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 in Moreover, are to have an background in brain that is in or and “a the effects of the other the “TMS to be to in a and to an physician” and have been in and to the “TMS be such as be for rTMS treatment The Indian Psychiatric Society in with and has been a of in such as the of and also are in rTMS. In recommendations for in have also been and not for also for and rTMS and the with for the rTMS including the and for of is an essential be for the delivering the sessions. the rTMS have a for and a The essential for including the for of and the availability of has to be has to be a for a to the coils, in are not The of the rTMS coil is and for the and A for the and a for the coil in the the be The be a The of for the coil to be for delivering be for for A and a be for the target technical for an rTMS are in technical for inclusion and has to be the of rTMS sessions and all the and their have to be with the psychiatric treatment and have to be a of in the and in the significant or recent brain of brain or that the be specifically of are to be the has to be informed the of a and the has to be It is important to that who have rTMS sessions in the are at than rTMS Moreover, the of are in the first three sessions the first and the first three and rTMS the rTMS sessions. The be supplemented by the use of such as the TMS or the for rTMS [Table by for rTMS for the use of rTMS of that is or magnetic or such in the and Brain where leads are in the etc., is also a the coil is other such as and the coil is be for the are the and such as or are considered in the the the treatment sessions be and their with the total be the rTMS treatment course be The following be the rTMS treatment than in of has to be of including and and etc., has to be that the is and is not and of or substance to the treatment be the motor of the motor is a for the of rTMS. it has to be for the of the and the that is the of the first be used for all sessions in the following in where the treatment sessions are more than a or are at an the has to be in where there are in or of or other substance to the rTMS or the is of headache or be is defined as the that a in the or the first on the for of applied defined as of following that is from to and The be by the of the or by of is a more in clinical it be noted that method than of that from the conventional i.e., the and i.e., magnetic both as as and have been developed for of target for TMS with that the have been by the It is that are more the use of the for the target is considered a and TMS and be for safety with or treatment with of such as by patients and TMS for of or with not of TMS in with other TMS can be with such as in the or and that the coil is not than to the in the important to is that TMS with and increase to the the TMS induced TMS in patients with be there are or and be by the of TMS in with Despite large of patients and TMS in the no have from the the is of The is with the use of stimulation and no be of the of and as and the TMS sessions be to systematically of effects be TMS safety in The of TMS studies to be and The effect was a other effects have been safety and TMS use are in with two and of is by a coil to the the was This is far than the safety to stimulate and it is to that rTMS has for the and TMS safety for the are for TMS being for several daily for several It is that the TMS i.e., than from the magnetic coil in to the use of or is for TMS safety and protocols of stimulation defined by to be to for conventional for safety guidelines, the use of the of motor stimulation as a for to be the of the the to be the of new of It is important to at the that in all the meta-analyses for recommendations on efficacy in for all conditions headache and a of studies for other rTMS has been used as an to the treatment as depression We meta-analyses for depression [Table on the effect of rTMS in of rTMS in depression for 1: depression, bipolar depression and treatment is for a significant effect of the use of rTMS for depression, for unipolar The pooled effect sizes for in depression range to The for and and and were for the use of rTMS. The was for high-frequency rTMS the for from to meta-analyses and the of for various rTMS forms. on the and high-frequency rTMS the has been to be by low-frequency rTMS the rTMS low-frequency bilateral TBS TMS and and rTMS have also been to have a significant A meta-analysis on TBS that the effects of are to high-frequency rTMS. is for the use of rTMS in bipolar depression OR for meta-analysis that unipolar and bipolar depression that the was to unipolar depression and not to bipolar bipolar depression the was for high-frequency rTMS the for In in bipolar depression, high-frequency rTMS the has been to significant effects. rTMS and low-frequency rTMS have not been to have significant effects. depression were rTMS was to have a significant on the and high-frequency rTMS the by low-frequency rTMS the has been to be TBS and rTMS a significant effects. One meta-analysis that both and bilateral stimulation not in of both and is that in to rTMS was it is as an to than rTMS (including accelerated was not to be associated with significant in a meta-analysis on accelerated protocols the more a accelerated daily sessions for has to have in patients with depression, such protocols to be in controlled One meta-analysis on and bilateral stimulation conventional and that the of stimulation the treatment the of and a number of treatment sessions a meta-analysis TBS studies that and treatment One meta-analysis on patients and number of sessions greater is The efficacy and of stimulation and for disorders were not The or among the and were The and a in depression in studies and a in authors deem are not as were on a of studies and were not rTMS to other brain stimulation In the two was associated with than high-frequency rTMS, continuous theta burst stimulation and transcranial magnetic was associated with a than continuous theta burst stimulation In was to be more than brain was more than TMS was more than is the to rTMS? in the in the and in the The further of as as of maintenance at specific This which included the of rTMS for The base for maintenance rTMS for in is and not for specific it has a for or the in patients with rTMS treatment is the effect of rTMS treatment in A meta-analysis of randomized controlled trials with on a large This was of the of and was associated with depression in the and associated with of of studies to of studies of effects were and that the effects are associated with in the dorsolateral prefrontal cortex and cortex of TMS for A meta-analysis including sham-controlled trials no of or to an there is a greater of and following rTMS treatment for depression with a with rTMS treatment was assessed in a recent meta-analysis of clinical trials where the of the studies the dorsolateral prefrontal The was described in the that rTMS protocols for the treatment of depression are not related to rTMS and studies that and were of of studies rTMS and as were rTMS with no significant effect in with rTMS three studies included patients where depression was a included of and rTMS for A meta-analysis of that rTMS to and of in patients with disorders. A in meta-analysis that rTMS among patients with depression not in with rTMS as a and more than sessions a effect meta-analysis included as as patients from It that the in were not significant in trials a significant in in a review that high-frequency rTMS at the dorsolateral prefrontal cortex as an to the has the for in has been assessed as a in of the trials considered for the meta-analyses and patients have been considered in studies accelerated rTMS, with a of with the so we do not rTMS for of rTMS in peripartum depression 2 for depression, post-stroke depression, brain injury depression and depression in Parkinson’s that rTMS has a significant effect on peripartum The pooled effect sizes range and meta-analysis has that the OR for (i.e. not for is significant for the use of rTMS in peripartum effect sizes for the use of high-frequency rTMS the were greater than for low-frequency rTMS the The treatment was for both and of rTMS in post-stroke depression 2 for is for a significant effect for the use of rTMS for post-stroke depression, both for as as effects The pooled effect sizes for in depression range to The for and and and were for the use of rTMS. The was for high-frequency rTMS the is that rTMS for post-stroke depression be more in than the high-frequency rTMS are more to and that high-frequency rTMS with be more rTMS no significant effect on cognitive in post-stroke depression of rTMS in post-traumatic brain injury depression 2 for One meta-analysis assessed the efficacy of rTMS in post-traumatic brain injury depression and that it has a significant effect effect The effect was significant for high-frequency rTMS the effect effects were and at a of rTMS in depression associated with Parkinson’s 2 for is for a effect of the use of rTMS for depression associated with Parkinson’s The pooled effect sizes for in depression range to The effect was significant for high-frequency rTMS effect and the effect The effects of rTMS were to be greater than effect and to be to were used number of and were to the efficacy of rTMS on depression associated with Parkinson’s bipolar for (OCD) and meta-analysis included of patients with bipolar rTMS, of which study with rTMS to The sham-controlled were not significant of the three included and included three studies used high-frequency rTMS the anxiety disorders for We One of other forms of with rTMS and not provide pooled statistics for rTMS, was not considered for synthesis. that rTMS has a significant effect on the treatment of anxiety disorder. The pooled effect sizes range and Moreover, depression associated with a anxiety disorder also significant rTMS was not to be in the treatment of the disorder. in has been to be for rTMS in anxiety the rTMS forms, both conventional rTMS and TBS have been The used stimulation is low-frequency rTMS to the rTMS has also been used to target the A studies have obsessive-compulsive disorder (OCD) and is for use of rTMS to to for for range from to and low-frequency protocols have been than are target for stimulation i.e., low-frequency high-frequency bilateral and low-frequency supplementary motor area bilateral and low-frequency stimulations have the of stimulation are by 2 of stimulation and have effects effects were with to pulses TBS was to be data is is as as with to the effect of TMS in effects were and nerve were no effects and no for for rTMS in disorder which included and trials and that rTMS not controlled for in disorder. and bilateral supplementary motor area stimulation a treatment Post-traumatic stress disorder for We three that rTMS has a significant effect on the treatment of post-traumatic stress disorder. The pooled effect sizes range and high-frequency rTMS and low-frequency rTMS at the significant significant for rTMS in post-traumatic stress disorder for and of rTMS in is for use of rTMS to sessions for range from to rTMS stimulation at temporoparietal is the on the effect of rTMS in of rTMS in is to large for use of rTMS for in [Table stimulation to and more than sessions were to be to protocols more than at an of motor be more than other of rTMS in cognitive rTMS has been to have efficacy of in and of rTMS in We meta-analysis that included rTMS as an strategy in It was that the effects of rTMS were not significant for or in use disorders for of and assessed other together with rTMS and not provide pooled statistics for rTMS or for substance use disorders, were not considered for synthesis. that rTMS at and high-frequency TMS bilateral has a significant effect on effect in in substance use disorders effect also in effect and effect rTMS at and TMS to and also have been to substance for effect and effect from the for high-frequency rTMS at to of a use both and of the other is for rTMS in substance use disorders We three meta-analyses for eating disorders. three of and not provide effect sizes separately for eating disorders and for rTMS included with and and rTMS and other One study also included and clinical eating disorders together be spectrum disorder and attention deficit hyperactivity disorder We meta-analysis for attention deficit hyperactivity disorder and two meta-analyses and for autism spectrum disorders The meta-analysis for included all studies on both and with and not rTMS study for the synthesis. no are from the two meta-analyses on studies on the effects on various and the other on associated with rTMS in were in the of repetitive and effect and effect One of the included studies that the effects on month the rTMS sessions. is a large in the stimulation the and the target in the included This specific recommendations for the use of rTMS in The effects were all and of are and for rTMS in autism spectrum disorder and cognitive for and and of meta-analyses on the effects of rTMS in patients with were on or One of which not was not included for study assessed cognitive attention and both of which were not to with rTMS The of the other studies is in that rTMS has a significant effect in the of for both cognitive effect sizes and and and effect sizes and While all studies high-frequency rTMS at or bilateral for both cognitive and low-frequency rTMS at has also been in in of specifically and with high-frequency rTMS. with high-frequency rTMS in in both the and also Studies including both and that the effects were to more sessions cognitive or cognitive and of cognitive have been as involved in a greater for rTMS in in other psychiatric disorders We two meta-analyses [Table that assessed the effect of rTMS on cognitive in various psychiatric depression, and substance use disorders. rTMS has been to have a significant effect on in substance use disorders. One which specifically the effects of rTMS on with that the effects of rTMS on are not greater as that the in are related to in depression meta-analyses the effects of rTMS for cognitive in were not included in the and for rTMS for cognitive in various psychiatric for and three from sham-controlled studies that rTMS has a significant effect in the treatment of on the the The pooled effect sizes range and The pooled effect sizes for all of and significant for pooled effect sizes for all total and significant It has been noted that in with treatment to It has also been that the significant in with rTMS even at effect The of studies have used low-frequency rTMS at the low-frequency rTMS at the is for the treatment of for rTMS in for meta-analyses were reviewed. One of not effect sizes for rTMS, separately and not used for The other two studies provided for a significant in the number of with high-frequency rTMS at the motor was for the use of high-frequency rTMS at the prefrontal cortex in the treatment of was that the for chronic and were for rTMS for and chronic pain for meta-analyses for and two for other chronic pain were [Table It was that high-frequency rTMS at the motor cortex was for pain effect sizes to both and also on of also with rTMS, rTMS at the prefrontal cortex was not to be other chronic pain we two meta-analyses [Table that high-frequency rTMS at the motor cortex and at the pain in patients with chronic pain the other that the was not significant in other chronic pain for rTMS for and chronic for We meta-analyses for the use of rTMS in chronic [Table i.e., at 2 and and not the was to with rTMS effect sizes and also to The used was low-frequency rTMS at the which was to be than other Moreover, it was that stimulation of bilateral to and to greater effects. The rTMS sessions were to be in for rTMS for chronic One meta-analysis that included of which were rTMS, a significant effect of rTMS on essential The rTMS form was low-frequency rTMS or at the or or motor area or the motor One meta-analysis that there is a of for the effects of rTMS on A meta-analysis for brain stimulation in borderline personality disorder no randomized controlled trials assessing the effects of rTMS. in rTMS was to have significant effects on various of We no meta-analyses for disorders. studies are many newer forms of rTMS i.e., TMS TBS with TBS and accelerated TMS and are many brain such as for orbitofrontal cortex for The meta-analyses we included do not systematically review many of Indian A recent on Indian studies the safety and efficacy of rTMS in various disorders a significant effect for all outcomes, with to large effect at both of treatment as as at to for that rTMS. rTMS was not to be for in the of for and and in studies a significant of and the two conditions that sham-controlled in significant was Indian that with rTMS were The of of both and the was and pain were the with the use of rTMS. are many other psychiatric disorders where rTMS has been there is The disorders where there are and disorders, and having for the rTMS or the is not significant or to It is important to that rTMS is to be used as an to other conventional the list of all and recommendations for rTMS in the treatment of various psychiatric disorders. for list of i.e., conditions with and conditions where there is of conditions with and or controlled and recommendations for rTMS in treatment of various psychiatric The strategy we chose i.e., umbrella review of in the clinical recommendations is by While the is reporting of and to provide Further, be in such an Moreover, the umbrella review we was a and we not and an important The recommendations we primarily on were supplemented by guidelines and recommendations the meta-analysis of Indian informed the GRADE we not the of the and recommendations have been by to an This CPG for the use of rTMS in across various psychiatric disorders and We provide an of the and emerging in for the and application of rTMS. We also the basic of rTMS and of rTMS sessions. The for the use of rTMS emerging and is not recommendations for use are in clinical is for for the the use of rTMS across different disorders, in various of various etc., and also in of specific rTMS protocols in of the number of sessions, for of the disorders. there is no with to stimulation with number of sessions to be considered for a to be termed for a particular is in of rTMS effects in conditions such as depression with with with to target for depression, and other conditions has is not for synthesis. and of interest are no of