBS with an increasing number of applied stimuli (Chistyakov et al. 2010). In contrast, more recent studies have found that a prolongation of cTBS and iTBS over the motor cortex can diminish or even reverse neuroplastic after-effects (Gamboa et al. 2010, 2011). Based on these findings the choice of TBS parameters in our study may have been suboptimal. An additional issue in brain stimulation protocols involving stimulation of multiple brain areas is the order of stimulation. Here we started with stimulation of the right DLPFC but this was an arbitrary choice. Further research should focus on the comparison of unilateral and bilateral TBS as well as on the systematic investigation of stimulation parameters like stimulation order, intensity and number of stimuli. The findings of this study suggest that the effect of TBS developed over time, since the effects were most pronounced at the last follow-up assessment. This is in line with earlier reports of delayed rTMS effects after multi-site stimulation (Kleinjung et al. 2008; Lehner et al. 2012) and should be considered in the design of future studies. One may speculate that the stimulation duration of 3 weeks in this study was too short (Carpenter et al. 2012) and that a longer study duration may have resulted in significant effects. Thus, the observed delayed effect may be considered as a further argument for testing longer stimulation periods up to 6 weeks of active treatment (Fitzgerald et al. 2006; Plewnia et al. 2014). The stimulation procedures were well tolerated in all three treatment groups. Apart from slight painful sensations in the stimulation area, which occurred in all treatment groups in a minority of treated patients, no side effects were reported during stimulation. Blinding assessment revealed that patients were not aware of their group assignment. Unfortunately two study participants committed suicide during the study. One suicide occurred
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before the beginning of treatment and one suicide was committed 1 week after end of rTMS treatment and after hospital discharge. In the first case a potential relationship between rTMS and the suicide can be reliably excluded since the patient had not received any rTMS treatment. In the second case a potential relationship cannot be entirely excluded. A potential relationship between suicide risk and treatment is discussed for serotonin reuptake inhibitors, particularly in adolescents (Barbui et al. 2009), however this effects seems to be specifically mediated by the serotonergic system (Makris et al. 2013). Previous studies did not indicate any evidence of emergent suicidal ideation during TMS treatment (Janicak et al. 2008) and a recent study of an accelerated protocol even suggests, that suicidal risk can be reduced by rTMS (George et al. 2014a). There is a considerable suicide risk in this patient group independent from treatment. Patients with medium to severe depressive episodes bear a 15% life time risk for suicide (Moller 2003). In the 6 months after hospital discharge the suicide risk is particularly high, possibly because incompletely remitted patients feel unable to cope with everyday life (Moller 2003). The suicide which occurred after rTMS treatment occurred 1 week after end of treatment and after hospital discharge. While a causal relationship between this suicide and TMS seems highly unlikely, suicidal ideation and suicides during and after treatment should be monitored in future TMS studies, especially when focusing on affective disorders. In summary, our data confirm the potential of bilateral TBS as a non-invasive, safe and well tolerated method of brain stimulation in the treatment of major depression. There were small but explicit effect sizes, warranting further studies of bilateral TBS with larger sample sizes and more stimulation sessions.
Acknowledgements We thank Helene Niebling, Sandra Pfluegl, Jan and Carina Brauner for their assistance in administering rTMS and data management. We also want to thank Sylvia Dorner-Mitschke for assistance with the preparation of the figures and Jessica Van-Doren for proof-reading of the manuscript.
Statement of Interest The authors have no conflicts of interest, financial or otherwise, related directly or indirectly to the submitted work.
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magnetic stimulation as adjuvant treatment in medicationresistant depression. Psychiatry Res 146:53–57. George MS, Lisanby SH, Avery D, McDonald WM, Durkalski V, Pavlicova M, et al. 2010. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Arch Gen Psychiatry 67: 507–516. George MS, Raman R, Benedek DM, Pelic CG, Grammer GG, Stokes KT, et al. 2014a. A two-site pilot randomized 3 day trial of high dose left prefrontal repetitive transcranial magnetic stimulation (rTMS) for suicidal inpatients. Brain Stimul 7:421–431. George MS, Schlaepfer T, Padberg F, Fitzgerald PB. 2014b. Brain stimulation treatments for depression. World J Biol Psychiatry 15:167–8. Hamilton M. 1967. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 6:278–296. Herwig U, Fallgatter AJ, Hoppner J, Eschweiler GW, Kron M, Hajak G, et al. 2007. Antidepressant effects of augmentative transcranial magnetic stimulation: randomised multicentre trial. Br J Psychiatry 191:441–448. Hinder MR, Goss EL, Fujiyama H, Canty AJ, Garry MI, Rodger J, Summers JJ. 2014. Inter- and intra-individual variability following intermittent theta burst stimulation: implications for rehabilitation and recovery. Brain Stimul 7:365–371. Holzer M, Padberg F. 2010. Intermittent theta burst stimulation (iTBS) ameliorates therapy-resistant depression: a case series. Brain Stimul 3:181–183. Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. 2005. Theta burst stimulation of the human motor cortex. Neuron 45:201–206. Janicak PG, O’Reardon JP, Sampson SM, Husain MM, Lisanby SH, Rado JT, et al. 2008. Transcranial magnetic stimulation in the treatment of major depressive disorder: a comprehensive summary of safety experience from acute exposure, extended exposure, and during reintroduction treatment. J Clin Psychiatry 69:222–232. Kleinjung T, Eichhammer P, Landgrebe M, Sand P, Hajak G, Steffens T, et al. 2008. Combined temporal and prefrontal transcranial magnetic stimulation for tinnitus treatment: A pilot study. Otolaryngol Head Neck Surg 138:497–501. Lehner A, Schecklmann M, Poeppl TB, Kreuzer PM, Vielsmeier V, Rupprecht R, et al. 2013. Multisite rTMS for the treatment of chronic tinnitus: stimulation of the cortical tinnitus network – a pilot study. Brain Topogr 26:501–510. Makris GD, Reutfors J, Osby U, Isacsson G, Frangakis C, Ekbom A, Papadopoulos FC. 2013. Suicide seasonality and antidepressants: a register-based study in Sweden. Acta Psychiatr Scand 127:117–125. McDonald WM, Easley K, Byrd EH, Holtzheimer P, Tuohy S, Woodard JL, et al. 2006. Combination rapid transcranial magnetic stimulation in treatment refractory depression. Neuropsychiatr Dis Treat 2:85–94. Moller HJ. 2003. Suicide, suicidality and suicide prevention in affective disorders. Acta Psychiatr Scand Suppl 418:73–80. Nyffeler T, Wurtz P, Luscher HR, Hess CW, Senn W, Pflugshaupt T, et al. 2006. Extending lifetime of plastic changes in the human brain. Eur J Neurosci 24:2961–2966. O’Reardon JP, Solvason HB, Janicak PG, Sampson S, Isenberg KE, Nahas Z, et al. 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. Padberg F, George MS. 2009. Repetitive transcranial magnetic stimulation of the prefrontal cortex in depression. Exp Neurol 219:2–13.
Bilateral TBS, rTMS and sham for treating depression
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Rossi S, Hallett M, Rossini PM, 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. Schutter DJ. 2009. Antidepressant efficacy of high-frequency transcranial magnetic stimulation over the left dorsolateral prefrontal cortex in double-blind sham-controlled designs: a meta-analysis. Psychol Med 39:65–75. Schutter DJ. 2010. Quantitative review of the efficacy of slow-frequency magnetic brain stimulation in major depressive disorder. Psychol Med 40:1789–1795.
ORIGINAL INVESTIGATION
Bilateral prefrontal rTMS and theta burst TMS as an add-on treatment for depression: A randomized placebo controlled trial
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JULIA PRASSER1, MARTIN SCHECKLMANN1, TIMM B. POEPPL1, ELMAR FRANK1, PETER M. KREUZER1, GOERAN HAJAK1,2, RAINER RUPPRECHT1, MICHAEL LANDGREBE1,3 & BERTHOLD LANGGUTH1 1Department
of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany, of Psychiatry, Psychosomatics, and Psychotherapy, Social Foundation Bamberg, Bamberg, Germany, and 3Department of Psychiatry, Psychosomatics and Psychotherapy, kbo-Lech-Mangfall-Klinik Agatharied, Germany 2Department
Abstract Objectives. Repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral-prefrontal cortex (DLPFC) exerts antidepressant effects. In this randomised controlled clinical trial we aimed to test the safety and therapeutic efficacy of bilateral theta-burst stimulation (TBS) as an add-on therapy to standard treatment of major depression. Methods. Fifty-six patients diagnosed with a moderate to severe depressive episode received 15 daily treatments of either rTMS (110% motor-threshold; rightDLPFC, 1000 stimuli at 1 Hz ⫹ leftDLPFC, 1000 stimuli at 10 Hz), theta-burst stimulation (80% motor-threshold; rightDLPFC, continuous TBS, 1200 stimuli ⫹ leftDLPFC, intermittent TBS, 1200 stimuli), or sham TMS (N ⫽ 17, sham coil with the TBS protocol). Results. There was no significant effect in the primary outcome measures (change of the 21-item Hamilton Rating Scale for Depression). However, there was a tendency towards an increased responder rate at the end of the follow-up period for both active treatments as compared to sham, and this tendency was most pronounced for the TBS group. Conclusions. This pilot study did not reveal significant advantages of bilateral TBS or rTMS over sham treatment as an add-on treatment for major depression. A tendency towards a superior effect of bilateral TBS at the end of the follow-up period may warrant further studies. Key words: depression, bilateral, theta burst, repetitive transcranial magnetic stimulation, prefrontal cortex
Introduction Depression is a common mental disorder in the general population and causes the highest burden of disease measured in disability adjusted life years (Collins et al. 2011). Standard treatments like antidepressant medication and structured forms of psychotherapy are effective only in 60–80% of those affected, while 20–40% of depressive patients never completely recover (Fava and Davidson 1996). Therefore, additional therapeutic strategies are greatly needed. Transcranial magnetic stimulation (TMS) of the prefrontal cortex has been proposed as a new therapeutic tool for the treatment of depression (George et al. 2014b). TMS is a non-invasive brain stimulation technique that applies the principles of electromagnetism to transmit an electrical field to the brain. By using a coil placed on the scalp over a cortical region,
a magnetic stimulus passes mostly undistorted through the skull and induces a neuronal depolarization in superficial cortical areas. TMS is a safe technique with only few side effects (Rossi et al. 2009), which has proven to be feasible for both in- and outpatient treatment (Frank et al. 2010). Repetitive rhythmic application of TMS (rTMS) can induce effects which outlast the stimulation period. Studies of the motor cortex demonstrated that high-frequency rTMS (ⱖ 5 Hz) tends to increase cortical excitability, whereas low-frequency rTMS (ⱕ 1 Hz) is supposed to act in the contrary (Ridding and Rothwell 2007). Based on the concepts that emotional reactivity (Allen et al. 2004) depends on the relationship between left and right frontal activity and that a right dominance relates to depression (Davidson 1992), high-frequency rTMS of the left dorsolateral
Correspondence: Berthold Langguth, MD, Department of Psychiatry and Psychotherapy, University of Regensburg, Universitätsstrasse 84, 93053 Regensburg, Germany. Tel: ⫹ 49-941-9412099. Fax: ⫹ 49-941-9412025. E-mail: [email protected] (Received 20 June 2014 ; accepted 2 September 2014 ) ISSN 1562-2975 print/ISSN 1814-1412 online © 2015 Informa Healthcare DOI: 10.3109/15622975.2014.964768
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58 J. Prasser et al. prefrontal cortex (DLPFC) and low-frequency rTMS of the right DLPFC have been investigated for the treatment of depression (for review see Berlim et al. 2013a,b; Schutter 2009, 2010). Antidepressive effects of both approaches are well documented and high-frequency rTMS of the left prefrontal cortex has been approved by the FDA as a treatment for depression based on positive results in some (O’Reardon et al. 2007; George et al. 2010), but not all (Herwig et al. 2007) multicentric studies. However effect sizes are only moderate and a substantial number of patients do not respond at all (Padberg and George 2009). Thus there is an urgent need for the development of more effective stimulation protocols. One approach has been bilateral rTMS, i.e. the combination of high-frequency rTMS to the left DLPFC with low-frequency rTMS to the right DLPFC. The first promising results of this technique (Fitzgerald et al. 2006; Garcia-Toro et al. 2006) could not be consistently replicated (McDonald et al. 2006; Pallanti et al. 2010; Fitzgerald et al. 2011). However, a recent systematic review and meta-analysis (Berlim et al. 2012) concluded that bilateral stimulation is more effective than sham stimulation and provides clinically relevant benefits comparable with standard antidepressant drug treatment and unilateral rTMS. Pilot data indicate that theta-burst stimulation (TBS), a special pattern of rTMS, might be a promising approach for increasing the antidepressant effects of rTMS therapy (Chistyakov et al. 2010; Holzer and Padberg 2010). The TBS protocol was first reported by Huang et al. (2005) and consists of bursts of three stimuli at 50 Hz which are applied every 200 ms (5 Hz ⫽ theta). This protocol has been found to reduce motor cortical excitability when applied continuously (cTBS) and to increase motor cortex excitability when applied intermittently (iTBS) (Huang et al. 2005), even if there is a considerable inter-individual variability in stimulation effects (Hinder et al. 2014). Here we performed a pilot study to investigate bilateral TBS and rTMS as add-on therapy to standard routine treatment of major depression. Specifically, we compared bilateral TBS of the DLPFC with bilateral rTMS and sham stimulation.
Methods and materials Patients Patients with a moderate to severe depressive episode (according to ICD-10) were recruited between April 2010 and September 2011 from the Department of Psychiatry and Psychotherapy at the University of Regensburg. All patients gave written informed consent to participate in the study, which was
approved by the ethics committee of the University of Regensburg and conducted according to the Code of Ethical Principles for Medical Research Involving Human Subjects of the World Medical Association (Declaration of Helsinki, 1964). The study trial was registered at the US National Institutes of Health (www.clinicaltrials.gov) under the access code NCT01240083. Exclusion criteria were baseline scores in the 21-item Hamilton Rating Scale for Depression (HAMD) below 18 points, contraindications for TMS treatment (cardiac pacemaker or other implanted electrical devices, history of epilepsy or organic brain damage), alcohol and substance abuse, instable medical conditions, concurrent medication with large doses of benzodiazepines (lorazepam ⬎ 1 mg/day, diazepam ⬎ 5 mg/day), and inability to comply with study procedures (e.g., insufficient knowledge of the German language to complete self-assessment questionnaires). TMS was performed as an add-on therapy to standard in- or out-patient treatment. Fifty-six patients (49 inpatients, seven outpatients, 29 (51.8%) women; mean age 47.1 ⫾ 11.3 years) were randomized to receive either rTMS (rTMSgroup), theta burst stimulation (TBS group), or sham treatment (sham group). An overview of the study design is given in Figure 1, the patient details throughout the study are shown in Figure 2. Transcranial magnetic stimulation rTMS and TBS were applied with a figure-of-eight coil (Cool-B 65, Magventure A/S, Denmark) connected to a stimulator (MagPro X 100, Magventure); sham stimulation was performed with a sham-coil (MCF-B 65, Magventure). rTMS was performed at 110% resting motor threshold (RMT) or at 60% maximum stimulator output (MSO), when RMT exceeded 54% MSO. TBS was performed at 80% resting motor threshold. RMT was defined as the lowest intensity sufficient to produce left thenar muscle activation (magnetic evoked potentials ⬎ 50 μV) with a single pulse delivered to the motor cortex in at least five of 10 trials. For treatment of the left DLPFC the coil was positioned 6 cm anterior of the left motor hotspot in the sagittal direction (Frank et al. 2010). For treatment of the right DLPFC this position was mirrored over the midsagittal line. Treatment was started on Mondays and patients received 2000 stimuli/day (rTMS group) or 2400 stimuli/day (TBS and sham group) on the 15 subsequent working days. The rTMS protocol consisted of 1000 stimuli at a frequency of 1 Hz to the right DLPFC, immediately followed by 1000 stimuli at a frequency of 10 Hz (20 trains with 50 stimuli and an intertrain interval of 25 s) to left DLPFC.
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Bilateral TBS, rTMS and sham for treating depression
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Figure 1. Study design. DLPFC, dorsolateral prefrontal cortex; RMT, resting motor threshold; cTBS, continuous theta burst stimulation; iTBS, intermittent theta burst stimulation.
The TBS treatment protocol consisted of 1200 stimuli of cTBS applied to the right DLPFC, immediately followed by 1200 stimuli of iTBS to the left DLPFC. For sham stimulation the TBS protocol was applied with the sham coil.
Outcome measurement The severity of depression was assessed by the 21-item version of the Hamilton Depression Rating Scale (HAMD; Hamilton 1967) at screening, at baseline, after each week of the 3-week treatment
Figure 2. Study participants. SAE, serious adverse event; DLPFC, dorsolateral prefrontal cortex; RMT, resting motor threshold; cTBS, continuous theta burst stimulation; iTBS, intermittent theta burst stimulation.
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60 J. Prasser et al. (week 1, week 2, week 3), 4 and 8 weeks after treatment (follow-up week 7 and 11). A HAMD reduction of 50% or more was defined as a response to therapy; a HAMD score below 11 points was defined as remission. Additional assessment instruments included the Beck Depression Inventory (BDI) (Beck and Steer 1984), the Clinical Global Impression scale (CGI) and the Global Assessment of Functioning scale (GAF). The comparison in the HAMD change between baseline and at the end of treatment (week 3) served as the primary outcome. Secondary outcome measures were HAMD change over the course of the trial, responder and remitter rates at end of treatment and at end of the follow-up period, as well as changes in the Beck Depression Inventory (BDI), the Clinical Global Impression scale (CGI) and the Global Assessment of Functioning scale (GAF) over the course of the trial.
Statistical analysis For statistical analysis, only data of patients who had at least one data entry for HAMD after the baseline visit were included. In case of missing data, the last observation was carried forward. For primary and secondary outcome measures we calculated analyses of variance (ANOVA) with the within-subjects factor “time” (primary: baseline vs. week 3; secondary: all visits) and the betweensubjects factor “group” (rTMS vs. TBS vs. sham). Responder and remitter rates were compared for the three treatments by chi-square tests of independence. All statistical tests that were conducted were two-tailed and unadjusted for multiple comparisons; statistical significance was set to P ⬍ 0.05. Effect size was defined according to Cohen’s d. Data in the text are given as mean ⫾ standard deviation. Statistical data analysis was performed with SPSS 15 (SPSS Inc., Chicago, IL).
Results Patient population Clinical characteristics and medication of the patients are given in Tables I and II. Two of the 56 randomized patients withdrew their consent (one patient of the rTMS group after randomization, but before the first treatment session; one patient of the sham group after the first treatment session) and were therefore not included in the analysis (see above). The comparison of participants in the three treatment groups revealed no differences in the clinical or demographic baseline characteristics. Safety Three serious adverse effects occurred during the study. Two patients committed suicide and one patient committed a suicide attempt. One patient committed suicide after the baseline assessment, but before randomisation and the start of treatment. One patient, who was treated with rTMS committed suicide 1 week after the end of treatment. In both cases the suicides were completely unexpected and were committed at home during weekend leave (case 1) and after discharge (case 2). There was no clinical suggestion for a potential causal relationship between TMS treatment and the suicides. The suicide attempt was committed by a patient 6 weeks after the end of a sham treatment. Seven patients (rTMS group: 3; TBS group: 3; sham group: 1) complained about irritations at the stimulation site or slight headaches during treatment. One patient (sham group) felt exhausted after treatment and one patient (rTMS group) reported imbalance after stimulation. All mentioned symptoms were reported to be mild, could well be tolerated by the patients and the treatment was regularly completed without the necessity to adapt stimulation procedures or initiate other medical diagnostic or therapeutic steps.
Table I. Baseline characteristics of patients who completed treatment.
Age (years) Gender (female/male) HAMD baseline BDI baseline Clinical global impression Global assessment of functioning
rTMS (N ⫽ 17)
TBS (N ⫽ 20)
Sham (N ⫽ 17)
Statistics
50.4 ⫾ 9.9 8/9 25.0 ⫾ 4.4 21.6 ⫾ 9.8 4.6 ⫾ 0.8 50.1 ⫾ 7.0
48.2 ⫾ 10.9 10/10 27.4 ⫾ 6.5 23.7 ⫾ 12.7 4.7 ⫾ 0.7 49.1 ⫾ 7.3
42.6 ⫾ 12.4 9/8 25.3 ⫾ 5.4 26.5 ⫾ 9.1 4.7 ⫾ 0.6 51.1 ⫾ 6.8
F ⫽ 2.258; df ⫽ 2,51; P ⫽ 0.115 χ2 ⫽ 0.118; df ⫽ 2; P ⫽ 0.943 F ⫽ 0.966; df ⫽ 2,51; P ⫽ 0.387 F ⫽ 0.882; df ⫽ 2,51; P ⫽ 0.420 F ⫽ 0.151; df ⫽ 2,51; P ⫽ 0.860 F ⫽ 0.354; df ⫽ 2,51; P ⫽ 0.703
rTMS, right frontal 1 Hz followed by left frontal 10 Hz; TBS, theta burst stimulation (right frontal continuous theta burst stimulation followed by left frontal intermittent theta burst stimulation); Sham, sham stimulation (TBS protocol with sham coil); HAMD, 21-item Hamilton Rating Scale for Depression; BDI, Beck Depression Inventory; data are given as mean ⫾ standard deviation.
Bilateral TBS, rTMS and sham for treating depression Table II. Medication intake.
Medication
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SSRI SNRI TCA Other antidepressants Lithium Anticonvulsants Antipsychotics
rTMS TBS Sham (N ⫽ 17) (N ⫽ 20) (N ⫽ 17) 2 7 6 6 4 2 7
7 10 5 13 3 5 12
7 7 5 10 2 1 8
Statistics P ⫽ 0.303 P ⫽ 0.768 P ⫽ 0.428 P ⫽ 0.561 P ⫽ 0.367 P ⫽ 0.286 P ⫽ 0.734
The number in each cell indicates how many patients of the respective treatment groups were taking medications of the indicated classification. SSRI, selective serotonin reuptake inhibitors; SNRI, serotonin and noradrenaline reuptake inhibitors; TCA, tricyclic antidepressants; “other antidepressants” were agomelatine, mirtazapine and bupropion in most cases. Benzodiazepines were categorized as “anticonvulsants”.
Outcome In the primary outcome criterion (HAMD change between baseline and end of treatment) there was a significant main effect of “time” (F ⫽ 55.434; df ⫽ 1,51; P ⬍ 0.001), but not for “group” (F ⫽ 0.122; df ⫽ 2,51; P ⫽ 0.886) or for “group ⫻ time” (F ⫽ 0.862; df ⫽ 2,51; P ⫽ 0.428). The HAMD change for TBS (week 3 minus baseline) was superior to sham (d ⫽ 0.359) and rTMS (d ⫽ 0.406) with medium effect sizes according to Cohen. Effect size between rTMS and sham was negligible (d ⫽ 0.088) (Figure 3). Regarding secondary outcome measures, there were also no statistically significant differences in response and remission rates among the three treatment groups neither at end of treatment (week 3: responders: χ2 ⫽ 2.468; df ⫽ 2; P ⫽ 0.291; remitters: χ2 ⫽ 0.117; df ⫽ 2; P ⫽ 0.943) nor at the last follow-up
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visit (week 11: responders: χ2 ⫽ 5.019; df ⫽ 2; P ⫽ 0.081; remitters: χ2 ⫽ 2.078; df ⫽ 2; P ⫽ 0.354). At week 11 responder rates were highest for TBS (12 out of 20), followed by rTMS (eight out of 17) and lowest for sham (four out of 17), but this difference failed to reach statistical significance (Figure 4). Secondary outcome measure ANOVAs did not show any significant main effects of “group” (HAMD: F ⫽ 0.065; df ⫽ 2,51; P ⫽ 0.937; BDI: F ⫽ 0.739; df ⫽ 2,51; P ⫽ 0.482; GAF: F ⫽ 0.195; df ⫽ 2,51; P ⫽ 0.823; CGI: F ⫽ 0.325; df ⫽ 2,51; P ⫽ 0.724) or “group by time” (HAMD: F ⫽ 1.316; df ⫽ 12,306; P ⫽ 0.208; BDI: F ⫽ 0.461; df ⫽ 10,255; P ⫽ 0.914; GAF: F ⫽ 0.994; df ⫽ 6,153; P ⫽ 0.432; CGI: F ⫽ 0.319; df ⫽ 6,153; P ⫽ 0.926). The main effect “time” was significant for all secondary outcomes (HAMD: F ⫽ 51.021; df ⫽ 6,306; P ⬍ 0.001; BDI: F ⫽ 19.360; df ⫽ 5,255; P ⬍ 0.001; GAF: F ⫽ 31.222; df ⫽ 3,153; P ⬍ 0.001; CGI: F ⫽ 28.113; df ⫽ 3,153; P ⬍ 0.001). However, on a descriptive level TBS tended to demonstrate larger effects compared to rTMS which in turn tended to have larger effects than sham. An exploratory comparison at the last follow-up visit (week 11) suggested a potential advantage of TBS compared to sham (T ⫽ 1.972; df ⫽ 35; P ⫽ 0.057; d ⫽ 0.651). Contrasts between TBS and rTMS (T ⫽ 0.963; df ⫽ 35; P ⫽ 0.342; d ⫽ 0.324) and between rTMS and sham (T ⫽ 1.357; df ⫽ 32; P ⫽ 0.184; d ⫽ 0.465) showed no significant effect with small effect sizes. This fits with the observed near-significant differences in response rate at the last follow-up visit (see above). Efficacy of blinding was assessed by asking both patients and rating physicians at week 11 to guess about their treatment group allocation. This analysis revealed that neither patients nor physicians were
Figure 3. Changes in HAMD. HAMD, 21-item Hamilton Rating Scale for Depression; TBS, right frontal continuous theta burst stimulation followed by left frontal intermittent theta burst stimulation; rTMS, right frontal 1 Hz followed by left frontal 10 Hz; sham, sham stimulation. There was no significant difference between the three treatment groups. Pairwise comparisons of the reduction in the HAMD score at the last follow-up assessment revealed a near-significant difference between TBS and sham treatment.
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62 J. Prasser et al.
Figure 4. Responder rates. Responder rates at the different visits. Response was defined as a reduction of the 21-item Hamilton Rating Scale for Depression by at least 50%. rTMS, right frontal 1 Hz followed by left frontal 10 Hz; TBS, right frontal continuous theta burst stimulation followed by left frontal intermittent theta burst stimulation. There was no significant difference in the response rates between the three treatment groups. At the last follow-up assessment there was a non-significant trend towards higher response rates for TBS treatment.
able to identify the treatment group allocation with a significant accuracy above chance level (patients’ rating: χ2 ⫽ 0.435; df ⫽ 4; P ⫽ 0.980; physicians’ ratings: χ2 ⫽ 4.083; df ⫽ 4; P ⫽ 0.395).
Discussion In our pilot study, 15 sessions of bilateral rTMS or TBS were not significantly superior to shamtreatment when used as an add-on therapy to standard treatment of depression. However, our data also suggest a possible delayed effect of both active TMS treatments. More specifically, there was a more pronounced HAMD improvement in the TBS group at the end of follow-up in contrast to rTMS, which in turn showed higher amelioration of symptoms in contrast to the sham group. These differences did not reach statistical significance, but with small effect sizes for the comparisions rTMS vs. sham and with a medium effect size for TBS vs. sham they may be clinically meaningful. The tendency towards a delayed effect was also reflected by a higher rate of responders at the end of the follow-up period, but this effect also failed to reach significance. The improvement over time, which has been observed in all three groups is probably related to the standard treatment, which all patients received. We are well aware that the investigation of TMS as an add-on treatment to a non-standardized treatment makes it more difficult to detect TMS effects (Herwig et al. 2007) since interindividual variability in the response to “standard treatment” may confound
results even if medication intake was similar in the three groups (Table I). However, the study design was chosen to provide an answer to the question whether a bilateral rTMS protocol as add-on to standard treatment has antidepressant efficacy. Based on the literature, best evidence for the antidepressant effect ofTMS is available from studies investigating its effect in drug-free treatment-resistant patients (O’Reardon et al. 2007; George et al. 2010). Whether bilateral rTMS or burst stimulation may be advantageous in treatment -esistant unmedicated patients, cannot be concluded from our data. However, our data enable a realistic estimation of the added value of TMS under “real life conditions”. We chose this study design, to answer the clinically important question whether response or remission rates can be enhanced by TMS as an add-on treatment to standard in-patient treatment. We are also aware of the limited power of our pilot study since both stimulation duration and sample size were relatively small, especially for the detection of add-on effects. Nevertheless, we found suggestion for a possible therapeutic effect of the two active stimulation protocols, which took place during the follow-up period. Even though this effect did not reach statistical significance the effect size was remarkable, especially for the TBS group. A recently published study (Plewnia et al. 2014), which compared 6 weeks of bilateral TBS with sham stimulation as an add-on to pharmacological and psychotherapeutical treatment, revealed very comparable responder rates. If this effect of bilateral TBS can be confirmed by further studies, it might represent a clinically relevant improvement of treatment options. The effect of bifrontal rTMS in our study (response rate at end of treatment of rTMS 41.2% and of sham 17.6%) corresponds largely to the results of a recent meta-analysis of bilateral rTMS in the treatment of major depression (Berlim et al. 2012) (average response rate of rTMS 24.7%, of sham 6.8%). The overall higher response rates in our study can be explained by the add-on treatment design and the fact that we did not primarily include treatmentresistant patients. Additionally we found that the effects of bilateral TBS were larger than those of bilateral rTMS. While this finding has to be interpreted carefully due to its statistical non-significance, it warrants the further investigation of TBS for the treatment of depression. An important advantage of TBS as compared to rTMS is the shorter duration of each treatment session which would allow substantially more treatments per hour on a given device, thus reducing cost and improving access several-fold over common protocols such as the standard 37.5 min FDA-approved protocol (O’Reardon et al. 2007). As access and cost
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Bilateral TBS, rTMS and sham for treating depression are among the major impediments to more widespread use of rTMS, the potential role of TBS is of considerable clinical interest even if it turns out to be not superior to rTMS in its efficacy. Studies investigating TBS for the treatment of depression are scarce (Chistyakov et al. 2010; Holzer and Padberg 2010; Plewnia et al. 2014). Very little is known about the exact influence of stimulation parameters, such as intensity or number of stimuli, in the use of TBS over the DLPFC. Here we doubled the duration of the original TBS protocols for both cTBS and iTBS in order to apply a comparable number of stimuli in the rTMS and TBS treatment groups. This approach was further motivated by a report of extended plastic changes after repeated application of the TBS protocol over the frontal eye field (Nyffeler et al. 2006) and by preliminary results of increasing antidepressant effects of cTBS with an increasing number of applied stimuli (Chistyakov et al. 2010). In contrast, more recent studies have found that a prolongation of cTBS and iTBS over the motor cortex can diminish or even reverse neuroplastic after-effects (Gamboa et al. 2010, 2011). Based on these findings the choice of TBS parameters in our study may have been suboptimal. An additional issue in brain stimulation protocols involving stimulation of multiple brain areas is the order of stimulation. Here we started with stimulation of the right DLPFC but this was an arbitrary choice. Further research should focus on the comparison of unilateral and bilateral TBS as well as on the systematic investigation of stimulation parameters like stimulation order, intensity and number of stimuli. The findings of this study suggest that the effect of TBS developed over time, since the effects were most pronounced at the last follow-up assessment. This is in line with earlier reports of delayed rTMS effects after multi-site stimulation (Kleinjung et al. 2008; Lehner et al. 2012) and should be considered in the design of future studies. One may speculate that the stimulation duration of 3 weeks in this study was too short (Carpenter et al. 2012) and that a longer study duration may have resulted in significant effects. Thus, the observed delayed effect may be considered as a further argument for testing longer stimulation periods up to 6 weeks of active treatment (Fitzgerald et al. 2006; Plewnia et al. 2014). The stimulation procedures were well tolerated in all three treatment groups. Apart from slight painful sensations in the stimulation area, which occurred in all treatment groups in a minority of treated patients, no side effects were reported during stimulation. Blinding assessment revealed that patients were not aware of their group assignment. Unfortunately two study participants committed suicide during the study. One suicide occurred
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before the beginning of treatment and one suicide was committed 1 week after end of rTMS treatment and after hospital discharge. In the first case a potential relationship between rTMS and the suicide can be reliably excluded since the patient had not received any rTMS treatment. In the second case a potential relationship cannot be entirely excluded. A potential relationship between suicide risk and treatment is discussed for serotonin reuptake inhibitors, particularly in adolescents (Barbui et al. 2009), however this effects seems to be specifically mediated by the serotonergic system (Makris et al. 2013). Previous studies did not indicate any evidence of emergent suicidal ideation during TMS treatment (Janicak et al. 2008) and a recent study of an accelerated protocol even suggests, that suicidal risk can be reduced by rTMS (George et al. 2014a). There is a considerable suicide risk in this patient group independent from treatment. Patients with medium to severe depressive episodes bear a 15% life time risk for suicide (Moller 2003). In the 6 months after hospital discharge the suicide risk is particularly high, possibly because incompletely remitted patients feel unable to cope with everyday life (Moller 2003). The suicide which occurred after rTMS treatment occurred 1 week after end of treatment and after hospital discharge. While a causal relationship between this suicide and TMS seems highly unlikely, suicidal ideation and suicides during and after treatment should be monitored in future TMS studies, especially when focusing on affective disorders. In summary, our data confirm the potential of bilateral TBS as a non-invasive, safe and well tolerated method of brain stimulation in the treatment of major depression. There were small but explicit effect sizes, warranting further studies of bilateral TBS with larger sample sizes and more stimulation sessions.
Acknowledgements We thank Helene Niebling, Sandra Pfluegl, Jan and Carina Brauner for their assistance in administering rTMS and data management. We also want to thank Sylvia Dorner-Mitschke for assistance with the preparation of the figures and Jessica Van-Doren for proof-reading of the manuscript.
Statement of Interest The authors have no conflicts of interest, financial or otherwise, related directly or indirectly to the submitted work.
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