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Accelerated transcranial magnetic stimulation (aTMS) to treat depression with treatment switching: study protocol of a pilot, randomized, delayed-start trial



Repetitive transcranial magnetic stimulation (rTMS) is a technique for stimulating brain activity using a transient magnetic field to induce an electrical current in the brain producing depolarization of focal groups of brain cells. TMS is a protocol approved by the U.S. Food and Drug Administration in routine clinical practice as a treatment for depression. A major limitation of rTMS is the large amount of time taken for a standard protocol (38 min a day for 20–30 working days). The optimal type and duration of TMS are still uncertain, as is the optimal strategy for continuing or changing the type of rTMS if there is a poor initial response.


The trial aims to assess whether a 1-week compressed course of left dorsolateral prefrontal (L DLPFC) 5 Hz accelerated rTMS (aTMS) treatment is as effective as an established 4-week course of non-accelerated rTMS and if additional 5 Hz L DLPFC aTMS treatments will be efficacious in non-responders as compared to 1 Hz right DLPFC aTMS treatment.


A randomized, single-blind, delayed-start trial was planned to commence in Jan 2020. A total of 60 patients will be enrolled from the Institute of Mental Health Singapore within a 2-year period and randomized into the early or delayed-start phase of the trial. The primary outcome of the trial is the improvement of Montgomery-Asberg Depression Rating scale at the end of the active treatment phase.


If this study protocol proves to be effective, the findings of this trial will be updated to the College of Psychiatrists, Academy of Medicine Singapore, as well as published in a peer-reviewed journal to enhance local and international TMS treatment guidelines.

Trial registration ID: NCT03941106

Peer Review reports


Depression confers a large burden of disease because of its early onset, high prevalence, and the profound disability involved [1]. In Singapore, the lifetime prevalence of depression is 5.8% [2]. The economic burden of depression in the Asia Pacific region [3] and Singapore [4] is high and up to 50% of indirect costs were associated with lost productivity and unemployment. Major depressive disorder (MDD) is a severe mental illness that affects major life domains, such as mental and psychosocial functioning [5, 6]. The current long-term treatment strategies remain suboptimal for patients with MDD. A large proportion of them do not respond satisfactorily to drug therapy and experience relapses over a prolonged period of their life [7, 8].

Electroconvulsive therapy (ECT) is considered to be one of the most effective treatment modalities yielding an 80–90% response rate in patients with the acute phase of depression [9] and 50–70% response rate in patients with treatment-resistant depression (TRD) [10]. Although a highly effective antidepressant treatment, the use of ECT is constrained by stigma and concern over cognitive side effects. Accordingly, great interest has developed in non-invasive brain stimulation (NIBS) therapies such as repetitive transcranial magnetic stimulation (rTMS). These NIBS techniques involve applying a weak electric current/pulse to the brain via an electromagnetic coil to depolarize neurons in targeted cortical regions (most commonly the dorsolateral prefrontal cortex, DLPFC) and thereby modulate mood.

There is now established evidence that rTMS is effective in treating depression [11,12,13] with approval for its clinical use in countries including the USA, Australia, Singapore, Canada, and Israel. rTMS also has an excellent safety profile, demonstrated in numerous clinical trials, including a substantial number of depressed participants [14]. Most research in rTMS has focused on the pulse frequency [15, 16] stimulation intensity [17] and duration of treatment [18, 19]. rTMS treatment of depression is cost-effective [20] compared to ECT. A local cost-effectiveness study of ECT vs. TMS shows that TMS is a highly cost-effective option compared to ECT for non-psychotic depression [21].

Although intermittent theta-burst stimulation (iTBS), a FDA-approved novel form of magnetic stimulation is undergoing intensive study as an alternative approach of rTMS [22,23,24], the original FDA approved protocol for rTMS, the left 10Hz Dorsolateral Pre-frontal cortex (10Hz L DLPFC) protocol, has a larger evidence base to date. However, there is relatively low efficacy of rTMS compared to ECT [25] and the optimal form of rTMS for patients not responding to initial rTMS modality is unclear [26]. More sessions [27], change of rTMS stimulation intensity [28], change from unilateral to bilateral rTMS treatment [29], or use iTBS to treat drug-resistant depression ([30, 31] have been studied but the results are inconclusive. Current clinical practice commonly changes rTMS modality from high-frequency Left DLFPC (L DLFPC) to low-frequency Right DLPFC (R DLPFC) [32], but there is no evidence that this is more efficacious as compared to adding more sessions of the same rTMS. Moreover, although there is a general acceptance that increased dose and duration of TMS is associated with increased efficacy of rTMS [33], there is preliminary evidence of a delayed response to rTMS [34, 35] suggesting that some patients could be treated effectively with a shorter period of treatment given every weekday, then waiting for several weeks for full clinical improvement from the treatment.

Furthermore, the original FDA-approved protocol for rTMS, which to date has the largest evidence base, is the 10Hz L DLPFC protocol. This involves one session in each working day and patients need to come for the treatment for continuously 4 weeks. For those patients with no or poor response, additional 2 weeks of treatment by rTMS will be supplemented. Therefore, a standard course of unilateral TMS is about 38 min a day for 20–30 working days, substantially limiting the capacity of TMS services to meet the treatment needs of all patients. rTMS requires a considerable time commitment from both patients and clinicians and is of limited utility for patients who do not live within convenient traveling distance from treatment centers. The time needed before treatment response in some patients also makes rTMS unsuitable for some acutely suicidal patients. Accelerating the administration of rTMS (aTMS) by administering multiple sessions of rTMS over a shorter period of time has been shown to potentially be as efficacious as standard rTMS therapy [36,37,38,39,40,41,42,43]. These studies showed that aTMS was safe and efficacious, with no significant side effects reported, with a high level of patient acceptability and significant improvements in subjects’ depression after the aTMS. Thus, aTMS can potentially offer a more cost-effective treatment for depression than standard TMS that can help alleviate the large economic burden of depression by allowing patients to return to their work more rapidly.



The primary aim of this study is to test the symptomatic efficacy of aTMS trial protocol. The 2nd aim is to compare the symptomatic efficacy of the early-start aTMS treatment group and delayed-start aTMS treatment group in patients with a DSM 5 Major Depressive Episode. The exploratory aim is to test whether the non-responders to a 1-week course of aTMS will have a higher chance of response to a change in aTMS than repeated the same aTMS modality (from 5 Hz L DLPFC aTMS to 1 Hz R DLPFC aTMS).


We hypothesize that accelerated 5 Hz L DLPFC rTMS is effective for the treatment of depressive symptoms with regard to reducing the MADRS scores from baseline to end week 3 in the overall study sample.

Design of the trial

Recruitment and screening

Participants will be recruited from inpatients and outpatients at the Institute of Mental Health (Singapore) by the research team psychiatrists and referrals from other psychiatrists at the Institute of Mental Health.

Inclusion criteria

  1. 1.

    Age ≥21 years.

  2. 2.

    DSM-5 diagnosis of current major depressive disorder.

  3. 3.

    Montgomery-Asberg Depression Rating Scale score of 20 or more.

  4. 4.

    Able to give informed consent.

Exclusion criteria

  1. 1.

    DSM-5 psychotic disorder.

  2. 2.

    Drug or alcohol abuse or dependence (preceding 3 months).

  3. 3.

    Inadequate response to ECT (current episode of depression).

  4. 4.

    Rapid clinical response required, e.g., high suicide risk.

  5. 5.

    Significant neurological disorder, which may pose increased risks with TMS, e.g., epilepsy.

  6. 6.

    Metal in the cranium, skull defects, pacemaker, cochlear implant, medication pump, or other electronic devices.

  7. 7.


The following clinical data will be collected at baseline: age, gender, ethnicity, duration of index episode, type of depression (unipolar/bipolar, melancholic/non-melancholic), number of failed antidepressant treatments, number of previous depressive episodes, age at the first depressive episode, and family history of affective disorder will be noted. Full informed written consent will be obtained from all participants.

Randomization at phase 1

In phase 1, subjects were randomly assigned either to the early-start group (immediate active treatment) or the delayed-start group (no TMS treatment for one week followed by active treatment, see Fig. 1). Randomization was done using a random sequence number generator.

Fig. 1

Graphical display of the delayed-start design

Treatment at phase 1

During the active treatment phase, all participants will receive 5 Hz aTMS over the L DLPFC, 4 treatment sessions a day (each session consisting of 3000 pulses for 12 000 pulses a day), every weekday for 1 week. We will use a Magventure X100 TMS Therapy System to conduct TMS stimulation. The first treatment session will take approximately 3 h as participants will also be familiarized with the TMS equipment/procedure and resting motor threshold (RMT) will be determined at this session. We use visual assessment of the respective dorsal interosseous muscle contraction (5 out of 10 stimulations) induced by TMS to determine RMT. Subsequent sessions are expected to last about 2 h each. Stimulation will be applied at the left prefrontal cortex (F3 according to the EEG 10/20 system). L DLPFC aTMS will be delivered at 120% of the RMT, as measured at the initial session. Each TMS train will last for 8 s and have a 12-s intertrain interval. Each session will have 75 trains. Thus, it will be taking about 25 min for each session which includes setting up time.

aTMS will be conducted in a room with facilities for managing seizures. Participants and experimenters will be offered earplugs during the sessions. Sessions will be done by staff trained and credentialed in TMS according to the Singapore College of Psychiatrists guidelines for TMS. Staff will also be trained for initial seizure management.

Patients in the delayed-start group will be treated as usual during the delayed week and will receive aTMS treatment at 1 week after recruitment. Subjects in the delayed-start group and early-start group will both be monitored with weekly outcome assessments. Subjects in the delayed start arm who still fulfill the criteria for study entry at the end of the delayed start phase will continue on to the active treatment phase of the study. No change in psychiatric medication will be allowed during this period.

Evaluation of clinical response at phase 1

A blinded, the trained rater will assess mood each week, from baseline to 2 weeks after treatment, using the Montgomery-Asberg Depression Rating Scale (MADRS) scale. MADRS scale is more sensitive to change in patients’ mental condition than Hamilton depression rating scale [44]. The primary outcome is response rate, which are assessed at end of week 4 and week 6. Secondary outcomes include remission rate, Clinician Global Impression –Improvement Scale (CGI-I) and the self-rated Quick Inventory of Depression (QIDS-16). Patient’s cognition will be monitored using the Montreal Cognitive Assessment Scale (MoCA) before and after the 1-week active treatment period and quality of life (QoL) measured by the Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form (Q-LES-Q-SF), assessed at baseline and end of week 2. MoCA is a brief cognitive instrument recommended for screening for cognitive impairment (CI) in patients. Several studies have compared the discriminant abilities of the MoCA and the Mini-Mental State Examination (MMSE) for screening post-stroke CI, and most studies have demonstrated that the MoCA is superior or equivalent to the MMSE for the detection of CI after stroke. Furthermore, the MoCA has been reported to be sensitive to changes in acute temporary CI after mild stroke/TIA, whereas the MMSE is reportedly not [45]. Therefore, in the current study, we use MoCA to assess acute changes in cognitive abilities.

After aTMS treatment, all subjects will then be followed up once a week for 2 weeks and subjects who achieve remission will exit the study.

Randomization at phase 2

Subjects who have not remitted from the 1st active treatment will enter phase 2 treatment. The second randomization will be stratified into three groups based on whether the participant showed <25% improvement in MADRS scores, between 25% and ≤50% improvement in MADRS scores or >50% improvement in MADRS scores. After that, participants in each group will be randomized (in permuted blocks) to either L DLPFC or R DLPFC treatment. The purpose of patient stratification basing on MADRS score before randomization is a method of permuted block randomization, which is a way to randomly allocate a participant to a treatment group, while maintaining a balance across treatment groups. Each “block” has a specified number of randomly ordered treatment assignments depending on the response to the initial aTMS treatment. Randomization will be generated by study team members who are not involved in the treatment. Treatment assignment is determined by treating doctors. Patients, their caregivers, nurse clinicians, and doctors who do the treatment and outcome assessments will be blinded to the randomization.

Treatment at phase 2

Subjects who entered phase 2 will receive another 1 week of 5 Hz L DLPFC aTMS (same protocol as above) or aTMS consisting of right DLPFC at 1Hz, 4 treatment sessions a day (each session consisting of 3000 pulses for 12000 pulses a day), every weekday for 1 week. These patients will also be followed up with weekly assessments for 2 weeks after the end of the second round of aTMS. Therefore, participants who receive a total of 1 week of daily aTMS would have received 60000 pulses while those who received a total of 2 weeks of daily aTMS would have received 120000 pulses.

We will use the Magventure X100 to carry out low-frequency R DLPFC. 1 Hz R DLPFC aTMS will take about 4 h a day. Stimulation will be delivered at the right prefrontal cortex (F4 according to the EEG 10/20 system). R DLPFC aTMS will be delivered at 120% of the RMT, as measured at the initial session. Each session will have 300 trains which is equivalent to a consensus protocol of delivering 3000 pulses per session over the L DLPFC [46].

Evaluation of clinical response at phase 2

Similar to the outcome assessment during phase 1, mood improvement and subject QoL will be assessed every week during acute treatment by a trained rater (blinded to treatment allocation) using the MADRS scale until 2 weeks after the initiation of 2nd round of treatment.

In summary, the primary outcome of this study will be a mean change in the MADRS score from baseline to the end of 4 weeks after treatment initiation. The primary endpoint of the trial will be the MADRS score <11 at any time points of follow-up after initiation of rTMS treatment which indicates the patients have achieved symptoms remission hence can exit from the study.

See Fig. 2 for the flowchart of the study design.

Fig. 2

Graphical display of the active treatment phase

Statistical analysis

Clinical, demographic characteristics and mood, cognitive, and QoL scores will be tested for any differences at baseline between the two randomized groups using t test or chi-square test wherever appropriate. The effect size of aTMS will be assessed by the proportion of response rate, which was defined as “Response: ≥50% MADRS score decrease from baseline” and “Non-response: <50% MADRS score decrease from baseline”. “Remission” is defined by score of 10 or less on MADRS score. Changes in mood and other ratings from baseline to each follow-up time point will be assessed with paired t test followed by repeated-measures analysis of variance (ANOVA). Statistical tests will be two-tailed.

Safety issues

Participants will undergo periodic observer-rated mood assessments during the study to check for any side effects or mood deterioration, including the emergence or exacerbation of psychiatric symptoms. In addition, before and after each TMS session, participants will be asked about any side effects or adverse events experienced. Responses will be documented, and spontaneous reports of the side effects will also be noted. An adverse event will be defined as any unfavorable medical change occurring that is accompanied by functional or clinical impairment. Participants who deteriorate to an unacceptable level during the trial (e.g., become acutely suicidal) will be withdrawn from the trial and appropriate clinical measures for their further treatment will be taken, including notification of their own treating doctor, referral to crisis team/community health center/public or private hospital.

  1. 1.

    Some participants have reported mild headache after TMS—this has not been problematic and has required mild analgesia at the most.

  2. 2.

    The TMS device emits a clicking noise when it delivers the stimulation. There have been reports of hearing impairment in animals (permanent) and human participants (temporary) when TMS was given without the use of earplugs. Participants and experimenters will be provided with earplugs and/or protective headphones during TMS in this study.

  3. 3.

    Seizures: Only a very small number of accidental seizures have been reported worldwide with TMS (n=11). Most of these have occurred with stimulus parameters outside current recommended safety guidelines [47]. There is no clear evidence of seizure induction with TMS in individuals who did not have an existing disorder which predisposes them to seizures. All TMS parameters used in this study are within safety guidelines. Our group has administered multiple sessions of TMS to over 26 subjects since November 2015 without accidental seizures or serious adverse effects. Safety precautions include training TMS staff in recognition and initial management of seizures. All subjects will be monitored for at least 30 min after each TMS session by trained staff nurses to monitor for possible seizures, headaches, or nausea.

  4. 4.

    Pregnancy: there are at least 2 case reports of the safe use of repeated sessions of TMS (given in the first, second, and/or third trimester) to treat depression in pregnant women [48, 49]. Further, there are no theoretical reasons to suggest that TMS would pose a specific risk to the pregnant woman or fetus [49]. However, as the aim of the study is not to assess the safety of TMS in pregnancy, and as the risks of TMS in pregnancy are still relatively unknown, pregnant women will be excluded from the study.

  5. 5.

    Mood switching: there are 6 case reports of TMS causing a mood switch into mania in participants with bipolar disorder [50]. The risk is relatively low, given the number of participants who have received TMS. Participants with unipolar depression who have had previous mood switching induced by an antidepressant treatment or with bipolar disorder will be advised that they may be at increased risk of mood switching with TMS and will be asked to consult their own doctor about the need for mood-stabilizing medication. There is no evidence that TMS is more likely to induce a manic switch than another course of antidepressant medication, i.e., the main alternative treatment for participants recruited into this study. Participants will be carefully monitored for mood changes suggestive of mood switching and if this occurs, will discontinue the trial and receive appropriate clinical treatment.

Sample size calculation

Based on our center’s TMS results to date, patients start TMS treatment with an average MADRS score of 25.4 (SD 7.3), which decreases significantly to 18.4 (SD 9.9) after 2 weeks of treatment with standard rTMS and to 14.1 (SD 10.7) after 4 weeks of treatment. Participants enrolled in the study would be expected to have similar improvements in MADRS with aTMS treatment.

This study is powered to test the primary aim, i.e., a significant reduction in MADRS scores from baseline to end week 3, in the overall study sample. Based on the MADRS scores cited above for baseline (25.4 ± 7.3) and end week 4 (14.1 ± 10.7) time points, detecting a similar significant change after a course of aTMS would require a sample of 12 participants (alpha 0.5, 95% power). However, given the lack of data on the efficacy of aTMS in an Asian population, and to give a better estimate of response and remission rates, we anticipated that 60% of those recruited will drop out before the end of the trial with an unequal allocation ratio of 2:1, we thus aim to recruit 40 subjects in the delayed start arm and 20 subjects in the immediate start arm for a total of 60 subjects.

No prior data exist on the comparative effects of delayed response with immediate treatment of aTMS (or TMS), we will also explore the aim that non-responders to a 1-week course of aTMS will have a higher chance of response to a change in aTMS from L 5 Hz DLPFC TMS to R 1 Hz DLPFC for depression. This study will produce pilot data for 2nd and exploratory aim, informing the power analysis for a future clinical trial if results reject a null hypothesis.


This research proposal both addresses important practical and scientific considerations in depression, a major international [1] and local [2] public health challenge that is a leading cause of years lived with disability [51]. TMS has the potential to be a significant treatment for depression if it can be efficiently delivered to patients in need. The ability to compress TMS via aTMS could multiply the practical applicability to many more patients in the community with depression who lack the time and resources for the standard 38-min daily session over 4 weeks.

In addition, there is the scientific question of how to optimize TMS treatment after initial poor response which has been poorly investigated thus far. There is insufficient evidence on the optimal duration of TMS treatment for patients with good response. The results of this study will be of significant interest to the wider research community looking into the optimization of TMS treatment in depression.

Moreover, the results of this study have significant potential to affect local and international routine clinical practice of TMS for depression. Potentially, all restructured hospitals and more private psychiatrists could be offering TMS treatment for depression and having evidence that it can be accelerated will significantly increase adoption of this novel treatment for depression. It will also improve patient care as patients can potentially respond in 1–2 weeks rather than the 4–6 weeks of standard TMS care today. This increased speed of response will not only relieve suffering and distress but improve patient productivity by reducing time spent on treatment and accelerate their return to work or societal duties.

Strengths and limitations

This trial has several strengths. The delayed start phase will decrease the likelihood of a significant placebo response by subjects who respond to increased attention in a clinical trial. The psychological response elicited by placebos is very specific depending on various factors such as the patient’s expectations, feelings, beliefs, volition, and hope for improvement [52, 53]. Growing placebo response is an important issue of antidepressant therapy for clinical trials involving patients with MDD [54,55,56,57]. A recent meta-analysis summarized from 61 large randomized clinical trials (RCTs) suggesting that there is a large placebo response for rTMS trial regardless of the modality of intervention [58]. In our trial, we designed a 1-week delay of treatment to possibly mitigate the placebo effect of active treatment by rTMS. However, it remains unclear whether this delayed-start phase may also reduce the anti-depressant effect of active treatment as some opinions exist that placebo response may be a component of therapeutic response to rTMS in MDD [58]. Patients will receive treatment as usual during the delayed week without coming to rTMS clinic. During the delayed phase, there is still weekly MADRS assessment and this will help patients maintain good adherence with the trial as the patients will keep informed about the study and establish a positive relationship and engagement with clinical staff.

We proposed a 2-week follow-up period after patients have been treated with compact 20 sessions of rTMS. Several open-label large-scale RCTs have shown that some patients with standard treatment of rTMS experienced a delayed response and required 4–6 weeks of stimulation before showing adequate response [12, 59,60,61]. Similarly, although the accelerated form of rTMS treatment with multiple sessions conducted daily may induce a rapid anti-depressant effect, there are still possibilities that some patients remain non-responding or poor-responding immediately after completion of prescribed sessions of rTMS. Therefore, 2 weeks follow-up period was proposed in this study to allow us to identify this specific group of patients with delayed responses.

The proposed study is an open-label single-blinded study and will have the limitations of a lack of a control group in which patients will receive sham-operated magnetic stimulation of the brain and a control group to minimize the expectancy bias by raters. TMS is now a standard treatment for depression [62, 63]. Depression is a severe illness that could result not only in significant distress and economic burden for patients and society, but even suicide. It would be difficult to argue for a placebo-controlled arm in a pilot study of TMS with the availability of effective treatments for depression. In addition, we have both international [29, 64,65,66] and local evidence of the effectiveness of TMS in actual clinical settings to be able to meaningfully interpret the data from this open-label single-blinded study of TMS in treating depression. Nevertheless, proposing various groups of control without proper treatment of rTMS is unrealistic, particularly with the current recruitment capacity of a single research institute. Future large trial with multi-site collaboration may help to solve this issue.


In summary, this trial is expected to clarify the clinical advantages of compressed TMS treatment vs. the standard treatment protocol of TMS. If this trial reveals the appropriate protocol of aTMS, this result can be published to enhance local and international TMS treatment guidelines.

Availability of data and materials

The datasets generated and/or analyzed during the current study are not publicly available due to restrictions from the Institutional Research Review Committee, Institute of Mental Health and the National Healthcare Group Domain Specific Review Board, Singapore, but are available from the corresponding author on reasonable request.


  1. 1.

    Kupfer DJ, Frank E. The interaction of drug-and psychotherapy in the long-term treatment of depression. J Affective Disorder. 2001;62(1):131–7.

    CAS  Article  Google Scholar 

  2. 2.

    Chong SA, Abdin E, Vaingankar JA, Heng D, Sherbourne C, Yap M, et al. A population-based survey of mental disorders in Singapore. Ann Acad Med Singapore. 2012;41(2):49.

    PubMed  Google Scholar 

  3. 3.

    Hu T-w. The economic burden of depression and reimbursement policy in the Asia Pacific region. Aust Psychiatry. 2004;12(1 suppl):S11–5.

    Article  Google Scholar 

  4. 4.

    Ho RC, Mak KK, Chua AN, Ho CS, Mak A. The effect of severity of depressive disorder on economic burden in a university hospital in Singapore. Expert Rev Pharmacoeconomics Outcomes Res. 2013;13(4):549–59.

    Article  Google Scholar 

  5. 5.

    Switaj P, Anczewska M, Chrostek A, Sabariego C, Cieza A, Bickenbach J, et al. Disability and schizophrenia: a systematic review of experienced psychosocial difficulties. BMC psychiatry. 2012;12(1):193.

    Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Lepine JP, Briley M. The increasing burden of depression. Neuropsychiatr Dis Treat. 2011;7(Suppl 1):3–7.

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Burcusa SL, Iacono WG. Risk for recurrence in depression. Clinical psychology review. 2007;27(8):959–85.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    John Rush A, Bobby Jain S. Clinical Implications of the STAR*D Trial. Handbook of experimental pharmacology. 2019;250:51–99.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Kennedy SH, Giacobbe P. Treatment resistant depression--advances in somatic therapies. Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists. 2007;19(4):279–87.

    Article  Google Scholar 

  10. 10.

    Rush AJ, Siefert SE. Clinical issues in considering vagus nerve stimulation for treatment-resistant depression. Experimental neurology. 2009;219(1):36–43.

    Article  PubMed  Google Scholar 

  11. 11.

    O’Reardon JP, Solvason HB, Janicak PG, Sampson S, Isenberg KE, Nahas Z, et al. Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biol Psychiatry. 2007;62(11):1208–16.

    Article  PubMed  Google Scholar 

  12. 12.

    George MS, Lisanby SH, Avery D, McDonald WM, Durkalski V, Pavlicova M, et al. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Archiv Gen Psychiatry. 2010;67(5):507–16.

    Article  Google Scholar 

  13. 13.

    Slotema CW, Dirk Blom J, Hoek HW, Sommer IE. Should we expand the toolbox of psychiatric treatment methods to include Repetitive Transcranial Magnetic Stimulation (rTMS)? A meta-analysis of the efficacy of rTMS in psychiatric disorders. J Clin Psychiatry. 2010;71(7):873–84.

    Article  PubMed  Google Scholar 

  14. 14.

    Loo CK, McFarquhar TF, Mitchell PB. A review of the safety of repetitive transcranial magnetic stimulation as a clinical treatment for depression. Int J Neuropsychopharmacol. 2008;11(1):131–47.

    Article  PubMed  Google Scholar 

  15. 15.

    Pascual-Leone A, Valls-Solé J, Wassermann EM, Hallett M. Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain. 1994;117(4):847–58.

    Article  PubMed  Google Scholar 

  16. 16.

    Sachdev PS, McBride R, Loo C, Mitchell PM, Malhi GS, Croker V. Effects of different frequencies of transcranial magnetic stimulation (TMS) on the forced swim test model of depression in rats. Biological psychiatry. 2002;51(6):474–9.

    Article  PubMed  Google Scholar 

  17. 17.

    Padberg F, Zwanzger P, Keck ME, Kathmann N, Mikhaiel P, Ella R, et al. Repetitive transcranial magnetic stimulation (rTMS) in major depression: relation between efficacy and stimulation intensity. Neuropsychopharmacology. 2002;27(4):638–45.

    Article  PubMed  Google Scholar 

  18. 18.

    Pridmore S, Bruno R, Turnier-Shea Y, Reid P, Rybak M. Comparison of unlimited numbers of rapid transcranial magnetic stimulation (rTMS) and ECT treatment sessions in major depressive episode. International Journal of Neuropsychopharmacology. 2000;3(2):129–34.

    Article  Google Scholar 

  19. 19.

    Cohen RB, Brunoni AR, Boggio PS, Fregni F. Clinical predictors associated with duration of repetitive transcranial magnetic stimulation treatment for remission in bipolar depression: a naturalistic study. J Nervous Mental Dis. 2010;198(9):679–81.

    Article  Google Scholar 

  20. 20.

    Donohue JM, Pincus HA. Reducing the societal burden of depression: a review of economic costs, quality of care and effects of treatment. PharmacoEconomics. 2007;25(1):7–24.

    Article  PubMed  Google Scholar 

  21. 21.

    Zhao YJ, Tor PC, Khoo AL, Teng M, Lim BP, Mok YM. Cost-effectiveness modeling of repetitive transcranial magnetic stimulation compared to electroconvulsive therapy for treatment-resistant depression in Singapore. Neuromodulation : journal of the International Neuromodulation Society. 2018;21(4):376–82.

    Article  Google Scholar 

  22. 22.

    Blumberger DM, Vila-Rodriguez F, Thorpe KE, Feffer K, Noda Y, Giacobbe P, et al. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. Lancet. 2018;391(10131):1683–92.

    Article  PubMed  Google Scholar 

  23. 23.

    Bulteau S, Sebille V, Fayet G, Thomas-Ollivier V, Deschamps T, Bonnin-Rivalland A, et al. Efficacy of intermittent Theta Burst Stimulation (iTBS) and 10-Hz high-frequency repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant unipolar depression: study protocol for a randomised controlled trial. Trials. 2017;18(1):17.

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Fitzgerald PB, Chen L, Richardson K, Daskalakis ZJ, Hoy KE. A pilot investigation of an intensive theta burst stimulation protocol for patients with treatment resistant depression. Brain Stimul. 2020;13(1):137–44.

    Article  PubMed  Google Scholar 

  25. 25.

    Magnezi R, Aminov E, Shmuel D, Dreifuss M, Dannon P. Comparison between neurostimulation techniques repetitive transcranial magnetic stimulation vs electroconvulsive therapy for the treatment of resistant depression: patient preference and cost-effectiveness. Patient preference and adherence. 2016;10:1481–7.

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Loo CK, Mitchell PB. A review of the efficacy of transcranial magnetic stimulation (TMS) treatment for depression, and current and future strategies to optimize efficacy. Journal of affective disorders. 2005;88(3):255–67.

    Article  PubMed  Google Scholar 

  27. 27.

    Schulze L, Feffer K, Lozano C, Giacobbe P, Daskalakis ZJ, Blumberger DM, et al. Number of pulses or number of sessions? An open-label study of trajectories of improvement for once-vs. twice-daily dorsomedial prefrontal rTMS in major depression. Brain Stimul. 2018;11(2):327–36.

    Article  PubMed  Google Scholar 

  28. 28.

    Lang N, Harms J, Weyh T, Lemon RN, Paulus W, Rothwell JC, et al. Stimulus intensity and coil characteristics influence the efficacy of rTMS to suppress cortical excitability. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology. 2006;117(10):2292–301.

    Article  Google Scholar 

  29. 29.

    Galletly CA, Carnell BL, Clarke P, Gill S. A comparison of right unilateral and sequential bilateral repetitive transcranial magnetic stimulation for major depression: a naturalistic clinical Australian study. The journal of ECT. 2017;33(1):58–62.

    Article  PubMed  Google Scholar 

  30. 30.

    Chung SW, Hoy KE, Fitzgerald PB. Theta-burst stimulation: a new form of TMS treatment for depression? Depress Anxiety. 2015;32(3):182–92.

    Article  PubMed  Google Scholar 

  31. 31.

    Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron. 2005;45(2):201–6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Berlim MT, Van den Eynde F, Jeff Daskalakis Z. 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 : official publication of the American College of Neuropsychopharmacology. 2013;38(4):543–51.

    CAS  Article  Google Scholar 

  33. 33.

    George MS, Taylor JJ, Short EB. The expanding evidence base for rTMS treatment of depression. Current opinion in psychiatry. 2013;26(1):13–8.

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Kelly D, Gill S, Clarke P, Burton C, Galletly C. Delayed response to repetitive transcranial magnetic stimulation treatment for intractable auditory hallucinations in schizoaffective disorder. Annals of clinical psychiatry: official journal of the American Academy of Clinical Psychiatrists. 2012;24(2):172–3.

    Google Scholar 

  35. 35.

    Avery DH, Isenberg KE, Sampson SM, Janicak PG, Lisanby SH, Maixner DF, et al. Transcranial magnetic stimulation in the acute treatment of major depressive disorder: clinical response in an open-label extension trial. Journal of Clinical Psychiatry. 2008;69(3):441–51.

    Article  Google Scholar 

  36. 36.

    Holtzheimer PE, McDonald WM, Mufti M, Kelley ME, Quinn S, Corso G, et al. Accelerated repetitive transcranial magnetic stimulation for treatment-resistant depression. Depress Anxiety. 2010;27(10):960–3.

    Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Theleritis C, Sakkas P, Paparrigopoulos T, Vitoratou S, Tzavara C, Bonaccorso S, et al. Two versus one high-frequency repetitive transcranial magnetic stimulation session per day for treatment-resistant depression: a randomized sham-controlled trial. The journal of ECT. 2017;33(3):190–7.

    Article  PubMed  Google Scholar 

  38. 38.

    Baeken C, Vanderhasselt M-A, Remue J, Herremans S, Vanderbruggen N, Zeeuws D, et al. Intensive HF-rTMS treatment in refractory medication-resistant unipolar depressed patients. Journal of affective disorders. 2013;151(2):625–31.

    Article  PubMed  Google Scholar 

  39. 39.

    George MS, Raman R, Benedek DM, Pelic CG, Grammer GG, Stokes KT, et al. A two-site pilot randomized 3 day trial of high dose left prefrontal repetitive transcranial magnetic stimulation (rTMS) for suicidal inpatients. Brain Stimulation. 2014;7(3):421–31.

    Article  PubMed  Google Scholar 

  40. 40.

    Seok J-H, Chung M-H. The efficacy and safety of accelerated repetitive transcranial magnetic stimulation in major depressive disorder: single-blind, randomized study. Brain Stimulation. 2015;8(2):384.

    Article  Google Scholar 

  41. 41.

    Dardenne A, Baeken C, Crunelle CL, Bervoets C, Matthys F, Herremans SC. Accelerated HF-rTMS in the elderly depressed: a feasibility study. Brain Stimulation. 2018;11(1):247–8.

    Article  PubMed  Google Scholar 

  42. 42.

    Tor P-C, Gálvez V, Goldstein J, George D, Loo CK. Pilot study of accelerated low-frequency right-sided transcranial magnetic stimulation for treatment-resistant depression. The journal of ECT. 2016;32(3):180–2.

    Article  PubMed  Google Scholar 

  43. 43.

    Loo CK, Mitchell PB, McFARQUHAR TF, Malhi GS, Sachdev PS. A sham-controlled trial of the efficacy and safety of twice-daily rTMS in major depression. Psychol Med. 2007;37(03):341–9.

    Article  PubMed  Google Scholar 

  44. 44.

    Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. The British journal of psychiatry : the journal of mental science. 1979;134(4):382–9.

    CAS  Article  Google Scholar 

  45. 45.

    Sivakumar L, Kate M, Jeerakathil T, Camicioli R, Buck B, Butcher K. Serial montreal cognitive assessments demonstrate reversible cognitive impairment in patients with acute transient ischemic attack and minor stroke. Stroke. 2014;45(6):1709–15.

    Article  PubMed  Google Scholar 

  46. 46.

    McClintock SM, Reti IM, Carpenter LL, McDonald WM, Dubin M, Taylor SF, et al. Consensus recommendations for the clinical application of repetitive transcranial magnetic stimulation (rTMS) in the treatment of depression. J Clin Psych. 2018;79(1):35-48.

  47. 47.

    Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5–7, 1996. Electroencephalography and Clinical Neurophysiology/Evoked Potentials Section. 1998;108(1):1–16.

    CAS  Article  Google Scholar 

  48. 48.

    Nahas Z, Bohning DE, Molloy MA, Oustz JA, George MS. Safety and feasibility of repetitive transcranial magnetic stimulation in the treatment of anxious depression in pregnancy: a case report. J Clin Psychiatry. 1999;60(1):50–2.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Dodick DW, Schembri CT, Helmuth M, Aurora SK. Transcranial magnetic stimulation for migraine: a safety review. Headache. 2010;50(7):1153–63.

    Article  Google Scholar 

  50. 50.

    Rossi S, Hallett M, Rossini PM, Pascual-Leone A. Group SoTC: Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin Neurophysiol. 2009;120(12):2008–39.

    Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2013;380(9859):2197–223.

    Article  Google Scholar 

  52. 52.

    Beauregard M. Mind does really matter: evidence from neuroimaging studies of emotional self-regulation, psychotherapy, and placebo effect. Progress in neurobiology. 2007;81(4):218–36.

    Article  PubMed  Google Scholar 

  53. 53.

    Beauregard M. Effect of mind on brain activity: evidence from neuroimaging studies of psychotherapy and placebo effect. Nordic journal of psychiatry. 2009;63(1):5–16.

    Article  PubMed  Google Scholar 

  54. 54.

    Baeken C, Wu GR, van Heeringen K: Placebo aiTBS attenuates suicidal ideation and frontopolar cortical perfusion in major depression. 2019, 9(1):38.

    Google Scholar 

  55. 55.

    Brunoni AR, Lopes M, Kaptchuk TJ, Fregni F. Placebo response of non-pharmacological and pharmacological trials in major depression: a systematic review and meta-analysis. PloS one. 2009;4(3):e4824.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Sikora M, Heffernan J, Avery ET, Mickey BJ, Zubieta JK, Pecina M. Salience network functional connectivity predicts placebo effects in major depression. Biological psychiatry Cognitive neuroscience and neuroimaging. 2016;1(1):68–76.

    Article  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Weimer K, Colloca L, Enck P. Placebo effects in psychiatry: mediators and moderators. The lancet Psychiatry. 2015;2(3):246–57.

    Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Razza LB, Moffa AH, Moreno ML, Carvalho AF, Padberg F, Fregni F, et al. A systematic review and meta-analysis on placebo response to repetitive transcranial magnetic stimulation for depression trials. Progress in neuro-psychopharmacology & biological psychiatry. 2018;81:105–13.

    Article  Google Scholar 

  59. 59.

    Levkovitz Y, Isserles M, Padberg F, Lisanby SH, Bystritsky A, Xia G, et al. Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial. World psychiatry : official journal of the World Psychiatric Association (WPA). 2015;14(1):64–73.

    Article  Google Scholar 

  60. 60.

    Lisanby SH, Husain MM, Rosenquist PB, Maixner D, Gutierrez R, Krystal A, et al. Daily left prefrontal repetitive transcranial magnetic stimulation in the acute treatment of major depression: clinical predictors of outcome in a multisite, randomized controlled clinical trial. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2009;34(2):522–34.

    Article  Google Scholar 

  61. 61.

    Yip AG, George MS, Tendler A, Roth Y, Zangen A, Carpenter LL. 61% of unmedicated treatment resistant depression patients who did not respond to acute TMS treatment responded after four weeks of twice weekly deep TMS in the Brainsway pivotal trial. Brain Stimul. 2017;10(4):847–9.

    Article  PubMed  Google Scholar 

  62. 62.

    Perera T, George MS, Grammer G, Janicak PG, Pascual-Leone A, Wirecki TS. The clinical TMS society consensus review and treatment recommendations for TMS therapy for major depressive disorder. Brain stimulation. 2016;9(3):336–46.

    Article  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Milev RV, Giacobbe P, Kennedy SH, Blumberger DM, Daskalakis ZJ, Downar J, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 4. neurostimulation treatments. Can J Psychiatry. 2016;61(9):561–75.

    Article  Google Scholar 

  64. 64.

    Connolly KR, Helmer A, Cristancho MA, Cristancho P, O’Reardon JP. Effectiveness of transcranial magnetic stimulation in clinical practice post-FDA approval in the United States: results observed with the first 100 consecutive cases of depression at an academic medical center. J Clin Psychiatry. 2012;73(4):e567–73.

    Article  PubMed  Google Scholar 

  65. 65.

    Carpenter LL, Janicak PG, Aaronson ST, Boyadjis T, Brock DG, Cook IA, et al. Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice. Depression and anxiety. 2012;29(7):587–96.

    Article  PubMed  Google Scholar 

  66. 66.

    Janicak PG, Dunner DL, Aaronson ST, Carpenter LL, Boyadjis TA, Brock DG, et al. Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of quality of life outcome measures in clinical practice. CNS Spectrums. 2013;18(06):322–32.

    Article  PubMed  Google Scholar 

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This study protocol was supported by the Singapore National Medical Research Council (NMRC) research funding (grant no: CNIG18May-0001). The funding body plays no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Author information




EA and PCT conceived and designed the study protocol; XWT, EA, and PCT wrote the manuscript; PCT and the clinician team are collecting the data; XWT and EA will perform the data analysis. PCT regularly provided feedback on the overall study protocol was involved in the development of the usability test. The authors reviewed and approved the final version of the manuscript before submission.

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Correspondence to Phern Chern Tor.

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An ethics application was submitted to the Institutional Research Review Committee (IRRC), IMH, and Domain Specific Review Board, National Healthcare Group (NHG DSRB). IRRC approved the study in March 2019 (reference no: 665-2219), and DSRB approved the study in July 2019 (reference no: 2019/00309). Consents will be obtained from all participants.

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Not applicable.

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The authors declared that there are no competing interests.

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Tan, X.W., Abdin, E. & Tor, P.C. Accelerated transcranial magnetic stimulation (aTMS) to treat depression with treatment switching: study protocol of a pilot, randomized, delayed-start trial. Pilot Feasibility Stud 7, 104 (2021).

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