Clinical Practice Guidelines for the Therapeutic Use of Repetitive Transcranial Magnetic Stimulation in Neuropsychiatric Disorders.

Abstract

INTRODUCTION Psychopharmacology and psychotherapy form the mainstay of treatment in psychiatric disorders. Despite advances in both the forms of treatments and their strategies, 20-60% of patients with psychiatric disorders do not respond.[1] This treatment non-response, which is now recognized across the whole range of psychiatric disorders, leads to a greater healthcare burden. Moreover, poor adherence, which is related to the stigma attached to psychopharmacological agents, their side-effect profiles, and poor feasibility in following psychotherapy sessions, contributes to poor treatment outcomes, specifically termed as ‘pseudo-resistance’.[1] In the background of this, and also in the wake of technical advances in the field of basic neurosciences, newer forms of treatments have been developed and investigated. One such newer treatment is the use of repetitive transcranial magnetic stimulation (rTMS). rTMS is a non-invasive, non-convulsive method of brain stimulation first described by Anthony Barker and his colleagues in 1985 and came to be used in clinical settings in the 1990s. It refers to a multisession treatment where magnetic fields induced by recurring TMS pulses stimulate nerve cells in a particular brain region. It has a neuromodulatory effect on neuronal excitability and has been implied to have neuroplastic effects. The development of rTMS as a form of treatment is supported by a large number of clinical studies across psychiatric disorders. Since 2008, the US Food and Drug Administration (FDA) has so far cleared many pieces equipments for the therapeutic use of rTMS as an adjunctive treatment strategy in various conditions [Table 1].[2]Table 1: The United States Food and Drug Administration (FDA) approval timeline for rTMS equipmentOver the course of the last 2 decades, there has been a significant increase in interest in the use of rTMS, and several forms of rTMS, various protocols, coils, target regions, etc., have been investigated. While high-frequency (>5/10 Hz) and low-frequency (≤1 Hz) stimulations are considered the conventional rTMS forms, patterned rTMS i.e., theta burst stimulation (TBS) and quadri-pulse stimulation (QPS) are the newer forms. Further, there are three sub-forms of TBS– intermittent TBS (iTBS), continuous TBS (cTBS), and intermediate TBS (imTBS). Several protocols- once daily, twice or more daily (also called intensive or accelerated protocols), 3-5/week to once weekly, fortnightly, or even once a month maintenance protocols are being investigated. Further, as many as 50 TMS coil designs are being examined.[3] Moreover, apart from the conventional target sites– dorsolateral prefrontal cortex (DLPFC) and the temporoparietal cortex (TPC), several new brain regions (cerebellum, orbitofrontal cortex (OFC), supplementary motor area (SMA), etc) including bilateral stimulations have been chosen to study the effects of rTMS in various psychiatric disorders. Given the rising interest among psychiatrists for the use of rTMS in routine clinical practice, increasing availability of TMS equipment, an array of numerous choices in modes of rTMS delivery forms, and increasing literature base for the use of rTMS in several psychiatric disorders,[4] even from India,[5] it is important to develop specific and up-to-date clinical practice guidelines (CPG). The Indian Psychiatric Society (IPS)- CPG for the use of rTMS in various psychiatric disorders intends to synthesize the emerging evidence-based literature and provide expert guidance for bringing consistency in the clinical application of rTMS. While we encourage practitioners to implement evidence-based recommendations, we also deem that the use of rTMS in clinical practice can vary and depends upon the clinician’s acumen and experience. METHODS Process of forming the CPG for use of rTMS The IPS-CPG task force delegated a team of five experts for drafting the CPG for use of rTMS. The experts met at IPS state/zonal conferences and via online meetings and developed the recommendations and the draft. The recommendations were informed primarily by an umbrella review of recent meta-analytic studies assessing the role of rTMS in various psychiatric disorders performed by the authors and supplemented by other clinical practice guidelines,[6] evidence-based guidelines, and umbrella reviews[7-9], and consensus or expert recommendations.[10-12] The experts involved in developing the recommendations were also abreast of the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) framework. Umbrella review- Search strategy and Inclusion criteria We performed an umbrella review of meta-analyses that have assessed the efficacy and/or safety of various rTMS protocols in different psychiatric disorders. We systematically searched the PubMed database until July 15th, 2022 supplemented with manual searches. The search string used was “(“rTMS”) OR (“theta burst stimulation”) OR (“Non-Invasive Brain Stimulation”)”. We applied the “Meta-Analysis” filter and adjusted the “timeline” to 2018–2022 (i.e. last five years). This resulted in a total of 168 articles, that were further screened for the following inclusion criteria: i) meta-analysis of randomized controlled trials (RCTs), and ii) reporting on efficacy and safety of rTMS (including theta burst stimulation (TBS)) in psychiatric disorders, specifically a) cognitive disorders and dementia; b) substance use disorders; c) schizophrenia; d) depression (including unipolar depression, bipolar depression, peripartum depression, post-stroke depression, post-traumatic brain injury depression, depression associated with Parkinson’s disease); e) bipolar disorder; f) anxiety disorders; g) obsessive-compulsive disorder (OCD) and related disorders; h) Post-traumatic stress disorder (PTSD); i) autism spectrum disorder (ASD); j) attention deficit hyperactivity disorder (ADHD); k) eating disorders; l) chronic pain disorders including headache and fibromyalgia; m) insomnia; n) chronic tinnitus; and o) essential tremors. We also included meta-analyses specifically aimed at assessing suicidality, impulsivity, empathy, and borderline personality disorder. The Exclusion criteria we chose were i) study designs other than MA of RCTs, ii) no safety or efficacy data reported, iii) non-English articles. Studies that assessed other (non-invasive brain stimulation (NIBS) together with rTMS, or two conditions together or not having specifically defined a clinical condition and not having provided pooled statistics for rTMS separately for distinct disorders were also excluded. Finally, 97 meta-analyses were reviewed. Only sham-controlled pooled effect sizes were noted and included for synthesis. A list of references for all the studies is submitted as supplementary material. CLINICAL PRACTICE GUIDELINES Who can provide rTMS? Provision of rTMS sessions can primarily be understood as i) prescribing or advising rTMS treatment and ii) delivering rTMS sessions. This two personnel are termed “TMS physician” and “TMS operator”. The “TMS physician” by definition is “a clinician with prescriptive privileges who is knowledgeable about, trained, and credentialed in rTMS”[8]. Moreover, they are essentially required to have an “extensive background in brain physiology that is obtained during residency training in psychiatry, neurology, or neurosurgery”, and “a deep understanding about the neurophysiological effects of rTMS”.[13] On the other hand, the “TMS operator” needs to be able to “recognize potentially serious changes in a patient’s mental status and know when to alert an attending physician” and have been trained in recognizing and effectively responding to seizures.[10,13] Therefore, the “TMS operator” may be any non-medical personnel. However, paramedical staff such as nurses may be preferred when available. Training for providing rTMS treatment The Indian Psychiatric Society (IPS) in collaboration with NIMHANS, Bengaluru, and AIIMS New Delhi, has been conducting a series of annual training workshops in this regard. Other institutes such as the Central Institute of Psychiatry, Ranchi, and Kasturba Medical College, Manipal also are providing training in rTMS. In fact, recommendations for training in NIBS have also been put forth and they recommend training not only for clinicians but also for technicians and scientists.[14] rTMS set-up and the device An air-conditioned suit with adequate space for the rTMS equipment including the participant sitting arrangement and space for storage of spare coils is an essential requisite. There should be enough space for the person delivering the sessions. Also, the rTMS suite must have a provision for participant waiting and a washroom. The essential needs for emergency seizure management set-up, including the need for storage of anticonvulsants, and the immediate availability of trained physicians has to be ensured. There has to be a provision for a powerful air conditioning unit to cool the coils, in case cooled coils are not used. The components of the rTMS device are: Electronic Main Unit Coil (the figure-of-eight coil is most commonly used) Cooling unit and control cable for the cooling unit Power Supply Unit and its cables EMG machine Coil Holder Computer system. A trolley for the machine and a flexible stand for fixing the coil in the right position near the seating set-up may be acquired. The sitting equipment must preferably be a comfortable recliner chair. The height of its back resting must allow for the coil to be placed for delivering stimulation. Disposable earplugs must be available for participants for each session. A skin marker and a measuring tape will be required for marking the target location. Sample technical specifications for an rTMS device are given in Table 2.Table 2: Sample technical specification for TMSPatient inclusion and pre-rTMS evaluation Informed consent has to be taken before the start of rTMS sessions and all the possible side-effects and their probability have to be explained. Along with the psychiatric evaluation, detailed medical, treatment and neurological history have to be taken. Particularly, a history of epilepsy (both in the patient and in the family), significant or recent traumatic brain injury, loss of consciousness, stroke, brain tumor or currently taking medication/s that lowers the seizure threshold should be specifically noted. If any of these are reported to be positive, then the patient has to be informed regarding the risk of a possible rTMS-related seizure, and the patient’s risk-benefit ratio has to be determined.[10] It is important to note that participants who have received rTMS sessions safely in the past are at less risk than those receiving rTMS newly.[12] Moreover, the chances of seizures are highest in the first three sessions (62% during the first session and 75% during the first three sessions)[12] and therefore rTMS operators/physicians must exercise high precaution during the initial rTMS sessions. The pre-rTMS evaluation may be supplemented by the use of tools such as the TMS Adult Safety Screen (TASS)[15] or the screening standard questionnaire for rTMS candidates [Table 3] suggested by Rossi et al.[16]Table 3: Rossi et al. (2009)[ 16 ] screening standard questionnaire for rTMS candidatesContraindications for the use of rTMS are: Presence of implanted medical devices that is ferromagnetic or magnetic sensitive or any such metal objects in the brain, head, and neck areas. Deep Brain Stimulation (DBS) where subcutaneous leads are placed in the scalp, etc., is also a contraindication, if the coil position is <10 cm away. Any other metallic medical devices such as chips, pumps, pacemakers, cochlear implants, dental implants, permanent piercings, and tattoos containing ferromagnetic containing ink, if the coil position is <10 cm away. X-rays may be helpful for screening but they cannot determine if the metals are ferromagnetic. Metallic implants below the head and neck, such as knee or hip prosthesis are considered safe.[12] Substance in the past week, the day before the treatment sessions must be documented. Current drugs and their doses, along with the total duration should be documented. Also, any medication changes during the rTMS treatment course must be noted. Patient preparation The following may be ensured before commencing the rTMS treatment session: Adequate sleep (other than in cases of insomnia) has to be ensured. Also, absence of any acute medical emergency including high fever, uncontrolled hypertension and elevated blood pressure, uncontrolled diabetes, and hyperglycaemia, acute headache, acute vertigo/giddiness/dizziness, any fresh scalp/facial injury, etc., has to be ascertained. Also ensure that the patient is cooperative and is not acutely violent, aggressive, and suicidal. Use of alcohol, tobacco, or any substance prior to the treatment session must be avoided. Determining the motor threshold Determination of the motor threshold (MT) is a must for determining the stimulus intensity of rTMS. Ideally, it has to be measured before every session. However, for the sake of ease the MT and the stimulus intensity that is determined before the start of the first session may be used for all subsequent sessions in the following week. However, in cases where the treatment sessions are lasting more than a week or are given at an interval >1 week, MT (and therefore the stimulus intensity) has to be ascertained again. Also in cases where there are changes in medication doses or heavy intake of alcohol or any other substance 24 hours prior to the rTMS session or if the participant is complaining of headache or scalp/facial pain, MT must be determined again. MT is defined as the “minimum stimulus intensity that elicits a response in either the abductor pollicis brevis (APB) or the first dorsal interosseous (FDI) on the contralateral side for ≥50% of applied stimuli (usually defined as ≥5 of 10 stimuli administered)”[10] following single-pulse TMS, that is graded from small to high and delivered every 5 seconds. The muscle response may be either determined by the amplitude of the EMG response or by visual observation of finger twitching. Although finger twitching is a more feasible alternative in busy clinical settings, it may be noted that this method yields “significantly higher MTs than EMG of that muscle.”[17] Target location Apart from the conventional scalp i.e., the “5-cm” and “International 10-20 electroencephalography (EEG)” system-based methods, neuroimaging i.e., magnetic resonance imaging (MRI, both structural & functional, resting & task-based as well as 3D), Single-photon emission computed tomography (SPECT) and positron emission tomography (PET), based methods too have been developed for precise location of target for stimulation.[18] TMS equipment with in-built neuronavigation systems, that utilize the neuroimages have been approved by the FDA.[2] It is suggested that although neuroimaging-based methods are more accurate, the use of the International 10-20 EEG system for the target location is considered a cost-effective alternative.[18] Safety issues and monitoring TMS and hearing Following steps shall be addressed for hearing safety during TMS:[12] Individuals with pre-existing noise-induced hearing loss or receiving simultaneous treatment with ototoxic medications (aminoglycosides) shall undergo risk/benefit considerations. Use of well-fitted hearing protection such as earplugs by patients and TMS operators ENT referral for any complaints of hearing loss, tinnitus, or ear fullness. Patients with Cochlear implants should not undergo TMS. Safety of TMS in combination with other devices TMS can be safely employed with devices such as implanted stimulators in the central or peripheral nervous system, cardiac pacemakers, and VNS systems given that the coil is not closer than 10 cm to the electronic components like Implanted pulse generator (IPG) in the neck. An important point to consider is that TMS should start with low intensity and progressively increase to the desired intensity. If overall risk-benefit analysis confers risk, then turning the IPG off during TMS may offer some protection against induced electrode currents. TMS in patients with DBS shall only be carried out if there are concrete scientific or medical reasons and shall be overseen by the institute’s ethics committee.[12] Safety of TMS in combination with drugs Despite large numbers of patients receiving drugs and TMS in the past decade, no detailed toxicities have arisen from the combination. Moreso, the observed seizure rate is very low despite most of them receiving CNS-activating medications. The situation is very reassuring with the use of traditional stimulation parameters and focal coils. So, currently, no caution shall be entertained. However, documentation of the simultaneous intake of drugs (like clozapine) and additional possible seizure threshold-lowering factors (such as alcohol intake, sleep deprivation, and infection) during the TMS sessions shall be done. All efforts to systematically capture reports of side effects shall be carried out.[12] TMS safety in special population Paediatric: The majority of TMS studies continue to be single and paired-pulse studies. The most common side effect reported was a headache. No other serious side effects have been reported. With suitable hearing safety measures, single-pulse and paired-pulse TMS use are safe in children with age two years and older.[12] Pregnancy: Approximately 100 mV/m of TMS-induced E-field is generated by a figure-of-eight coil (adjacent to the DLPFC) when the coil-uterus distance was 60 cm. This is far less than the safety threshold to stimulate myelinated central and peripheral nerves (800 mV/m). So, it is viable to conclude that rTMS (figure-of-eight coil) has minimal risk for the mother and child.[12] TMS safety for the operators Safety issues are seldom addressed for TMS operators, despite being exposed for several hours daily for several years. It is pertinent that the TMS operator should avoid (or minimize) proximity i.e., less than 40 cm distance from the magnetic coil in order to derail exposures. Also, the use of earplugs or earmuffs is mandatory for operators.[12] TMS safety and protocols intensity Safety parameters of stimulation defined by Rossi et al.[12] needs to be adhered to for conventional protocols. But for parameters exceeding these safety guidelines, the use of neurophysiological monitoring (i.e., the appearance of motor twitches during stimulation as a warning for increased cortical stimulation) needs to be carried out. If any de novo seizure arises, kindly reconsider the protocol of the trial. Also, the scientific community needs to be alerted about the unsafety of any new combination of parameters.[12] Evidence It is important to note at the beginning that in all the meta-analyses reviewed for recommendations on efficacy in this document, for all conditions except headache and a small minority of studies for other conditions, rTMS has been used as an adjunct to the treatment as usual. Evidence- depression We reviewed 23 meta-analyses for depression [Table 4].Table 4: Meta-analyses on the effect of rTMS in depressionEfficacy of rTMS in major depression (please see Figure 1 for recommendation)Figure 1: Recommendation A: Depression- I: Unipolar depression, bipolar depression and treatment resistant depressionThere is strong evidence for a significant positive effect of the use of rTMS for treating acute depression, especially for unipolar depression. The pooled effect sizes for improvement in depression severity range between 0.302 to 0.83. The odds for response (pooled odds ratios (ORs) ranging between 3.26 and 3.64) and remission rates (pooled ORs ranging between 2.45 and 4.63) were significantly higher for the use of rTMS. The strongest evidence was for high-frequency rTMS over the left DLPFC (pooled ORs for response ranging from 3.17 to 3.75). Two network meta-analyses [Supplementary Table 1; sl.no. 6 and 10] compared the odds of response for various rTMS forms. Based on the ORs and narrow confidence intervals, high-frequency rTMS over the left DLPFC has been shown to be superior followed by low-frequency rTMS over the right DLPFC. Bilateral rTMS (high-frequency over left DLPFC + low-frequency over right DLPFC), iTBS over left DLPFC, bilateral TBS (iTBS over left DLPFC + cTBS over right DLPFC), deep TMS and iTBS and priming rTMS have also been found to have a significant positive effect. A meta-analysis focussing on TBS [Supplementary Table 1; sl.no. 3] though claims that the effects of iTBS are similar to high-frequency rTMS. There is moderate positive evidence for the use of rTMS in acute bipolar depression (effect size 0.302, OR for response 2.72), one meta-analysis that compared unipolar and bipolar depression [Supplementary Table 1; sl.no. 9] found that the significance was restricted to only unipolar depression and not to bipolar depression. For bipolar depression too, the strongest evidence was for high-frequency rTMS over the left DLPFC (pooled ORs for response 2.17). In fact, in bipolar depression, only high-frequency rTMS over the left DLPFC has been shown to cause significant effects. Bilateral rTMS and low-frequency rTMS over right DLPFC have not been shown to have significant effects. When only treatment-resistant depression (TRD) cases were considered, rTMS was found to have a significant positive effect. Based on the ORs and narrow confidence intervals, high-frequency rTMS over the left DLPFC followed by low-frequency rTMS over the right DLPFC has been shown to be superior. Bilateral TBS and priming rTMS too showed a significant positive effects. One meta-analysis [Supplementary Table 1; sl.no. 11] though showed that both unilateral and bilateral stimulation paradigms did not differ significantly in terms of both response and remission rates. There is clear evidence that in TRD, response to rTMS was better when it is added as an augment to antidepressants rather than stand-alone. Accelerated rTMS (including accelerated TBS) paradigm targeted over left DLPFC was not found to be associated with significant response, in a meta-analysis focussing on accelerated protocols [Supplementary Table 1; sl.no. 8]. Although the more recent, Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) protocol,[19] a high dose- accelerated (10 daily sessions for 5 days), resting-state functional connectivity functional MRI-guided iTBS, has shown to have 86.4% remission rates in patients with treatment-resistant depression, such protocols remain to be tested in controlled studies. One meta-analysis focussing on unilateral and bilateral stimulation paradigms (both conventional and TBS) [Supplementary Table 1; sl.no. 11] find that only the frequency of stimulation could predict the treatment outcome, while the intensity of stimulation, train duration and a number of treatment sessions did not. However, a meta-analysis involving only TBS studies find that ≥1800 pulses/session, subthreshold intensity, and ≤2-week treatment duration predict higher response rates [Supplementary Table 1; sl.no. 3]. One meta-analysis focussing on MDD patients aged >50 years found higher age and number of sessions predicted greater response [Supplementary Table 1; sl.no. 1]. Which device/coil is better? The efficacy and acceptability of 3 stimulation devices (NeuroStar, MagPro, and Magstim) for depressive disorders were not significantly different. The response rates, all-cause discontinuation, or remission rates among the devices (P = 0.12, P = 0.84, and P = 0.07, respectively) were comparable [Supplementary Table 1; sl.no. 24]. The comparison between H1 and F8 coils showed a larger reduction in depression severity in H1-coil vs. F8-coil studies and a trend towards higher remission rates in F8-coil vs. H1-coils. However, authors deem these differences are not clinically-relevant as they were based on a low volume of studies and were not placebo-controlled [Supplementary Table 1; sl.no. 25]. How does rTMS fare compared to other non-invasive brain stimulation strategies? In the comparisons between two active treatments, bitemporal ECT was associated with higher response than high-frequency left rTMS, continuous theta burst stimulation and deep transcranial magnetic stimulation. High dose right unilateral ECT was associated with a higher response than continuous theta burst stimulation [Supplementary Table 1; sl.no. 6]. In TRD, BL-rTMS was found to be more effective than deep brain stimulation. BL-rTMS was more acceptable than bitemporal ECT. Priming TMS was more acceptable than BT-ECT [Supplementary Table 1; sl.no. 10]. How sustained is the antidepressant response to rTMS? Among initial responders, 66.5 (57.1-74.8)% sustained response in the 3rd month, 52.9 (40.3-65)% in the 6th month, and 46.3 (32.6-60.7)% in the 12th month. The further higher proportion of women, as well as receipt of maintenance treatment, predicted higher responder rates at specific time points. This meta-analysis, which included 19 studies, showed the absence of major bias [Supplementary Table 1; sl.no. 26]. Maintenance rTMS for MDD The evidence base for maintenance rTMS for relapse prevention in MDD is still accumulating and not enough for making specific recommendations. However, it has shown a promise for effectively reducing or preventing the relapses in treatment-resistant MDD patients when scheduled along with rTMS treatment during acute phases.[20] How much is the placebo effect of rTMS treatment in depression? A meta-analysis of randomized controlled trials (RCTs) involving participants with MDD on this issue showed a large placebo response (g = 0.8 (0.65-0.95). This was regardless of the modality of intervention and was directly associated with depression improvement in the active group, and inversely associated with higher levels of treatment-resistant depression. Most of these studies had low to unclear risk of bias [Supplementary Table 1; sl.no. 27]. Recently, 34 neuroimaging studies of placebo effects were meta-analyzed and showed that the placebo effects are associated with activation in the left dorsolateral prefrontal cortex and left sub-genual anterior cingulate cortex (sgACC)/ventral striatum [Supplementary Table 1; sl.no. 28]. Safety of TMS for MDD A meta-analysis including 53 sham-controlled trials found no increased risk of either serious adverse events or drop-outs due to an adverse event [see Table 5]. However, there is a significantly greater risk of non-serious adverse events (mild and transient) following rTMS treatment for depression [Supplementary Table 1; sl.no. 29].Table 5: Adverse events with rTMSSpecifically, a Hypomanic/manic switch with rTMS treatment was assessed in a recent meta-analysis of 25 clinical trials where the majority of the studies targeted the left dorsolateral prefrontal cortex. The hypomanic switch was described in 4 studies. Overall, the results suggest that rTMS protocols for the treatment of depression are not related to affective switch [Supplementary Table 1; sl.no. 30]. Combined rTMS and psychosocial interventions Seventeen studies that combined NIBS and psychosocial interventions were meta-analyzed [Supplementary Table 1; sl.no. 31]. Three out of four of these studies using rTMS (2-HF-L and 1-LF-R) as NIBS modality were analyzed. rTMS combined with psychosocial intervention had no significant effect in alleviating depressive symptoms when compared with sham rTMS plus psychosocial intervention (SMD 0.31 (0.76-1.38)). These three studies though included patients where depression was a secondary outcome variable (these included cases of TBI, post-stroke, and fibromyalgia). rTMS for suicidality A meta-analysis of 10 RCTs showed that rTMS significantly reduced suicidal ideation (Hedges’ g 0.390 (0.193 to 0.588) and severity of depressive symptoms (Hedges’ g 0.698 (0.372-1.023) in patients with major mental disorders. A subgroup analysis in this meta-analysis found that rTMS reduced suicidal ideation among patients with non-treatment-resistant depression (non-TRD) but not in those with TRD. rTMS as a combination therapy and more than 10 sessions had a larger effect [Supplementary Table 1; sl.no. 32]. Another meta-analysis included only TRD (unipolar as well as bipolar) patients from 16 studies. It found that the reductions in suicidal ideation were not significant (g 0.158 (0.078-0.393) in RCTs. However, uncontrolled trials showed a significant decrease in suicidal ideation scores (g 0.692 (0.463-0.922) [Supplementary Table 1; sl.no. 33]. Godi et al. (2021),[21] in a systematic review showed that high-frequency rTMS at the left dorsolateral prefrontal cortex as an adjunct to the antidepressant medication has the highest evidence for reducing suicidal behavior in treatment-resistant depression. Suicidality has been assessed as a secondary outcome variable in most of the trials considered for the meta-analyses and excluded acutely suicidal patients. Acutely suicidal patients have been considered in some studies using accelerated rTMS, but with a lack of positive evidence. Essentially, therefore, with the evidence so far, we do not recommend rTMS for acutely suicidal patients. Efficacy of rTMS in peripartum depression (please see Figure 2 for recommendation)Figure 2: Recommendation B: Depression- II: Peripartum depression, post-stroke depression, post traumatic brain injury (TBI) depression and depression in Parkinson’s diseaseEvidence [see Table 4] suggests that rTMS has a significant positive effect on peripartum depression. The pooled effect sizes range between 0.65 and 1.39. However, one meta-analysis has found that the OR for remission rates (i.e. 1.83) but not for response rates is significant for the use of rTMS in peripartum depression. Pooled effect sizes for the use of high-frequency rTMS over the left DLPFC were greate