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Optimized Repetitive Transcranial Magnetic Stimulation Techniques for the Treatment of Major Depression: A Proof of Concept Study

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Abstract

Although effective in major depressive disorder (MDD), repetitive transcranial magnetic stimulation (rTMS) is costly and complex, limiting accessibility. To address this, we tested the feasibility of novel rTMS techniques with cost-saving opportunities, such as an open-room setting, large non-focal parabolic coils, and custom-built coil arms. We employed a low-frequency (LF) 1 Hz stimulation protocol (360 pulses per session), delivered on the most affordable FDA-approved device. MDD participants received an initial accelerated rTMS course (arTMS) of 6 sessions/day over 5 days (30 total), followed by a tapering course of daily sessions (up to 25) to decrease the odds of relapse. The self-reported Beck Depression Inventory II (BDI-II) was used to measure severity of depression. Forty-eight (48) patients completed the arTMS course. No serious adverse events occurred, and all patients reported manageable pain levels. Response and remission rates were 35.4% and 27.1% on the BDI-II, respectively, at the end of the tapering course. Repeated measures ANOVA showed significant changes of BDI-II scores over time. Even though our protocol will require further improvements, some of the concepts we introduced here could help guide the design of future trials aiming at increasing accessibility to rTMS.

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... Adult (18-85 years of age) outpatients were eligible for study participation if they 1) had a Mini International Neuropsychiatric Interview (MINI) confirmed MDD diagnosis and 2) maintained a stable medication regimen from 4 weeks before treatment start until study completion. Exclusion criteria included a history of substance dependence or abuse within the last 3 months, cardiac pacemaker or implanted medication pump, active suicidal intent and a diagnosis of any psychotic or neurological disorder or insult (e.g. a history of seizures) (see (Miron et al., 2021) for full list of inclusion/exclusion criteria). All participants provided written, informed consent and the study was approved by the Research Ethics Board of the University Health Network. ...
... Details on study screening and enrollment are summarized elsewhere (Miron et al., 2021). ...
... Detailed information about participants and clinical outcome are specified elsewhere (Miron et al., 2021). In summary, 57 participants with MDD were assessed for study eligibility, of which 50 were enrolled. ...
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Background Repetitive transcranial magnetic stimulation (rTMS) is an effective intervention for major depressive disorder (MDD). Completing a full treatment course, however, is costly and time-consuming. Biomarkers of clinical outcome such as baseline resting-state brain activity measured with electroencephalography (EEG) may spare people futile treatment and conserve limited clinical resources. Additionally, investigating changes in EEG power post-treatment could provide insights into the working mechanism of rTMS. Methods 39 MDD patients received 6 daily sessions of accelerated low-frequency (LF) rTMS over the right dorsolateral prefrontal cortex (DLPFC) for 5 days followed by a tapering course of 25 once-daily sessions. Resting-state EEG and heart rate (HR) measures were acquired immediately before and after a single rTMS session at 3 different timepoints: baseline, one week after the final accelerated session, and upon completion of the tapering course. The primary clinical outcome measure was the Beck Depression Inventory II (BDI-II). Results High relative baseline theta power in prefrontal areas and high baseline HR were associated with poorer clinical outcome. HR decreased acutely at the beginning of the patients’ first rTMS session but this effect was not associated with treatment outcome. Limitations The main limitations were small sample size and a lack of sham and healthy control group. Conclusion Our results suggest that high relative theta power at baseline may be a marker of poorer response to right-sided LF rTMS. If validated, this easily applicable measure could inform rTMS protocol choice for the individual, thereby potentially speeding up patient recovery and saving clinical resources.
... Each rTMS session began with a 2 min, 600 pulse, 100% MT, right DLPFC continuous TBS (cTBS) treatment (10), directly followed by the above describe iTBS protocol. cTBS was delivered over the right DLPFC with the coil centered on the F4 EEG location (using the BeamF3 algorithm, but on the right-side of the head) (11). During the consolidation phase of treatment, the patient received intramuscular (IM) racemic ketamine (same dosage as IV) once a week for 6weeks and then once every 2 weeks (eight sessions total). ...
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2022) Transcranial magnetic stimulation and intravenous ketamine combination therapy for treatment-resistant bipolar depression: A case report. Front. Psychiatry 13:986378. About a third of patients suffering from major depression develop treatment-resistant depression (TRD). Although repetitive transcranial magnetic stimulation (rTMS) and intravenous ketamine have proven effective for the management of TRD, many patients remain refractory to treatment. We present the case of a patient suffering from bipolar TRD. The patient was referred to us after failure to respond to first-and second-line pharmacotherapy and psychotherapy. After minimal response to both rTMS and ketamine alone, we attempted a combination rTMS and ketamine protocol, which led to complete and sustained remission. Various comparable and complimentary mechanisms of antidepressant action of ketamine and rTMS are discussed, which support further study of this combination therapy. Future research should focus on the feasibility, tolerability, and efficacy of this novel approach.
... Repetitive transcranial magnetic stimulation (rTMS) has been increasingly used as a therapeutic solution for depression for more than a decade and evidence regarding its efficacy has been reported in several meta-analyses (Brunoni et al., 2017;Cao et al., 2018;Mutz et al., 2018). Worth noting is that the United States Food and Drug Administration (FDA) has approved certain rTMS protocols to treat major depressive disorder (MDD) (Berlim et al., 2017;Hung et al., 2020), however, the question remains on how to improve response to this treatment by optimizing stimulation protocols (Cash et al., 2017;Pitkänen et al., 2017;Miron et al., 2021) and developing markers to enable prediction of its therapeutic effects on patients. In that light, predictors of treatment response to rTMS, potentially identifying patients who will likely respond to the intervention, play an essential role in the pursuit to deliver personalized rTMS treatment. ...
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Background Cognitive impairments are prevalent in patients with unipolar and bipolar depressive disorder (UDD and BDD, respectively). Considering the fact assessing cognitive functions is increasingly feasible for clinicians and researchers, targeting these problems in treatment and using them at baseline as predictors of response to treatment can be very informative. Method In a naturalistic, retrospective study, data from 120 patients (Mean age: 33.58) with UDD ( n = 56) and BDD ( n = 64) were analyzed. Patients received 20 sessions of bilateral rTMS (10 Hz over LDLPFC and 1 HZ over RDLPFC) and were assessed regarding their depressive symptoms, sustained attention, working memory, and executive functions, using the Beck Depression Inventory (BDI-II) and Neuropsychological Test Automated Battery Cambridge, at baseline and after the end of rTMS treatment course. Generalized estimating equations (GEE) and logistic regression were used as the main statistical methods to test the hypotheses. Results Fifty-three percentage of all patients ( n = 64) responded to treatment. In particular, 53.1% of UDD patients ( n = 34) and 46.9% of BDD patients ( n = 30) responded to treatment. Bilateral rTMS improved all cognitive functions (attention, working memory, and executive function) except for visual memory and resulted in more modulations in the working memory of UDD compared to BDD patients. More improvements in working memory were observed in responded patients and visual memory, age, and sex were determined as treatment response predictors. Working memory, visual memory, and age were identified as treatment response predictors in BDD and UDD patients, respectively. Conclusion Bilateral rTMS improved cold cognition and depressive symptoms in UDD and BDD patients, possibly by altering cognitive control mechanisms (top-down), and processing negative emotional bias.
... Repetitive magnetic transcranial stimulation (rTMS) is a non-invasive neuromodulation modality that has been utilized within the neurological and psychiatric communities [1][2][3][4]. Since its development as a therapeutic tool in 1985 [5], rTMS has been shown to provide various degrees of symptomatic relief for conditions such as depressive disorders, pain, aphasia, movement disorders, motor stroke, multiple sclerosis, epilepsy, disorders of consciousness, Alzheimer's disease, schizophrenia, substance abuse, and addiction [6][7][8][9]. Considering the beneficial effects, there has been an emerging interest in utilizing rTMS for auditory disorders such as tinnitus [10][11][12][13]. ...
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Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive, neuromodulating technique for brain hyperexcitability disorders. The objective of this paper is to discuss the mechanism of action of rTMS as well as to investigate the literature involving the application of rTMS in the treatment of tinnitus. The reviewed aspects of the protocols included baseline evaluation, the total number of sessions, frequency and the total number of stimuli, the location of treatment, and the outcome measures. Even with heterogeneous protocols, most studies utilized validated tinnitus questionnaires as baseline and outcome measures. Low frequency (1 Hz) stimulation throughout 10 consecutive sessions was the most widely used frequency and treatment duration; however, there was no consensus on the total number of stimuli necessary to achieve significant results. The auditory cortex (AC) was the most targeted location, with most studies supporting changes in neural activity with multi-site stimulation to areas in the frontal cortex (FC), particularly the dorsolateral prefrontal cortex (DLPFC). The overall efficacy across most of the reviewed trials reveals positive statistically significant results. Though rTMS has proven to impact neuroplasticity at the microscopic and clinical level, further studies are warranted to demonstrate and support the clinical use of rTMS in tinnitus treatment with a standardized protocol.
... With an advantageous side effect profile over medication, response and remission rates have been estimated to be as high as 40-60% and 25-35%, respectively, in recent meta-analyses . Unfortunately, rTMS is burdened by several limitations that decreases accessibility (Miron et al., 2021a(Miron et al., , 2021b(Miron et al., , 2020: equipment costs are high, technical operation complex, and treatment courses lengthy, requiring daily sessions over several weeks. This reinforces the need for careful patient selection to maximize treatment outcomes and avoid futile treatment courses. ...
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BACKGROUND Major depressive disorder (MDD) is now the first cause of disability worldwide. So far, no validated and scalable biomarker has been identified to help with response prediction to antidepressant treatment. Cardiac biomarkers such as heart rate variability (HRV) have been studied in MDD, but few studies have examined its potential use for outcome prediction to repetitive transcranial magnetic stimulation (rTMS). OBJECTIVE We recorded pre-treatment HRV in MDD participants prior to an rTMS course. We hypothesized that higher pre-treatment HRV would be correlated with better clinical outcomes. METHODS HRV was recorded as part of a single-arm, open-label rTMS feasibility study. Pre-treatment HRV was assessed in N = 30 MDD participants before they underwent a one-week (5 days, 8 daily sessions, 40 sessions total) accelerated rTMS (arTMS) course using a low-frequency 1 Hz course (600 pulses per session, 50-minute intersession interval) over the right dorsolateral prefrontal cortex at 120% of the resting motor threshold. Clinical outcomes were captured using the Beck Depression Inventory-II (BDI-II). We tested for an association between pre-treatment HRV and clinical outcomes on the BDI-II using a linear mixed effects model. RESULTS Although average BDI-II score significantly changed over time, these changes were not significantly associated with pre-treatment HRV (p = 0.60). This finding remained when adjusting for age, sex, and HR, individually and collectively. CONCLUSION The current study did not find a relationship between pre-treatment HRV and response to low frequency rTMS. Other approaches using cardiac biomarkers may have potential for response prediction.
... Parabolic coils could be a solution to this and have just started to be studied using safe and effective 1 Hz protocols. 67,68 Their central opening allows for direct visualization of scalp landmarks and therefore easier and more reliable positioning. Their shape also fits the natural curvature of the head and their large stimulation area could decrease the need for precise positioning. 1 Hz stimulation also has the advantage to only require basic stimulators that do not require cooling, further decreasing costs. ...
Article
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Repetitive transcranial magnetic stimulation (rTMS) is a safe and well-tolerated intervention for major depressive disorder (MDD). Over 150 randomized controlled trials (RCTs) have been carried out, and its efficacy has been confirmed in dozens of meta-analyses. Real world data has also confirmed the effectiveness of rTMS for MDD in clinical practice, with the most recent literature indicating response rates of 40–50% and remission rates of 25–30%. In this review, we first offer an historical perspective, followed by a review of basic principles, such as putative mechanisms, procedures and protocols, stimulation targets, efficacy and durability of response, side effects, and the placebo controversy. In the second part of this review, we first discuss solutions to increase accessibility to rTMS, such as modifications to treatment equipment, protocols and setting. We continue with possible means to further increase effectiveness, such as treatment personalization and extension. We conclude by addressing the scheduling issue, with accelerated rTMS (arTMS) as a possible solution.
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Background Accelerated transcranial magnetic stimulation (aTMS) is an emerging delivery schedule of repetitive TMS (rTMS). TMS is “accelerated” by applying two or more stimulation sessions within a day. This three-part review comprehensively reports the safety/tolerability, efficacy, and stimulation parameters affecting response across disorders. Methods We used the PubMed database to identify studies administering aTMS, which we defined as applying at least two rTMS sessions within one day. Results Our targeted literature search identified 85 aTMS studies across 18 diagnostic and healthy control groups published from July 2001 to June 2022. Excluding overlapping populations, 63 studies delivered 43,873 aTMS sessions using low frequency, high frequency, and theta burst stimulation in 1543 participants. Regarding safety, aTMS studies had similar seizure and side effect incidence rates to those reported for once daily rTMS. One seizure was reported from aTMS (0.0023% of aTMS sessions, compared with 0.0075% in once daily rTMS). The most common side effects were acute headache (28.4%), fatigue (8.6%), and scalp discomfort (8.3%), with all others under 5%. We evaluated aTMS efficacy in 23 depression studies (the condition with the most studies), finding an average response rate of 42.4% and remission rate of 28.4% (range = 0–90.5% for both). Regarding parameters, aTMS studies ranged from 2 to 10 sessions per day over 2–30 treatment days, 10–640 min between sessions, and a total of 9–104 total accelerated TMS sessions per participant (including tapering sessions). Qualitatively, response rate tends to be higher with an increasing number of sessions per day, total sessions, and total pulses. Discussion The literature to date suggests that aTMS is safe and well-tolerated across conditions. Taken together, these early studies suggest potential effectiveness even in highly treatment refractory conditions with the added potential to reduce patient burden while also expediting response time. Future studies are warranted to systematically investigate how key aTMS parameters affect treatment outcome and durability.
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Treatment resistant depression is challenging because patients who fail their initial treatments often do not respond to subsequent trials and their course of illness is frequently marked by chronic depression. Repetitive transcranial magnetic stimulation (rTMS) is a well-established treatment alternative, but there are several limitations that decreases accessibility. Identifying biomarkers that can help clinicians to reliably predict response to rTMS is therefore necessary. Allostatic load (AL), which represents the ‘wear and tear’ on the body and brain which accumulates as an individual is exposed to chronic stress could be an interesting staging model for TRD and help predict rTMS treatment response. We propose an open study which aims to test whether patients with a lower pre-treatment AL will have a stronger antidepressant response to 4 week-rTMS treatment. We will also assess the relation between healthy lifestyle behaviors, AL, and rTMS treatment response. Blood samples for AL parameters will be collected before the treatment. The AL indices will summarize neuroendocrine (cortisol, Dehydroepiandrosterone), immune (CRP, fibrinogen, ferritin), metabolic (glycosylated hemoglobin, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, uric acid, body mass index, waist circumference), and cardiovascular (heart rate, systolic and diastolic blood pressure) functioning. Mood assessment (Montgomery-Åsberg Depression Rating Scale and Inventory of Depressive symptomatology) will be measured before the treatment and at two-week intervals up to 4 weeks. With the help of different lifestyle questionnaires, a healthy lifestyle index (i.e., a single score based on lifestyle factors) will be created. We will use linear and logistic regressions to assess AL in relation to changes in mood score. Hierarchical regression will be done in order to assess the association between AL, healthy lifestyle index and mood score. Long-lasting and unsuccessful antidepressant trials may increase the chance of not responding to future trials of antidepressants and it can therefore increase treatment resistance. It is essential to identify reliable biomarkers that can predict treatment responses.
Article
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BACKGROUND Repetitive transcranial magnetic stimulation (rTMS) is an effective intervention in major depressive disorder (MDD) but requires daily travel to a treatment clinic over several weeks. Shorter rTMS courses retaining similar effectiveness would thus increase the practicality and scalability of the technique, and therefore its accessibility. OBJECTIVE We assessed the feasibility of a novel 5 day accelerated 1 Hz rTMS protocol. We hypothesized that this novel rTMS protocol would be safe and well-tolerated while shortening the overall treatment course. METHODS We conducted a prospective, single-arm, open-label feasibility study. Thirty (30) participants received a one-week (5 days) accelerated (8 sessions per day, 40 sessions total) course of 1 Hz rTMS (600 pulses per session, 50-minute intersession interval) over the right dorsolateral prefrontal cortex (R-DLPFC) using a figure-of-eight coil at 120% of the resting motor threshold (rMT). Primary outcomes were response and remission rates on the Beck Depression Inventory-II (BDI-II). RESULTS Response and remission rates 1 week after treatment were 33.3% and 13.3% respectively and increased to 43.3% and 30.0% at follow-up 4 weeks after treatment. No serious adverse events occurred. All participants reported manageable pain levels. CONCLUSION 1 Hz rTMS administered 8 times daily for 5 days is safe and well-tolerated. Validation in a randomized trial will be required. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04376697.
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BACKGROUND Repetitive transcranial magnetic stimulation (rTMS) is effective in major depressive disorder (MDD). However, technical complexity and operational costs might have been barriers for its wide use and implementation in some jurisdictions, thereby decreasing accessibility. OBJECTIVE Our main goal was to test the feasibility of a novel rTMS protocol optimized for practicality, scalability and cost-effectiveness. We hypothesized that our novel rTMS protocol would be simple to implement and well-tolerated, but less costly and allow for more treatment capacity. METHODS Treatment was administered in an open-room setting, allowing a single technician to attend to multiple patients. Large non-focal parabolic coils held by custom-built arms allowed simple yet efficient and accurate placement. We employed a low-frequency (LF) 1 Hz stimulation protocol (360 pulses per session), delivered on the most affordable FDA-approved devices. MDD participants received an initial accelerated rTMS course (arTMS) of 6 sessions/day over 5 days (30 total), followed by a tapering course of daily sessions (up to 25) to decrease the odds of relapse. The self-reported Beck Depression Inventory II (BDI-II) was used to measure severity of depression. RESULTS Forty-eight (48) patients completed the arTMS course. No serious adverse events occurred, and all patients reported manageable pain levels. Response and remission rates were 35.4% and 27.1% on the BDI-II, respectively, at the end of the tapering course. CONCLUSION If rTMS could be delivered for lower cost at higher volume, while preserving efficacy, safety and tolerability, it could warrant further investigation of this treatment as a first-line intervention in MDD. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04376697
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Background To determine if an accelerated rTMS protocol results in distinct depressive symptom response trajectories, compared to a standard rTMS protocol. We also sought to validate previous analyses that identified distinct depressive symptom response trajectories with rTMS treatment using an external dataset. Method Data from two recent clinical trials comparing accelerated rTMS protocol delivered to the left dorsolateral prefrontal cortex (DLPFC) with standard once-daily rTMS protocol were used to identify depressive symptom response trajectories. The accelerated protocol in Trial 1 was conventional 10-Hz rTMS, while Trial 2 employed intermittent theta burst stimulation (iTBS). Participants were adult outpatients (18–70 years old) with bipolar or unipolar depression and moderate-severe depression (Montgomery Asberg Depression Rating Scale score >19) who had failed to respond to adequate courses of two different antidepressants. We used group-based trajectory modeling to identify MADRS response trajectories, and regression techniques adjusting for baseline depressive symptom severity to determine the association between treatment protocol and depressive symptom response trajectory. Results Treatment outcomes of 189 participants were analysed. We identified four distinct response trajectories: “nonresponse” (N = 59; 30.7%), “minimal response” (N = 65; 34.1%), “higher symptoms, response” (N = 26; 14.6%), “lower symptoms, response” (N = 39; 20.6%). We failed to find an association between rTMS protocol (accelerated vs standard) with depressive symptom response trajectory even after adjusting for baseline depressive symptom severity. Conclusion The accelerated rTMS protocol in this study did not impact depressive symptom response trajectories. This work provides further confirmatory evidence that there are distinct depressive symptom response trajectories with rTMS delivered to the left DLPFC. Australian new zealand clinical trials registry ACTRN12616000443493 and ACTRN12613000044729.
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A group of European experts reappraised the guidelines on the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS) previously published in 2014 [Lefaucheur et al., Clin Neurophysiol 2014;125:2150-206]. These updated recommendations take into account all rTMS publications, including data prior to 2014, as well as currently reviewed literature until the end of 2018. Level A evidence (definite efficacy) was reached for: high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the painful side for neuropathic pain; HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC) using a figure-of-8 or a H1-coil for depression; low-frequency (LF) rTMS of contralesional M1 for hand motor recovery in the post-acute stage of stroke. Level B evidence (probable efficacy) was reached for: HF-rTMS of the left M1 or DLPFC for improving quality of life or pain, respectively, in fibromyalgia; HF-rTMS of bilateral M1 regions or the left DLPFC for improving motor impairment or depression, respectively, in Parkinson's disease; HF-rTMS of ipsilesional M1 for promoting motor recovery at the post-acute stage of stroke; intermittent theta burst stimulation targeted to the leg motor cortex for lower limb spasticity in multiple sclerosis; HF-rTMS of the right DLPFC in posttraumatic stress disorder; LF-rTMS of the right inferior frontal gyrus in chronic post-stroke non-fluent aphasia; LF-rTMS of the right DLPFC in depression; and bihemispheric stimulation of the DLPFC combining right-sided LF-rTMS (or continuous theta burst stimulation) and left-sided HF-rTMS (or intermittent theta burst stimulation) in depression. Level A/B evidence is not reached concerning efficacy of rTMS in any other condition. The current recommendations are based on the differences reached in therapeutic efficacy of real vs. sham rTMS protocols, replicated in a sufficient number of independent studies. This does not mean that the benefit produced by rTMS inevitably reaches a level of clinical relevance.
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A recent study by Williams et al. (2018) used accelerated, high-dose intermittent theta burst stimulation (iTBS) to treat highly treatment-resistant depression patients. Remarkably, most patients remitted, but the durability of therapeutic response was weak and all patients relapsed within two weeks post-treatment. This mini-review examines the "fast on, fast off" effects of accelerated, high-dose iTBS for depression and suggests a new treatment that would combine the strengths of multiple extant iTBS protocols.
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Background: Repetitive transcranial magnetic stimulation (rTMS) is an evidence-based treatment for depression that is increasingly implemented in healthcare systems across the world. A new form of rTMS called intermittent theta burst stimulation (iTBS) can be delivered in 3 min and has demonstrated comparable effectiveness to the conventional 37.5 min 10Hz rTMS protocol in patients with depression. Objectives: To compare the direct treatment costs per course and per remission for iTBS compared to 10Hz rTMS treatment in depression. Methods: We conducted a cost analysis from a healthcare system perspective using patient-level data from a large randomized non-inferiority trial (THREE-D). Depressed adults 18 to 65 received either 10Hz rTMS or iTBS treatment. Treatment costs were calculated using direct healthcare costs associated with equipment, coils, physician assessments and technician time over the course of treatment. Cost per remission was estimated using the proportion of patients achieving remission following treatment. Deterministic sensitivity analyses and non-parametric bootstrapping was used to estimate uncertainty. Results: From a healthcare system perspective, the average cost per patient was USD$1,108 (SD 166) for a course of iTBS and $1,844 (SD 304) for 10Hz rTMS, with an incremental net savings of $735 (95% CI 688 to 783). The average cost per remission was $3,695 (SD 552) for iTBS and $6,146 (SD 1,015) for 10Hz rTMS, with an average incremental net savings of $2,451 (95% CI 2,293 to 2,610). Conclusions: The shorter session durations and treatment capacity increase associated with 3 min iTBS translate into significant cost-savings per patient and per remission when compared to 10Hz rTMS.
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Objective: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for refractory major depressive disorder, yet no studies have characterized trajectories of rTMS response. The aim of this study was to characterize response trajectories for patients with major depression undergoing left dorsolateral prefrontal cortex rTMS and to determine associated baseline clinical characteristics. Methods: This was a secondary analysis of a randomized noninferiority trial (N=388) comparing conventional 10-Hz rTMS and intermittent theta burst stimulation (iTBS) rTMS. Participants were adult outpatients who had a primary diagnosis of major depressive disorder, had a score ≥18 on the 17-item Hamilton Depression Rating Scale (HAM-D), and did not respond to one to three adequate antidepressant trials. Treatment was either conventional 10-Hz rTMS or iTBS rTMS applied to the dorsolateral prefrontal cortex, 5 days/week over 4-6 weeks (20-30 sessions). Group-based trajectory modeling was applied to identify HAM-D response trajectories, and regression techniques were used to identify associated characteristics. Results: Four trajectories were identified: nonresponse (N=43, 11%); rapid response (N=73, 19%); higher baseline symptoms, linear response (N=118, 30%); and lower baseline symptoms, linear response (N=154, 40%). Significant differences in response and remission rates between trajectories were detectable by week 1. There was no association between treatment protocol and response trajectory. Higher baseline scores on the HAM-D and the Quick Inventory of Depression Symptomatology-Self-Report (QIDS-SR) were associated with the nonresponse trajectory, and older age, lower QIDS-SR score, and lack of benzodiazepine use were associated with the rapid response trajectory. Conclusions: Major depression shows distinct response trajectories to rTMS, which are associated with baseline clinical characteristics but not treatment protocol. These response trajectories with differential response to rTMS raise the possibility of developing individualized treatment protocols.
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Background: The clinical efficacy of repetitive transcranial magnetic stimulation (rTMS) in treatment resistant patients (at least 4 medication trials) appears to be well accepted and forms the coverage policies and rTMS's use in many of the largest US payers. However, less is known about rTMS's use in patients who have undergone ≤1 failed medication trial. The purpose of this analysis was to determine the clinical efficacy of rTMS in patients after ≤1 medication trials. Methods: A systematic review of the literature was undertaken to identify all articles which addressed the use of rTMS in ≤1 medication trial. All types of study designs were included and assessed for quality and strength of evidence using: GRADE and CEBM. Searches of peer reviewed articles were undertaken for the year 2000 to the present. All languages were considered. Electronic databases were searched and included: PubMed and EBSCO. Evidence assessment websites were also searched and included: Cochrane, NICE, AHRQ, and ICER. Additionally, the clinical guidelines for specialty societies which use rTMS was searched. Hand searches of the reference sections of identified articles was also undertaken. Results: Electronic and other sources identified 165 after duplicates were removed. Twenty two articles were assessed for eligibility and ultimately 10 articles were included in the systematic review and graded. Six articles were graded high quality (CEBM/GRADE: 1c/B) demonstrating that the use of rTMS was clinically efficacious in patients after ≤1 medication trial. Four additional trials demonstrated a positive effect of rTMS in patients after ≤1 medication trial but were of a lower quality. Conclusion: The use of rTMS in patients after ≤1 medication trial should be considered. US payers should consider revising their coverage policies to include the use of rTMS in these patients.
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Three decades of clinical research on repetitive transcranial magnetic stimulation (rTMS) has yielded one clear treatment indication in psychiatry for major depression disorder (MDD). Although the clinical response equals the standard treatment algorithms, the effect sizes on the beneficial outcome remain rather modest. Over the last couple of years, to improve the efficacy in resistant depression, two new avenues have been developed: personalization and intensifying rTMS treatment. For the latter, we retrospectively compared accelerated high-frequency rTMS (arTMS) with accelerated intermittent theta burst stimulation (aiTBS) in the refractory depressed state. Although the clinical efficacy was not significantly different between both protocols, our observations substantiate the potential of the accelerated stimulation to shorten the treatment duration from the depressed state to the response state. Any time gain from the depressed state to the recovered state is in the patients’ interest.
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Background: High-frequency (HF) repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (L-DLPFC) is the most widely applied treatment protocol for major depressive disorder (MDD), while low-frequency (LF) rTMS over the right DLPFC (R-DLPFC) also exhibits similar, if not better, efficacy for MDD. Therefore, a meta-analysis is warranted to compare the efficacy of the two protocols for MDD. Method: We searched the literature from 1990 through to August 1, 2017 using MEDLINE, and the literature from 1995 through to August 1, 2017 using EMBASE, PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), SCOPUS, and ProQuest Dissertations and Theses (PQDT). We included randomized controlled trials (RCT) comparing the efficacy of HF rTMS over the L-DLPFC and LF rTMS over the R-DLPFC for MDD, which used response and/or remission rates as the primary endpoints, with and without sham-controlled. Results: (1) The meta-analysis of the response rates was based on 12 studies, including 361 patients with MDD (175 for HF (> 5 Hz) over the L-DLPFC, and 186 for LF (<5 Hz) over the R-DLPFC; odds ratio = 1.08; 95%, confidence interval = 0.88–1.34). (2) The meta-analysis of the remission rate was based on 5 studies, including 131 MDD patients (64 for HF over the L-DLPFC and 67 for LF over the R-DLPFC; odds ratio = 1.29; 95% confidence interval = 0.54–3.10). Conclusion: Both HF rTMS over the L-DLPFC and LF over the R-DLPFC demonstrated similar therapeutic efficacy for the treatment of patients with MDD. The results suggested that further investigation on treatment efficacy indicators before/during treatment is necessary and helpful for optimizing a personalized protocol for patients.
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Background: Treatment-resistant major depressive disorder is common; repetitive transcranial magnetic stimulation (rTMS) by use of high-frequency (10 Hz) left-side dorsolateral prefrontal cortex stimulation is an evidence-based treatment for this disorder. Intermittent theta burst stimulation (iTBS) is a newer form of rTMS that can be delivered in 3 min, versus 37·5 min for a standard 10 Hz treatment session. We aimed to establish the clinical effectiveness, safety, and tolerability of iTBS compared with standard 10 Hz rTMS in adults with treatment-resistant depression. Methods: In this randomised, multicentre, non-inferiority clinical trial, we recruited patients who were referred to specialty neurostimulation centres based at three Canadian university hospitals (Centre for Addiction and Mental Health and Toronto Western Hospital, Toronto, ON, and University of British Columbia Hospital, Vancouver, BC). Participants were aged 18-65 years, were diagnosed with a current treatment-resistant major depressive episode or could not tolerate at least two antidepressants in the current episode, were receiving stable antidepressant medication doses for at least 4 weeks before baseline, and had an HRSD-17 score of at least 18. Participants were randomly allocated (1:1) to treatment groups (10 Hz rTMS or iTBS) by use of a random permuted block method, with stratification by site and number of adequate trials in which the antidepressants were unsuccessful. Treatment was delivered open-label but investigators and outcome assessors were masked to treatment groups. Participants were treated with 10 Hz rTMS or iTBS to the left dorsolateral prefrontal cortex, administered on 5 days a week for 4-6 weeks. The primary outcome measure was change in 17-item Hamilton Rating Scale for Depression (HRSD-17) score, with a non-inferiority margin of 2·25 points. For the primary outcome measure, we did a per-protocol analysis of all participants who were randomly allocated to groups and who attained the primary completion point of 4 weeks. This trial is registered with ClinicalTrials.gov, number NCT01887782. Findings: Between Sept 3, 2013, and Oct 3, 2016, we randomly allocated 205 participants to receive 10 Hz rTMS and 209 participants to receive iTBS. 192 (94%) participants in the 10 Hz rTMS group and 193 (92%) in the iTBS group were assessed for the primary outcome after 4-6 weeks of treatment. HRSD-17 scores improved from 23·5 (SD 4·4) to 13·4 (7·8) in the 10 Hz rTMS group and from 23·6 (4·3) to 13·4 (7·9) in the iTBS group (adjusted difference 0·103 [corrected], lower 95% CI -1·16; p=0·0011), which indicated non-inferiority of iTBS. Self-rated intensity of pain associated with treatment was greater in the iTBS group than in the 10 Hz rTMS group (mean score on verbal analogue scale 3·8 [SD 2·0] vs 3·4 [2·0] out of 10; p=0·011). Dropout rates did not differ between groups (10 Hz rTMS: 13 [6%] of 205 participants; iTBS: 16 [8%] of 209 participants); p=0·6004). The most common treatment-related adverse event was headache in both groups (10 Hz rTMS: 131 [64%] of 204; iTBS: 136 [65%] of 208). Interpretation: In patients with treatment-resistant depression, iTBS was non-inferior to 10 Hz rTMS for the treatment of depression. Both treatments had low numbers of dropouts and similar side-effects, safety, and tolerability profiles. By use of iTBS, the number of patients treated per day with current rTMS devices can be increased several times without compromising clinical effectiveness. Funding: Canadian Institutes of Health Research.
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Background Current medication and transcranial magnetic stimulation (TMS) treatments for depression bring only approximately one-third of patients to remission. Newer TMS techniques such as bilateral treatment, neuronavigation, and theta burst stimulation (TBS) show promise in improving remission rates. However, it is unclear whether newer off-label techniques improve outcomes enough to justify widespread implementation. Methods An IRB approved retrospective chart review examined 58 primarily treatment-resistant (79%) depressed patients who received bilateral neuronavigated TBS-20Hz in a private outpatient clinic. Results 72% (42/58) of patients remitted (Beck Depression Inventory-II (BDI-II) < 13) with an 81% decrease in BDI-II scores. 83% (48/58) of patients responded (BDI-II ≤ 50%). Average time to remission was 7.3 treatment weeks (SD = 4.5, Range 0.6–21.2). Overall, 40% (17/42) of remitters also successfully discontinued one or more pretreatment medications. Conclusions Bilateral Neuronavigated TBS-20Hz TMS brought more than two-thirds of treatment refractory depressed patients to remission. TBS-20Hz may be critical for obtaining higher remission rates. Controlled trials are warranted.
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Objectives: We aimed to examine the effects and safety of accelerated intermittent Theta Burst Stimulation (iTBS) on suicide risk in a group of treatment-resistant unipolar depressed patients, using an extensive suicide assessment scale. Methods: In 50 therapy-resistant, antidepressant-free depressed patients, an intensive protocol of accelerated iTBS was applied over the left dorsolateral prefrontal cortex (DLPFC) in a randomized, sham-controlled crossover design. Patients received 20 iTBS sessions over 4 days. Suicide risk was assessed using the Beck Scale of Suicide ideation (BSI). Results: The iTBS protocol was safe and well tolerated. We observed a significant decrease of the BSI score over time, unrelated to active or sham stimulation and unrelated to depression-response. No worsening of suicidal ideation was observed. The effects of accelerated iTBS on mood and depression severity are reported in Duprat et al. (2016). The decrease in suicide risk lasted up to 1 month after baseline, even in depression non-responders. Conclusions: This accelerated iTBS protocol was safe. The observed significant decrease in suicide risk was unrelated to active or sham stimulation and unrelated to depression response. Further sham-controlled research in suicidal depressed patients is necessary. (Clinicaltrials.gov identifier: NCT01832805).
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Background: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. Methods: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. "Neurostimulation Treatments" is the fourth of six sections of the 2016 guidelines. Results: Evidence-informed responses were developed for 31 questions for 6 neurostimulation modalities: 1) transcranial direct current stimulation (tDCS), 2) repetitive transcranial magnetic stimulation (rTMS), 3) electroconvulsive therapy (ECT), 4) magnetic seizure therapy (MST), 5) vagus nerve stimulation (VNS), and 6) deep brain stimulation (DBS). Most of the neurostimulation treatments have been investigated in patients with varying degrees of treatment resistance. Conclusions: There is increasing evidence for efficacy, tolerability, and safety of neurostimulation treatments. rTMS is now a first-line recommendation for patients with MDD who have failed at least 1 antidepressant. ECT remains a second-line treatment for patients with treatment-resistant depression, although in some situations, it may be considered first line. Third-line recommendations include tDCS and VNS. MST and DBS are still considered investigational treatments.
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Background: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. Methods: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. "Pharmacological Treatments" is the third of six sections of the 2016 guidelines. With little new information on older medications, treatment recommendations focus on second-generation antidepressants. Results: Evidence-informed responses are given for 21 questions under 4 broad categories: 1) principles of pharmacological management, including individualized assessment of patient and medication factors for antidepressant selection, regular and frequent monitoring, and assessing clinical and functional outcomes with measurement-based care; 2) comparative aspects of antidepressant medications based on efficacy, tolerability, and safety, including summaries of newly approved drugs since 2009; 3) practical approaches to pharmacological management, including drug-drug interactions and maintenance recommendations; and 4) managing inadequate response and treatment resistance, with a focus on switching antidepressants, applying adjunctive treatments, and new and emerging agents. Conclusions: Evidence-based pharmacological treatments are available for first-line treatment of MDD and for management of inadequate response. However, given the limitations of the evidence base, pharmacological management of MDD still depends on tailoring treatments to the patient.
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Background: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. Methods: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. This section is the first of six guidelines articles. Results: In Canada, the annual and lifetime prevalence of MDD was 4.7% and 11.3%, respectively. MDD represents the second leading cause of global disability, with high occupational and economic impact mainly attributable to indirect costs. DSM-5 criteria for depressive disorders remain relatively unchanged, but other clinical dimensions (sleep, cognition, physical symptoms) may have implications for depression management. e-Mental health is increasingly used to support clinical and self-management of MDD. In the 2-phase (acute and maintenance) treatment model, specific goals address symptom remission, functional recovery, improved quality of life, and prevention of recurrence. Conclusions: The burden attributed to MDD remains high, whether from individual distress, functional and relationship impairment, reduced quality of life, or societal economic cost. Applying core principles of care, including comprehensive assessment, therapeutic alliance, support of self-management, evidence-informed treatment, and measurement-based care, will optimize clinical, quality of life, and functional outcomes in MDD.
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Background: Prefrontal Transcranial Magnetic Stimulation (TMS) therapy repeated daily over 4-6 weeks (20-30 sessions) is US Food and Drug Administration (FDA) approved for treating Major Depressive Disorder in adults who have not responded to prior antidepressant medications. In 2011, leading TMS clinical providers and researchers created the Clinical TMS Society (cTMSs) (www.clinicaltmssociety.org, Greenwich, CT, USA), incorporated in 2013. Methods: This consensus review was written by cTMSs leaders, informed by membership polls, and approved by the governing board. It summarizes current evidence for the safety and efficacy of the use of TMS therapy for treating depression in routine clinical practice. Authors systematically reviewed the published TMS antidepressant therapy clinical trials. Studies were then assessed and graded on their strength of evidence using the Levels of Evidence framework published by the University of Oxford Centre for Evidence Based Medicine. The authors then summarize essentials for using TMS therapy in routine clinical practice settings derived from discussions and polls of cTMSs members. Finally, each summary clinical recommendation is presented with the substantiating peer-reviewed, published evidence supporting that recommendation. When the current published clinical trial evidence was insufficient or incomplete, expert opinion was included when sufficient consensus was available from experienced clinician users among the membership of the cTMSs, who were polled at the Annual Meetings in 2014 and 2015. Conclusions: Daily left prefrontal TMS has substantial evidence of efficacy and safety for treating the acute phase of depression in patients who are treatment resistant or intolerant. Following the clinical recommendations in this document should result in continued safe and effective use of this exciting new treatment modality.
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Clinical trials on low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) over the right dorsolateral prefrontal cortex have yielded conflicting evidence concerning its overall efficacy for treating major depression (MD). As this may have been the result of limited statistical power of individual trials, we have carried the present systematic review and meta-analysis to examine this issue. We searched the literature for English language randomized, double-blind and sham-controlled trials (RCTs) on LF-rTMS for treating MD from 1995 through July 2012 using EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, SCOPUS, and ProQuest Dissertations & Theses, and from October 2008 until July 2012 using MEDLINE. The main outcome measures were response and remission rates as well as overall dropout rates at study end. We used a random-effects model, odds ratios (ORs) and number needed to treat (NNT). Data were obtained from eight RCTs, totaling 263 subjects with MD. After an average of 12.6±3.9 rTMS sessions, 38.2% (50/131) and 15.1% (20/132) of subjects receiving active LF-rTMS and sham rTMS were classified as responders (OR=3.35; 95% CI=1.4-8.02; p=0.007). Also, 34.6% (35/101) and 9.7% (10/103) of subjects receiving active LF-rTMS and sham rTMS were classified as remitters (OR=4.76; 95% CI=2.13-10.64; p<0.0001). The associated NNT for both response and remission rates was 5. Sensitivity analyses have shown that protocols delivering >1200 magnetic pulses in total as well as those offering rTMS as a monotherapy for MD were associated with higher rates of response to treatment. No differences on mean baseline depression scores and dropout rates for active and sham rTMS groups were found. Finally, the risk of publication bias was low. In conclusion, LF-rTMS is a promising treatment for MD, as it provides clinically meaningful benefits that are comparable to those of standard antidepressants and high-frequency rTMS. Furthermore, LF-rTMS seems to be an acceptable intervention for depressed subjects.Neuropsychopharmacology advance online publication, 19 December 2012; doi:10.1038/npp.2012.237.
Article
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Background: Bilateral repetitive magnetic stimulation (rTMS) is a promising novel therapeutic intervention for major depression (MD). However, clinical trials to date have reported conflicting evidence concerning its overall efficacy, which might have resulted from low statistical power. Thus, meta-analytical approaches could be useful in examining this issue by allowing the integration of findings from multiple studies and thus producing more accurate estimates of the treatment effect. Method: We searched the literature for randomized, double-blind and sham-controlled trials (RCTs) on bilateral rTMS for treating MD from 1995 to July 2012 using EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, SCOPUS, and ProQuest Dissertations and Theses, and from October 2008 until May 2012 using Medline. The main outcome measures were response and remission rates. We used a random-effects model, odds ratios (ORs) and the number needed to treat. Results: Data were obtained from seven RCTs, totaling 279 subjects with MD. After an average of 12.9 (s.d. = 2.7) sessions, 24.7% (40/162) and 6.8% (8/117) of subjects receiving active bilateral rTMS and sham rTMS were classified as responders [OR 4.3, 95% confidence interval (CI) 1.95-9.52, p < 0.0001]. Also, 19% (23/121) and 2.6% (2/77) of subjects were remitters following active bilateral rTMS and sham rTMS, respectively (OR 6.0, 95% CI 1.65-21.8, p = 0.006). No difference between baseline mean depression scores for the bilateral and sham rTMS groups was found, and the former was comparable with the latter in terms of drop-out rates at study end. Furthermore, we did not find significant differences efficacy- and acceptability-wise between active bilateral and unilateral rTMS at study end. Finally, heterogeneity between the included RCTs was not significant, and the risk of publication bias was found to be low. Conclusions: Bilateral rTMS is a promising treatment for MD as it provides clinically meaningful benefits that are comparable with those of standard antidepressants and unilateral rTMS. Furthermore, bilateral rTMS seems to be an acceptable treatment for depressed subjects.
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To assess the efficacy of increasing the number of fast left repetitive transcranial magnetic stimulations (rTMS) (10 Hz @ 120% of motor threshold (MT) over the left dorsolateral prefrontal cortex (DLPFC)) needed to achieve remission in treatment-resistant depression (TRD). And, to determine if patients who do not remit to fast left will remit using slow right rTMS (1 Hz @ 120% MT over the right DLPFC). Patients were part of a multicenter sham-controlled trial investigating the efficacy of fast left rTMS. Patients who failed to meet minimal response criteria in the sham-controlled study could enroll in this open fast left rTMS study for an additional 3-6 weeks. Patients who failed to remit to fast left could switch to slow right rTMS for up to 4 additional weeks. The final outcome measure was remission, defined as a HAM-D score of <3 or 2 consecutive HAM-D scores less than 10. Forty-three of 141 (30.5%) patients who enrolled in the open phase study eventually met criteria for remission. Patients who remitted during fast left treatment received a mean of 26 active treatments (90,000 pulses). Twenty-six percent of patients who failed fast left remitted during slow right treatment. The total number of rTMS stimulations needed to achieve remission in TRD may be higher than is used in most studies. TRD patients who do not respond to fast left rTMS may remit to slow right rTMS or additional rTMS stimulations.
Article
Objective: New antidepressant treatments are needed that are effective, rapid acting, safe, and tolerable. Intermittent theta-burst stimulation (iTBS) is a noninvasive brain stimulation treatment that has been approved by the U.S. Food and Drug Administration for treatment-resistant depression. Recent methodological advances suggest that the current iTBS protocol might be improved through 1) treating patients with multiple sessions per day at optimally spaced intervals, 2) applying a higher overall pulse dose of stimulation, and 3) precision targeting of the left dorsolateral prefrontal cortex (DLPFC) to subgenual anterior cingulate cortex (sgACC) circuit. The authors examined the feasibility, tolerability, and preliminary efficacy of Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), an accelerated, high-dose resting-state functional connectivity MRI (fcMRI)-guided iTBS protocol for treatment-resistant depression. Methods: Twenty-two participants with treatment-resistant depression received open-label SAINT. fcMRI was used to individually target the region of the left DLPFC most anticorrelated with sgACC in each participant. Fifty iTBS sessions (1,800 pulses per session, 50-minute intersession interval) were delivered as 10 daily sessions over 5 consecutive days at 90% resting motor threshold (adjusted for cortical depth). Neuropsychological testing was conducted before and after SAINT. Results: One participant withdrew, leaving a sample size of 21. Nineteen of 21 participants (90.5%) met remission criteria (defined as a score <11 on the Montgomery-Åsberg Depression Rating Scale). In the intent-to-treat analysis, 19 of 22 participants (86.4%) met remission criteria. Neuropsychological testing demonstrated no negative cognitive side effects. Conclusions: SAINT, an accelerated, high-dose, iTBS protocol with fcMRI-guided targeting, was well tolerated and safe. Double-blinded sham-controlled trials are needed to confirm the remission rate observed in this initial study.
Article
Background: Repetitive transcranial magnetic stimulation treatment (rTMS) is an effective treatment for depression but the optimal methods of administration have yet to be determined. In particular, it is unclear whether there is a relationship between elements of the dose of stimulation (i.e., number of pulses) and clinical response. To address one aspect of dose, we conducted a trial comparing standard and high dose versions of high frequency left sided and low frequency right sided rTMS protocols (left standard = 50 trains, left high = 125 trains, right standard = 20 min, right high = 60 min, all per day in a single session). Method: 300 patients with treatment resistant depression were enrolled in a four arm randomized controlled trial across a four week time period. The primary outcome assessment was a comparison of response and remission rates on data from the 17-item Hamilton Rating Scale for Depression Rating Scale (HRSD-17). Results: The rate of response exceeded 45% in all groups. There was no significant difference between groups on initial analysis of the primary or secondary outcome measures (response rates: standard left = 52.5%, high left = 47.3%, standard right = 49.1%, high right = 48.4%). There was a greater remission rate with high compared to moderate dose left sided treatment when controlling for illness duration. We also found significant improvements in quality of life across all treatment groups. Illness duration was weakly associated with response. Conclusions: There was no consistent association between the antidepressant effect of rTMS and the number of TMS pulses provided across the ranges investigated in this study. Increasing TMS pulse number in individual sessions seems unlikely to be a method to substantially improve clinical outcomes, and future research should explore alternative means of improving clinical response. The study was registered on the Australian and New Zealand Clinical Trials Register (ACTRN12612000321842) https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=362063&isReview=true.
Article
Low-frequency and high-frequency repetitive transcranial magnetic stimulation (rTMS) are similarly efficacious for treatment-resistant depression. Low-frequency is posited to be better tolerated than high-frequency rTMS, however, this is not supported by empirical evidence to date. This study aimed to quantify and compare the tolerability of low-versus high-frequency rTMS. Twenty healthy participants (mean age 38.6 ± 13.9 years) underwent low- and high-frequency rTMS administered on left frontal, fronto-central and central sites at 100% resting motor threshold. For the low-frequency protocol, 60 s of 1 Hz stimulation was applied at each site and for the high-frequency protocol, 3 × 5 s trains of 10 Hz stimulation with a 30 s inter-train interval were applied at each site. Tolerance for each stimulation type was assessed immediately after stimulation through participant ratings of overall intensity of scalp sensations, pain, muscle twitching, discomfort and any other sensation. Low-frequency rTMS was significantly less intense than high-frequency rTMS in overall intensity, pain, muscle twitching (all p <.01) and discomfort (p <.001). Limitations of this study include the healthy participant sample and administration of a single session of rTMS. While further work is needed in clinical samples using typical rTMS treatment protocols, these data provide the first evidence that low-frequency is better tolerated than high-frequency. These findings may inform clinical practice of rTMS treatment for depression (and other illnesses) by supporting the application of low-frequency protocols.
Article
Repetitive transcranial magnetic stimulation (TMS) is now widely available for the clinical treatment of depression, but the associated financial and time burdens are problematic for patients. Accelerated TMS (aTMS) protocols address these burdens and attempt to increase the efficiency of standard TMS. This systematic review and meta-analysis aimed to examine accelerated TMS studies for depressive disorders in accordance with PRISMA guidelines. Inclusion criteria consisted of studies with full text publications available in English describing more than one session of TMS (repetitive or theta burst stimulation) per day. Studies describing accelerated TMS protocols for conditions other than depression or alternative neuromodulation methods, preclinical studies, and neurophysiology studies regarding transcranial stimulation were excluded. Eighteen articles describing eleven distinct studies (seven publications described overlapping samples) met eligibility criteria. A Hedges’ g effect size and confidence intervals were calculated. The summary analysis of three suitable randomized control trials revealed a cumulative effect size of 0.39 (95% CI 0.005–0.779). A separate analysis including open-label trials and active arms of suitable RCTs revealed a g of 1.27 (95% CI 0.902–1.637). Overall, the meta-analysis suggested that aTMS improves depressive symptom severity. In general, study methodologies were acceptable, but future efforts could enhance sham techniques and blinding.
Article
Repetitive transcranial magnetic stimulation (rTMS) is increasingly used clinically in the treatment of patients with major depressive disorder (MDD). However, rTMS treatment response can be slow. Early research suggests that accelerated forms of rTMS may be effective but no research has directly evaluated a schedule of accelerated rTMS compared to standard rTMS. To assess the efficacy of accelerated rTMS compared to standard daily rTMS., 115 outpatients with MDD received either accelerated rTMS (n = 58) (i.e., 63,000 high frequency rTMS pulses delivered as 3 treatments per day over 3 days in week 1, 3 treatments over 2 days in week 2 and 3 treatments on a single day in week 3) or standard rTMS (n = 57) (i.e., 63,000 total high frequency rTMS pulses delivered over 5 days per week for 4 weeks) following randomization. There were no significant differences in remission or response rates (p > 0.05 for all analyses) or reduction in depression scores (Time by group interaction (F (5, 489.452) = 1.711, p = 0.130) between the accelerated and standard rTMS treatment groups. Accelerated treatment was associated with a higher rate of reported treatment discomfort. It is feasible to provide accelerated rTMS treatment for outpatients with depression and this is likely to produce meaningful antidepressant effects.
Article
Background: Repetitive transcranial magnetic stimulation (rTMS) shows efficacy in the treatment of major depressive episodes (MDEs), but can require ≥4-6 weeks for maximal effect. Recent studies suggest that multiple daily sessions of rTMS can accelerate response without reducing therapeutic efficacy. However, it is unresolved whether therapeutic effects track cumulative number of pulses, or cumulative number of sessions. Objective: This open-label study reviewed clinical outcomes over a 20-30 session course of high-frequency bilateral dorsomedial prefrontal cortex (DMPFC)-rTMS among patients receiving 6000 pulses/day delivered either in twice-daily sessions 80 min apart (at 20 Hz) or single, longer, once-daily sessions (at 10 Hz). Methods: A retrospective chart review identified 130 MDD patients who underwent 20-30 daily sessions of bilateral DMPFC-rTMS (Once-daily, n = 65; Twice-daily, n = 65) at a single Canadian clinic. Results: Mixed-effects modeling revealed significantly faster improvement (group-by-time interaction) for twice-daily versus once-daily DMPFC-rTMS. Across both groups, the pace of improvement showed a consistent relationship with number of cumulative sessions, but not with cumulative number of pulses. Although the twice-daily group completed treatment in half as many days, final clinical outcomes did not differ significantly between groups on dichotomous measures (response/remission rates: once-daily, 35.4%/33.8%; twice-daily, 41.5%/35.4%), or continuous measures, or on overall response distribution. Conclusions: Twice-daily rTMS appears feasible, tolerable, and capable of achieving comparable results to once-daily rTMS, while also reducing course length approximately twofold. Therapeutic gains tracked the cumulative number of sessions, not pulses. Future randomized studies comparing once-daily to multiple-daily rTMS sessions, while controlling for number of pulses, may be warranted.
Article
Objective: To provide expert recommendations for the safe and effective application of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder (MDD). Participants: Participants included a group of 17 expert clinicians and researchers with expertise in the clinical application of rTMS, representing both the National Network of Depression Centers (NNDC) rTMS Task Group and the American Psychiatric Association Council on Research (APA CoR) Task Force on Novel Biomarkers and Treatments. Evidence: The consensus statement is based on a review of extensive literature from 2 databases (OvidSP MEDLINE and PsycINFO) searched from 1990 through 2016. The search terms included variants of major depressive disorder and transcranial magnetic stimulation. The results were limited to articles written in English that focused on adult populations. Of the approximately 1,500 retrieved studies, a total of 118 publications were included in the consensus statement and were supplemented with expert opinion to achieve consensus recommendations on key issues surrounding the administration of rTMS for MDD in clinical practice settings. Consensus process: In cases in which the research evidence was equivocal or unclear, a consensus decision on how rTMS should be administered was reached by the authors of this article and is denoted in the article as "expert opinion." Conclusions: Multiple randomized controlled trials and published literature have supported the safety and efficacy of rTMS antidepressant therapy. These consensus recommendations, developed by the NNDC rTMS Task Group and APA CoR Task Force on Novel Biomarkers and Treatments, provide comprehensive information for the safe and effective clinical application of rTMS in the treatment of MDD.
Article
Background: Repetitive transcranial magnetic stimulation (rTMS) is an effective option for treatment-resistant depression but requires prolonged repeated daily treatments for 4 to 6 weeks. Pilot studies have showed the possibility of accelerating rTMS safely and efficaciously but thus far only investigated high-frequency left-sided rTMS. We sought to investigate the safety and efficacy of accelerated low-frequency right-sided rTMS. Methods: Our study was an open label accelerated rTMS pilot in 7 treatment-resistant patients (4 unipolar, 3 BP). Accelerated rTMS was given over the right dorsolateral prefrontal cortex at 120% of resting motor threshold at 1 Hz, and 900 pulses were delivered per session. A single rTMS treatment was administered on the first day to test for tolerability, followed by 5 rTMS sessions a day for 2 days, then 7 days of daily rTMS sessions. The total course consisted of 16,200 pulses across 18 sessions given over 10 consecutive weekdays. The primary outcomes of interest were self- and clinician-rated depression scores (BDI-II and MADRS). Results: All patients successfully and safely completed the accelerated rTMS treatment. MADRS scores decreased significantly by the third day of treatment and BDI II scores by the end of the 10-day treatment. No patients achieved response or remission. Conclusions: Accelerated low-frequency right-sided rTMS was a safe and possibly efficacious treatment for treatment-resistant depression. More research is recommended, including a controlled trial with longer duration of exposure, to establish the efficacy of left- and right-sided accelerated rTMS.
Article
The possibility of a non-invasive, focal stimulation of distinct cortical brain regions as treatment of neurological and psychiatric diseases by repetitive transcranial magnetic stimulation (rTMS) is at present investigated in numerous open and controlled clinical trials. Prefrontal rTMS can modulate the function of fronto-limbic circuits, which is reversibly altered in major depression. Effects of rTMS on neurotransmitter systems involved in the pathophysiology of depressive disorders have been shown, e.g. stimulation of subcortical dopamine release. Though conducted with small sample sizes, the majority of controlled trials demonstrated significant antidepressant effects of verum rTMS compared to a sham condition. Larger multicenter-trials should be conducted to investigate the efficacy of rTMS as antidepressant treatment and to test specific applications.
Article
Major depressive disorder (MDD) is a prevalent and disabling condition, and many patients do not respond to available treatments. Deep transcranial magnetic stimulation (dTMS) is a new technology allowing non-surgical stimulation of relatively deep brain areas. This is the first double-blind randomized controlled multicenter study evaluating the efficacy and safety of dTMS in MDD. We recruited 212 MDD outpatients, aged 22–68 years, who had either failed one to four antidepressant trials or not tolerated at least two antidepressant treatments during the current episode. They were randomly assigned to monotherapy with active or sham dTMS. Twenty sessions of dTMS (18 Hz over the prefrontal cortex) were applied during 4 weeks acutely, and then biweekly for 12 weeks. Primary and secondary efficacy endpoints were the change in the Hamilton Depression Rating Scale (HDRS-21) score and response/remission rates at week 5, respectively. dTMS induced a 6.39 point improvement in HDRS-21 scores, while a 3.28 point improvement was observed in the sham group (p=0.008), resulting in a 0.76 effect size. Response and remission rates were higher in the dTMS than in the sham group (response: 38.4 vs. 21.4%, p=0.013; remission: 32.6 vs. 14.6%, p=0.005). These differences between active and sham treatment were stable during the 12-week maintenance phase. dTMS was associated with few and minor side effects apart from one seizure in a patient where a protocol violation occurred. These results suggest that dTMS constitutes a novel intervention in MDD, which is efficacious and safe in patients not responding to antidepressant medications, and whose effect remains stable over 3 months of maintenance treatment.
Article
Background Suicide attempts and completed suicides are common, yet there are no proven acute medication or device treatments for treating a suicidal crisis. Repeated daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) for 4-6 weeks is a new FDA-approved treatment for acute depression. Some open-label rTMS studies have found rapid reductions in suicidality. Design This study tests whether a high dose of rTMS to suicidal inpatients is feasible and safe, and also whether this higher dosing might rapidly improve suicidal thinking. This prospective, 2-site, randomized, active sham-controlled (1:1 randomization) design incorporated 9 sessions of rTMS over 3 days as adjunctive to usual inpatient suicidality treatment. The setting was two inpatient military hospital wards (one VA, the other DOD). Patients Research staff screened approximately 377 inpatients, yielding 41 adults admitted for suicidal crisis. Because of the funding source, all patients also had either post-traumatic stress disorder [17], mild traumatic brain injury [1], or both [23]. TMS Methods Repetitive TMS (rTMS) was delivered to the left prefrontal cortex with a figure-eight solid core coil at 120% motor threshold, 10 hertz (Hz), 5 second (s) train duration, 10s intertrain interval for 30 minutes (6000 pulses) 3 times daily for 3 days (total 9 sessions; 54,000 stimuli). Sham rTMS used a similar coil that contained a metal insert blocking the magnetic field and utilized electrodes on the scalp, which delivered a matched somatosensory sensation. Main Outcome Measure Primary outcomes were the daily change in severity of suicidal thinking as measured by the Beck Scale of Suicidal Ideation (SSI) administered at baseline and then daily, as well as subjective visual analog scale measures before and after each TMS session. Mixed model repeated measures (MMRM) analysis was performed on modified intent to treat (mITT) [37] and completer [27] populations. Results This intense schedule of rTMS with suicidal inpatients was feasible and safe. Minimal side effects occurred, none differing by arm, and the 3-day retention rate was 88%. No one died of suicide within the 6 month followup. From the mITT analyses, SSI scores declined rapidly over the 3 days for both groups (sham change -15.3 points, active change -15.4 points), with a trend for more rapid decline on the first day with active rTMS (sham change -6.4 points, active -10.7 points, p=0.12). This decline was more pronounced in the completers subgroup [sham change -5.9 (95% CI: -10.1, -1.7), active -13 points (95% CI: -18.7, -7.4); p=0.054]. Subjective ratings of ‘being bothered by thoughts of suicide’ declined non-significantly more with active rTMS than with sham at the end of 9 sessions of treatment in the mITT analysis [sham change -31.9 (95% CI: -41.7, -22.0), active change -42.5 (95% CI: -53.8, -31.2); p=0.17]. There was a significant decrease in the completers sample [sham change -24.9 (95% CI: -34.4, -15.3), active change -43.8 (95% CI: -57.2, -30.3); p=0.028]. Conclusions Delivering high doses of left prefrontal rTMS over three days (54,000 stimuli) to suicidal inpatients is possible and safe, with few side effects and no worsening of suicidal thinking. The suggestions of a rapid anti-suicide effect (day 1 SSI data, Visual Analogue Scale data over the 3 days) need to be tested for replication in a larger sample.
Article
Purpose: This study was designed to evaluate the therapeutic effect of low-frequency repetitive transcranial magnetic stimulation (rTMS) on patients with refractory partial epilepsy. Methods: Sixty-four patients with refractory focal epilepsy were screened and 60 patients were randomly divided into two groups by stimulation intensity: 90% (group 1) or 20% (group 2) of resting motor threshold (rMT). Seizure frequency and interictal EEG epileptic discharges were compared between the baseline and follow-up periods. Key Findings: Seizures significantly decreased following 2-weeks high intensity (90% rMT) rTMS treatment compared with baseline level (p < 0.05). rTMS also decreased interictal epilepsy discharges and improved the scales of Symptom Checklist-90 significantly (p < 0.05). Seizures and spikes in the follow-up period in the patients who received low intensity (20% rMT) rTMS did not show any difference compared with baseline data (p > 0.05, respectively). Significance: Low-frequency high intensity rTMS (90% rMT) delivered into the epileptogenic zone had a significant antiepileptic effect on patients with refractory partial seizures. rTMS treatment can also reduce the interictal epileptic discharge frequency and improve the psychological condition of these patients.
Article
Background: The majority of studies investigating the effectiveness of repetitive transcranial magnetic stimulation (rTMS) as a treatment for major depression have focused on high-frequency rTMS to the left prefrontal cortex (HFL-rTMS). In addition, low-frequency right prefrontal rTMS (LFR-rTMS) has also been shown to have antidepressant properties. To date only a small number of studies have directly compared the efficacy of these two approaches. Methods: The aim of this study, therefore, was to investigate further whether LFR-rTMS is as effective as HFL-rTMS in the treatment of major depression. Twenty-seven patients were randomized to one of two treatment arms (HFL-rTMS or LFR-rTMS) for 3 weeks with a possible 1-week extension. Non-responders were offered the opportunity of crossing over to the other treatment type. Stimulation parameters for HFL-rTMS were 30 stimulation trains of 5 s duration at 100% of the resting motor threshold (RMT); for LFR-rTMS, stimulation was applied in four trains of 180 s duration (30 s inter-train interval) at 110% of the RMT. Stimulation was provided 5-week days per week. Results: There were significant improvements seen from baseline to end point irrespective of group and on all clinical outcome measures. In addition, there was no deterioration in any of the measures used to assess cognitive change, and significant improvements were seen on measures of immediate verbal memory and verbal fluency. Conclusions: HFL-rTMS and LFR-rTMS appear to be equally efficacious in treating major depression. This study adds to the growing literature supporting LFR-rTMS as an additional viable method of rTMS delivery in the treatment of depression.
Article
Repetitive transcranial magnetic stimulation (rTMS) has shown safety and efficacy for treatment-resistant depression, but requires daily treatment for 4-6 weeks. Accelerated TMS, with all treatments delivered over a few days, would have significant advantages in terms of access and patient acceptance. Open-label accelerated TMS (aTMS), consisting of 15 rTMS sessions administered over 2 days, was tested in 14 depressed patients not responding to at least one antidepressant medication. Effects on depression, anxiety, and cognition were assessed the day following treatment, then after 3 and 6 weeks. No seizure activity was observed and only one patient had a serious adverse event (increased suicidal ideation). Two patients failed to complete a full course of aTMS treatments, and 36% did not complete all study visits. Depression and anxiety significantly decreased following aTMS treatments and improvements persisted 3 and 6 weeks later. Response rates immediately following treatment and at 3 and 6 weeks were 43, 36, and 36%, respectively. Remission rates at the same timepoints were 29, 36, and 29%. Accelerated TMS demonstrated an excellent safety profile with efficacy comparable to that achieved in daily rTMS in other trials. Limitations primarily include open-label treatment and a small sample size.
Article
Remission and response were suggested as the most relevant outcome criteria for the treatment of depression. There is still marked uncertainty as to what cut-offs should be used on current depression rating scales. The goal of the present study was to compare the validity of different HAMD, MADRS and BDI cut-offs for response and remission. The naturalistic prospective study was performed in 12 psychiatric hospitals in Germany. All evaluable patients (n=846) were hospitalized and had to meet DSM-IV criteria for major depressive disorder. Biweekly ratings were assessed using HAMD-21, MADRS and BDI. A CGI-S score of 1 and a CGI-I score of at least 2 was used as the primary comparative measure of remission and response, respectively. A HAMD-21 cut-off ≤7 (AUC: 0.92), HAMD-17 cut-of ≤6 (AUC: 0.90), MADRS cut-off ≤7 (AUC: 0.94) and BDI cut-off ≤12 (AUC: 0.83) were associated with a maximum of specificity and sensitivity for defining remission. A minimum decrease of 47% of the HAMD-21 (AUC: 0.90), ≤57% for HAMD-17 (AUC: 0.89), ≤ 46% for MADRS (0.91) and a decrease of 47% for the BDI baseline score (AUC: 0.78) best corresponded CGI response criteria. Our data largely confirmed currently used remission and response criteria in naturalistically treated patients.
Article
During the past decade the Montgomery-Asberg Depression Rating Scale (MADRS) has been used with increasing frequency to measure outcome in antidepressant efficacy trials (AETs). In characterizing treatment outcome in AETs it is common to define treatment remission as a score below a predetermined cutoff score on the scale. Various cutoffs have been used to define remission on the MADRS. The goal of the present paper is to determine the cutoff on the MADRS that most closely corresponds to the cutoff most frequently used on the Hamilton Rating Scale for Depression to define remission. Three hundred and three psychiatric outpatients who were being treated for a DSM-IV major depressive episode were rated on the HRSD and the MADRS. A linear regression equation was computed to estimate MADRS scores from HRSD scores. After deriving the regression equation, we computed the MADRS score corresponding to an HRSD score of 7. We also examined the sensitivity, specificity and overall classification rate of the MADRS for identifying remission on the HRSD. Based on the equation from a linear regression analysis for the entire sample, a MADRS score of </=11 would correspond to a score of </=7 on the HRSD. We repeated the analysis after excluding the more severely depressed patients who currently met criteria for MDD, and based on the equation from this regression analysis a MADRS score of </=10 would correspond to a score of </=7 on the HRSD. In a complementary analysis, we examined the sensitivity, specificity and overall classification rate of the MADRS at different cutoff points for identifying remission, and found that a cutoff of </=10 maximized the level of agreement with the HRSD definition of remission. In conclusion, the regression equation relating HRSD and MADRS scores is dependent, in part, on the range and severity of scores in the sample. To facilitate comparisons of studies using the HRSD and MADRS our results suggest that a cutoff of 10 on the MADRS is equivalent to the HRSD cutoff of 7.
Evaluation of a Novel Therapeutic Repetitive Transcranial Magnetic Stimulation Technique Optimized for Increased Accessibility in Major Depression
  • Miron
Repetitive Transcranial Magnetic Stimulation for the Acute Treatment of Major Depressive Episodes
  • Brunoni